Medications for Obesity Management: Effectiveness and Value

©Institute for Clinical and Economic Review, 2022

Medications for Obesity Management:

Effectiveness and Value

Evidence Report

August 31, 2022

Prepared for

©Institute for Clinical and Economic Review, 2022 Page i

Evidence Report – Medications for Obesity Management

ICER Staff and Consultants

University of Illinois at Chicago Modeling Group

Steven J. Atlas, MD, MPH

Associate Professor of Medicine

Harvard Medical School

Director of Practice-Based Research and Quality

Improvement

Division of General Internal Medicine

Massachusetts General Hospital

Molly Beinfeld, MPH

(Former) Senior Research Lead, Evidence Synthesis

Institute for Clinical and Economic Review

Victoria Lancaster, PharmD, MSc, MBA

Health Technology Assessment Fellow

Institute for Clinical and Economic Review

Emily Nhan

Research Assistant

Institute for Clinical and Economic Review

Ashton Moradi, PharmD, MS

Health Economist

Institute for Clinical and Economic Review

David M. Rind, MD, MSc

Chief Medical Officer

Institute for Clinical and Economic Review

Steven D. Pearson, MD, MSc

President

Institute for Clinical and Economic Review

Francesca L. Beaudoin, MD, PhD, MS

Senior Medical Advisor

Institute for Clinical and Economic Review

Kibum Kim, PhD

Assistant Professor

University of Illinois at Chicago

Pei-Wen (Hilary) Lien, MSc

PhD Candidate

University of Illinois at Chicago

Kanya Shah, PharmD, MS, MBA

PhD Candidate

University of Illinois at Chicago

Daniel R. Touchette, PharmD, MA

Professor, University of Illinois at Chicago

Director, Center for Pharmacoepidemiology and

Pharmacoeconomic Research

The role of the University of Illinois at Chicago is

limited to the development of the cost-effectiveness

model, and the resulting ICER report does not

necessarily represent the views of the University of

Illinois at Chicago.

None of the above authors disclosed any conflicts of interest defined as more than $10,000 in health care company

stock or more than $5,000 in honoraria or consultancies relevant to this report during the previous year from

health care manufacturers or insurers.

DATE OF

PUBLICATION: August 31, 2022

How to cite this document: Atlas SJ, Kim K, Beinfeld M, Lancaster V, Nhan E, Lien PW, Shah K, Touchette DR,

Moradi A, Rind DM, Pearson SD, Beaudoin, FL. Medications for Obesity Management: Effectiveness and Value;

Evidence Report. Institute for Clinical and Economic Review, August 31, 2022.

https://icer.org/assessment/obesity-

management-2022/.

Steven J. Atlas served as the lead author for the Report. Molly Beinfeld led the systematic review and authorship

of the comparative clinical effectiveness section of this Report in collaboration with Victoria Lancaster and Emily

©Institute for Clinical and Economic Review, 2022 Page ii

Evidence Report – Medications for Obesity Management

Nhan. Kibum Kim developed the cost-effectiveness model and authored the corresponding sections of the Report

with assistance from Daniel R. Touchette, Pei-Wen Lien, and Kanya Shah. Development of the cost-effectiveness

model was also assisted by Jessica Benitez-Burke and Lauren Lee. Ashton Moradi provided consultation on the

cost-effectiveness analyses and developed the budget impact model. Francesca Beaudoin, David M. Rind, and

Steven D. Pearson provided methodologic guidance on the clinical and economic evaluations. We would also like

to thank Laura Cianciolo, Monica Frederick, and Foluso Agboola for their contributions to this Report.

©Institute for Clinical and Economic Review, 2022 Page iii

Evidence Report – Medications for Obesity Management

About ICER

The Institute for Clinical and Economic Review (ICER) is an independent non-profit research organization that

evaluates medical evidence and convenes public deliberative bodies to help stakeholders interpret and apply

evidence to improve patient outcomes and control costs. Through all its work, ICER seeks to help create a future in

which collaborative efforts to move evidence into action provide the foundation for a more effective, efficient, and

just health care system. More information about ICER is available at https://icer.org/

The funding for this report comes from government grants and non-profit foundations, with the largest single

funder being the Arnold Ventures. No funding for this work comes from health insurers, pharmacy benefit

managers, or life science companies. ICER receives approximately 29% of its overall revenue from these

health industry organizations to run a separate Policy Summit program, with funding approximately equally split

between insurers/PBMs and life science companies. There are no life science companies relevant to this review

who participate in this program. For a complete list of funders and for more information on ICER's support, please

visit https://icer.org/who-we-are/independent-funding/

For drug topics, in addition to receiving recommendations from the public

, ICER scans publicly available

information and also benefits from a collaboration with IPD Analytics, an independent organization that performs

analyses of the emerging drug pipeline for a diverse group of industry stakeholders, including payers,

pharmaceutical manufacturers, providers, and wholesalers. IPD provides a tailored report on the drug pipeline on

a courtesy basis to ICER but does not prioritize topics for specific ICER assessments.

About New England CEPAC

The New England Comparative Effectiveness Public Advisory Council (CEPAC) – a core program of ICER – provides a

public venue in which the evidence on the effectiveness and value of health care services can be discussed with

the input of all stakeholders. New England CEPAC seeks to help patients, clinicians, insurers, and policymakers

interpret and use evidence to improve the quality and value of health care.

New England CEPAC is an independent committee of medical evidence experts from across New England, with a

mix of practicing clinicians, methodologists, and leaders in patient engagement and advocacy. All council members

meet strict conflict of interest guidelines and are convened to discuss the evidence summarized in ICER reports and

vote on the comparative clinical effectiveness and value of medical interventions. More information about New

England CEPAC is available at

https://icer.org/who-we-are/people/independent-appraisal-committees/new-

england-cepac/.

The findings contained within this Report are current as of the date of publication. Readers should be aware that

new evidence may emerge following the publication of this Report that could potentially influence the results.

ICER may revisit its analyses in a formal update to this report in the future.

The economic models used in ICER Reports are intended to compare the clinical outcomes, expected costs, and

cost-effectiveness of different care pathways for broad groups of patients. Model results therefore represent

average findings across patients and should not be presumed to represent the clinical or cost outcomes for any

specific patient. In addition, data inputs to ICER models often come from clinical trials; patients in these trials may

differ in real-world practice settings.

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Evidence Report – Medications for Obesity Management

In the development of this report, ICER’s researchers consulted with several clinical experts, patients,

manufacturers, and other stakeholders. The following experts provided input that helped guide the

ICER team as we shaped our scope and report. It is possible that expert reviewers may not have had

the opportunity to review all portions of this revised Evidence Report. None of these individuals is

responsible for the final contents of this report, nor should it be assumed that they support any part

of it. The report should be viewed as attributable solely to the ICER team and its affiliated

researchers.

For a complete list of stakeholders from whom we requested input, please visit:

https://icer.org/wp-content/uploads/2022/03/ICER_Obesity_Stakeholder-List_030322.pdf

Expert Reviewers

Harold Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC

Medical Director and President

Louisville Metabolic and Atherosclerosis Research Center

Clinical Associate Professor

University of Louisville School of Medicine

Louisville Metabolic and Atherosclerosis Research Center has received research grants from

Allergan, Alon Medtech/Epitomee, Altimmune, Amgen, Boehringer Ingelheim, Eli Lilly, Novartis,

NovoNordisk, Pfizer, and Vivus. Dr. Bays has served as a consultant/advisor for Altimmune, Amgen,

and Boehringer Ingelheim.

Joseph Nadglowski, Jr.

President and Chief Executive Officer

Obesity Action Coalition

Joseph Nadglowski, Jr. has no personal financial relationships with any obesity-related industry. He

is an employee of the Obesity Action Coalition (OAC) and OAC does receive funding from a wide-

variety of obesity related industry including those providing behavioral, pharmaceutical, device, and

surgical interventions.

Fatima Cody Stanford, MD, MPH, MPA, MBA, FAAP, FACP, FAHA, FAMWA, FTOS

Associate Professor of Medicine and Pediatrics

Obesity Medicine Physician Scientist

Equity Director, Massachusetts General Hospital Endocrine Division

Massachusetts General Hospital and Harvard Medical School

Dr. Stanford has received consulting fees and/or honoraria from Novo Nordisk, Eli Lilly, Boehringer

Ingelheim, GoodRX, Calibrate, and Coral Health.

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Evidence Report – Medications for Obesity Management

Table of Contents

Executive Summary ............................................................................................................................ ES1

1. Background ........................................................................................................................................ 1

2. Patient and Caregiver Perspectives ................................................................................................... 4

3. Comparative Clinical Effectiveness .................................................................................................... 6

3.1. Methods Overview ...................................................................................................................... 6

Scope of Review ............................................................................................................................. 6

Evidence Base ................................................................................................................................ 6

3.2. Results ....................................................................................................................................... 13

Clinical Benefits ............................................................................................................................ 13

Harms ........................................................................................................................................... 24

Subgroup Analyses and Heterogeneity ........................................................................................ 33

Uncertainty and Controversies .................................................................................................... 33

3.3. Summary and Comment ........................................................................................................... 36

4. Long-Term Cost Effectiveness .......................................................................................................... 40

4.1. Methods Overview .................................................................................................................... 40

Scenario Analyses......................................................................................................................... 43

4.2. Key Model Assumptions and Inputs ......................................................................................... 44

Model Assumptions ..................................................................................................................... 44

4.3. Results ....................................................................................................................................... 49

Base-Case Results......................................................................................................................... 49

Sensitivity Analyses ...................................................................................................................... 50

Scenario Analyses......................................................................................................................... 51

Threshold Analyses ...................................................................................................................... 53

Model Validation .......................................................................................................................... 53

Uncertainty and Controversies .................................................................................................... 54

4.4. Summary and Comment ........................................................................................................... 56

5. Contextual Considerations and Potential Other Benefits ................................................................ 57

6. Health-Benefit Price Benchmarks .................................................................................................... 59

7. Potential Budget Impact .................................................................................................................. 60

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Evidence Report – Medications for Obesity Management

7.1. Overview of Key Assumptions .................................................................................................. 60

7.2. Results ....................................................................................................................................... 61

References ........................................................................................................................................... 62

Supplemental Materials

A. Background: Supplemental Information .........................................................................................A1

A1. Definitions ..................................................................................................................................A1

A2. Potential Cost-Saving Measures in Obesity Management ........................................................A2

A3. Future Therapies ........................................................................................................................A2

B. Patient Perspectives: Supplemental Information ............................................................................ B1

B1. Methods ..................................................................................................................................... B1

C. Clinical Guidelines ............................................................................................................................ C1

Veterans’ Health Administration/Department of Defense.......................................................... C1

Canadian Clinical Practice Guideline ............................................................................................ C1

Endocrine Society ......................................................................................................................... C2

National Institute for Health and Care Excellence (NICE) ............................................................ C3

D. Comparative Clinical Effectiveness: Supplemental Information .................................................... D1

D1. Detailed Methods ..................................................................................................................... D1

PICOTS ......................................................................................................................................... D1

Data Sources and Searches ......................................................................................................... D5

Study Selection ............................................................................................................................ D9

Data Extraction and Quality Assessment .................................................................................... D9

Assessment of Level of Certainty in Evidence .......................................................................... D10

Assessment of Bias .................................................................................................................... D10

Data Synthesis and Statistical Analyses .................................................................................... D10

Supplemental NMA Methods ................................................................................................... D10

Supplemental NMA Results ...................................................................................................... D11

D2. Additional Clinical Evidence .................................................................................................... D16

Evidence Base ........................................................................................................................... D16

Results ....................................................................................................................................... D20

Harms ........................................................................................................................................ D35

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Evidence Report – Medications for Obesity Management

D3. Evidence Tables ...................................................................................................................... D39

D4. Ongoing Studies ...................................................................................................................... D83

D5. Previous Systematic Reviews and Technology Assessments ................................................. D89

E. Long-Term Cost-Effectiveness: Supplemental Information ............................................................. E1

E1. Methods ..................................................................................................................................... E1

Rationale for Not Including Certain Health States in the Base Case ........................................... E1

Impact Inventory .......................................................................................................................... E1

Description of evLY Calculations .................................................................................................. E3

Target Population......................................................................................................................... E3

Treatment Strategies ................................................................................................................... E4

E2. Model Inputs and Assumptions ................................................................................................. E4

Model Inputs ................................................................................................................................ E5

E3. Results ........................................................................................................................................ E9

Cost-Effectiveness Plane .............................................................................................................. E9

Undiscounted Base-Case Results ............................................................................................... E10

Cumulative Incidence of Cardiovascular Conditions and Mortality .......................................... E11

E4. Sensitivity Analyses .................................................................................................................. E13

One-Way Sensitivity Analysis ..................................................................................................... E13

Probabilistic Sensitivity Analysis ................................................................................................ E16

E5. Scenario Analyses ..................................................................................................................... E19

E6. Heterogeneity and Subgroups ................................................................................................. E22

E7. Prior Economic Models ............................................................................................................ E23

F. Potential Budget Impact: Supplemental Information .................................................................... F25

Methods ..................................................................................................................................... F25

Results ........................................................................................................................................ F26

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Evidence Report – Medications for Obesity Management

List of Acronyms and Abbreviations Used in this Report

A1C Glycated hemoglobin

ACC American College of Cardiology

AHA American Heart Association

AHRQ Agency for Healthcare Research and Quality

BMI Body mass index

CI Confidence interval

CPAP Continuous positive airway pressure

dL Deciliter

evLY Equal-value life year

FDA Food and Drug Administration

GLP-1 Glucagon-like peptide-1

GIP Glucose-dependent insulinotropic polypeptide

HRQoL Health-related quality of life

IBT Intensive behavioral therapy

IDS-SR Inventory of Depressive Symptomatology Self-Report

IWQOL Impact of Weight on Quality of Life

kg Kilogram

LDL Low density lipoprotein

m Meters

MCS Mental component summary

mg Milligram

mmHg Millimeter of mercury

mmol/L Millimoles per liter

n number

N Total number

NMA Network meta-analysis

PCS Physical component summary

PHQ-9 Patient Health Questionnaire

QALY Quality-adjusted life year

SBP Systolic blood pressure

US United States

USPSTF United States Preventive Services Task Force

WAC Wholesale acquisition cost

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Evidence Report – Medications for Obesity Management Return to Table of Contents

Executive Summary

Obesity is a common chronic disease that increases the risk of other conditions such as diabetes

mellitus, cancer, and heart disease as well as death.

1,2

Individuals with overweight and obesity also

face considerable social stigma that can have both direct (e.g., mental health, wellbeing) and

indirect consequences (e.g., engagement with health care providers).

Body mass index (BMI,

weight in kilograms/height in meters

) is commonly used to assess for obesity because it is easy to

measure and correlates with body fat measurements.

4,5

In 2015, the number of adults in the

United States (US) with overweight or obesity was estimated to be 79 million and 70 million,

respectively.

6,7

The prevalence of obesity surpassed 40% of US adults in 2018,

but among some

racial and ethnic groups obesity is even more prevalent with higher proportions for Hispanic adults

and highest proportions among non-Hispanic Black women.

9,10

The direct medical costs

attributable to obesity are staggering, estimated to be $260 billion in the US in 2016.

Given the

high of obesity and its many adverse clinical and cost consequences, cost-effective treatments for

this chronic condition are imperative.

Interest in medications to reduce weight and improve health in individuals with obesity has

increased due to more non-surgical alternatives and data suggesting that newer medications have

an acceptable safety profile and may be more effective in promoting weight loss. Limitations of

medications for weight loss include side effects that lead to patient discontinuation, and weight

regain when stopped. Under a chronic disease framework, clinical experts concluded that long-

term anti-obesity medication use would likely be needed, particularly to prevent complications of

obesity such as heart disease. This Report reviews four medications approved by the US Food and

Drug Administration (FDA): semaglutide (Wegovy®, Novo Nordisk, June 2021), liraglutide (Saxenda®,

Novo Nordisk, 2014), phentermine/topiramate (Qysmia®, Vivus, 2012), and bupropion/naltrexone

(Contrave®, Currax Pharmaceuticals, 2014). Semaglutide and liraglutide are glucagon-like peptide-1

(GLP-1) receptor agonists that are also approved for diabetes mellitus and given by subcutaneous

injection, whereas phentermine/topiramate and bupropion/naltrexone are combination oral agents

that work via other mechanisms. Other promising therapies (e.g., tirzepatide) are still under

investigation and are therefore not included in the scope of this review.

For adults without pre-existing diabetes mellitus and either a BMI ≥30 kg/m

or ≥27 kg/m

with at

least one weight-related comorbid condition (such as hypertension or dyslipidemia), the four

interventions added to usual care all reduced body weight compared to usual care alone, which

included standard diet and activity and lifestyle recommendations. Indirect mean and categorical

weight loss reduction comparisons across the drugs as well as direct head-to-head evidence

between two of the agents (semaglutide and liraglutide) suggest that semaglutide and

phentermine/topiramate achieve greater weight loss than liraglutide and bupropion/naltrexone.

Semaglutide and liraglutide improved blood sugar and blood pressure compared to usual care, but

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how they compare to phentermine/topiramate and bupropion/naltrexone is less certain. In

addition, none of these drugs have assessed long-term outcomes in adults without pre-existing

diabetes mellitus, and thus there is uncertainty around long-term benefits such as cardiovascular

morbidity and mortality. Adverse events were common among all interventions, but few serious

harms were noted. All interventions had greater discontinuation due to adverse events than for

placebo, though semaglutide appears to have lower rates than the other drugs. For all

interventions, there is uncertainty about whether sustained weight loss leads to decreased clinical

endpoints, and if weight regain occurs over time despite continued therapy.

Given the strength of the evidence on weight loss outcomes in the trials and uncertainty around

long-term outcomes for adults without pre-existing diabetes mellitus and with obesity or

overweight with at least one comorbid condition, Table ES1 presents the ICER evidence ratings

comparing each intervention with lifestyle modification to lifestyle modification alone and

comparing semaglutide and the other interventions with lifestyle modification.

Table ES1. Evidence Ratings for Treatment of Adults with Obesity

Treatment

Comparator

Evidence Rating

Semaglutide

Lifestyle modification

B+

Liraglutide

Lifestyle modification

Phentermine/Topiramate

Lifestyle modification

C++

Bupropion/Naltrexone

Lifestyle modification

C+

Semaglutide

Liraglutide

C+

Phentermine/topiramate

C+

Bupropion/naltrexone

C++

Information about ICER’s Evidence Rating Matrix may be found here.

At current prices and with commonly accepted cost-effectiveness benchmarks, results suggest that

phentermine/topiramate in addition to lifestyle modification is cost effective compared with

lifestyle modification alone. The cost effectiveness of treatment of obesity with semaglutide or

liraglutide in patients without diabetes mellitus exceeds commonly used thresholds.

Bupropion/naltrexone is cost effective only at higher thresholds (see Table 4.5

The health-benefit price benchmark for semaglutide is $7,500 to $9,800 per year; this would require

a discount from the wholesale acquisition cost of 44-57%.

In summary, among the agents we reviewed, greater weight loss was seen with semaglutide and

with phentermine/topiramate; less weight loss was seen with liraglutide and with

bupropion/naltrexone. Although few serious harms were noted for all the interventions,

semaglutide may have lower rates of discontinuation and, along with liraglutide, may have

additional cardiovascular benefits that extend beyond weight loss effects. Phentermine/topiramate

is substantially less expensive than semaglutide and liraglutide, meets commonly accepted cost-

effectiveness thresholds and is actually cost-saving when prescribed generically.

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Bupropion/naltrexone is cost effective only at higher thresholds, but is cost effective when

prescribed generically. Semaglutide requires substantial discounts from the wholesale acquisition

cost to meet typical thresholds, but it is more effective, less burdensome, and more cost effective

than liraglutide.

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1. Background

Obesity is a common chronic disease that increases the risk of other conditions such as diabetes

mellitus, hypertension, dyslipidemia, cancer, heart disease, and death.

1,2

Individuals with

overweight or obesity face a considerable social stigma that can make them feel judged, shamed,

and ostracized, and can affect interactions with family, friends, and even health professionals.

Because obesity can start in childhood, the stigma can affect social interactions, educational

development, relationships, and work.

5,13

The net effect is that obesity can have a profound impact

on all aspects of patients’ lives and those of their families and caregivers.

Obesity is defined by the World Health Organization as abnormal or excessive fat accumulation that

presents a risk to a person’s health.

While not optimal for assessing individuals with high or low

muscle mass, body mass index (BMI, weight in kilograms/height in meters

) is commonly used to

assess obesity because it is easy to reliably measure and correlates with body fat measurements.

4,5

More than two-thirds of the United States (US) population have overweight (BMI ≥25) or obesity

(BMI ≥30). The prevalence of obesity among adults has increased over time and was 40-45% in

2017-2018.

8,15

Among children and adolescents, the prevalence of obesity is almost 20%.

The

total number of adults with overweight was estimated at 79 million with another 70 million

estimated to have obesity in 2015, and with half the US population projected to have obesity by

2030.

6,7

The prevalence of obesity varies among racial and ethnic groups, being higher for Hispanic

adults and highest among non-Hispanic Black women.

9,10

Screening adults for obesity is

recommended by the US Preventive Services Task Force.

Given the prevalence of obesity and its

impact on health, the direct medical costs of obesity are staggering, estimated to be $260 billion in

the US in 2016.

The financial impact of obesity on individuals includes not only direct medical

costs but also indirect costs of lower wages and greater work loss and disability.

17,18

The stigma of obesity in society includes perceptions that attribute the problem to an individual’s

inability to control caloric intake and physical activity. However, it is recognized that energy

balance dysregulation is the result of interactions among complex genetic factors associated with

the body’s mechanisms that control energy balance and contribute to developing obesity.

19,20

individual’s lifestyle is also impacted by societal, economic, and cultural factors, which have

contributed to the rise in obesity. This complexity supports the idea that treating obesity and its

consequences must consider the potential range of causes that contribute to any one individual

with obesity.

The goal of therapy for obesity is to broadly prevent, treat, or reverse its complications, including its

impact on quality of life.

21,22

Patients cite a variety of reasons for wanting to lose weight including

improved health, self-esteem, and body image. Treatments to promote weight loss are intended to

improve health and prevent the health risks associated with obesity (e.g., diabetes, hypertension,

dyslipidemia, heart disease, cancer, fatty liver, osteoarthritis, sleep apnea) and ultimately improve

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quality of life and longevity.

5,23

Observational studies support an association between weight loss

and reductions in mortality.

Initial weight loss treatments focus on lifestyle interventions that

variably combine healthful nutrition, increased physical activity, and behavioral modifications.

24,25

Though helpful for some, weight loss is usually modest and regaining weight over time occurs in the

vast majority of individuals. Earlier generation medications also had modest effects on weight loss,

and some were found to pose significant health risks. The introduction of surgical procedures to

promote weight loss demonstrated that, for severe obesity, significant weight loss was possible and

was associated with decreased weight-related complications.

26,27

This supports the notion that

successfully managing obesity as a chronic condition can lead to long-term health benefits.

For individuals who have not achieved desired weight loss with lifestyle changes, there are multiple

pharmacotherapy options indicated to promote weight loss and prevent complications of obesity.

Pharmacotherapy is often considered first-line before more invasive weight loss techniques are

considered (e.g., bariatric surgery). Currently, approved medications by the US Food and Drug

Administration (FDA) include the single agents: phentermine (1959), orlistat (Xenical®, H2 Pharma,

2007), liraglutide (Saxenda®, Novo Nordisk, 2014), and semaglutide (Wegovy®, Novo Nordisk, June

2021), and the combination drugs: phentermine/topiramate (Qysmia®, Vivus, 2012) and

bupropion/naltrexone (Contrave®, Currax Pharmaceuticals, 2014).

Semaglutide and liraglutide are glucagon-like peptide-1 (GLP-1) receptor agonists that are also

approved for diabetes mellitus due to their effect in stimulating insulin production. Their weight

loss effect is mediated in part by decreasing hunger and delaying gastric emptying.

Both are given

by subcutaneous injection with liraglutide administered daily and semaglutide weekly. The other

FDA-approved medications are administered by mouth and taken daily. Because orlistat results in

modest weight loss and causes intestinal side effects, it is less commonly used for initial medication

management and is not reviewed in this Report. Phentermine is an amphetamine-like medication

that suppresses appetite and is approved for short-term use (less than 12 weeks). It is also

available in combination with topiramate, a carbonic anhydrase inhibitor used to treat seizures.

The combination of bupropion and naltrexone works in the brain to decrease hunger.

Bupropion

is an inhibitor of norepinephrine and dopamine and is an antidepressant and anti-anxiety

medication. Naltrexone is an opioid antagonist and blocks the effect of opioid pain medications.

Since phentermine, topiramate, bupropion, and naltrexone are available as single agents, clinicians

may also use them “off label” alone and in various combinations for weight loss.

There are a host of other more invasive treatments including endoscopic surgical procedures and

devices placed into the stomach to promote early satiety. Though these may also be used for

individuals who have not achieved desired weight loss with lifestyle changes, patients and experts

felt that the limited time duration of weight loss and/or invasive nature of these procedures would

make them less comparable to medications that could be taken for longer periods.

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Practical issues in using medications for weight loss are modest weight reduction, potential side

effects, long-term safety, durability of treatment effect, and concerns about insurance coverage.

Consequently, there is a need to understand the comparative benefits and costs of the newer

branded medications for individuals interested in weight loss after not achieving their goals with

initial lifestyle modification. Because semaglutide appears to promote greater weight loss than

other FDA-approved medications, there has been considerable interest among patients and

providers despite being administered as an injection and more costly.

Finally, a number of newer medications that promote weight loss are being investigated. An oral

version of semaglutide has been approved for the treatment of diabetes mellitus and is under

investigation for use in weight loss. Another medication, tirzepatide, is both a GLP-1 receptor

agonist and also a glucose-dependent insulinotropic polypeptide receptor agonist, and has been

approved for treatment of diabetes mellitus. Data on weight loss with tirzepatide have been

published,

and these results are discussed in Supplement A3.

Table 1.1. Interventions of Interest

Intervention

Mechanism of Action

Delivery Route

Prescribing Information

Semaglutide

GLP-1 receptor agonist

Subcutaneous

2.4 mg once weekly

Liraglutide

GLP-1 receptor agonist

Subcutaneous

3 mg once daily

Phentermine/Topiramate

Sympathomimetic amine/

GABA receptor modulation

Oral 7.5-15 mg/46-92 mg daily

Bupropion/Naltrexone

Opioid antagonist/NE and DA

inhibitor

Oral 32 mg/360 mg daily

CA: carbonic anhydrase, DA: dopamine, GABA: gamma-aminobutyric acid, GLP-1: glucagon-like peptide-1, mg:

milligram, NE: norepinephrine

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2. Patient and Caregiver Perspectives

Discussions with individual patients and patient organizations identified important insights and

perspectives. Common themes emphasized included: the considerable physical and mental burden

on patients with obesity; the broad recognition that the social stigma associated with obesity can

begin at a young age and affect an individual throughout their life; the need for better treatment

options; the impact on all aspects of life including education, work and social/family relationships;

the importance of measuring treatment outcomes that are most meaningful to patients; and the

affordability of increasingly expensive treatments that may not be covered by health insurance.

Patients and clinicians emphasized that obesity is a serious, chronic disease with important health

consequences affecting both physical and mental well-being. Individuals with obesity are at

increased risk of chronic health conditions such as high blood pressure or cholesterol, diabetes

mellitus, heart disease, sleep apnea, arthritis, immobility, depression, and cancer. As a result,

obesity is associated with reduced disease-free life and increased risk of premature death.

Despite these risks, patients and advocates said that societal biases further the perception that

those living with obesity are not able to make the personal lifestyle choices to manage weight. This

simplistic focus on “blame the patient” overlooks considerable evidence that the causes of obesity

are complex and multifactorial. The resulting social stigma associated with obesity is widely felt by

individuals with obesity, begins at a young age, and affects individuals throughout their lives. This

stigma and bias can lead to anxiety, depression, and behaviors that make self-care harder, and may

impact willingness to engage with health care providers around weight loss and the consequences

of obesity.

We also heard that there are diverse perspectives about obesity that broadly reflect the many

individuals with obesity and the variety of underlying factors that contribute to obesity and its

management. Though many individuals with obesity are interested in weight loss, the cycle of

weight loss and gain, the many “fad” diets and treatments that offer unrealistic expectations, and

the cost of treatments that are often not covered by health insurance all impact perceptions about

weight loss. We heard some advocate more for efforts focused on managing the medical issues

associated with obesity, especially for those individuals who have suffered through failed

treatments, weight cycling, and the psychological harms associated with such prior experiences.

Even among those more interested in weight-neutral treatment efforts, there was recognition that

more can be done in the health care system to reduce the stigma of obesity and better support

individuals interested in weight loss treatment.

Patients and patient organizations identified that the impact of obesity is particularly high among

women and individuals from certain racial and ethnic groups. For example, the prevalence of

obesity is higher for Hispanic adults and highest among non-Hispanic Black women.

9,10

Moreover

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disparities in access to health care and treatments for obesity may exacerbate the morbidity and

mortality associated with obesity across racial and ethnic groups. It was also highlighted that trials

of interventions for obesity need to ensure a diversity of individuals from different racial and ethnic

backgrounds.

Patients and clinicians highlighted that there is a need for new therapeutic options for individuals

with obesity who are interested in weight loss treatments, particularly for individuals who have not

responded to lifestyle treatments or who responded but then regained lost weight over time. They

emphasized that no one treatment is a panacea, and this reflects the various underlying

mechanisms that contribute to obesity as well as the benefits and harms associated with all

therapies. Given the wide variety of treatments available for those interested in weight loss

treatment, they supported focusing on medical therapies for those who have not responded to

lifestyle interventions and are interested in additional treatments. Though patients may also

consider invasive surgical and other device interventions while also considering the use of medical

therapies, patients felt that many individuals had treatment preferences that made direct

comparison of medical and non-medical therapies less important. This also reflected increased

interest in medications that provide substantial weight loss to an increasing percentage of users,

with weight reduction that is becoming comparable to results associated with some bariatric

procedures.

Patients and clinicians also reported that individuals with obesity commonly use medications

approved in combination products for weight loss but available as individual drugs in an off-label

manner. This reflected that they often saw this route as minimizing side effects when starting

treatment and being less costly for patients given the higher costs of approved combination

medications that are often not covered by insurers. The net effect is that many patients end up on

a combination of medications, but not always using the approved combination products. There was

also recognition that the addition of medications, such as the GLP-1 receptor agonists, represents a

step forward in the magnitude of weight loss achieved, but they do not work for everyone, and the

weight loss achieved is still less than that seen for bariatric surgery for many individuals. Finally, it is

acknowledged that most patients will require chronic use to maintain the weight loss achieved, not

unlike the need to use medications to manage diabetes mellitus, but there was concern about the

safety of long-term use and the willingness of individuals to remain on therapy for many years,

especially if it requires considerable out-of-pocket costs to the individual.

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3. Comparative Clinical Effectiveness

3.1. Methods Overview

Procedures for the systematic literature review assessing the evidence on semaglutide, liraglutide,

phentermine/topiramate, and bupropion/naltrexone for the management of obesity are detailed in

Section D1

of the Supplement.

Scope of Review

We reviewed the clinical effectiveness of the medications plus lifestyle interventions compared to

placebo plus lifestyle interventions. For studies evaluating multiple doses or combinations of the

medications, we reviewed only the FDA-approved dose and/or combination for the obesity

indication. Lifestyle interventions were variably defined in the clinical trials as interventions ranging

from diet and exercise counseling to intensive behavioral therapy (IBT) and meal replacement

programs. We sought evidence on weight loss outcomes, including percentage weight loss from

baseline and proportion of participants achieving 5%, 10%, or 15% body weight loss as well as

patient-important outcomes, including functional status, health-related quality of life (HRQoL), and

weight regain. We also sought evidence on changes in glycated hemoglobin (A1C), systolic blood

pressure (SBP), low density lipoprotein (LDL), and waist circumference. The full scope of the review

is available in Section D1

of the Supplement.

Evidence Base

Semaglutide

Evidence informing our review of semaglutide for obesity management was derived from five of the

STEP trials. STEP 1, STEP 2, STEP 3, STEP 5, and STEP 8 were selected as studies of interest due to

their study design, relevant population, and length of follow-up.

29-33

Additional studies of

semaglutide are described in Section D2 and Tables D8, D13, and D19

in the Supplement.

STEP 1, STEP 2, and STEP 5 evaluated subcutaneous semaglutide 2.4 mg plus lifestyle intervention

versus placebo plus lifestyle intervention.

27,28,32

STEP 2 also evaluated subcutaneous semaglutide at

1.0 mg, but we only reviewed evidence for the subcutaneous semaglutide 2.4 mg as it is the

approved dose for obesity treatment (Table 3.3).

STEP 3 evaluated subcutaneous semaglutide 2.4

mg plus IBT versus placebo plus IBT (Table 3.1).

STEP 8 evaluated subcutaneous semaglutide 2.4

mg plus lifestyle intervention versus subcutaneous liraglutide 3.0 mg plus lifestyle intervention, and

compared both to placebo plus lifestyle intervention.

STEP 8 was open label due to dosing

differences between semaglutide and liraglutide, however, active treatment groups were double-

blinded to whether they were receiving the intervention or comparable placebo (Table 3.1).

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Participants in STEP 1, 3, 5, and 8 included adults with BMI ≥30 kg/m

or ≥27 kg/m

with at least one

weight-related comorbid condition (Table 3.1).

29,31-33

History of type 1 or type 2 diabetes mellitus or

HbA1C equal to or above 6.5% were exclusion criteria for these trials. Participants in STEP 2

included adults with BMI of ≥27 kg/m² diagnosed with type 2 diabetes mellitus and excluded

individuals with renal disease (Table 3.3).

Participants in STEP 1, 3, 5, and 8 trials were of similar age and baseline weight and BMI.

29,31-33

Participants in STEP 2 who had diabetes mellitus were somewhat older, had lower BMI, and were

less likely to be female or White.

Baseline characteristics for the STEP trials are outlined in Tables

3.1 and 3.3. Outcomes were assessed at week 68 for all STEP trials except STEP 5, which evaluated

outcomes at weeks 52 and 104.

STEP 4, which was a withdrawal study, was not included in the base evidence review or network

meta-analysis (NMA) due to differences in study design and baseline weight loss during a run-in

dose escalation period.

However, we did review its unique data regarding weight regain. See

additional information regarding this trial in Section D2

of the Supplement.

Table 3.1. Overview of Key Trials of Semaglutide for the Management of Obesity

29,31,33-39

STEP 1

STEP 3

STEP 5

STEP 8

Study Arms

PBO

SEM

PBO

SEM

PBO

SEM

PBO

SEM

LIR

655

1,306

204

407

152

126

127

Lifestyle

Intervention

Monthly counseling,

reduced-calorie

diet, and increased

physical activity

Low calorie meal

replacement diet for

8 weeks and IBT visits

Monthly counseling,

reduced-calorie

diet, and increased

physical activity

Monthly counseling,

reduced-calorie diet,

and increased physical

activity

Mean Age,

Years

47 46 46 46 47 47 51 48 49

Female

Gender, %

76 73.1 88.2 77.4 74.3 80.9 77.6 81 76.4

Baseline

Weight, kg

105.2 105.4 103.7 106.9 106 108.8 102.5 103.7

Baseline

BMI, kg/m

38 37.8 37.8 38.1 38.5 38.8 37 37.2

Race, White,

76 74.5 77.5 75.4 93.4 92.8 70.6 74.6 74.8

Pre-Diabetes,

40.2 45.4 52.9 48.2 46.4 40 34.1 35.4

IBT: intensive behavioral therapy, kg: kilogram, LIR: liraglutide, m: meter, N: total number, NR: not reported, PBO:

placebo, SEM: semaglutide

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Liraglutide

Evidence informing our review of liraglutide for obesity management was derived from six of the

SCALE Phase III randomized trials, which evaluated subcutaneous liraglutide 3.0 mg versus

placebo.

40-45

STEP 8, described previously, is included in the liraglutide evidence analysis as well.

Additional studies of liraglutide are described in Section D2 and in Tables D8, D13, and D19

of the

Supplement.

SCALE (Maintenance), SCALE (Sleep Apnea), SCALE (Obesity and Pre-Diabetes), and SCALE (Type 2

Diabetes) evaluated subcutaneous liraglutide 3.0 mg plus lifestyle intervention versus placebo plus

lifestyle intervention.

40-45

SCALE (IBT) and SCALE (Insulin) evaluated subcutaneous liraglutide 3.0 mg

plus IBT versus placebo plus IBT.

44,45

Participants in SCALE (IBT) included adults ages ≥18 with a BMI

≥30 kg/m

Participants in SCALE (Maintenance), SCALE (Sleep Apnea), and SCALE (Obesity and

Pre-Diabetes) included adults ages ≥18 with BMI ≥30kg/m

or ≥27kg/m

with untreated

dyslipidemia or hypertension.

40,41,43

SCALE

(Sleep Apnea) had additional inclusion criteria of

individuals with moderate to severe obstructive sleep apnea who were unable or unwilling to use

continuous positive airway pressure (CPAP).

Participants in SCALE (Type 2 Diabetes) included

adults ages ≥18 with overweight or obesity (BMI ≥27kg/m

) with a diagnosis of type 2 diabetes

mellitus treated with diet and exercise alone or one to three oral hypoglycemic medications.

Participants in SCALE (Insulin) included adults ages ≥18 with a BMI ≥27kg/m

, a

diagnosis of type 2

diabetes mellitus, and receiving stable treatment with any basal insulin and ≤2 oral hypoglycemic

medications.

All trials except SCALE (IBT) and SCALE (Insulin) excluded individuals with a history of

previous surgical treatment of obesity. Additionally, all studies excluded individuals with a recent

history of major depressive disorder or a lifetime suicide attempt. Any history of drug-induced

obesity or an endocrine disorder that could contribute to obesity (e.g., Cushing syndrome) was also

exclusion criteria across all trials. History of multiple endocrine neoplasia and familial medullary

thyroid carcinoma were also exclusionary due to the increased risk of medullary cancer of the

thyroid with GLP-1 receptor agonists.

46,47

Participants across all included trials were primarily

female, and of similar age and baseline weight and BMI, with some notable differences. SCALE

(Sleep Apnea) participants had higher baseline weight and were primarily male and participants in

SCALE (Type 2 Diabetes) and SCALE (Insulin) had higher baseline A1C and SBP.

41,42,45

Baseline

characteristics for the SCALE trials are outlined in Tables 3.2 and 3.3.

Outcomes were assessed at week 56 for all SCALE trials except SCALE (Sleep Apnea), which assessed

outcomes at week 32. SCALE (Type 2 Diabetes) additionally evaluated some relevant outcomes at

week 68.

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Table 3.2. Overview of Key Trials of Liraglutide for the Management of Obesity

40,41,43,44,48-51

SCALE

Maintenance

SCALE

Sleep Apnea

SCALE

Obesity and

Pre-Diabetes

SCALE

IBT

Study Arms

PBO

LIR

PBO

LIR

PBO

LIR

PBO

LIR

210

212

179

180

1,244

2,487

140

142

Lifestyle

Intervention

Low-calorie run-in with

weekly counseling then

reduced-calorie diet,

and increased physical

activity

Monthly counseling,

reduced-calorie

diet, and increased

physical activity

Monthly counseling,

reduced-calorie diet,

and increased

physical activity

IBT, reduced-calorie

diet, and increased

physical activity

Mean Age,

Years

46.5 45.9 48.4 48.6 45 45.2 49 45.4

Female

Gender, %

78.6 84 27.9 28.3 78.1 78.7 82.9 83.8

Baseline

Weight, kg

98.7 100.4 118.7 116.5 106.2 106.2 106.7 108.5

Baseline

BMI, kg/m

35.2 36 39.4 38.9 38.3 38.3 38.7 39.3

Race, White,

88.1 80.2 75.4 72.2 85.3 84.7 82.1 78.9

Pre-Diabetes,

NR NR 62.6 63.9 60.9 61.4 NR NR

IBT: intensive behavioral therapy, kg: kilogram, LIR: liraglutide, m: meter, N: total number, NR: not reported, PBO:

placebo

Table 3.3. Overview of Key Trials of Semaglutide and Liraglutide for the Management of Obesity

with Diabetes

30,42,45,52

STEP 2

SCALE

Type 2 Diabetes

SCALE

Insulin

Study Arms

PBO

SEM

PBO

LIR

PBO

LIR

403

404

212

423

198

Lifestyle

Intervention

Monthly counseling,

reduced-calorie diet, and

increased physical activity

Monthly counseling,

reduced-calorie diet, and

increased physical activity

IBT, reduced-calorie diet, and

increased physical activity

Mean Age,

Years

55 55 54.7 55 57.6 55.9

Female

Gender, %

47.1 55.2 54.2 48 50 45.5

Baseline

Weight, kg

100.5 99.9 106.5 105.7 98.9 100.6

Baseline

BMI, kg/m

35.9 35.9 37.4 37.1 35.3 35.9

Race, White, %

58.7

82.5

83.5

90.9

87.9

IBT: intensive behavioral therapy, kg: kilogram, LIR: liraglutide, m: meter, N: total number, PBO: placebo, SEM:

semaglutide

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Phentermine/Topiramate

Evidence informing our review of phentermine/topiramate for obesity management was derived

from three Phase III studies (EQUIP, EQUATE, and CONQUER). One additional Phase I/II study, OB-

204, is described in Section D2 and Tables D9, D16, and D20

of the Supplement.

EQUIP, EQUATE, and CONQUER were multi-center, Phase III randomized controlled trials that

evaluated phentermine 15 mg/topiramate 92 mg (high dose) plus lifestyle intervention versus

placebo plus lifestyle intervention (Table 3.4 and 3.5).

53-57

EQUIP also evaluated phentermine 3.75

mg/topiramate 23 mg and CONQUER evaluated the phentermine 7.5/topiramate 46 mg dose.

EQUATE had seven arms evaluating multiple doses of phentermine and topiramate monotherapy, in

addition to phentermine 7.5 mg/topiramate 46 mg. Evidence was reviewed only for phentermine

15 mg/topiramate 92 mg (high dose) and phentermine 7.5 mg/topiramate 46 mg doses (low dose),

and the NMA focused solely on the high dose.

The EQUIP, EQUATE, and CONQUER trials included adults ages 18-70, but each trial had varying BMI

requirements. EQUIP required that participants have a BMI of at least 35 kg/m

and EQUATE

included participants with a BMI of 30-45 kg/m

(Table 3.4).

53-57

The CONQUER trial required that

participants have a BMI of 27-45 kg/m

(with no lower BMI limit for patients who have diabetes

mellitus) and have at least two of the following comorbidities: SBP 140-160 mmHg (or 130-160

mmHg if diabetic), diastolic blood pressure 90-100 mmHg (or 85-100 mmHg if diabetic), or taking at

least two antihypertensive medications (Table 3.5).

The CONQUER trial additionally included both

adults with and without type 2 diabetes mellitus. For the purposes of our clinical review and NMA,

and due to the lack of data available in the subgroup of participants without diabetes mellitus, we

focused specifically on the diabetes mellitus subgroup in this trial because it comprised the majority

of participants (68%).

Having a serious medical condition, obesity of known endocrine origin, stage 2 hypertension,

previous surgery for obesity, or a weight change of >5 kg within three months were common

exclusion criteria for these trials. Patients in EQUIP and EQUATE were also excluded if they had

type 2 diabetes mellitus.

54,56

Additional exclusion criteria for CONQUER included fasting glucose

greater than 13 mmol/L, triglycerides greater than 4.52 mmol/L, use of antidiabetic medication

other than metformin, or a history of seizures or serious psychiatric illness.

EQUIP and EQUATE trials had similar baseline characteristics, except for BMI and weight.

54-57

The

BMI requirement was higher in EQUIP than in other trials, meaning that all participants in this trial

had severe obesity. As a result, the mean baseline BMI and body weight of participants was higher

in this trial compared to other trials in our review.

Compared to participants in EQUIP and

EQUATE, the diabetes mellitus subgroup of CONQUER had a higher mean age and fewer female

participants.

Baseline characteristics for these trials are reported in Tables 3.4 and 3.5.

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Bupropion/Naltrexone

Evidence to inform our review of bupropion/naltrexone in patients with overweight or obesity was

derived from four Phase III randomized controlled trials, COR-I, COR-II, COR-BMOD, and COR

Diabetes. Two additional Phase III trials, CVOT Light and Ignite, are described in Section D2

and

Tables D9, D16, and D20 of the Supplement.

COR-I, COR-II, and COR Diabetes were multi-center, Phase III randomized controlled trials that

evaluated bupropion SR 360 mg/naltrexone SR 32 mg plus lifestyle intervention versus placebo plus

lifestyle intervention.

59-64

COR-I additionally evaluated a lower dose of bupropion SR 360

mg/naltrexone SR 16 mg, but we only reviewed the higher approved dose of the medication. COR-

BMOD was a multi-center, Phase III randomized controlled trial that evaluated bupropion SR 360

mg/naltrexone SR 32 mg plus IBT versus placebo plus IBT (Table 3.4 and 3.5).

65,66

COR-I, COR-II, and COR-BMOD included adults ages 18-65 years who had a BMI of 30-45 kg/m

, or a

BMI of 27-45 kg/m

with controlled hypertension and/or dyslipidemia (Table 3.4).

61,63,65

Inclusion

criteria for COR Diabetes included patients ages 18-70 years with a BMI of 27-45 kg/m

, who were

diagnosed with type 2 diabetes mellitus, had an HbA1C between 7-10%, fasting blood glucose <270

mg/dL, fasting triglycerides <400 mg/dL, SBP <145 mmHg, and diastolic blood pressure <95 mmHg

(Table 3.5).

Having type 1 diabetes mellitus, a serious medical condition, obesity of known endocrine origin,

surgery for obesity, a history of seizures, drug, or alcohol abuse, or using medications that affected

body weight were common exclusion criteria among the trials. Adults with overweight or obesity in

COR-I, COR-II, and COR-BMOD were additionally excluded if they had type 2 diabetes mellitus or a

weight change of >4 kg within three months.

61,63,65

In COR Diabetes, patients were also excluded if

they had diabetes mellitus secondary to pancreatitis or pancreatectomy, weight change >5 kg

within three months, or used diabetes medication or were not on a stable dose of oral antidiabetic

drugs.

Baseline characteristics for COR-I, COR-II, and COR-BMOD trials were similar,

61,63,65

except

participants in COR Diabetes were slightly older in age and less likely to be female.

Baseline data

for patients in these trials are reported in Tables 3.4 and 3.5.

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Table 3.4. Overview of Key Trials of Phentermine/Topiramate and Bupropion/Naltrexone for the

Management of Obesity

54-57,61-66

EQUIP

EQUATE

COR-I

COR-II

COR-BMOD

Study Arms PBO

P/T

(high)

PBO

P/T

(low)

P/T

(high)

PBO B/N PBO B/N PBO B/N

514

512

109

107

108

581

583

495

1,001

202

591

Lifestyle

Intervention

LSM counseling,

reduced-calorie

diet, increased

physical activity

LSM counseling,

reduced-calorie diet,

increased physical

activity

LSM

counseling,

reduced-calorie

diet, increased

physical activity

LSM counseling,

reduced-calorie

diet, increased

physical activity

IBT, reduced-

calorie diet,

increased physical

activity

Mean Age,

Years

43 41.9 45 44.6 44.6 43.7 44.4 44.4 44.3 45.6 45.9

Female

Gender, %

82.7 82.8 78.9 79.4 78.7 85 85 84.8 84.6 91.6 89.3

Baseline

Weight, kg

115.8 115.2 100 102.2 99.3 99.5 99.7 99.2 100.3 101.9 100.2

Baseline

BMI, kg/m

42 41.9 36.2 36.6 35.9 36.2 36.1 36.1 36.2 37 36.3

Race,

White, %

79.7 80.4 76.1 74.8 81.5 75.7 75 83.6 83.4 73.7 68.5

Pre-

Diabetes, %

NR NR NR NR NR NR NR NR NR NR NR

B/N: bupropion/naltrexone, IBT: intensive behavioral therapy, kg: kilogram, LSM: lifestyle modification, m: meter,

N: total number, NR: not reported, PBO: placebo, P/T: phentermine/topiramate

Table 3.5. Overview of Key Trials of Phentermine/Topiramate and Bupropion/Naltrexone for the

Management of Obesity with Diabetes

53,58-60

CONQUER (Diabetes Subgroup)

COR Diabetes

Study Arms

PBO

P/T (low)

P/T (high)

PBO

B/N

157

164

159

265

Lifestyle Intervention

LSM counseling, reduced-calorie diet, increased

physical activity

LSM counseling, reduced-calorie

diet, increased physical activity

Mean Age, Years

52.6

52.5

52.1

53.8

53.9

Female Gender, %

71.3

65.6

62.1

52.8

54.3

Baseline

Weight, kg

99.3 97.2 103.2 105 106.3

Baseline

BMI, kg/m

36.2 35.3 37.1 36.3 36.7

Race, White, %

84.7

82.9

78.1

B/N: bupropion/naltrexone, kg: kilogram, LSM: lifestyle modification, m: meter, N: total number, PBO: placebo,

P/T: phentermine/topiramate

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3.2. Results

The most common primary outcome reported was percentage weight loss from baseline to one

year after treatment initiation with dose escalation periods ranging from four to 16 weeks. Other

outcomes variably included categorical weight loss (participants achieving 5% or 10% weight loss),

and changes in metabolic and cardiovascular risk factors such as SBP, A1C, and LDL. As noted in the

prior section, trials differed in populations studied (such as participants with or without diabetes

mellitus or other conditions and baseline BMI) and intensity of lifestyle modification interventions

offered alongside active treatment or placebo (ranging from diet and exercise counseling to IBT).

To ensure comparability and generalizability of results, we present trials of participants with obesity

alone separately from trials of participants with obesity and diabetes mellitus.

Clinical trial participants for all interventions were also assessed for improvements in physical

function and mental HRQoL using a variety of instruments: Short Form 36v2 Health Survey (SF-

36v2), Impact of Weight on Quality of Life (IWQOL) Lite Clinical Trials Version, Patient Health

Questionnaire (PHQ-9), and Inventory of Depressive Symptomatology – Self Report (IDS-SR).

Changes in weight, SBP, A1C, and HRQoL as well as harms and discontinuation rates are

summarized below, and additional outcomes are available in Section D2

of the Supplement.

Clinical Benefits

For each medication, weight loss outcomes are summarized first followed by other outcomes (e.g.,

SBP and A1C). HRQoL outcomes are summarized for all drugs at the end of this section. For each

medication, results of trials conducted in patients with obesity are presented first, followed by trials

conducted in patients with obesity and diabetes mellitus.

Semaglutide versus Placebo

The efficacy of semaglutide compared with placebo for the management of obesity in patients

without diabetes mellitus was evaluated in three Phase III trials (STEP 1, 3, and 5).

29,31,38

In the STEP

1, 3, and 5 trials, participants in the subcutaneous semaglutide 2.4 mg arm consistently achieved

greater percent weight loss at one year (-15.6%, -16.5%, and -15.8%, respectively) versus placebo (-

2.8%, -5.8%, and -3.3%, respectively).

29,31,38

Similarly, for the co-primary outcomes of proportion of

participants who achieved at least 5% weight loss, at least 10% weight loss, and at least 15% weight

loss, a greater proportion of participants in the semaglutide arm achieved each categorical outcome

compared to participants in the placebo arm. Participants in the semaglutide arms of STEP 1, 3, and

5 trials also had greater improvements in SBP from baseline (-6.2 mmHg, -5.6 mmHg, and -6 mmHg,

respectively) compared to those in the placebo arms (-1.1 mmHg, -1.6 mmHg, and -1 mmHg,

respectively).

29,31

In the STEP 1, 3, and 5 trials, the absolute change in percentage A1C (change in

A1C) from baseline improved in the semaglutide arm (-0.45%, -0.51%, and -0.5%, respectively)

compared to the placebo arm (-0.15%, -0.27%, and -0.2%, respectively).

29,31,38

The absolute change

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in percentage A1C for STEP 8 improved for the semaglutide arm (-0.2%) compared to an increase in

A1C for the placebo arm (0.1%).

31,33

See Table 3.6 for detailed results.

The efficacy of semaglutide for the management of obesity and type 2 diabetes mellitus was

evaluated through one Phase III trial (STEP 2).

Participants in the subcutaneous semaglutide 2.4

mg arm achieved greater percent weight loss at one year (-9.6%) versus placebo (-3.4%), but the

magnitude of weight loss appeared less than in the trials of participants without diabetes mellitus.

Similarly, for the co-primary outcomes of proportion of participants who achieved at least 5%

weight loss and at least 10% weight loss, a greater proportion of participants in the semaglutide

arm achieved each categorical outcome compared to participants in the placebo arm. Participants

in the semaglutide arm also had modest improvement in SBP (-3.6 mmHg) compared to those in the

placebo arm (-0.5 mmHg). Change in A1C from baseline was consistent across both the semaglutide

and placebo arms (-0.4% vs. -0.4%). See Table 3.8 for detailed results.

Physical functioning was assessed in the STEP 1, STEP 2, and STEP 3 trials using the SF-36v2 Physical

Functioning Score.

29-31

STEP 1 and 3 also assessed the mean change in baseline of the SF-36v2 PCS.

STEP 1 and 2 also assessed physical function utilizing the IWQOL-Lite-CT instrument.

29,30

Overall,

semaglutide resulted in greater improvement in the physical component across all HRQoL

instruments compared to placebo, indicating the intervention resulted in greater improvement in

health status for physical patient-reported outcomes. See Table D17

in the Supplement for detailed

results.

STEP 1, 2, and 3 trials all reported baseline SF-36v2 MCS scores, but only STEP 1 and 3 reported the

change from baseline to week 68. STEP 2 reported estimated treatment differences. In STEP 1,

participants in the semaglutide arm experienced improvement in SF-36 MCS scores (1.5) versus

placebo, which had a reduction in score (-2.1). Conversely, in STEP 3, participants in both treatment

arms experienced decreased SF-36 MCS, although there was a smaller decrease in the semaglutide

arm (-0.8) compared to placebo (-2.9). See Table D18 in the Supplement for detailed results.

Semaglutide versus Liraglutide

The efficacy of subcutaneous semaglutide versus subcutaneous liraglutide with a placebo

comparator for the management of obesity was evaluated in one Phase III trial (STEP 8).

Participants in the semaglutide 2.4 mg arm achieved greater weight loss at one year (-15.8%) versus

liraglutide 3.0 mg (-6.4%) and placebo (-1.9%). Similarly, for the co-primary outcomes of proportion

of participants who achieved at least 5% weight loss, at least 10% weight loss, and at least 15%

weight loss, a greater proportion of participants in the semaglutide arm achieved each categorical

outcome compared to participants in the liraglutide and placebo arms. Participants in the

semaglutide arm also had greater improvements in SBP from baseline (-5.7 mmHg) compared to

participants in the liraglutide arm (-2.9 mmHg), and participants in both the semaglutide and

liraglutide arms had greater improvement compared to those in the placebo arm, who had a

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modest increase in SBP (3.2 mmHg). Minimal changes in A1C were seen in all arms of the trial. See

Table 3.6 for detailed results.

Table 3.6. Results of Key Trials of Semaglutide for the Management of Obesity

29,31,33-38,67

STEP 1

STEP 3

STEP 5

STEP 8

Study Arms

PBO

SEM

PBO

SEM

PBO

SEM

PBO

SEM

LIR

577

1,212

189

373

129

149

117

% Weight Loss from

Baseline to One Year,

Mean (SE)

-2.8

(0.3)†

-15.6

(0.3)†

-5.8

(0.4)†

-16.5

(0.5)†

-3.3

(0.6)†

-15.8

(0.8)†

-1.9

(1.1)†

-15.8

(0.9)†

-6.4

(0.9)†

Participants with at Least

5% Weight Loss, n (%)

182

(31.5)

1,047

(86.4)

(47.6)

323

(86.6)

(29.5)

132

(88.6)

(29.5)

102

(87.2)

(58.1)

Participants with at Least

10% Weight Loss, n (%)

(12)

838

(69.1)

(27)

281

(75.3)

(13.2)

102

(68.5)

(15.4)

(70.9)

(25.6)

Change in SBP from

Baseline, mmHg, Mean

(SE)

-1.1

(0.5)†

-6.2

(0.4)†

-1.6*

(1.1)

-5.6*

(0.7)

-1*

(1.2)‡

-7*

(1.1)†

3.2*

(1.5)†

-5.7*

(1.2)†

-2.9*

(1.2)†

Change in %HbA1C from

Baseline, Mean (SE)

-0.15*

(0.01)†

-0.45*

(0.01)†

-0.27*

(0.01)†

-0.51*

(0.02)†

-0.2*

(0.02)†

-0.5*

(0.03)†

0.1*

(0.02)†

-0.2*

(0.03)†

-0.1*

(0.03)†

HbA1C: glycated hemoglobin, LIR: liraglutide, mmHg: millimeters of mercury, n: number, N: total number, PBO:

placebo, SBP: systolic blood pressure, SE: standard error, SEM: semaglutide

*The number of patients for this outcome may differ from the primary analysis population.

†SE manually derived from standard deviation or 95% CIs.

Liraglutide versus Placebo

The efficacy of liraglutide compared with placebo for the management of obesity was evaluated in

four Phase III trials in the SCALE clinical trial program (Maintenance, Sleep Apnea, Obesity and Pre-

Diabetes, IBT).

40,41,43,44

In the Maintenance, Obesity and Pre-Diabetes, and IBT trials, participants in

the subcutaneous liraglutide 3.0 mg arm consistently achieved greater percent weight loss at one

year (-6.2%, -8%, and -7.4%, respectively) versus placebo (-0.2%, -2.6%, and -4%, respectively).

40,43,44

Similarly, for the co-primary outcomes of proportion of participants who achieved at least 5%

weight loss and at least 10% weight loss, a greater proportion of participants in the liraglutide arm

achieved each categorical outcome compared to participants in the placebo arm. Changes in SBP

varied across trials with liraglutide demonstrating modest improvements relative to placebo, except

in the Maintenance trial in which participants in both the liraglutide and placebo arms experienced

an increase in SBP from baseline (0.2 mmHg and 2.8 mmHg, respectively).

Across all four SCALE

trials, greater improvements in change in A1C were consistently demonstrated in the liraglutide

arm compared to the placebo arm, although the results varied between studies.

40,41,43,44

See Table

3.7 for detailed results.

The efficacy of subcutaneous liraglutide compared with placebo for the management of obesity

with diabetes mellitus was evaluated in two Phase III trials in the SCALE clinical trial program (Type

2 Diabetes, Insulin).

42,45

In both the SCALE (Type 2 Diabetes) and SCALE (Insulin) trials, participants

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in the liraglutide 3.0 mg arm had greater percent weight loss at one year (-5.9% and -5.8%,

respectively) compared to placebo (-2% and -1.5%, respectively). Similarly, liraglutide

demonstrated a greater proportion of participants who achieved at least 5% or 10% weight loss

compared to placebo. Liraglutide also demonstrated greater improvements in SBP compared to

placebo. Across both trials, improvements in A1C were greater in the liraglutide arms (-1.3% and -

1.1%, respectively) compared to the placebo arms (-0.3% and -0.6%, respectively). See Table 3.8 for

detailed results.

The SCALE (Sleep Apnea, Obesity and Pre-Diabetes, IBT, and Insulin) trials assessed physical patient-

reported outcomes utilizing the SF-36v2 PCS instrument.

41,43-45

The IWQOL-Lite-CT instrument

assessed physical function score in the SCALE (Type 2 Diabetes, Obesity and Pre-Diabetes, IBT, and

Insulin) studies.

42-45

Overall, liraglutide resulted in greater improvement in the physical component

across all HRQoL instruments compared to placebo, indicating the intervention resulted in greater

improvement in health status for physical patient-reported outcomes. The one exception was

SCALE (IBT), which reported slightly less improvement in SF-36v2 PCS scores for liraglutide (3.4)

compared to placebo (3.8). See Table D17

in the Supplement for detailed results.

Four studies for liraglutide, SCALE (Sleep Apnea, Obesity and Pre-Diabetes, IBT, and Insulin) trials

also evaluated the mental component utilizing the SF-36v2 MCS instrument with minimal

improvements compared to baseline in the liraglutide arm for the SCALE (Sleep Apnea and Obesity

and Pre-Diabetes) trials (1.4 and 0.2, respectively), less improvement in the SCALE (Sleep Apnea)

placebo arm (0.9), and a decrease in health quality in the SCALE (Obesity and Pre-Diabetes) placebo

arm (-0.9).

41,43

The SCALE (IBT and Insulin) trials reported a decrease in SF-36v2 scores across both

the liraglutide and placebo arms of the trial, indicating a decreased mental health status. See

Table

D18 in the Supplement for detailed results.

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Table 3.7. Results of Key Trials of Liraglutide for the Management of Obesity

40,41,43,44,48-51,67

SCALE

Maintenance

SCALE

Sleep Apnea‡

SCALE

Obesity and

Pre-Diabetes

SCALE

IBT

Study Arms

PBO

LIR

PBO

LIR

PBO

LIR

PBO

LIR

188

194

178

175

1,220

2,432

130

141

% Weight Loss from

Baseline to One Year,

Mean (SE)

-0.2†

(0.5)*

-6.2†

(0.5)*

N/A N/A

-2.6

(0.2)*

-8

(0.1)*

-4

(0.6)*

-7.4

(0.7)*

Participants with 5%

Weight Loss, n (%)

(21.8)

(50.5)

(18.5)

(46.3)

331

(27.1)

1,537

(63.2)

(38.8)

(61.5)

Participants with 10%

Weight Loss, n (%)

(6.3)

(26.1)

(1.7)

(23.4)

129

(10.6)

805

(33.1)

(19.8)

(30.5)

Change in SBP from

Baseline, mmHg,

Mean (SE)

2.8†

(0.7)*

0.2†

(0.8)*

0† (1)

-3.4†

(0.9)

-1.5†

(0.4)*

-4.2†

(0.2)*

-0.6† (NR)

-2.8†

(NR)

Change in %HbA1C

from Baseline, Mean

(SE)

0.1†

(0.03)*

-0.1†

(0.03)*

-0.2† (0) -0.4† (0)

-0.06†

(0.01)*

-0.3†

(0.01)*

-0.06†

(0.02)*

-0.16†

(0.03)*

A1C: glycated hemoglobin, LIR: liraglutide, mmHg: millimeters of mercury, n: number, N: total number, N/A: not

applicable, NR: not reported, PBO: placebo, SBP: systolic blood pressure, SE: standard error

*SE manually derived from standard deviation or 95% CIs.

†The number of patients for this outcome may differ from the primary analysis population.

‡Timepoint is at week 32 for all outcomes.

Table 3.8. Results of Key Trials of Semaglutide and Liraglutide for the Management of Obesity

with Diabetes Mellitus

30,42,45,52,67

STEP 2

SCALE

Type 2 Diabetes

SCALE

Insulin

Study Arms

PBO

SEM

PBO

LIR

PBO

LIR

376

388

211

412

193

191

% Weight Loss from

Baseline to One Year,

Mean (SE)

-3.4 (0.4) -9.6 (0.4) -2 (0.3)* -5.9 (0.3)* -1.5 (0.4) -5.8 (0.4)

Participants with 5%

Weight Loss, n (%)

107 (28.5) 267 (68.8) 45 (21.4) 224 (54.3) 46 (24) 100 (51.8)

Participants with 10%

Weight Loss, n (%)

31 (8.2) 177 (45.6) 14 (6.7) 104 (25.2) 13 (6.6) 44 (22.8)

Change in SBP from

Baseline, mmHg,

Mean (SE)

-0.5† (0.8) -3.9† (0.7) -0.4† (0.9)* -2.8† (0.7)* -1.6† (0.9) -5.6† (0.9)

Change in %HbA1C

from Baseline, Mean

(SE)

-0.4† (0.1) -0.4† (0.1)

-0.3†

(0.06)*

-1.3† (0.04)* -0.6† (NR) -1.1† (NR)

A1C: glycated hemoglobin LIR: liraglutide, mmHg: millimeters of mercury, n: number, N: total number, NR: not

reported, PBO: placebo, SBP: systolic blood pressure, SE: standard error, SEM: semaglutide

*SE manually derived from standard deviation or 95% CIs.

†The number of patients for this outcome may differ from the primary analysis population.

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Phentermine/Topiramate versus Placebo

In the EQUIP trial, participants in the phentermine 15 mg/topiramate 92 mg arm achieved greater

weight loss at one year (-10.9%) than participants in the placebo arm (-1.6%).

56,57

For the co-

primary outcome of proportion of participants who lost at least 5% of their weight, more

participants in the phentermine/topiramate arm achieved this outcome compared to participants in

the placebo group. Similarly, more participants in the high-dose treatment arm achieved 10%

weight loss compared to the placebo arm (Table 3.9).

One-year outcomes were not available in the EQUATE trial, whose timepoints went out to only 28

weeks.

Participants in the diabetes mellitus subgroup of the CONQUER trial receiving phentermine 15 mg/

topiramate 92 mg treatment (high dose) and phentermine 7.5 mg/topiramate 46 mg (low dose)

achieved a greater weight improvement at one year (-8.8% and -6.8%, respectively) than

participants in the placebo arm (-1.9%).

53,58

Categorical weight loss of at least 5% and 10% were not

assessed in this diabetes mellitus subgroup population. See Table 3.10 for detailed results.

In terms of secondary outcomes, in the EQUIP trial, SBP decreased by 2.9 mmHg in the high-dose

phentermine/topiramate arm and increased by 0.9 mmHg in the placebo arm (Table 3.9).

In the

CONQUER diabetes mellitus subgroup, patients in the high-dose phentermine/topiramate arm and

low-dose phentermine/topiramate arm experienced HbA1C decreases of 0.4% compared to the

placebo decreases of 0.1%.

Similarly, in patients with diabetes mellitus in CONQUER, SBP

decreased by 4.2 mmHg in the phentermine 15 mg/topiramate 92 mg group, by 2.9 mmHg in the

phentermine 7.5 mg/topiramate 46 mg group, and by 2.1 mmHg in the placebo group (Table

3.10).

Physical function outcomes were not assessed. Depression was assessed in the EQUATE and EQUIP

trials using the PHQ-9 instrument. For both trials, a greater improvement in this measure was

observed in the high-dose phentermine/topiramate arms, compared to the placebo arms. In

EQUATE, participants in the high-dose and low-dose phentermine/topiramate arms improved by 1.1

and 1.3 points, respectively, while participants in placebo improved by 0.5 points.

54,55

Depression

scores in the EQUIP trial improved more from baseline in the high-dose phentermine/topiramate

group (1.5), compared to the placebo group (1.3).

56,57

PHQ-9 was not assessed in the diabetes

mellitus subgroup of the CONQUER trial. See Table D18

in the Supplement for detailed results.

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Bupropion/Naltrexone versus Placebo

In the COR-I, COR-II, and COR-BMOD trials of adults with obesity, participants in the bupropion 360

mg/naltrexone 32 mg (high dose) arm achieved greater weight loss at one year (-6.1%, -6.4%, and

-9.3%, respectively), than participants in the placebo arm (-1.3%, -1.2%, and -5.1%, respectively).

61-

63,65,66

For the co-primary outcome of participants who lost at least 5% of their weight, a greater

proportion of participants in the intervention arm achieved this outcome compared to placebo. A

similar pattern was observed for the secondary outcome of proportion of participants who achieved

10% weight loss between the arms. See Table 3.9 for detailed results.

Participants in the bupropion 360 mg/naltrexone 32 mg arm in the COR Diabetes trial achieved

greater percent weight loss at one year (-5%) than participants in the placebo arm (-1.8%).

59,60

For

the co-primary outcome of proportion of participants who lost at least 5% of their weight, more

participants in the bupropion/naltrexone arm achieved this outcome compared to participants in

the placebo group. Additionally, more participants in the treatment arm achieved 10% weight loss

than in the placebo arm (Table 3.10).

In COR-I, SBP decreased by 0.1 mmHg in participants receiving the intervention and by 1.9 mmHg in

participants receiving placebo (Table 3.9).

57,58,61,62

A similar pattern was observed in the COR-

BMOD trial, where SBP decreased by 1.3 mmHg in the bupropion/naltrexone group versus 3.9

mmHg in the placebo group.

In the COR-II trial, SBP increased by 0.6 mmHg in the treatment

group and decreased by 0.5 mmHg in the placebo group (p=0.039).

None of these trials assessed

HbA1C levels.

In the COR Diabetes trial, change from baseline in HbA1C was -0.63% in the treatment group, and

-0.14% in the placebo arm.

Participants receiving the treatment experienced no change in SBP,

while participants receiving placebo experienced a mean decrease in SBP of 1.1 mmHg. See Table

3.10 for detailed results.

HRQoL was assessed using the IWQOL-Lite, an obesity-specific instrument and the IDS-SR, which

assesses depressive symptoms. In COR-I, COR-II, and COR-BMOD, patients in the

bupropion/naltrexone group showed a greater improvement in the IWQOL-LITE physical function

and total scores than patients in the placebo group.

61-63,65,66

However, changes in depression scores

were not consistent across trials. In COR-I and COR-II, patients in the placebo arm reported a

greater improvement in their depressive symptoms (-0.7 and -0.5, respectively) compared to the

high-dose bupropion/naltrexone arm (-0.3) (lower is better).

61-63

In COR-BMOD, patients in the

treatment arm reported a 0.1 increase from baseline in IDS-SR score, meaning their depressive

symptoms worsened, while patients in placebo reported no change.

65,66

In the COR Diabetes trial,

patients in the bupropion/naltrexone treatment arm reported no change in depression score, while

patients in the placebo arm reported that their mean score improved by 1.6.

59,60

See Tables D17

and D18 in the Supplement for detailed results.

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Table 3.9. Results of Key Trials of Phentermine/Topiramate and Bupropion/Naltrexone for the

Management of Obesity

56,57,61-66

EQUIP

COR-I

COR-II

COR BMOD

Study Arms PBO

P/T

(high)

PBO B/N PBO B/N PBO B/N

498

511

471

456

702

193

482

% Weight Loss from

Baseline to One Year,

Mean (SE)

-1.6

(0.4)

-10.9

(0.4)

-1.3

(0.3)

-6.1

(0.3)

-1.2

(0.3)

-6.4

(0.3)

-5.1

(0.6)

-9.3

(0.4)

Participants with 5%

Weight Loss, n (%)

(17.3)

332

(66.7)

84 (16) 226 (48)

(17.1)

354

(50.5)

(42.5)

320

(66.4)

Participants with 10%

Weight Loss, n (%)

37 (7.4)

235

(47.2)

38 (7) 116 (25) 26 (5.7)

199

(28.3)

(20.2)

200

(41.5)

Change in SBP from

Baseline, mmHg, Mean

(SE)

0.9

(0.6)*

-2.9

(0.6)*

-1.9

(0.4)

-0.1

(0.4)

-0.5

(0.4)

0.6

(0.3)

-3.9

(0.7)

-1.3

(0.5)

Change in %HbA1C from

Baseline, Mean (SE)

NR NR NR NR NR NR NR NR

A1C: glycated hemoglobin, B/N: bupropion/naltrexone, mmHg: millimeters of mercury, n: number, N: total

number, NR: not reported, PBO: placebo, P/T: phentermine/topiramate, SBP: systolic blood pressure, SE: standard

error

*SE manually derived from standard deviation or 95% CIs.

Table 3.10. Results of Key Trials of Phentermine/Topiramate and Bupropion/Naltrexone for the

Management of Obesity with Diabetes Mellitus

53,58-60

CONQUER (Diabetes Subgroup)

COR Diabetes

Study Arms

PBO

P/T (low)

P/T (high)

PBO

B/N

157

164

159

265

% Weight Loss from

Baseline to One Year, Mean

(SE)

-1.9 (0.6)* -6.8 (0.9)* -8.8 (0.6)* -1.8 (0.4) -5 (0.3)

Participants with 5%

Weight Loss, n (%)

NR NR NR 30 (18.9) 118 (44.5)

Participants with 10%

Weight Loss, n (%)

NR NR NR 9 (5.7) 49 (18.5)

Change in SBP from

Baseline, mmHg, Mean (SE)

-2.1 (1.1) -2.9 (1.6) -4.2† (1) -1.1 (0.9) 0 (0.7)

Change in %HbA1C from

Baseline, Mean (SE)

-0.1†

(0.05)*

-0.4† (1.5)* -0.4† (0.6)* -0.14† (0.09) -0.63† (0.07)

A1C: glycated hemoglobin, BN: bupropion/naltrexone, mmHg: millimeters of mercury, n: number, N: total number,

NR: not reported, PBO: placebo, PT: phentermine/topiramate, SBP: systolic blood pressure, SE: standard error

*SE manually derived from standard deviation or 95% CIs.

†The number of patients for this outcome may differ from the primary analysis population.

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NMA Results of Percentage Weight Loss from Baseline at One Year

We conducted NMAs of trials including participants with obesity alone separately from trials of

participants with obesity and diabetes mellitus and excluded trials that included IBT as an adjunct to

medication. The primary outcome NMAs are reported below, and additional outcomes are

available in Supplement D1

Participants with Obesity Alone

For the trials of the medications conducted in participants with obesity without diabetes mellitus

that included standard diet and exercise counseling and reported percentage weight loss at one

year, we present the results of the baseline risk-adjusted random effects model, given its better fit

for the model compared to the unadjusted model in Table 3.11. All medications, in combination

with diet and exercise counseling, showed statistically significantly greater mean weight loss than

placebo with diet and exercise counseling at one year. Compared to placebo, the interventions

demonstrated 4.6-13.7% mean greater weight loss. Semaglutide demonstrated the greatest

percentage weight loss at one year and was superior to all other medications in our review for this

outcome. Phentermine/topiramate (high dose) demonstrated greater weight loss than liraglutide

and bupropion/naltrexone, however, liraglutide was not statistically more effective in

demonstrating weight loss than bupropion/naltrexone (Table 3.11).

Table 3.11. NMA Results of Medications for the Management of Obesity, Mean Percentage

Weight Loss from Baseline at One Year (95% CI)

Semaglutide

-4.6 (-2.4 to -7.2)

Phentermine/

Topiramate*

-8.7 (-7.3 to -10.4) -4.1 (-1.9 to -6.3) Liraglutide

-9.1 (-7.2 to -11.5) -4.5 (-2.2 to -6.9) -0.4 (-2.3 to +1.3)

Bupropion/

Naltrexone

-13.7 (-12.6 to -15.1) -9.1 (-7.1 to -11) -5.0 (-3.9 to -6.1) -4.6 (-3.0 to -6.0) Placebo

Legend: Each cell represents estimated absolute differences in percentage weight loss and 95% credible interval

for the combined direct and indirect comparisons between two medications or one medication and placebo.

Estimates in bold indicate the 95% credible interval does not contain 1.

*High dose.

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Participants with Obesity and Diabetes Mellitus

For the trials of the medications conducted in participants with obesity and diabetes mellitus (using

the approved obesity indication dose) that reported percentage weight loss at one year, we present

the results of the baseline risk-adjusted random effects model, given its better fit for the model

compared to the unadjusted model in Table 3.12. All medications, in combination with diet and

exercise counseling, showed statistically significantly greater mean weight loss than placebo with

diet and exercise counseling at one year among participants with obesity with diabetes mellitus,

although the magnitude of the weight loss was somewhat lower than in trials of participants with

obesity alone, especially for semaglutide. Compared to placebo, the medications demonstrated

2.9-7.6% mean greater weight loss at one year. Semaglutide demonstrated a greater percentage

weight loss among the medications, however, these differences were not statistically significant.

Phentermine/topiramate (high dose) demonstrated greater weight loss than liraglutide and

bupropion/naltrexone, however, the results were only statistically significant compared to

bupropion/naltrexone. Liraglutide was not statistically more effective in demonstrating weight loss

than bupropion/naltrexone (Table 3.12).

Table 3.12. NMA Results of Medications for the Management of Obesity with Diabetes Mellitus,

Mean Percentage Weight Loss from Baseline at One Year (95% CI)

Semaglutide

-0.9 (-6.3 to +6.2)

Phentermine/

Topiramate*

-3.9 (-9.3 to +3.7) -2.9 (-0.05 to -5.8) Liraglutide

-4.7 (-10.3 to +2.8) -3.8 (-0.4 to -7.1) -0.9 (-3.8 to +2.1)

Bupropion/

Naltrexone

-7.6 (-1.7 to -11.9) -6.7 (-4.2 to -9.2) -3.7 (-1.7 to -6) -2.9 (-0.4 to -5.6) Placebo

Legend: Each box represents estimated absolute differences in percentage weight loss and 95% credible interval

for the combined direct and indirect comparisons between two medications or one medication and placebo.

Estimates in bold indicate the 95% credible interval does not contain 1.

*High dose.

NMA Results of Change in SBP from Baseline at One Year

Participants with Obesity Alone

For the trials of the medications conducted in participants with obesity without diabetes mellitus

that included standard diet and exercise counseling and reported change in SBP at one year, we

present the results of the baseline risk-adjusted random effects model, given its better fit for the

model compared to the unadjusted model in Table 3.13. All medications, in combination with diet

and exercise counseling, showed statistically significantly greater improvements in SBP than

placebo with diet and exercise counseling at one year except bupropion/naltrexone, which was

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Evidence Report – Medications for Obesity Management Return to Table of Contents

comparable to placebo. Compared to placebo, the interventions demonstrated 3.8-7.1 mmHg

improvements in SBP. Semaglutide demonstrated the greatest improvement in SBP at one year and

was superior to all other medications in our review except for phentermine/topiramate (high dose)

for this outcome. Phentermine/topiramate (high dose) and liraglutide both demonstrated greater

improvements in SBP than bupropion/naltrexone, however, the interventions were statistically

equivalent (Table 3.13).

Table 3.13. NMA Results of Medications for the Management of Obesity, Mean Change in SBP

from Baseline at One Year (95% CI)

Semaglutide

-2.9 (-6.2 to 0.4)

Phentermine/

Topiramate*

-3.3 (-5.3 to -1.2) -0.4 (-3.6 to 2.9) Liraglutide

-6.3 (-7.9 to -4.7) -3.4 (-6.3 to -0.6) -3.1 (-4.7 to -1.4) Placebo

-7.1 (-9.8 to -4.4) -4.2 (-7.9 to -0.6) -3.9 (-6.8 to -1.0) -0.8 (-3.0 to 1.3)

Bupropion/

Naltrexone

Legend: Each box represents estimated absolute differences in SBP and 95% credible interval for the combined

direct and indirect comparisons between two medications or one medication and placebo. Estimates in bold

indicate the 95% credible interval does not contain 1.

*High dose.

Participants with Obesity and Diabetes Mellitus

For the trials of the medications conducted in participants with obesity and diabetes mellitus and

reported change in SBP at one year, we present the results of the baseline risk-adjusted random

effects model, given its better fit for the model compared to the unadjusted model in Table 3.14.

Semaglutide and liraglutide, in combination with diet and exercise counseling, showed statistically

significantly greater improvements in SBP than placebo with diet and exercise counseling at one

year, while phentermine/topiramate (high dose) and bupropion/naltrexone did not. Compared to

placebo, semaglutide and liraglutide demonstrated 4.3 mmHg and 3.4 mmHg improvements in SBP,

respectively (Table 3.14).

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Table 3.14. NMA Results of Medications for the Management of Obesity and Diabetes Mellitus,

Mean Change in SBP from Baseline at One Year (95% CI)

Semaglutide

-0.9 (-4.2 to 2.5) Liraglutide

-3.5 (-8.9 to 2.1) -2.7 (-6.8 to -1.6)

Phentermine/

Topiramate*

-4.3 (-1.2 to -7.2) -3.4 (-1.6 to -5.2) -0.7 (-4.4 to 2.8)

Placebo

-5.3 (-1.4 to -9.2) -4.4 (-1.3 to -7.6) -1.8 (-6.3 to 2.6) -1.1 (-4.6 to 1.5)

Bupropion/

Naltrexone

Legend: Each box represents estimated absolute differences in SBP and 95% credible interval for the combined

direct and indirect comparisons between two medications or one medication and placebo. Estimates in bold

indicate the 95% credible interval does not contain 1.

*High dose.

Harms

Adverse events reported in the trials are detailed below by medication. It is worth noting that three

of the medications carry black box warnings and the fourth has a Risk Evaluation and Mitigation

Strategies in place. The GLP-1 medications, semaglutide and liraglutide, carry a black box warning

for thyroid carcinoma and bupropion/naltrexone carries a warning for suicidality.

Phentermine/topiramate has a Risk Evaluation and Mitigation Strategy in place for a risk of birth

defects. These outcomes were not observed in any of the trials but relate to real-world data and

should be taken into consideration when prescribing.

Semaglutide

The most frequent adverse events in the STEP trials for semaglutide were gastrointestinal-related

symptoms, including nausea, constipation, and diarrhea.

29-38

Beyond gastrointestinal events,

semaglutide appeared relatively well-tolerated. Rates of adverse events and serious adverse events

were higher in the semaglutide arm compared to placebo, except STEP 5, which had a higher rate of

serious adverse events in the placebo arm (11.8%) versus the semaglutide arm (7.9%) (Table 3.15).

The higher rate of serious adverse events in the placebo arm of STEP 5 seems to be a chance event

associated with events that are not expected to be associated with the intervention within the

placebo arm, including COVID-19 infections, foot deformity, jaw and rib fractures, and several

occurrences of cancer.

37,38

Across all trials, there were higher rates of discontinuation due to adverse events in the

semaglutide arms compared to placebo, and discontinuation was most often attributed to

gastrointestinal events. In STEP 8, participants in the liraglutide arm were more likely to

discontinue due to adverse events (12.6%) compared to both the semaglutide and placebo arms

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(3.2% and 3.5%, respectively) (safety analysis set).

STEP 2, which evaluated participants with

obesity and diabetes mellitus, did not exhibit any significant differences in harms compared to

other trials in the STEP clinical trial program, which evaluated participants with obesity without

diabetes mellitus.

See Table 3.15 for detailed harms results.

There were several areas of focus for safety in the STEP clinical trial program due to therapeutic

experience with GLP-1 receptor agonists and regulatory feedback and requirements. These

included gastrointestinal disorders, gallbladder-related disorders, cardiovascular disorders, and

psychiatric disorders. As expected, there were higher rates of gastrointestinal disorders in

semaglutide arms as compared to placebo across all trials.

In STEP 1, 3, and 5 trials, gallbladder-

related disorders were more frequent in the semaglutide arms compared to placebo, and

cardiovascular disorders were observed more in the placebo arm than in semaglutide

29,31,38

In STEP

2 and STEP 8, rates of gallbladder-related disorders were higher in placebo arm than in semaglutide,

and rates of cardiovascular disorders were higher in the semaglutide arms than placebo

30,33

Psychiatric disorder event rates were higher in semaglutide arms versus placebo arms in the STEP 2,

STEP 3, and STEP 5 trials. In the STEP 8 trial, there were higher rates of psychiatric disorder events

in the liraglutide arm (15%) compared to the semaglutide (5.6%) and placebo arms (10.6%).

See

Supplement Table D33

for detailed safety focus area results.

Table 3.15. Harms in Key Trials of Semaglutide for the Management of Obesity or Obesity with

Diabetes Mellitus

29-38

STEP 1

STEP 2*

STEP 3

STEP 5

STEP 8

Study Arms

PBO

SEM

PBO

SEM

PBO

SEM

PBO

SEM

PBO

SEM

LIR

655

1,306

402

403

204

407

152

126

127

Any AE, n (%)

566

(86.4)

1,171

(89.7)

309

(76.9)

353

(87.6)

196

(96.1)

390

(95.8)

136

(89.5)

146

(96.1)

(95.3)

120

(95.2)

122

(96.1)

SAE, n (%)

(6.4)

128

(9.8)

(9.2)

(9.9)

(2.9)

(9.1)

(11.8)

(7.9)

(7.1)

(7.9)

14 (11)

AEs Leading to

Discontinuation, n

(%)

(3.1)

(7)

(3.5)

(6.2)

(2.9)

(5.9)

(4.6)

(5.9)

(3.5)

(3.2)

(12.6)

GI Disorders

Leading to

Discontinuation, n

(%)

(0.8)

(4.5)

4 (1)

(4.2)

0 (0)

(3.4)

NR NR

(1.2)

(0.8)

8 (6.3)

Nausea, n (%)

114

(17.4)

577

(44.2)

(9.2)

136

(33.7)

(22.1)

237

(58.2)

NR NR

(22.4)

(61.1)

(59.1)

Constipation, n (%)

(9.5)

306

(23.4)

(5.5)

(17.4)

(24.5)

150

(36.9)

NR NR

(23.5)

(38.9)

(31.5)

Diarrhea, n (%)

104

(15.9)

412

(31.5)

(11.9)

(21.3)

(22.1)

147

(36.1)

NR NR

(25.9)

(27.8)

(18.1)

AE: adverse event, GI: gastrointestinal, LIR: liraglutide, n: number, N: total number, NR: not reported, PBO:

placebo, SAE: serious adverse event, SEM: semaglutide

*Included participants with obesity and diabetes mellitus.

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Liraglutide

Like semaglutide, the most frequent adverse events in the SCALE trials for liraglutide compared with

placebo were gastrointestinal-related symptoms, including nausea, constipation, and diarrhea.

40-

45,48,50-52

The frequency of any adverse events was similar between liraglutide and placebo across all

trials, with the exception of the SCALE (Obesity and Pre-Diabetes) trial, in which participants in the

liraglutide arm experienced a higher rate of any adverse events (80.3%), regardless of causality,

compared to participants in the placebo arm (63.3%).

Rates of discontinuation due to adverse

events were higher in the liraglutide arms compared to placebo. SCALE (Type 2 Diabetes) and

SCALE (Insulin), which both included participants with obesity and diabetes mellitus, exhibited

higher rates of serious adverse events compared to trials in the SCALE clinical trial program, which

evaluated participants with obesity without diabetes mellitus.

42,44

Across all SCALE trials, there

were generally higher rates of gallbladder-related and pancreatic adverse events in the intervention

arm compared to placebo. See Table 3.16 below for detailed harms results.

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Table 3.16. Harms in Key Trials of Liraglutide for the Management of Obesity and Obesity with Diabetes Mellitus

40-45,48,50-52

SCALE

Maintenance

SCALE

Sleep Apnea

SCALE

Obesity and

Pre-Diabetes

SCALE

IBT

SCALE

Type 2 Diabetes*

SCALE

Insulin*

Study Arms

PBO

LIR

PBO

LIR

PBO

LIR

PBO

LIR

PBO

LIR

PBO

LIR

210

212

179

176

1,242

2,481

140

142

212

422

197

195

Any AE, n (%)

186

(88.6)

194

(91.5)

124

(69.3)

141

(80.1)

786

(63.3)

1,992

(80.3)

124

(88.6)

136

(95.8)

182

(85.8)

392

(92.9)

175

(88.8)

180

(92.3)

SAE, n (%) 5 (2.4) 9 (4.3) 6 (3.4) 6 (3.4) 62 (5)

154

(6.2)

2 (1.4) 6 (4.2) 21 (9.9)

(12.3)

19 (9.6) 16 (8.2)

AE Leading to

Discontinuation, n (%)

18 (8.6) 18 (8.5) NR NR 47 (3.8)

240

(9.7)

6 (4.3) 12 (8.5) 7 (3.3) 39 (9.2) 6 (3) 15 (7.7)

Nausea, n (%)

(17.1)

101

(47.6)

12 (6.7)

(26.7)

183

(14.7)

997

(40.2)

(17.9)

(47.9)

(13.7)

138

(32.7)

(11.7)

(29.7)

Constipation, n (%)

(12.4)

(26.9)

6 (3.4)

(11.9)

108

(8.7)

495 (20)

(18.6)

(30.3)

13 (6.1)

(16.1)

17 (8.6)

(14.4)

Diarrhea, n (%)

(12.4)

(17.9)

14 (7.8)

(16.5)

115

(9.3)

518

(20.9)

(16.4)

(21.8)

(12.7)

108

(25.6)

(15.2)

(23.1)

AE: adverse event, LIR: liraglutide, n: number, N: total number, NR: not reported, PBO: placebo, SAE: serious adverse event

*Included participants with obesity and diabetes mellitus.

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Phentermine/Topiramate

Adverse events of any cause in the EQUIP, EQUATE, and CONQUER trials were mostly mild to

moderate in severity. Rates of any adverse events were relatively high among all arms (73-86%),

with highest rates in the high-dose phentermine/topiramate arm, followed by the low-dose

phentermine/topiramate arm, and the placebo arm (Table 3.17).

54-56,58

Adverse reactions that

occurred more frequently in the high-dose and low-dose phentermine/topiramate treatment

groups included paresthesia, nausea, dry mouth, constipation, and headache. EQUIP and CONQUER

also assessed psychiatric adverse events, such as insomnia, anxiety, and depression, which were

more common in the high-dose and low-dose phentermine/topiramate arms,

54,56

with the

exception of depression in the CONQUER trial, where the incidence of depression in the low-dose

intervention arm (3%) was similar to the placebo arm (3.2%).

Serious adverse reactions were relatively low among all trials and arms (0-6%). In the EQUIP trial,

participants in all arms reported serious adverse events at the same rate (2.5%),

while in the

EQUATE trial, more participants in the high-dose treatment arm (1.9%) and low-dose treatment arm

(0.9%) reported more serious adverse events than in the placebo arm (0%).

In the CONQUER trial,

incidence of serious adverse events was 3.7% in the high-dose phentermine/topiramate arm, 6% in

the low-dose phentermine/topiramate arm, and 3.2% in the placebo arm.

Serious adverse events

that occurred infrequently in the phentermine/topiramate arms were chest pain, nephrolithiasis,

appendicitis, blurred vision, humerus fracture, and myelogenous leukemia. Among all trials,

discontinuation due to adverse events occurred most frequently in the high-dose arm (16-21%),

followed by the low-dose arm (9-15%), and placebo (7-8%). See Table 3.17 for more details on

harms.

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Table 3.17. Harms in Key Trials of Phentermine/Topiramate for the Management of Obesity and

Obesity with Diabetes Mellitus

EQUIP

EQUATE

CONQUER (Diabetes Subgroup)*

Study Arms PBO

P/T

(high)

PBO

P/T

(low)

P/T

(high)

PBO P/T (low)

P/T

(high)

513

511

109

106

108

157

164

Any AE, n (%)

374

(72.9)

432

(84.5)

(79.8)

(80.2)

(83.3)

125

(79.6)

54 (80.6) 141 (86)

SAE, n (%)

13 (2.5)

0 (0)

1 (0.9)

2 (1.9)

5 (3.2)

4 (6)

6 (3.7)

AE Leading to

Disc., n (%)

43 (8.4) 82 (16) 8 (7.3)

(15.1)

(23.1)

13 (8.3) 6 (9) 31 (18.9)

Paresthesia, n (%) 10 (1.9) 96 (18.8) 4 (3.7) 17 (16)

(23.1)

6 (3.8) 5 (7.5) 29 (17.7)

Dry Mouth, n (%) 19 (3.7) 87 (17) 0 (0)

(13.2)

(18.5)

6 (3.8) 5 (7.5) 22 (13.4)

Headache, n (%)

(10.1)

61 (11.9)

(12.8)

(15.1)

(15.7)

9 (5.7) 3 (4.5) 18 (11)

Constipation, n (%) 35 (6.8) 72 (14.1) 9 (8.3) 7 (6.6)

(15.7)

10 (6.4) 10 (14.9) 29 (17.7)

Nausea, n (%)

24 (4.7)

37 (7.2)

5 (4.6)

9 (8.5)

8 (7.4)

8 (5.1)

1 (1.5)

13 (7.9)

Insomnia, n (%) 25 (4.9) 40 (7.8) 6 (5.5)

(12.3)

(10.2)

8 (5.1) 5 (7.5) 23 (14)

Anxiety, n (%)

6 (1.2)

19 (3.7)

Depression, n (%)

6 (1.2)

24 (4.7)

5 (3.2)

2 (3)

10 (6.1)

AE: adverse event, Disc.: discontinuation, n: number, N: total number, NR: not reported, PBO: placebo, P/T:

phentermine/topiramate, SAE: serious adverse event

*Included participants with obesity and diabetes mellitus.

Bupropion/Naltrexone

Any adverse events in COR-I, COR-II, COR-BMOD, and COR Diabetes occurred at a higher rate in the

bupropion/naltrexone arms (83-90%) than in placebo (67-75%).

59,61,63,65,66

Nausea, dry mouth,

headache, constipation, and upper respiratory tract infection occurred more frequently in the

treatment arms compared to placebo. Occurrence of psychiatric events, such as insomnia, anxiety,

depression, and stress, varied among all trials. Insomnia occurred more frequently in the

bupropion/naltrexone group versus placebo in COR-I, COR-II, and COR-BMOD. Rates of anxiety

were higher in the intervention arms than in placebo arms in COR-II and COR-BMOD but were lower

than in the placebo arm in COR-I (Table 3.18). Depression occurred at a higher rate in the

treatment groups in all studies except COR-BMOD. Participants in the bupropion/naltrexone group

in COR-BMOD also experienced less stress than participants in the placebo arm.

In COR-I, COR-II and COR-BMOD, serious adverse events were more frequent in the intervention

arms (2-4%) versus the placebo arm (1%).

61-66

In the COR Diabetes trial assessing participants with

obesity and diabetes mellitus, serious adverse events were more common in the placebo arm

(4.7%) than in the treatment arm (3.9%).

59,60

Serious adverse events that occurred infrequently in

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the bupropion/naltrexone arm were cholecystitis, cardiac failure, and seizures. Discontinuation due

to adverse events occurred more frequently in the bupropion/naltrexone arms (20-29%) than in the

placebo arms across the trials (10-15%). See Table 3.18 below for more details on harms.

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Table 3.18. Harms in Key Trials of Bupropion/Naltrexone for the Management of Obesity and Obesity with Diabetes Mellitus

59-66

COR-I

COR-II

COR-BMOD

COR Diabetes*

Study Arms

PBO

B/N

PBO

B/N

PBO

B/N

PBO

B/N

569

573

492

992

200

584

169

333

Any AE, n (%)

390 (68.5)

476 (83.1)

370 (75.2)

852 (85.9)

133 (66.5)

487 (83.4)

144 (85.2)

301 (90.4)

SAE, n (%)

8 (1.4)

9 (1.6)

7 (1.4)

21 (2.1)

1 (0.5)

22 (3.8)

13 (4.7)

8 (3.9)

AE leading to

Disc., n (%)

56 (9.8) 112 (19.5) 68 (13.8) 241 (24.3) 25 (12.4) 150 (25.4) 26 (15.4) 98 (29.4)

Death, n (%)

0 (0)

1 (0.2)

0 (0)

Dry mouth, n (%)

11 (1.9)

43 (7.5)

13 (2.6)

90 (9.1)

6 (3)

47 (8)

5 (3)

21 (6.3)

Headache, n (%)

53 (9.3)

79 (13.8)

43 (8.7)

174 (17.5)

35 (17.5)

139 (23.8)

15 (8.9)

46 (13.8)

Constipation, n

(%)

32 (5.6) 90 (15.7) 35 (7.1) 189 (19.1) 28 (14) 141 (24.1) 12 (7.1) 59 (17.7)

URTI, n (%)

64 (11.2)

57 (9.9)

55 (11.2)

86 (8.7)

16 (9.5)

26 (7.8)

Nausea, n (%)

30 (5.3)

171 (29.8)

34 (6.9)

290 (29.2)

21 (10.5)

199 (34.1)

12 (7.1)

141 (42.3)

Insomnia, n (%)

29 (5.1)

43 (7.5)

33 (6.7)

97 (9.8)

12 (6)

51 (8.7)

9 (5.3)

37 (11.1)

Anxiety, n (%)

12 (2.1)

9 (1.6)

21 (4.3)

48 (4.8)

7 (3.5)

30 (5.1)

2 (1.2)

18 (5.4)

Depression, n (%)

6 (1.1)

3 (0.5)

8 (1.6)

13 (1.3)

5 (2.5)

2 (0.3)

3 (1.8)

2 (0.6)

Stress, n (%)

4 (2)

3 (0.5)

AE: adverse event, B/N: bupropion/naltrexone, Disc.: discontinuation, n: number, N: total number, NR: not reported, PBO: placebo, SAE: serious adverse event,

URTI: upper respiratory tract infection

*Included participants with obesity and diabetes mellitus.

†N=202.

‡N=591.

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NMA Results of Discontinuation

For the outcome of discontinuation due to adverse events, we conducted an NMA of trials including

participants with obesity alone and excluded trials of participants with obesity and diabetes

mellitus. The discontinuation NMA included more trials than in the efficacy NMAs as we did not

exclude trials that included IBT programs as part of the lifestyle component of the trial arms. The

NMA of discontinuation due to adverse events is reported below, and the network diagram is

presented in the Supplement

Participants with Obesity Alone

For the trials of the medications conducted in participants with obesity without diabetes mellitus

and reported discontinuation due to adverse events, we present the results of the unadjusted

random effects model in Table 3.19, given its better fit for the model compared to the baseline risk

adjusted model. Discontinuation rates due to adverse events were higher for all medications

compared to placebo. Semaglutide may have lower discontinuation rates than liraglutide,

phentermine/topiramate, and bupropion/naltrexone, however, these results were not statistically

significant (Table 3.19).

Table 3.19. NMA Results of Medications for the Management of Obesity, Odds Ratio of

Discontinuation Rates due to Adverse Events (95% CI)

Semaglutide

0.7 (0.3-1.3) Liraglutide

0.8 (0.3-1.5) 1.1 (0.5-2.2)

Bupropion/

Naltrexone

0.7 (0.2-1.5) 1.0 (0.4-2.3) 0.9 (0.4-2.1)

Phentermine/

Topiramate*

1.7 (0.9-2.8) 2.4 (1.4-4.0) 2.2 (1.3-3.7) 2.4 (1.3-5.2)

Placebo

Legend: Each box represents the estimated odds ratio of discontinuation due to adverse events and 95% credible

interval for the combined direct and indirect comparisons between two medications or one medication and

placebo. Estimates in bold indicate the 95% credible interval does not contain 1.

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Subgroup Analyses and Heterogeneity

We sought evidence on obesity management in subgroups of interest such as in individuals with

higher or lower baseline BMI, pre-diabetes, or previous weight loss surgery. We also sought

evidence comparing obesity management based on sex and race/ethnicity. However, data were

generally not available or were provided to ICER as confidential. In the STEP 1 and 2 trials of

semaglutide, SCALE Obesity and Pre-Diabetes trial of liraglutide, and EQUIP trial of

phentermine/topiramate in adults with obesity, percentage weight loss was generally consistent

across BMI subgroups corresponding to obesity classes I/II/III, suggesting a benefit across the range

of obesity severity included in these trials. In a post-hoc analysis of the STEP 1, 3, and 4 trials of

semaglutide (which enrolled 40-50% of participants with pre-diabetes), improvements in A1C and

blood glucose were comparable or better among participants with pre-diabetes than among the

overall study population, suggesting a benefit in glycemic status consistent with the drug’s

mechanism of action.

In abstract reports from the STEP 1, 2 and 3 trials of semaglutide, race and ethnicity were not

associated with weight loss outcomes, though female gender was reported to be associated with

greater weight loss.

32,69,70

In analysis of pooled data from four SCALE trials, mean change in weight

loss for liraglutide compared to placebo for White, Black/African American and Asian patients were

-5.3%, -4.8% and -4.0%, respectively.

The CONQUER trial provided subgroup data on sex, race,

and ethnicity in the Supplement. In participants receiving phentermine/topiramate high- and low-

dose treatment, weight loss in this trial was greater in females than males (11.0% vs. 9.1% and 8.8%

vs. 7.5%, respectively, in females vs. males). Additionally, participants in the

phentermine/topiramate arms who were Black experienced a similar amount of weight loss

compared to participants who were non-Black (9.7% vs. 10.5% and 9.7% vs. 8.5%, respectively).

Uncertainty and Controversies

Though pharmacy claims data suggest that many individuals who take medications for weight loss

do not use them for long periods of time, experts and patients we spoke with highlighted that

weight regain after stopping treatment is common.

This points to the need for long-term use of

these medications. All key trials reported outcomes over approximately one year follow-up. Few

comparative trials have examined longer-term outcomes making the benefits and harms of these

medications over prolonged periods uncertain. For individuals without diabetes mellitus, heart

disease, arthritis, sleep apnea, or cancer, studies have not shown whether weight loss prevents

disease morbidity and mortality. Studies of treatments for obesity in individuals undergoing weight

loss surgery for severe obesity demonstrate decreased incidence of cardiovascular- and cancer-

related outcomes and lower mortality.

4,26,27

However, these results primarily come from

observational studies and the benefit in individuals without diabetes mellitus or lower baseline

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weights is less clear. Thus, there is a need for studies examining long-term outcomes in individuals

without diabetes mellitus who are chronically using weight loss medications.

We primarily used indirect quantitative methods (NMAs) to compare semaglutide, liraglutide,

phentermine/topiramate, and bupropion/naltrexone to each other because there was only a single

head-to-head study of semaglutide and liraglutide. Differences in study populations, lifestyle

interventions offered, and escalation schedules that led to different follow-up intervals all

contribute to indirect analyses having more uncertainty than if the therapies had been compared

directly in randomized controlled trials.

All of the pivotal Phase III randomized controlled trials compared the active agents to placebo

among patients receiving lifestyle interventions. As a result, the studies assessed the additive

benefit of the drugs in addition to lifestyle interventions that varied among the studies. Because we

expect that medications when used in routine clinical practice will more commonly be given with

less intensive lifestyle interventions, our primary analyses included trials with standard lifestyle

interventions and may represent the best evidence for the efficacy of the active therapies. Other

trials compared drugs to placebo along with more intensive lifestyle interventions that included IBT

or structured meal programs. These trials also demonstrated benefit of the drugs compared to

placebo, but in general, the amount of weight loss was slightly less than seen in the trials with

standard lifestyle interventions.

These trials examined the relative benefits of the individual and fixed dose combination agents as

single interventions. The drugs that make up the phentermine/topiramate and

bupropion/naltrexone combinations are also approved for other indications as individual drugs at

somewhat different doses. We heard from experts that these individual drugs are used singly or in

various combinations in an “off-label” manner. Clinicians said such use may mitigate side effects

and be less costly to patients. Semaglutide and liraglutide are FDA-approved for treatment of

diabetes mellitus at lower doses, and while these doses may be associated with less weight loss

than the doses used in our primary outcome analyses, these lower doses may be used, especially in

those with co-existing diabetes mellitus, because they may be better covered by insurers and result

in fewer out-of-pocket expenses to patients.

We only compared results of individual drugs or approved fixed dose combinations. Using multiple

drugs that target different mechanisms or newer drugs that have more than one mechanism of

action (e.g., tirzepatide) may achieve synergistic effects and provide greater weight loss. In addition

to their weight loss properties, semaglutide and liraglutide as GLP-1 receptor agonists have also

been shown to decrease blood sugar in individuals with pre-diabetes and diabetes mellitus, and to

decrease major adverse cardiovascular events among individuals with diabetes mellitus. It is not

known whether GLP-1 receptor agonists provide benefits to individuals with obesity that go beyond

their weight loss effects compared to other approved weight loss drugs with different mechanisms

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of action. At present, this remains uncertain for individuals without diabetes mellitus using GLP-1

receptor agonists for weight loss and warrants future investigation.

There is limited information available about the relative benefits and harms of these drugs in

important subgroups including patients with lower BMIs. Similarly, for those with BMIs of greater

than 40 where weight loss surgery is an option, the relative benefits and harms of these drugs

compared to weight loss surgery is uncertain. Moreover, experts discussed that these medications

are being used in individuals after weight loss surgery to treat or prevent weight regain, and the

effects of their use here is also uncertain. For women of childbearing age, there is a lack of data on

the potential impact of medications for weight reduction on fertility, maternal morbidity and

mortality, and infant health.

Trials of weight loss medications include populations that are underrepresented in terms of the

percentage of men and minority groups. Weight reductions seen in these trials among men and

women appeared similar. Since most trials included mostly White patients and given the large

impact of obesity in Black Americans and other racial and ethnic groups, there is a need for more

studies evaluating the outcomes of the various medications in these populations. For example, a

post-hoc analysis of liraglutide trials showed similar weight reduction across racial and ethnic

groups.

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3.3. Summary and Comment

An explanation of the ICER Evidence Rating Matrix (Figure 3.1) is provided here.

Figure 3.1. ICER Evidence Rating Matrix

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Results from the clinical trials and from our NMAs demonstrate that semaglutide, liraglutide,

phentermine/topiramate, and bupropion/naltrexone, when used as adjuncts to usual care, improve

weight loss outcomes of patients with obesity compared to usual care alone (e.g., standard lifestyle

management). The magnitude of the weight loss appears to be greater for semaglutide and

phentermine/topiramate than for liraglutide and bupropion/naltrexone based on the one head-to-

head trial of semaglutide and liraglutide and our indirect NMA results. Other outcomes show that

semaglutide and liraglutide improved blood sugar, blood pressure, and physical function compared

to usual care. Blood pressure was lower with phentermine/topiramate than usual care. Blood

sugar results were not reported in the phentermine/topiramate and bupropion/naltrexone trials for

patients without diabetes mellitus.

Semaglutide, liraglutide, phentermine/topiramate, and bupropion/naltrexone all had common

adverse events, but few serious harms were reported in the trials. Discontinuation due to adverse

events was higher for each intervention compared to placebo. Patients taking liraglutide,

phentermine/topiramate, and bupropion/naltrexone may have higher discontinuation rates due to

adverse events than for semaglutide.

There is uncertainty about the relative benefit and safety among the four medications due to

differences in the trials with regards to their size, patient characteristics, concomitant lifestyle

interventions, outcomes assessed, and duration of follow-up that the indirect nature of the NMAs

do not fully capture. For all of the drugs, there is a lack of long-term efficacy and safety data that

includes whether sustained weight loss leads to decreased clinical endpoints and if weight regain

may occur over time despite continued therapy as has been seen with weight loss surgery.

Differences among the medications in their mechanisms of action may also lead to differences in

clinical endpoints, such as heart disease, that go beyond their effects on weight loss. For example,

semaglutide and liraglutide have been shown to reduce cardiovascular disease endpoints in

patients with type 2 diabetes mellitus,

but this is uncertain for individuals with obesity without

diabetes mellitus.

In summary, for adults with obesity who have not had sufficient weight loss with lifestyle

interventions alone and are interested trying weight loss medications, we assessed the benefits and

harms of these four medications added to lifestyle modification compared to standard lifestyle

modification alone and to each other. As such:

• We consider the evidence for the net health benefit of semaglutide added to lifestyle

modification compared to lifestyle modification alone to be incremental or better (“B+”),

demonstrating a moderate certainty of a small or substantial net health benefit, with high

certainty of at least a small net health benefit. This rating is based upon demonstration of

substantial short-term weight loss from multiple high-quality studies with few serious

harms, but higher rates of discontinuation due to adverse events than placebo, uncertainty

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about long-term ability to sustain weight loss, and whether the degree of weight loss in this

population results in improved clinical outcomes.

• We consider the evidence for the net health benefit of liraglutide added to lifestyle

modification compared to lifestyle modification alone to be incremental (“B”),

demonstrating a high certainty of a small net health benefit. This rating is based upon

demonstration of small to moderate short-term weight loss from multiple high-quality

studies with few serious harms; our expectation is that even if the weight loss were

sustained, the benefits would only be incremental.

• We consider the evidence for the net health benefit of phentermine/topiramate added to

lifestyle modification compared to lifestyle modification alone to be comparable or better

(“C++”), demonstrating a moderate certainty of a comparable, small, or substantial net

health benefit, with high certainty of at least a comparable net health benefit. This rating is

based upon demonstration of moderate to substantial short-term weight loss from a limited

number of trials with few serious harms, but higher rates of discontinuation due to adverse

events than placebo, uncertainty about long-term ability to sustain weight loss, and

whether the degree of weight loss seen translates into improved clinical outcomes given the

limited data from clinical process measures.

• We consider the evidence for the net health benefit of bupropion/naltrexone added to

lifestyle modification compared to lifestyle modification alone to be comparable or

incremental (“C+”), demonstrating a moderate certainty of a comparable or small net health

benefit, with high certainty of at least a comparable net health benefit. This rating is based

upon demonstration of small to moderate short-term weight loss from several trials with

few serious harms, but higher rates of discontinuation due to adverse events than placebo,

uncertainty about long-term ability to sustain weight loss, and whether the degree of

weight loss seen translates into improved clinical outcomes given the limited data from

clinical process measures.

• We consider the evidence for the net health benefit of semaglutide compared to liraglutide

and phentermine/topiramate to be comparable or incremental (“C+”), and compared to

bupropion/naltrexone to be comparable or better (“C++”). The rating comparing

semaglutide to liraglutide is based upon greater weight loss and fewer adverse reactions

leading to discontinuation with semaglutide, but uncertainty about long-term ability to

sustain weight loss and, given the same mechanism of action, whether the incremental

amount of weight loss results in improved clinical outcomes in this population. The rating

comparing semaglutide to phentermine/topiramate is based upon similar weight loss and

fewer adverse reactions leading to discontinuation, but differences in the number and

quality of the trials, differences in mechanisms of action that may impact clinical outcomes,

and uncertainty about long-term ability to sustain weight loss. The rating comparing

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semaglutide to bupropion/naltrexone is based upon greater weight loss and fewer adverse

reactions leading to discontinuation with semaglutide, but differences in mechanisms of

action that may impact clinical outcomes, and uncertainty about long-term ability to sustain

weight loss.

Table 3.20. Evidence Ratings of Medications for Obesity Management

Treatment

Comparator

Evidence Rating

Semaglutide

Lifestyle modification

B+

Liraglutide

Lifestyle modification

Phentermine/Topiramate

Lifestyle modification

C++

Bupropion/Naltrexone

Lifestyle modification

C+

Semaglutide

Liraglutide

C+

Phentermine/topiramate

C+

Bupropion/naltrexone

C++

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4. Long-Term Cost Effectiveness

4.1. Methods Overview

The primary aim of this analysis was to estimate the cost effectiveness of semaglutide, liraglutide,

phentermine/topiramate, and bupropion/naltrexone plus lifestyle modification compared to

standard lifestyle modification alone, and to each other, for life-long weight management in the

treatment of overweight and obesity. The base-case analysis comparatively evaluated each therapy

option in a cohort of patients consistent with clinical trials and real-world evidence. Patients were

80% female with an average age of 45 years, BMI of 38 kg/m

, SBP of 125 mmHg, and HbA1C of

5.7% without confirmed diabetes mellitus. Additional scenarios were evaluated as described in

Section 4.3.

We built a Markov state transition model informed by key clinical trials, prior relevant economic

models, systematic literature reviews, and input from a diverse set of stakeholders (patients,

advocacy groups, clinicians, payers, researchers, and manufacturers of these agents) from the

health care sector perspective (i.e., focused on direct medical care costs) using a lifetime time

horizon. The model cycle length was one year, and all costs and outcomes were discounted at a

rate of 3% per year.

As shown in the model diagram below (Figure 4.1), simulated patients entered the model through

their medication regimen to the initial Markov state “No diabetes mellitus.” From the first cycle

onward, patients could remain in the starting state, or transition to any of four non-heart-failure

cardiovascular comorbid health states (myocardial infarction, stroke, stroke plus myocardial

infarction, or other cardiovascular disease) with or without developing diabetes mellitus. Other

cardiovascular disease included peripheral artery disease, angina, and transient ischemic attack.

Myocardial infarction was a prerequisite to developing heart failure because of the strong causal

association between obesity and heart failure mediated by myocardial changes.

The model

assumed all patients with hypertension were optimally controlled with antihypertensive

medication. As it is uncertain whether obesity is an independent risk factor for non-ischemic heart

failure in patients with controlled blood pressure, we opted to not account for any additional risk of

heart failure through alternate pathways. At any state in the model, patients could transition to the

terminal “Death” state.

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Figure 4.1. Model Diagram

CVD: cardiovascular disease, DM: diabetes mellitus, HF: heart failure, LM: lifestyle management, LIR: liraglutide,

MI: myocardial infarction, B/N: bupropion/naltrexone, P/T: phentermine/topiramate, SEM: semaglutide

Average BMI reduction with therapy was the primary factor used to estimate differences in

cardiovascular comorbidity and risk of progression to diabetes mellitus. The annual risk of

developing cardiovascular conditions at the beginning of each cycle was calculated using a

published risk equation model based on BMI, presence of diabetes mellitus, population

demographics, and clinical characteristics. Specifically, the 2013 American College of Cardiology/

American Heart Association (ACC/AHA) guideline risk equation was used to calculate the 10-year

risk of non-heart-failure cardiovascular conditions.

The resulting 10-year risks were then used to

calculate the annual probability of a cardiovascular event and were updated in each cycle of the

model using the equation []=1−

(−



. BMI was included as a time-varying input in the risk

calculation for each cycle.

The risk of a cardiovascular event was calculated for each combination of patient factors (e.g., male

vs. female, smokers vs. nonsmokers, and active hypertension treatment vs. no hypertension

treatment, diagnosis of diabetes mellitus vs. no diabetes mellitus, age, and BMI) and the weighted

average was used to calculate overall risk. Cardiovascular event risks were then further stratified

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into specific stroke, myocardial infarction, and other cardiovascular disease event probabilities

given the proportion of each condition observed in a US population.

79-82

Our model captured the impact of weight loss in delaying the onset of diabetes mellitus. In

addition, the HbA1C-lowering effect of semaglutide and liraglutide was expected to further delay

the onset of diabetes mellitus.

83,84

Therefore, we calculated the annual incidence of diabetes

mellitus for each cycle using BMI and HbA1C data.

Furthermore, weight loss from medication

therapy may result in hypertension remission. We therefore incorporated an association between

BMI and hypertension to allow for a decreased prevalence of hypertension as BMI decreased.

86,87

Although we did not explicitly include some conditions known to be associated with obesity, the

anticipated benefit of weight loss in reducing the onset of such conditions was implicitly captured.

For example, the impact of weight loss on sleep apnea is captured by the mortality benefits

mediated by cardiovascular conditions. Chronic kidney disease was not included as a separate

Markov state in the base-case simulation as most chronic kidney disease results from diabetes

mellitus or hypertension. By including costs and quality of life changes from studies with a broad

selection of patients with diabetes mellitus, we implicitly addressed the influence of chronic kidney

disease in the model. Chronic kidney disease resulting from hypertension was not captured in the

base case, as we assumed that hypertension management was optimal in patients with and without

weight loss. However, a scenario analysis (described below as “Comorbidity X”) captured the

potential impact of weight-related chronic kidney disease (and cancer) on the cost effectiveness of

medications for obesity management. Improvements in lipids were not explicitly included in the

model. The ACC/AHA risk equations for cardiovascular risk account for either changes in weight or

LDL, but not both simultaneously. Therefore, including changes to lipids in the model would likely

double count the cardiovascular benefits from treatment. Supplement Section E1

details additional

rationale behind our choice of health states in the base case.

Health gains in the model were mainly derived from increased utility in those with improved BMI

associated with enhanced daily functioning, decreased risk of developing diabetes

mellitus/cardiovascular disease, and reduced complications/comorbidities. The estimated utility

gains from enhanced daily functioning included improvements in conditions such as sleep apnea,

gastroesophageal reflux disease, and osteoarthritis as well as improved mobility and self-image.

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Scenario Analyses

In order to address several uncertainties, we conducted multiple scenario analyses:

• Societal perspective (including labor costs)

• Evaluation of patients with a starting BMI of ≥40 kg/m

(i.e., weight class III with average

BMI of 42.5 and 47.5 kg/m

)

• Use of generic phentermine/topiramate and bupropion/naltrexone

• Patient population consisting of a similar proportion of men and women (50:50)

• Comorbidity X scenario individually assessing the potential impact of BMI change resulting

from medications for obesity management on chronic kidney disease and cancer

• Evaluation of a “Drug X” with the effect on weight loss seen in the SUPPORT 1 trial of

tirzepatide and pricing of semaglutide for overweight and obesity and effects on blood

pressure and diabetes mellitus similar to semaglutide.

Further details on the economic modeling methods used are available in Supplement E.

Based on public comment, the following changes were made:

1) Updated the discontinuation rate from estimates for serious adverse event rates from

clinical trials to values reported in the NMA, which estimated adverse events leading to

discontinuation

2) Included the full results of two scenario analyses that had been omitted from the results

section of the Draft Evidence Report. These scenarios were: a) Evaluation of patients with a

starting BMI of ≥40 kg/m

(i.e., weight class III with average BMI of 42.5 and 47.5 kg/m

);

and b) Patient population consisting of a similar proportion of men and women (50:50)

3) Removed the direct influence of bupropion/naltrexone on HbA1C; cardiovascular benefits of

bupropion/naltrexone were made through weight reduction.

The following scenario analyses were included in the Model Analysis Plan but were either changed

to sensitivity analyses or were not conducted:

1) Weight regain scenario: Scenarios evaluating short-term treatment followed by weight-

regain were evaluated and removed due to a potential overestimation of benefits

2) Subgroup of patients who respond to the lower maintenance dose of

phentermine/topiramate: We chose to only model the maximum dose and effect of Qsymia

with the understanding that providers would attempt to maximize weight loss, provided

patients tolerated treatment

3) Patients with diabetes mellitus at baseline: Since the effectiveness of semaglutide and

liraglutide have previously been evaluated by ICER, our model was designed to evaluate the

impact of weight management in patients without diabetes. We assumed that for patients

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with diabetes, there would be no difference in the management of diabetes (i.e., HbA1C

levels) between patients on different medications or lifestyle management alone for obesity

management. Therefore, with the exception of delays to diabetes onset resulting from the

effects of the drugs on HbA1C, we did not include the impact of treatments on HbA1C

4) Optimistic and conservative assumptions regarding the benefit of treatment: We tested the

optimistic and conservative weight reduction scenarios in one-way sensitivity analyses

4.2. Key Model Assumptions and Inputs

Model Assumptions

Several assumptions were required to estimate the cost effectiveness of treatments for obesity.

These assumptions were based on clinical expert opinion, a review of the available evidence and

published models, and the investigators’ experience with developing similar models. The key model

assumptions and rationales for each assumption are listed below in Table 4.1. Additional model

assumptions are described in the Supplement

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Table 4.1. Key Model Assumptions

Assumption

Rationale

Cardiovascular risk

equations provide the best

estimate of treatment

benefit on cardiovascular

outcomes

Certain drug treatments may have benefits unrelated to weight loss achieved

or changes in HbA1C. In the absence of strong evidence for the effects of

medications on cardiovascular risk in patients with obesity and without

diabetes mellitus, we did not include such a benefit. Should evidence emerge

supporting additional benefits, the model can be updated to include these

benefits. The potential benefits on cardiovascular outcomes of delays in

diabetes mellitus onset from therapies that directly reduce A1C, beyond

those associated with weight reduction, provided sufficient evidence exists,

will be considered in the model.

Patients continue to receive

the intervention or lifestyle

modification throughout

the model time horizon

Expert opinion suggests that since obesity is increasingly considered as a

chronic metabolic disease requiring long-term management to affect

outcomes, long-term treatment is required for most individuals. After

stopping therapy, weight regain is common. Further, repeated fluctuations in

body weight, i.e., “weight cycling,” is associated with adverse health

outcomes.

Treatment discontinuation

is included in the model

prior to the first model

cycle; longitudinal changes

in the persistence and

adherence to medications

were not considered in the

model

Including the impact of poor long-term persistence requires the addition of

several “discontinuation” health states, thereby increasing model complexity.

Further, there is no information on the impact of short-term treatment on

cardiovascular outcomes, especially after discontinuation of treatment.

Proportion of actively

treated hypertension is a

function of BMI without a

significant influence on the

incremental cost-

effectiveness ratio

BMI significantly influences the proportion of patients in need of

hypertension treatment. Assuming hypertension treatment effectively

manages overall SBP, average SBP would be similar across the treatment

strategies over the model time horizon. The cost of hypertension medication

is small and is therefore unlikely to influence the incremental cost-

effectiveness ratio.

In patients with

hypertension, blood

pressure is equally well

managed across all weight

loss treatments

Weight loss treatments may affect blood pressure differently. The impact of

treatments on reducing the likelihood of needing treatment for hypertension

was included in the model. For those who continued to require treatment for

hypertension, we assumed that all patients would have similar outcomes

related to hypertension treatment.

HbA1C: glycated hemoglobin, SBP: systolic blood pressure

Model Inputs

The key model inputs are listed in Table 4.2. The clinical inputs for the model were weighted over

time and by associated probabilities of cardiovascular disease (myocardial infarction, stroke, other

cardiovascular disease), heart failure, and diabetes mellitus. Weight change resulting from

treatment was determined from an NMA of trials conducted as part of this review. The risk of

myocardial infarction, stroke, and other cardiovascular disease was obtained from a risk equation

model.

87-89

Risk of heart failure and diabetes mellitus was determined from a systematic review of

the literature and published risk equations.

85,90-94

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BMI and weight trajectory over time were used as model inputs to assess cardiovascular risk.

Percent weight change (and thus BMI change, assuming no change in height) from baseline at year

one and maximum percent weight change by the end of the second year were incorporated into the

model. We assumed patients received the maintenance dose continuously, the medication

maintained long-term effectiveness, and there was no additional weight change beyond the

maximum weight reduction until the end of the model time horizon in the base case.

The impact of weight loss on mortality was incorporated as reduction of fatal cardiovascular events,

as estimated from a review of existing literature and a direct extraction of general population all-

cause mortality from the Human Mortality Database US-specific life tables.

95,96

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Table 4.2. Key Model Inputs*

Parameter

Input

Source

Clinical Inputs

Absolute Difference in % Weight Change, SEM vs. LSM

-13.7%

ICER NMA, Table 3.11

Absolute Difference in HbA1C Change, SEM vs. LSM

-0.30

STEP 1

Absolute Difference in % Weight Change, LIR vs. LSM

-5.0%

ICER NMA, Table 3.11

Absolute Difference in HbA1C Change, LIR vs. LSM

-0.20

SCALE (Maintenance)

Absolute Difference in % Weight Change, P/T vs. LSM

-9.1%

ICER NMA, Table 3.11

Absolute Difference in HbA1C Change, P/T vs. LSM

0.00

EQUATE

53,57,58

Absolute Difference in % Weight Change, B/N vs. LSM

-4.6%

ICER NMA, Table 3.11

Absolute Difference in HbA1C Change, B/N vs. LSM

0.00

61,65

Baseline Risk of CV Event, Female Non-Smoker without Treated HTN

0.04

Framingham Risk Calculation Coefficient

Baseline Risk of CV Event, Male Smoker with Treated HTN

0.23

Framingham Risk Calculation Coefficient

Multiplier for Probability of MI from CV Risk

0.22

Landi 2018

D’Agostino 2008

Schultz 2021

Multiplier for Probability of Stroke from CV Risk

0.23

Multiplier for Probability of Other CV Disease from CV Risk

0.55

Risk Equations

Onset of Cardiovascular Condition, 10-Year Risk: Office-Based Non-Laboratory Pred. Model

Baseline and Beta Coefficient

Women

Men

So(10)

0.94833

0.8843

Log of Age

2.72107

3.113

BMI

0.51125

0.7928

Log of SBP if Not Treated

2.81291

1.8551

Log of SBP if Treated

2.88267

1.9267

Smoking

0.61868

0.7095

Diabetes

0.77763

0.5316

Framingham Risk Calculation Coefficient

Onset of Diabetes, Annual Risk: 1.46×10

-6

exp (1.87×HbA1C) × 1.97×10

-2

exp (0.101×BMI)

Exponential regression from Edelman et al.

Comorbidity Annual Cost Inputs

Cost Other CV Disease

$14,279

Scully 2017

Cost Acute Stroke

$17,316

HCUP

Cost Post Stroke

$6,500

Kazi 2019

Cost Acute MI

$26,034

HCUP

Cost Post MI

$3,117

Kazi 2016

100

Cost, First Year

$27,030

Patel 2021

101

; Urbich 2020

102

Cost HF, Second Year or Later

$15,605

Patel 2021

101

Cost DM

$11,425

ADA 2018

103

Quality of Life Inputs

Utility with Normal BMI†

0.9442-

0.0007×Age

Sullivan 2006

104

Disutility per BMI Unit Increase

-0.0033

Kim 2022

105

; Pi-Sunyer 2015

Multiplicative Utility – Other CV Disease

0.959

Sullivan 2006

104

Disutility – Acute Stroke‡

-0.190

Matza 2015

Multiplicative Utility – Post-Stroke

0.943

Sullivan 2006

104

Disutility – Acute MI‡

-0.150

Matza 2015

Multiplicative Utility – Post-MI

0.955

Sullivan 2006

104

Multiplicative Utility – HF

0.930

Multiplicative Utility – DM

0.962

BMI: body mass index, B/N: bupropion/naltrexone, CV: cardiovascular, DM: diabetes mellitus, HbA1C: glycated hemoglobin, HF: heart failure, HTN:

hypertension, ICER: Institute for Clinical and Economic Review, LIR: liraglutide, LSM: lifestyle modification, NMA: network meta-analysis, P/T:

phentermine/topiramate, SBP: systolic blood pressure, SEM: semaglutide

*This cardiovascular model does not include inputs of anti-obesity medication changes in blood pressure, lipids, sleep apnea, cancer, and physical

inactivity (e.g., immobility or osteoarthritis).

†Midpoint of the normal BMI range of 18.5-25 kg/m

‡Disutility for a 30-day acute condition management.

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Starting utility was derived from age-specific utility values for patients with the characteristics of

the target population.

104

A utility gain was applied for each unit of weight loss due to treatment.

The linear association between weight gain and utility loss was extracted from a recent cost-

effectiveness analysis and trial data.

43,105

For comorbidities associated with higher BMI, we used consistent health state utility values across

all evaluated treatments. Health state disutilities due to cardiovascular comorbid conditions,

diabetes mellitus, and heart failure were derived from systematic literature reviews, utility-specific

patient preference research articles cited in prior cost-effectiveness assessments, and

manufacturer-submitted data. A multiplicative approach was used to apply the health utility value

changes for each of the Markov states. To address the significant decrease in the health utility for

acute event management, we applied daily disutilities for acute myocardial infarction and acute

stroke management for 30 days, an anticipated duration influenced by the significant loss of

mobility and self-care. Subcutaneous injections of GLP-1 receptor agonists are expected to have a

small impact on the overall health state utility compared to the impact of chronic conditions. Thus,

we did not include a utility decrease for the subcutaneous administration of semaglutide or

liraglutide.

For estimates of net pricing, drug costs, and discounts, data are available from both the SSR Health

pricing database and US Department of Veterans Affairs Federal Supply Schedule Service (FSS)

database. Since SSR discount/rebate data were not available for semaglutide for weight loss,

phentermine/topiramate for the most recent quarter, and bupropion/naltrexone for the most

recent quarter, we opted to use the net price from the US FSS database.

Table 4.3. Drug Costs

Drug

List Price

Rebates/

Discounts from

WAC

Model Inputs from FSS Data

Year One

Annual WAC

Year 2+ Annual

WAC

Year One

Annual Net

Year 2+ Annual

Net

Semaglutide

$17,597

22.6%*

$13,618

Liraglutide

$15,795

$16,424

28.4%†

$11,309

$11,760

Phentermine/

Topiramate

$2,382 $2,429 39.7-57.8%* $1,355 $1,465

Bupropion/

Naltrexone

$7,393 $7,612 72.5%* $2,034 $2,095

FSS: Federal Supply Schedule, WAC: wholesale acquisition cost

*Rebates taken from FSS due to no available net price evidence in SSR Health for the most recent year.

†Rebates taken from SSR Health.

Standard lifestyle modification, consisting of diet and physical activity recommendations, was a

background health care intervention across all treatment arms of the model. The cost of lifestyle

modification was identified by review of prior economic outcome assessment studies.

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Cost of care for cardiovascular comorbid conditions was identified from targeted literature reviews.

The acute care costs of myocardial infarction and stroke were identified from a Healthcare Cost and

Utilization Project National Inpatient Sample database online query. Long-term care costs for post-

myocardial infarction, post-stroke, other cardiovascular disease, heart failure, and diabetes mellitus

were identified from review of prior economic outcome assessments.

Productivity costs, such as those due to patient absenteeism or presenteeism, and caregiver costs

were identified from a review of prior economic assessments and were used to calculate the

indirect costs of the cardiovascular conditions in question under the modified societal

perspective.

103,106-108

4.3. Results

Base-Case Results

The discounted total life years gained, QALYs gained, evLYs gained, and total costs over the lifetime

horizon are shown for each of the obesity treatment strategies in Table 4.4. Incremental values

compared to lifestyle modification are presented in Table 4.5. Undiscounted base-case results are

presented in Supplement E.

Table 4.4. Discounted Base-Case Results

Treatment

Drug Cost

Non-Drug Cost

Total Cost

Life Years

QALYs

evLYs

Semaglutide

$285,800

$106,200

$392,100

21.04

17.85

17.86

Liraglutide

$241,800

$135,200

$377,000

20.86

17.36

17.37

Phentermine/Topiramate

$39,700

$142,800

$182,600

20.85

17.40

17.41

Bupropion/Naltrexone

$52,200

$155,100

$207,300

20.78

17.18

17.19

Lifestyle Modification*

$11,400

$167,800

$179,200

20.70

16.95

evLY: equal-value life year, QALY: quality-adjusted life year

*Reference for evLY calculation for all active treatments.

Table 4.5. Select Discounted Incremental Results for the Base Case

Incremental Values vs. Lifestyle Modification

Treatment

Drug Cost

Non-Drug Cost

Total Cost

Life Years

QALYs

evLYs

Semaglutide

$274,400

- $61,600

$212,900

0.34

0.90

0.91

Liraglutide

$230,400

- $32,600

$197,800

0.16

0.41

0.42

Phentermine/Topiramate

$28,300

- $25,000

$3,400

0.16

0.45

0.46

Bupropion/Naltrexone

$40,800

-$12,700

$28,100

0.08

0.23

Lifestyle Modification*

evLY: equal-value life year, QALY: quality-adjusted life year

*Reference for incremental calculation for all active treatments.

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Incremental cost per QALY, life year gained, and evLY gained over the lifetime horizon are shown in

Table 4.6 for each of the obesity treatment strategies.

Table 4.6. Incremental Cost-Effectiveness Ratios for the Base Case

Treatment Comparator

Cost per Life

Year Gained

Cost per QALY

Gained

Cost per

evLY Gained

Semaglutide

Lifestyle modification

$624,000

$238,000

$235,000

Liraglutide

Lifestyle modification

$1,210,000

$485,000

$475,000

Phentermine/Topiramate

Lifestyle modification

$22,000

$8,000

$7,000

Bupropion/Naltrexone

Lifestyle modification

$359,000

$124,000

$121,000

Semaglutide

Liraglutide

$85,000

$31,000

$30,800

Phentermine/topiramate

$1,128,000

$472,000

$468,000

Bupropion/naltrexone

$703,000

$277,000

$274,000

evLY: equal-value life year, QALY: quality-adjusted life year

Sensitivity Analyses

The model was sensitive to several inputs, including the disutility per BMI change, effectiveness of

each treatment in weight loss, baseline HbA1C, and cost of diabetes mellitus. Disutility per BMI

change was most important for semaglutide and liraglutide. The cost of diabetes mellitus

management was most impactful for phentermine/topiramate. Varying the weight-lowering effect

of each treatment compared to lifestyle management and varying the baseline HbA1C had a

considerable influence across all four treatment options. The full one-way sensitivity analysis

results are shown in the Supplement

. Probabilistic sensitivity analysis results in are shown in Table

4.7.

Table 4.7. Results of Probabilistic Sensitivity Analysis by Cost per QALY Gained

Treatment Comparator

Cost

Effective at

$50,000

per QALY

Gained

Cost

Effective at

$100,000

per QALY

Gained

Cost

Effective at

$150,000

per QALY

Gained

Cost

Effective at

$200,000

per QALY

Gained

Semaglutide

Lifestyle modification

0.0%

1.0%

8.7%

Liraglutide

Lifestyle modification

0.0%

Phentermine/Topiramate

Lifestyle modification

67.4%

87.0%

92.5%

94.9%

Bupropion/Naltrexone

Lifestyle modification

1.1%

12.4%

38.4%

59.0%

Semaglutide

Phentermine/topiramate

0.0%

Bupropion/naltrexone

0.0%

2.0%

QALY: quality-adjusted life year

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Scenario Analyses

Conducting the analysis from a societal perspective had some impact on estimates of cost

effectiveness (see Tables 4.8 and 4.9 and Supplement Tables E11 and E12

). Having the same

proportion of men and women (50:50) in the model or changing baseline BMI in scenario analyses

had a modest impact on the estimates (see Supplement Tables

E16-E18). Table 4.10 presents

scenarios with use of an additional Drug X (scenario with effect on weight loss seen in the SUPPORT

1 trial of tirzepatide and pricing of semaglutide for overweight and obesity and effects on blood

pressure and diabetes mellitus similar to semaglutide), use of generic phentermine/topiramate, and

use of generic bupropion/naltrexone. The incremental cost-effectiveness ratio for the lifetime

weight management with Drug X versus lifestyle modification was $145,300 per QALY gained at the

annual Drug X cost of $13,618. The lifetime drug cost for generic phentermine/topiramate was

$14,000 (compared to $39,700 for branded therapy in the base case) and for generic

bupropion/naltrexone was $25,500 (compared to $52,200 for branded therapy in the base case).

Two scenario analyses evaluating the potential impact of cancer or chronic kidney disease (i.e.,

Comorbidity X scenario analyses) had modest impacts on the cost effectiveness of most

medications for obesity management (see Supplement Tables

E13-E15).

Table 4.8. Discounted Results from the Societal Perspective

Treatment Drug Cost

Non-Drug

Cost

Total Cost

Life

Years

QALYs evLYs

Semaglutide

$285,800

$145,300

$431,200

21.04

17.85

17.86

Liraglutide

$241,800

$183,500

$425,200

20.86

17.36

17.37

Phentermine/Topiramate

$39,700

$193,100

$232,800

20.85

17.40

17.41

Bupropion/Naltrexone

$52,200

$209,200

$261,400

20.78

17.18

17.19

Lifestyle Modification*

$11,400

$226,000

$237,400

20.70

16.95

evLY: equal-value life year, QALY: quality-adjusted life year

*Reference for evLY calculation for all active treatments.

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Table 4.9. Discounted Incremental Results from the Societal Perspective

Incremental Values vs. Lifestyle Modification

Treatment Drug Cost

Non-Drug

Cost

Total

Cost

Life Years QALYs evLYs

Semaglutide

$274,400

-$80,700

$193,800

0.34

0.90

0.91

Liraglutide

$230,400

-$42,500

$187,800

0.16

0.41

0.42

Phentermine/Topiramate

$28,300

-$32,900

-$4,600

0.15

0.45

0.46

Bupropion/Naltrexone

$40,800

-$16,755

$24,058

0.08

0.23

Lifestyle Modification*

Incremental Cost Effectiveness Ratio vs. Lifestyle Modification

Cost/Life

Year Gained

Cost/QALY

Gained

Cost/evLY

Gained

Semaglutide

$568,300

$216,600

$213,900

Liraglutide

$1,149,200

$460,900

$451,400

Phentermine/Topiramate

Less costly, more effective

Bupropion/Naltrexone

$307,000

$106,000

$104,000

evLY: equal-value life year, QALY: quality-adjusted life year

*Reference for incremental calculation for all active treatments.

Table 4.10. Scenario Analysis Results (Drug X and Generic Combination)

Treatment Drug Cost

Non-Drug

Cost

Total Cost Life Years QALYs evLYs

Drug X

$283,600

$83,500

$367,100

21.18

18.25

18.26

Generic P/T

$14,000

$142,800

$156,800

20.85

17.40

17.41

Generic B/N

$25,500

$155,100

$180,600

20.78

17.18

17.19

LSM

$11,400

$167,800

$179,200

20.70

16.95

Incremental Value vs. LSM

Drug X

$272,200

-$84,300

$188,000

0.48

1.30

1.31

Generic P/T

$2,600

-$24,900

-$22,400

0.15

0.45

0.46

Generic B/N

$14,100

-$12,700

$1,400

0.08

0.23

Incremental Cost-Effectiveness (QALY) Ratio

vs. Lifestyle Management

Cost/Life Year

Gained

Cost/QALY

Gained

Cost/evLY

Gained

Drug X

$387,400

$145,300

$144,400

Generic P/T

Generic P/T less costly, more effective

Generic B/N

$18,000

$6,000

B/N: bupropion/naltrexone, evLY: equal-value life year, LSM: lifestyle modification, LY: life year, P/T:

phentermine/topiramate, QALY: quality-adjusted life year

Note: Drug X is assumed to achieve 17.8% BMI reduction with 0.44 decrease in HbA1C with an overall

discontinuation rate of 6.5%.

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Threshold Analyses

The annualized prices required to achieve thresholds of $50,000 to $200,000 per QALY and evLY

gained are presented in Tables 4.11 and 4.12.

Table 4.11. QALY-Based Threshold Analysis Results

Annual

Net Price

Annualized

Price to

Achieve

$50,000 per

QALY Gained

Annualized

Price to

Achieve

$100,000 per

QALY Gained

Annualized

Price to

Achieve

$150,000 per

QALY Gained

Annualized

Price to

Achieve

$200,000 per

QALY Gained

Semaglutide

$13,618

$5,275

$7,494

$9,714

$11,933

Liraglutide

$11,760

$2,714

$3,753

$4,791

$5,830

Phentermine/Topiramate

$1,465

$2,440

$3,591

$4,741

$5,892

Bupropion/Naltrexone

$2,094

$1,241

$1,823

$2,396

$2,980

Lifestyle Modification

Reference

QALY: quality-adjusted life year

Table 4.12. evLY-Based Threshold Analysis Results

Annual

Net Price

Annualized

Price to

Achieve

$50,000 per

evLY Gained

Annualized

Price to

Achieve

$100,000 per

evLY Gained

Annualized

Price to

Achieve

$150,000 per

evLY Gained

Annualized

Price to

Achieve

$200,000 per

evLY Gained

Semaglutide

$13,618

$5,298

$7,547

$9,793

$12,048

Liraglutide

$11,760

$2,725

$3,791

$4,851

$5,912

Phentermine/Topiramate

$1,465

$2,471

$3,656

$4,840

$6,021

Bupropion/Naltrexone

$2,094

$1,252

$1,844

$2,434

$3,025

Lifestyle Modification

Reference

evLY: equal-value life year

Model Validation

Model validation followed standard practices in the field. All mathematical functions in the model

were tested to assess face validity and to ensure consistency with the Report. We also conducted

sensitivity analyses with null input values to ensure the model was producing findings consistent

with expectations. Further, the model was subjected to internal and external review to evaluate

the mathematical functions as well as the specific inputs and corresponding outputs.

Model validation was also conducted in terms of comparisons to other model findings. We

searched the literature to identify models that were similar to our analysis, with comparable

populations, settings, perspective, and treatments. We also identified a publication that evaluated

semaglutide and other drugs for medication-assisted treatment of weight loss.

105

This recently

published model differed from ours in structure and inputs, including having additional Markov

states and differences in the handling of multiple comorbidities, a two-year treatment period

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instead of lifetime, a 30-year time horizon instead of lifetime, handling excess mortality due to

obesity in a different manner, using a higher cost of semaglutide, and having different utility inputs.

When we changed our model inputs to resemble theirs (i.e., higher semaglutide unit cost, utility

inputs, two-year treatment, and 30-year time horizon), our incremental cost-effectiveness estimate

comparing semaglutide to lifestyle modification ($115,500) approached their reported estimate

comparing semaglutide to diet and exercise ($122,549). The remaining difference in these

incremental cost-effectiveness estimates could likely be explained by a much shorter 30-year life

expectancy in all treatments reported in their model.

Finally, a targeted literature search was conducted to review mortality and cardiovascular events

from real-world evidence and to compare the real-world data with those predicted by the model.

The average remaining life expectancy of a 45-year-old US female is 38.08 years.

109

In one study,

class I obesity shortened life expectancy by approximately 3.5 years in middle-aged women.

110

Our

model estimate was comparable to this real-world data, with an expected remaining median

survival of 34 years and a predominantly female population taking semaglutide. Our model

produced estimates for the cumulative incidence of cardiovascular conditions of 59.5% in patients

receiving lifestyle management. The cumulative estimated incidence in patients receiving

semaglutide was 52.1%. These model findings reflect the lifetime cardiovascular risk estimates

from real-world studies in patients with an average age of 45 years living with major risk factors or

obesity.

111,112

Supplement E7

contains additional information about model validation results.

Uncertainty and Controversies

In 2013, the American Medical Association recognized obesity as a chronic disease.

113

As a result,

long-term weight management includes both weight loss and maintenance of weight reduction.

However, medications for weight management are often not covered or require a stepped

approach to care, with access granted only after lifestyle changes and other treatments have

failed.

114

Where medications are covered, restrictions may be imposed on the duration of

treatment (e.g., through day supply/quantity limits or reauthorization criteria). The Government

Accountability Office showed that, between 2008 and 2017, 78.4% of first treatment episodes users

had a medication duration of 91 days or less.

114

In contrast, after discussions with several experts in

our scoping discussions, most stated that lifetime treatment with medications is now the preferred

approach to managing obesity and overweight, given weight regain after discontinuation and the

need for long-term use to prevent comorbid disease and mortality. As a result of this input, we

decided to evaluate lifetime treatment as the base-case analysis.

Another important uncertainty in the model was that the medications used for weight management

often had multiple effects on the body in addition to weight loss. To limit the complexity of the

cost-effectiveness model and to prevent double-counting of treatment benefits, we limited the

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long-term effects of treatments for weight management to cardiovascular risk and delays in the

onset and/or diagnosis of diabetes mellitus (in patients starting in the model without diabetes) due

to the effect of medications on A1C. As a result, there may be additional benefits with certain

therapies that were not captured in the model. For example, GLP-1 receptor agonists have been

shown to improve cardiovascular risk to a greater extent than expected by changes to HbA1C and

weight loss alone in patients with diabetes mellitus.

29,43

These effects of GLP-1 receptor agonists

have not yet been well elucidated in patients without diabetes mellitus, the starting population

within the base-case model.

The long-term benefits of preventing other comorbidities including cancer, chronic kidney disease,

osteoarthritis, and sleep apnea were not explicitly modeled in the base case. Though obesity is

associated with cancer risk, a clear causal relationship has not been established between weight

loss and the extent to which cancer-specific outcomes change. The short-term quality of life gains

from decreased pain from osteoarthritis and improved sleep were included as general

improvements in health-related utility associated with changes in BMI. With regard to chronic

kidney disease, the costs and disutility of chronic kidney disease secondary to diabetes mellitus and

heart failure were implicitly captured in the model. The impact of treatment on chronic kidney

disease risk arising from overweight and obesity, independent of the effects on diabetes mellitus

and heart failure, could not be quantified and was not included in the base case. Similarly, the

cardiovascular benefits of reduced sleep apnea were already implicitly included in the equation

used to estimate cardiovascular risk. However, the potential cost savings arising from a reduced

need for osteoarthritis or sleep apnea treatments with substantial weight loss were believed to be

small relative to the costs of cardiovascular conditions and diabetes mellitus and were not included

in the base-case simulation. To further explore the potential impact of comorbid conditions

partially included or excluded from the base-case analysis, we tested the potential impact of weight

loss on cancer risk and chronic kidney disease using add-on Comorbidity X Markov states. These

scenario analyses did not significantly alter the incremental cost-effectiveness ratios, alleviating

concerns about the effects of these comorbidities on the cost effectiveness of weight management

strategies.

Bupropion is an approved treatment for smoking cessation, which may also improve cardiovascular

risk. Additionally, smoking cessation can lead to weight gain.

115

Since we wanted to evaluate the

impact of these treatments on weight loss alone, the potential benefits of bupropion for patients

wanting to quit smoking were not included in the model.

The key drivers of cost effectiveness in our model were health state utility, effectiveness of

medication in reducing weight, and factors associated with prevention of diabetes mellitus, such as

reduction in HbA1C with treatment and baseline HbA1C. Cardiovascular benefits of GLP-1 receptor

agonists that appear to extend beyond their impact on weight loss and HbA1C improvements have

been shown in patients with diabetes mellitus. Although not evaluated in our model, additional

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cardiovascular benefits, if present for GLP-1 receptor agonists in patients without diabetes mellitus,

could result in improved cost effectiveness of treatment with semaglutide and liraglutide.

There are several important limitations in this analysis. As described above, we did not include the

full potential impact of weight loss on chronic kidney disease and other conditions for which weight

loss may be beneficial, such as preventing a number of cancers. Some conditions (e.g., sleep apnea,

chronic kidney disease) were purposely excluded due to a concern over double-counting the

beneficial effects of weight loss. Other conditions (e.g., cancer) were excluded due to insufficient

evidence documenting the impact of weight loss on reductions in those conditions or their related

costs.

The equations used in our model were developed to determine the associations among patient-

related factors, including weight and first cardiovascular events. These equations may have

limitations when attempting to predict the impact of medication-assisted treatment for weight loss,

especially in the case of medications that have complex actions on the body.

Because the analysis

was limited by available evidence, the outcomes of preventing or treating obesity in subpopulations

with larger potential benefits (e.g., younger individuals, women of childbearing age, or underserved

populations) were not specifically addressed.

4.4. Summary and Comment

We conducted an analysis of the cost effectiveness of medication-assisted therapy for weight loss,

administered over an individual’s lifetime, using a Markov health state transition model. All

therapies added to lifestyle modification conferred health gains as compared to lifestyle

modification alone in accordance with their incremental weight loss and corresponding

cardiovascular and metabolic benefits. Revised results suggest that at current estimates of net

price, neither semaglutide nor liraglutide were cost effective given commonly accepted thresholds.

In contrast, phentermine/topiramate in addition to lifestyle modification was cost effective per

commonly accepted thresholds owing to its comparatively smaller net acquisition costs.

Bupropion/naltrexone was cost effective at higher thresholds only and would require discounted

prices to meet lower thresholds.

When the treatments were compared to each other, phentermine/topiramate plus lifestyle

modification was less costly and more effective than bupropion/naltrexone plus lifestyle

modification. However, for patients not achieving desired weight loss or unable to tolerate

phentermine/topiramate, bupropion/naltrexone may be a cost-effective alternative. Semaglutide

(plus lifestyle modification) was more effective and more costly than both phentermine/topiramate

and bupropion/naltrexone but did not meet commonly accepted cost-effectiveness thresholds for

either comparison. As such, semaglutide may be considered in patients not achieving desired

weight loss or unable to tolerate phentermine/topiramate or bupropion/naltrexone, but only with a

significant discount.

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5. Contextual Considerations and Potential

Other Benefits

Our reviews seek to provide information on potential other benefits offered by the intervention to

the individual patient, caregivers, the delivery system, other patients, or the public that was not

available in the evidence base nor could be adequately estimated within the cost-effectiveness

model. These elements are listed in the table below, with related information gathered from

patients and other stakeholders. Following the public deliberation on this report the appraisal

committee will vote on the degree to which each of these factors should affect overall judgments of

long-term value for money of the intervention(s) in this review.

Table 5.1. Contextual Considerations

Contextual Consideration

Relevant Information

Acuity of need for treatment of individual

patients based on short-term risk of death

or progression to permanent disability

Not applicable

Magnitude of the lifetime impact on

individual patients of the condition being

treated

Obesity is a chronic disease that usually begins early in life and can

continue throughout the course of a patient’s life broadly affecting

physical, psychosocial, and emotional health. As such, it can affect

educational achievement, workplace opportunities and

performance assessments, and personal relationship.

There is uncertainty about how short-term

mild to moderate weight loss translates into

long-term benefits in preventing obesity-

related disease morbidity and mortality

Though evidence from trials of semaglutide, liraglutide,

phentermine/topiramate, and bupropion/naltrexone in patients

with obesity showed sustained weight loss and few serious side

effects over short-term follow-up, the long-term benefits of the

chronic use of these medications remains uncertain. This relates to

the ability to maintain use over long periods given evidence for

weight regain upon discontinuation, the benefits of mild to

moderate weight loss on clinical outcomes, and potential

differences in the medications underlying mechanisms that may be

associated with other beneficial or harmful aspects on clinical

outcomes beyond any sustained weight loss.

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Table 5.2. Potential Other Benefits or Disadvantages

Potential Other Benefit or Disadvantage

Relevant Information

Patients’ ability to achieve major life goals

related to education, work, or family life

New medications for obesity that lead to sustained weight loss and

improve the symptoms and complications of obesity may help

improve quality of life across a range of different outcomes

including social interactions with family, friends and other relations,

educational achievement, and work opportunities and

performance. This is particularly true for women of childbearing age

where the potential effect of weight reduction on fertility, maternal

morbidity and mortality, and infant health may be improved with

weight loss. However, it is uncertain whether semaglutide,

liraglutide, phentermine/topiramate, and/or bupropion/naltrexone

will improve these outcomes.

Caregivers’ quality of life and/or ability to

achieve major life goals related to

education, work, or family life

Though children and adolescents with obesity often require care

involving family members and other caregivers, this Report focused

on adults with obesity. Even among adults with obesity, its impact

may fall not only on the patient, but also on caregivers. As such,

new medications that promote sustained weight loss offer the

possibility of improving the quality of life for caregivers as well as

for patients.

Patients’ ability to manage and sustain

treatment given the complexity of regimen

Use of phentermine/topiramate and bupropion/naltrexone, which

are oral therapies and do not require the daily or weekly injections,

may decrease the complexity of care. All four medications may be

less complex to use on a long-term basis than constant attention to

diet and physical activity.

Society’s goal of reducing health inequities

Obesity disproportionally impacts certain racial and ethnic groups,

and emphasizes the need for and potential impact of improved

treatment options. However, the costs of medications for obesity

are often not covered by health insurance, and there are

differences among individuals in their ability to access health care.

This may exacerbate existing health inequities by selectively limiting

access of these medications to those patients who are able to

afford them and have access to health care providers who can

prescribe them.

Additionally, ICER calculated the Health Improvement Distribution

Index, looking at the relative proportion of any health gains from

treatment of overweight with one or more comorbidities and

obesity for the following groups who have a higher prevalence of

overweight with comorbidities and obesity than the general US

population.

116

• African American/Black female: 1.3

•

Hispanic: 1.1

These medications offer new mechanisms of

action that may allow more patients to

achieve meaningful weight loss among those

who have failed other treatments or may

wish to avoid surgical therapies

Semaglutide and liraglutide, GLP-1 receptor agonists, represent

medications that reflect research in which improved understanding

of the mechanisms of disease have led to new therapies.

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6. Health-Benefit Price Benchmarks

Health-benefit price benchmarks for the annual cost of treatment with the semaglutide are

presented in Table 6.1. The health-benefit price benchmark for a drug is defined as the price range

that would achieve incremental cost-effectiveness ratios between $100,000 and $150,000 per QALY

or evLY gained. Based on our model analyses, we estimate a health-benefit price benchmark range

for semaglutide from $7,500 to $9,800 per QALY or evLY gained compared to lifestyle modification

alone. Corresponding discounts from WAC to achieve the health-benefit price benchmark range for

semaglutide compared to lifestyle modification alone range from 44-57%.

Table 6.1. Annual Cost-Effectiveness Health-Benefit Price Benchmarks for Semaglutide plus

Lifestyle Modification vs. Lifestyle Modification Alone plus Background Therapy

Outcome for

Annual Health-

Benefit Price

Benchmark

Calculation

Annual WAC

Annual Price at

$100,000 Threshold

Annual Price at

$150,000 Threshold

Discount from WAC

to Reach Threshold

Prices

Semaglutide plus Lifestyle Modification vs. Lifestyle Modification Alone

QALYs Gained

$17,597.48

$7,500

$9,700

45-57%

evLYs Gained

$17,597.48

$7,600

$9,800

44-57%

evLY: equal-value life year, QALY: quality-adjusted life-year, WAC: wholesale acquisition cost

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7. Potential Budget Impact

7.1. Overview of Key Assumptions

Using results from the cost-effectiveness model, we estimated the potential budget impact of

adding semaglutide to current lifestyle modification for US adults with BMI ≥30 or 27.0

kg/m

≤BMI<30 kg/m

with one or more weight-related comorbidities. In accordance with the

Reference Case

, semaglutide is treated as an intervention in the budget impact analysis, as it has

been on the market for less than two years as of posting the Model Analysis Plan. In contrast,

liraglutide, phentermine/topiramate, and bupropion/naltrexone are treated as comparators, as

they have been on the market for two years or more.

For potential budget impact analyses, we used semaglutide’s list price and net price and three

threshold prices (at $50,000, $100,000, and $150,000 per QALY) compared to lifestyle modification

alone. These additional analyses on semaglutide threshold prices were conducted to inform

budgetary impact estimations aligned with notions of semaglutide’s cost effectiveness as calculated

within the cost-effectiveness analyses. Potential budget impact is defined as the total differential

cost of using semaglutide rather than the relevant existing therapies for the treated population,

calculated as intervention costs minus any offsets in these costs from averted health care events or

other resource utilization. All costs were undiscounted and estimated over a five-year time horizon.

To estimate the size of the potential candidate populations for treatment, we used the US adult

population and prevalence of overweight and obesity given specific weight-related comorbidities or

biomarkers as reported within National Health and Nutrition Examination Survey datasets over the

2017-2018 and 2019-March 2020 data collection cycles.

117

Accordingly, we estimated a combined

prevalence value for US adults with BMI ≥30 kg/m

(41.96%) or 27.0 kg/m

≤BMI<30 kg/m

with one

or more weight-related comorbidities (11.57%) at 53.53%. To quantify the number of these

patients eligible for semaglutide therapy, we identified two cohorts: those currently on medication

treatment for weight management and those seeking medication treatment for weight

management. Accordingly, we estimated that 1.3% of all US adults in the prevalent cohort receive

medication, with another 1.3% seeking medication therapy but not currently receiving it. These

estimates were derived from electronic health record data on 2.2 million adults eligible for weight

loss medication from eight geographically dispersed health care systems across the US, and from

manufacturer data submissions, respectively.

118,119

Applied to the projected US adult population

over 2022-2026, we estimated 3,700,000 adults would be eligible for treatment with semaglutide.

For this analysis, we assumed that 20% of these patients would initiate treatment with semaglutide

in each of the five years (~740,000 per year), for a total of 100% of the cohort being treated with

semaglutide at the end of five years.

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Of the 1.3% of individuals on medication therapy at baseline, 53%, 30%, and 17% are assigned to

liraglutide, phentermine/topiramate, and bupropion/naltrexone, respectively.

119

The remaining

individuals seeking medication therapy are assigned to lifestyle modification alone at baseline. In

our potential budget impact analyses, semaglutide draws market share proportionally from each of

the model comparators over the five-year time horizon.

7.2. Results

At semaglutide’s estimated net price of $13,618.22 per year, 3.77% of eligible patients could be

treated within five years (assuming 20% uptake each year) without crossing the ICER potential

budget impact threshold of $777 million per year. In contrast, 2.65%, 6.30%, 10.18%, and 26.41% of

eligible patients could be treated within five years without crossing the ICER potential budget

impact threshold at the annual price to reach list price ($17,597.48), $150,000 per QALY ($9,700),

$100,000 per QALY ($7,500), and $50,000 per QALY ($5,300), respectively. The modest percentages

were primarily driven by the large population eligible for treatment with semaglutide. Figure 7.1.

depicts the potential budgetary impact of semaglutide at the annual list price, net price, and three

threshold prices compared to lifestyle modification alone.

Figure 7.1. Budgetary Impact of Semaglutide in US Adults Seeking or Using Medication Therapy

for Weight Management with BMI ≥30 or 27.0 kg/m

≤BMI<30 kg/m

with One or More Weight-

Related Comorbidities

BI: budget impact, QALY: quality-adjusted life year, WAC: wholesale acquisition cost

Annual WAC

Annual Net Price

$50,000/QALY Annual Price

$100,000/QALY Annual Price

$150,000/QALY Annual Price

$2,000

$4,000

$6,000

$8,000

$10,000

$12,000

$14,000

$16,000

$18,000

$20,000

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Annual Semaglutide Price

Percentage of Patients Treated Without Crossing Potential BI Threshold Each Year

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Supplemental Materials

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A. Background: Supplemental Information

A1. Definitions

Obesity: BMI is the most common way that obesity is defined in clinical practice. Overweight is

considered a BMI of 25 kg/m

to 29.9 kg/m

. Obesity is considered a BMI of 30 kg/m2 or greater. It

is further subclassified as level I (30 kg/m

to 34.9 kg/m

), level II (35 kg/m

to 39.9 kg/m

), or level

III (40 kg/m

or more).

Pre-diabetes: The clinical trials assessed patients for pre-diabetes using slightly different criteria.

Pre-diabetes is defined by the American Diabetes Association based on an HbA1C result of 5.7%-

6.4% (39-47 mmol/mol), a fasting glucose of 100-125 mg/dL (5.6-6.9 mmol/L), or a two-hour oral

glucose tolerance test of 140-mg-199 mg/dL (7.8-11.0 mmol/L).

120

Important outcomes in the pivotal trials studied include:

Percentage weight loss: This primary outcome in most studies represents the mean percentage

point change in weight at follow-up relative to the baseline body weight.

Categorical weight loss (≥5%): This is a co-primary outcome in many studies and represents the

percentage of individuals who achieve a ≥5% change in body weight from baseline to follow-up

assessment. Greater weight loss can be assessed using ≥10%, ≥15%, or higher percentages.

Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT): The IWQOL was

the first quality of life instrument specifically developed to assess individuals with obesity.

121

measures those aspects of quality of life that were identified by individuals with moderate or severe

obesity to be of greatest concern. Eight domains assessed include health, social/interpersonal,

work, mobility, self-esteem, sexual life, activities of daily living, and comfort with food. Originally a

74-item instrument, the IWQOL-Lite is a shorter, 31-item, self-reported version that consists of a

total score and scores on each of five scales: Physical Function, Self-Esteem, Sexual Life, Public

Distress, and Work.

122

The IWQOL-Lite Clinical Trials Version (IWQOL-Lite-CT), was developed and

validated for use in clinical trials.

123,124

It is a 20-item measure used to assess weight-related

physical and psychosocial functioning in three composite scores (physical, physical function, and

psychosocial) and a total score. The range of possible scores for the IWQOL-Lite-CT is 0-100. For

the IWQOL-Lite-CT, an increase in score is representative of an improvement in health status.

Short Form-36 v2® Health Survey, Acute Version (SF-36): The SF-36 is a generic quality of life

measure widely used to assess patient-reported functional outcomes.

125

It includes 36 questions

across eight domains (physical functioning, role limitations due to physical health problems, body

pain, general health, vitality, social functioning, role limitations due to emotional problems, and

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mental health). Additionally, the SF-36 domains can be aggregated into two scores, the Physical

Component Summary (PCS) and the Mental Component Summary (MCS). For the SF-36, an increase

in score is representative of an improvement in health status.

Patient Health Questionnaire (PHQ-9): The PHQ-9 is a self-administered instrument to measure

symptoms of depression.

126

It was derived from the PRIME-MD diagnostic instrument for common

mental disorders. Each item asks the individual to rate daily symptoms from "0" (not at all) to "3"

(nearly every day). A higher score indicated worse depressive symptoms.

Inventory of Depressive Symptomatology (Self-Report) (IDS-SR): The IDS-SR is a 30-item

questionnaire measuring depressive symptoms. Each item has four statements that reflect various

degrees of symptom severity, scored on a four-point scale from 0 to 3.

127

A higher score indicated

worse depressive symptoms.

A2. Potential Cost-Saving Measures in Obesity Management

ICER includes in its reports information on wasteful or lower-value services in the same clinical area

that could be reduced or eliminated to create headroom in health care budgets for higher-value

innovative services (for more information, see

https://icer.org/our-approach/methods-

process/value-assessment-framework/). These services are ones that would not be directly

affected by semaglutide, liraglutide, phentermine/topiramate, and/or bupropion/naltrexone (e.g.,

need for obstructive sleep apnea treatment), as these services will be captured in the economic

model. Rather, we are seeking services used in the current management of obesity beyond the

potential offsets that arise from a new intervention. During stakeholder engagement and public

comment periods, ICER encouraged all stakeholders to suggest services (including treatments and

mechanisms of care) currently used for individuals with obesity that could be reduced, eliminated,

or made more efficient. No suggestions were received.

A3. Future Therapies

In June 2022, results from the SURMOUNT-1 trial of tirzepatide were published.

Tirzepatide is

both a GLP-1 receptor agonist and also a glucose-dependent insulinotropic polypeptide receptor

agonist. ICER previously reviewed tirzepatide

as a treatment for type 2 diabetes mellitus. The

manufacturer of tirzepatide requested that it not be added to this report as the current ICER

evaluation process was already underway. Tirzepatide is neither an intervention nor a comparator

in this Report. However, to provide context, we review the results of SURMOUNT-1 here.

SURMOUNT-1 was a 72-week Phase III trial comparing three doses of tirzepatide and placebo in

2,539 adults without diabetes and with a BMI ≥30 kg/m

or ≥27 kg/m

with one weight-related

complication. Tirzepatide was administered by weekly subcutaneous injection at doses of 5 mg, 10

mg, or 15 mg, with an initial 20-week dose-escalation period.

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The mean baseline BMI in the study population was 38. Tirzepatide at doses of 5 mg, 10 mg, and 15

mg resulted in greater percentage reductions in weight than placebo (15.0%, 19.5%, and 20.9% vs.

3.1%, respectively). More patients achieved categorical weight reduction targets as well. For

example, a ≥5% target was achieved by 85.1%, 88.9%, and 90.9% of patients, respectively, with the

tirzepatide doses, versus 34.5% with placebo. A ≥25% target was achieved by 15.3%, 32.3%, and

36.2% of patients, respectively, with tirzepatide versus 1.5% with placebo.

Patients treated with tirzepatide also experienced improvements in physical functioning, decreases

in systolic and diastolic blood pressure, improvements in lipids, and decreases in fasting insulin

levels.

Most adverse events with tirzepatide were gastrointestinal in nature and discontinuation for

adverse events occurred in more patients treated with tirzepatide than placebo (4.3%, 7.1%, and

6.2% vs. 2.6%, respectively). Gastrointestinal adverse events were typically worse at initiation or

dose escalation of tirzepatide, with improvement over time.

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B. Patient Perspectives: Supplemental

Information

B1. Methods

In developing and executing this Report, we received valuable input from individual patients and

patient organizations throughout the scoping and evidence development process. We received

public comments on our draft scoping document from the Obesity Action Coalition. We also

conducted a focus group with six patients that was arranged through the Obesity Action Coalition.

These interviews with patients helped to illustrate the diversity of experiences of patients living

with obesity as well as highlighting the health outcomes that were most important to them.

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C. Clinical Guidelines

Veterans’ Health Administration/Department of Defense

Clinical Practice Guideline for the Management of Adult Overweight and Obesity

128

The Evidence-Based Practice Work Group of the Department of Veterans Affairs and the

Department of Defense released updated guideline recommendations in 2020. These

recommendations updated a prior evidence review released in 2014. A number of key elements of

weight loss and management were highlighted. Obesity is recognized as a chronic disease requiring

long-term management. Shared decision-making involving patients and providers is seen as a

fundamental aspect of weight management. Managing obesity involves addressing all of the

factors that may be involved for a given patient. This may include assessing whether medications or

treatments for other conditions may exacerbate weight issues for a patient. Lifestyle interventions

involving comprehensive use of behavioral, dietary, and physical activity components are central to

success in reducing and sustaining weight loss. Pharmacotherapy and weight loss surgery should be

considered along with comprehensive lifestyle interventions, and when instituted they require long-

term follow-up.

In terms of pharmacotherapy, the use of FDA-approved medications needs to consider potential

side effects as well as patient tolerability and preferences. Weight regain can occur with any

medication after discontinuation, so long-term use to maintain weight loss is often needed. Specific

pharmacotherapies that can be offered to patients include bupropion/naltrexone, liraglutide,

orlistat, or phentermine/topiramate. Eligibility includes patients with a BMI ≥30 kg/m

and for

those with a BMI ≥27 kg/m

who also have obesity-associated conditions. There is insufficient

information to recommend phentermine monotherapy or other stimulants for intermittent, short-

term, or long-term use.

Canadian Clinical Practice Guideline

Obesity in Adults: A Clinical Practice Guideline

This guideline was funded by the Canadian Institutes of Health Research Strategic Patient-Oriented

Research initiative, Obesity Canada’s Fund for Obesity Collaboration and Unified initiative, and the

Canadian Association of Bariatric Physicians and Surgeons. An executive and steering committee

with broad expertise and geographic representation was created. The scope of the guideline was

developed by the executive committee. A literature review was performed by the McMaster

Evidence Review and Synthesis Team. Guideline recommendations were formulated by the

steering committee along with chapter leads and authors. Seven individuals living with obesity

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were engaged and one participated on the steering committee. This guideline updated the first

Canadian obesity guideline published in 2006.

Key points emphasized that obesity is a common, complex, progressive, and relapsing disease. It is

characterized by abnormal or excessive body fat that impairs health. Newer insights into appetite

regulation and the underlying mechanisms leading to obesity have opened new approaches for

treating this chronic disease. People living with obesity face substantial bias and stigma, and this

contributes independently of weight or BMI to morbidity and mortality. Reducing weight bias and

stigma, better understanding of the underlying causes of obesity, and supporting patient-centered

care can improve the wellbeing of those living with obesity. Obesity care should be based on

evidence-based principles of chronic disease management, validate patients’ lived experiences, and

move beyond the simplistic notion that obesity requires eating less and increasing activity.

In terms of pharmacotherapy, the guideline focuses on individuals with BMI ≥30 kg/m

or BMI ≥27

kg/m

with comorbid conditions. Pharmacotherapy is meant to be an adjunctive for weight loss and

weight loss maintenance in addition to medical nutrition therapy, physical activity, and

psychological interventions. Recommended options include liraglutide 3.0 mg,

bupropion/naltrexone, and orlistat. Details of the recommendations are available online in the

chapter titled “Pharmacotherapy in Obesity Management.” Pharmacotherapy is intended to

augment the magnitude of weight loss beyond what can be achieved with health behavior changes

alone. It is also emphasized as being important for the prevention of weight regain.

Endocrine Society

Pharmacological Management of Obesity Guideline

129

This evidence-based guideline was developed by members of the Endocrine Society, the European

Society of Endocrinology, and the Obesity Society. Weight loss is seen as a path to achieving

improved health for patients with obesity-associated risk factors and comorbidities. Medications

approved for chronic weight management can be useful adjuncts to lifestyle interventions for

patients that have not met weight loss goals on their own. Diet, exercise, and behavioral

modification are recommended for patients with BMI ≥25 kg/m

and should be included with other

obesity management interventions. Pharmacotherapy can be considered for those with BMI ≥27

kg/m

with comorbidity or BMI over 30 kg/m

. Patients with a history of being unable to

successfully lose and maintain weight are candidates for weight loss medications. Patients

responding well to weight loss (5% or more after three months) should continue with therapy. In

addition to addressing medications that can promote weight loss, the guidelines emphasize

attention to the use of medications for other conditions that are weight-neutral and avoiding those

that are associated with weight gain.

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Specific pharmacotherapy recommendations include avoiding sympathomimetic agents such as

phentermine in patients with diabetes mellitus and uncontrolled hypertension or a history of heart

disease. In patients with type 2 diabetes mellitus who are overweight or have obesity, antidiabetic

medications that may promote weight loss, such as GLP-1 receptor agonists or sodium-glucose-

linked transporter-2 inhibitors, are suggested. Off-label use of medications approved for other

conditions is not recommended for the sole purpose of weight loss.

National Institute for Health and Care Excellence (NICE)

Obesity: Identification, Assessment, and Management Clinical Guideline

130

NICE released recommendations for managing obesity in 2014. Areas of focus for this guideline

included identification, assessment, and management of obesity. Interventions assessed included

lifestyle, behavioral, physical activity, dietary, pharmacological, and surgical interventions. In terms

of lifestyle interventions, multi-component ones are considered the treatment of choice, and

should include behavioral change strategies that can support increased physical activity and

improved eating habits.

Pharmacological treatment is recommended only after dietary, exercise, and behavioral approaches

have been initiated. One should consider drug treatment of interested individuals who have not

reached their target weight loss. Pharmacological treatments may be continued to maintain weight

loss. For those who have not reached their weight loss target, consideration should be given for

stopping the drug. Since weight loss may be slower in individuals who also have type 2 diabetes

mellitus, less strict goals and longer duration of therapy may be appropriate. Orlistat should only

be prescribed when it is part of an overall plan for managing obesity, should not be co-prescribed

with other weight loss drugs, and should not be continued beyond three months if the person has

not lost at least 5% of their initial body weight. Phentermine/topiramate was not mentioned in this

document, but is listed as being in development.

In December 2017, NICE released recommendations for bupropion/naltrexone. It was not

recommended for managing overweight and obesity in adults alongside a reduced-calorie diet and

increased physical activity. In February, 2022, NICE released a draft guideline for the use of

semaglutide for weight management. It is an option when given in addition to diet and activity

recommendations for individuals with a BMI of at least 35 kg/m

or 30-34.9 kg/m

with other

comorbid conditions that meet NICE criteria. It can be used for a maximum of two years and needs

to be given by a specialist weight management service. Consideration for stopping semaglutide if

less than 5% initial weight loss has been achieved after six months of maintenance therapy.

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D. Comparative Clinical Effectiveness:

Supplemental Information

D1. Detailed Methods

PICOTS

Population

The population of focus for the review is adults with a BMI ≥30 kg/m

or ≥27 kg/m

with at least one

weight-related comorbid condition (such as hypertension, type 2 diabetes mellitus, obstructive

sleep apnea, or hyperlipidemia) who are actively seeking medical management for weight loss.

Data permitting, we sought to examine the following patient subgroups, including but not limited

to:

• BMI categories: 27-29.9, 30-34.9, 35-39.9, or greater than 40 kg/m

• Pre-diabetes or diabetes mellitus

• Prior bariatric surgery

Interventions

The full list of interventions is as follows:

• Semaglutide

• Liraglutide

• Bupropion and naltrexone in combination

• Phentermine and topiramate in combination

Comparators

We intended to compare each intervention with lifestyle modification to placebo with lifestyle

modification. Data permitting, we also compared the interventions to one another.

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Outcomes

The outcomes of interest are described in the list below.

• Patient-Important Outcomes

o Quality of life and functional status

o Anxiety and depression

o Body image

o Long-term health outcomes such as cardiovascular disease, cancer, and mortality

o Weight loss (as measured by % weight loss, categorical weight loss [e.g., 5%, 10%, or

15%], BMI, etc.)

o Weight re-gain

o Adverse events including:

 Side effects

 Psychological harm

 Serious adverse events

• Other Outcomes

o Metabolic profile, such as LDL, hemoglobin A1C, and blood pressure

o Weight cycling

o Waist circumference

o Progression from pre-diabetes to diabetes mellitus or pre-hypertensive to

hypertensive

o Withdrawal or dose reduction in concomitant medications for weight-related

comorbidities

o Subsequent surgical interventions for weight loss

o Discontinuation due to adverse events

Timing

Evidence on intervention effectiveness was derived from studies of at least 12 weeks duration and

evidence on harms from studies of any duration.

Settings

All relevant settings were considered, with a focus on outpatient settings in the US.

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Table D1. PRISMA 2020 Checklist

Section and Topic

Item

Checklist item

Reported

on Page #

TITLE

Title

Identify the report as a systematic review.

ABSTRACT

Abstract

See the PRISMA 2020 for Abstracts checklist.

INTRODUCTION

Rationale 3

Describe the rationale for the review in the context of existing

knowledge.

Objectives 4

Provide an explicit statement of the objective(s) or question(s) the

review addresses.

METHODS

Eligibility Criteria 5

Specify the inclusion and exclusion criteria for the review and how

studies were grouped for the syntheses.

Information

Sources

Specify all databases, registers, websites, organizations, reference

lists and other sources searched or consulted to identify studies.

Specify the date when each source was last searched or consulted.

Search Strategy 7

Present the full search strategies for all databases, registers, and

websites, including any filters and limits used.

Selection Process 8

Specify the methods used to decide whether a study met the

inclusion criteria of the review, including how many reviewers

screened each record and each report retrieved, whether they

worked independently, and if applicable, details of automation

tools used in the process.

Data Collection

Process

Specify the methods used to collect data from reports, including

how many reviewers collected data from each report, whether

they worked independently, any processes for obtaining or

confirming data from study investigators, and if applicable, details

of automation tools used in the process.

Data Items

10a

List and define all outcomes for which data were sought. Specify

whether all results that were compatible with each outcome

domain in each study were sought (e.g., for all measures, time

points, analyses), and if not, the methods used to decide which

results to collect.

10b

List and define all other variables for which data were sought (e.g.,

participant and intervention characteristics, funding sources).

Describe any assumptions made about any missing or unclear

information.

Study Risk of Bias

Assessment

Specify the methods used to assess risk of bias in the included

studies, including details of the tool(s) used, how many reviewers

assessed each study and whether they worked independently, and

if applicable, details of automation tools used in the process.

Effect Measures 12

Specify for each outcome the effect measure(s) (e.g., risk ratio,

mean difference) used in the synthesis or presentation of results.

Synthesis Methods 13a

Describe the processes used to decide which studies were eligible

for each synthesis (e.g., tabulating the study intervention

characteristics and comparing against the planned groups for each

synthesis [item #5]).

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Section and Topic

Item

Checklist item

Reported

on Page #

13b

Describe any methods required to prepare the data for

presentation or synthesis, such as handling of missing summary

statistics, or data conversions.

13c

Describe any methods used to tabulate or visually display results of

individual studies and syntheses.

13d

Describe any methods used to synthesize results and provide a

rationale for the choice(s). If meta-analysis was performed,

describe the model(s), method(s) to identify the presence and

extent of statistical heterogeneity, and software package(s) used.

13e

Describe any methods used to explore possible causes of

heterogeneity among study results (e.g. subgroup analysis, meta-

regression).

13f

Describe any sensitivity analyses conducted to assess robustness of

the synthesized results.

Reporting Bias

Assessment

Describe any methods used to assess risk of bias due to missing

results in a synthesis (arising from reporting biases).

Certainty

Assessment

Describe any methods used to assess certainty (or confidence) in

the body of evidence for an outcome.

RESULTS

Study Selection

16a

Describe the results of the search and selection process, from the

number of records identified in the search to the number of

studies included in the review, ideally using a flow diagram.

16b

Cite studies that might appear to meet the inclusion criteria, but

which were excluded, and explain why they were excluded.

Study

Characteristics

17 Cite each included study and present its characteristics.

Risk of Bias in

Studies

18 Present assessments of risk of bias for each included study.

Results of

Individual Studies

For all outcomes, present, for each study: (a) summary statistics

for each group (where appropriate) and (b) an effect estimates and

its precision (e.g., confidence/credible interval), ideally using

structured tables or plots.

Results of

Syntheses

20a

For each synthesis, briefly summarize the characteristics and risk of

bias among contributing studies.

20b

Present results of all statistical syntheses conducted. If meta-

analysis was done, present for each the summary estimate and its

precision (e.g., confidence/credible interval) and measures of

statistical heterogeneity. If comparing groups, describe the

direction of the effect.

20c

Present results of all investigations of possible causes of

heterogeneity among study results.

20d

Present results of all sensitivity analyses conducted to assess the

robustness of the synthesized results.

Reporting Biases 21

Present assessments of risk of bias due to missing results (arising

from reporting biases) for each synthesis assessed.

Certainty of

Evidence

Present assessments of certainty (or confidence) in the body of

evidence for each outcome assessed.

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Section and Topic

Item

Checklist item

Reported

on Page #

DISCUSSION

Discussion

23a

Provide a general interpretation of the results in the context of

other evidence.

23b

Discuss any limitations of the evidence included in the review.

23c

Discuss any limitations of the review processes used.

23d

Discuss implications of the results for practice, policy, and future

research.

OTHER INFORMATION

Registration and

Protocol

24a

Provide registration information for the review, including register

name and registration number, or state that the review was not

registered.

24b

Indicate where the review protocol can be accessed, or state that a

protocol was not prepared.

24c

Describe and explain any amendments to information provided at

registration or in the protocol.

Support 25

Describe sources of financial or non-financial support for the

review, and the role of the funders or sponsors in the review.

Competing

Interests

26 Declare any competing interests of review authors.

Availability of Data,

Code, and Other

Materials

Report which of the following are publicly available and where

they can be found: template data collection forms; data extracted

from included studies; data used for all analyses; analytic code; any

other materials used in the review.

From: Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting

systematic reviews. PLoS Med. 2021;18(3):e1003583.

Data Sources and Searches

Procedures for the systematic literature review assessing the evidence on treatments for obesity

management followed established best research methods.

131,132

We conducted the review in

accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses

(PRISMA) guidelines.

133

The PRISMA guidelines include a checklist of 27 items.

We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Cochrane Central

studies of human subjects and excluded articles indexed as guidelines, letters, editorials, narrative

reviews, case reports, or news items. We included abstracts from conference proceedings

identified from the systematic literature search. All search strategies were generated utilizing the

Population, Intervention, Comparator, and Study Design elements described above. The proposed

search strategies included a combination of indexing terms (MeSH terms in MEDLINE and EMTREE

terms in EMBASE) as well as free-text terms.

To supplement the database searches, we performed manual checks of the reference lists of

included trials and systematic reviews and invited key stakeholders to share references germane to

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the scope of this project. We also supplemented our review of published studies with data from

conference proceedings, regulatory documents, information submitted by manufacturers, and

other grey literature when the evidence met ICER standards (for more information, see

https://icer.org/policy-on-inclusion-of-grey-literature-in-evidence-reviews/

. Where feasible and

deemed necessary, we also accepted data submitted by manufacturers “in-confidence,” in

accordance with ICER’s published guidelines on acceptance and use of such data

(

https://icer.org/guidelines-on-icers-acceptance-and-use-of-in-confidence-data-from-

manufacturers-of-pharmaceuticals-devices-and-other-health-interventions/).

Table D2. Search Strategy of EMBASE Search

Search Term

‘obesity’/exp OR ‘obesity’

‘body weight loss’/exp OR ‘body weight loss’

(‘obes*’ OR ‘body mass ind*’ OR ‘adiposity’ OR ‘overweight’ OR ‘over weight’ OR ‘anti-obesity’ OR ‘body-

weight’ OR ‘body weight’):ti,ab

#1 OR #2 OR #3

‘phentermine plus topiramate’/exp

((‘phentermine’ AND ‘topiramate’) OR ‘phentermine plus topiramate’ OR ‘qysmia’ OR ‘qsiva’ OR ‘VI-0521’

OR ‘VI0521’ OR ‘VI 0521’):ti,ab

‘amfebutamone plus naltrexone’/exp

(‘amfebutamone plus naltrexone’ OR ‘contrave’ OR (‘amfebutamone’ AND ‘naltrexone’) OR (‘bupropion’

AND ‘naltrexone’) OR ‘CID 11556075’ OR ‘CID11556075’ OR ‘CID-11556075’):ti,ab

‘glucagon like peptide 1 receptor agonist’/exp

#10

‘liraglutide’/exp

#11

(‘liraglutide’ OR ‘saxenda’ OR ‘victoza’ OR ‘NN 2211’ OR ‘NN2211’ OR ‘NN-2211’):ti,ab

#12

‘semaglutide’/exp

#13

(‘semaglutide’ OR ‘ozempic’ OR ‘wegovy’ OR ‘NN 9535’ OR ‘NN9535’ OR ‘NN-9535’):ti,ab

#14

(‘phentermine’ OR ‘Adipex-P’ OR ‘Lomaira’ OR ‘Suprenza’):ti,ab

#15

#5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14

#16

#4 AND #15

#17

#16 NOT ('addresses' OR 'autobiography' OR 'bibliography' OR 'biography' OR 'case report' OR 'comment'

OR 'congresses' OR 'consensus development conference' OR 'duplicate publication' OR 'editorial' OR

'guideline' OR 'in vitro' OR 'interview' OR 'lecture' OR 'legal cases' OR 'legislation' OR 'letter' OR 'news' OR

'newspaper article' OR 'patient education handout' OR 'periodical index' OR 'personal narratives' OR

'portraits' OR 'practice guideline' OR 'review' OR 'video audio media')/it

#18

('animal'/exp OR 'nonhuman'/exp OR 'animal experiment'/exp) NOT 'human'/exp

#19

#17 NOT #18

#20

#19 AND [English]/lim

#21

#20 NOT [medline]/lim

#22

#21 AND [01/07/2020]/sd

*Search last updated on July 18, 2022.

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Table D3. Search Strategy of Medline 1996 to Present with Daily Update and Cochrane Central

Search Term

exp Obesity/

exp Weight Loss/

exp Overweight/

(obes* or "body mass inde*" or adiposity or overweight or "over weight" or antiobesity or "anti-obesity"

or bodyweight or "body weight").ti,ab.

1 or 2 or 3 or 4

((phentermine and topiramate) or "phentermine topiramate" or phenterminetopiramate or qsymia or

qsiva or topiramatephentermine or "phentermine-topiramate" or VI0521 or "VI 0521" or "VI-0521").ti,ab.

((amfebutamone and naltrexone) or (bupropion and naltrexone) or contrave or "bupropion-naltrexone"

or CID11556075 or "CID 11556075" or "CID-11556075").ti,ab.

exp Glucagon-Like Peptides/

exp liraglutide/

(liraglutide or saxenda or victoza or NN2211 or "NN 2211" or "NN-2211").ti,ab.

(semaglutide or ozempic or wegovy or NN9535 or "NN 9535" or "NN-9535").ti,ab.

(phentermine or Adipex-P or Lomaira or Suprenza).ti,ab.

6 or 7 or 8 or 9 or 10 or 11 or 12

5 and 13

14 not ("address" or "autobiography" or "bibliography" or "biography" or "case reports" or "comment" or

"congress" or "consensus development conference" or "duplicate publication" or "editorial" or

"guideline" or "interview" or "lecture" or "legal case" or "legislation" or "letter" or "news" or "newspaper

article" or "patient education handout" or "periodical index" or "personal narrative" or "portrait" or

"practice guideline" or "review" or "video-audio media").pt.

15 not (animals not (humans and animals)).sh.

limit 16 to english language

remove duplicates from 17

limit 18 to ed=20200701-20220330

*Search last updated on July 18, 2022.

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Figure D1. PRISMA Flowchart Showing Results of Literature Search for Medications for Obesity

Management

37 references identified

through other sources

1,408 references after

duplicate removal

115 references assessed

for eligibility in full text

1,421 references

identified through

literature search

1,293 citations excluded

1,408 references screened

63 citations excluded

13 population

19 study design

10 outcomes

21 duplicate data

51 total references

24 RCTs, 2 SLRS

37 references included in

quantitative synthesis

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Study Selection

We performed screening at both the abstract and full-text level. A single investigator screened all

abstracts identified through electronic searches according to the inclusion and exclusion criteria

described earlier. We did not exclude any study at abstract-level screening due to insufficient

information. For example, an abstract that did not report an outcome of interest would be

accepted for further review in full text. We retrieved the citations that were accepted during

abstract-level screening for full text appraisal. One investigator reviewed full papers and provided

justification for exclusion of each excluded study.

Data Extraction and Quality Assessment

We used criteria published by the US Preventive Services Task Force to assess the quality of

randomized controlled trials and comparative cohort studies, using the categories “good,” “fair,” or

“poor” (see Table D21).

134

Guidance for quality ratings using these criteria is presented below, as is

a description of any modifications we made to these ratings specific to the purposes of this review.

Good: Meets all criteria: Comparable groups are assembled initially and maintained throughout the

study; reliable and valid measurement instruments are used and applied equally to the groups;

interventions are spelled out clearly; all important outcomes are considered; and appropriate

attention is paid to confounders in analysis. In addition, intention-to-treat analysis is used for

randomized controlled trials.

Fair: Studies were graded "fair" if any or all of the following problems occur, without the fatal flaws

noted in the "poor" category below: Generally comparable groups are assembled initially but some

question remains whether some (although not major) differences occurred with follow-up;

measurement instruments are acceptable (although not the best) and generally applied equally;

some but not all important outcomes are considered; and some but not all potential confounders

are addressed. Intention-to-treat analysis is done for randomized controlled trials.

Poor: Studies were graded "poor" if any of the following fatal flaws exists: Groups assembled

initially are not close to being comparable or maintained throughout the study; unreliable or invalid

measurement instruments are used or not applied equally among groups (including not masking

outcome assessment); and key confounders are given little or no attention. For randomized

controlled trials, intention-to-treat analysis is lacking.

Note that case series are not considered under this rating system – because of the lack of

comparator, these are generally considered to be of poor quality.

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Assessment of Level of Certainty in Evidence

We used the ICER Evidence Rating Matrix to evaluate the level of certainty in the available evidence

of a net health benefit among each of the interventions of focus.

135,136

Assessment of Bias

As part of our quality assessment, we evaluated the evidence base for the presence of potential

publication bias. Given the emerging nature of the evidence base for these newer treatments, we

performed an assessment of publication bias on for semaglutide, liraglutide,

phentermine/topiramate, and bupropion/naltrexone using the ClinicalTrials.gov. We scanned the

site to identify studies which would have met our inclusion criteria and for which no findings have

been published and did not find any evidence of publication bias. We provided qualitative analysis

of the objectives and methods of these studies to ascertain whether there may be a biased

representation of study results in the published literature.

Data Synthesis and Statistical Analyses

The results of the studies were summarized in the evidence tables and described narratively in the

body of the report. In addition, we evaluated the comparative efficacy of semaglutide, liraglutide,

phentermine/topiramate, and bupropion/naltrexone by means of NMA, where feasible. Based on

data availability, our NMA evaluated the outcomes of change in body weight and SBP, and

categorical weight loss at one year. NMA Supplemental Information below contains a detailed

description of the NMA methods. Due to inconsistent or limited data reporting, other outcomes

were only described narratively in the body of the Report and in Section D2.

Supplemental NMA Methods

As described in the Report, we conducted random effect NMAs where feasible. An NMA extends

pairwise meta-analyses by simultaneously combining both the direct estimates (i.e., estimates

obtained from head-to-head comparisons) and indirect estimates (i.e., estimates obtained from

common comparator[s]).

137,138

NMAs were conducted using a Bayesian framework. For continuous outcomes, the NMA model

corresponds to a generalized linear model with identity link.

139

For binary outcomes (e.g.,

proportion of patients discontinuing due to adverse events), the NMA model corresponds to a

generalized linear model with a logit link.

139

For all analyses, we included random effects on the

treatment parameters, and the amount of between-study variance (i.e., heterogeneity) was

assumed constant across all treatment comparisons. We used noninformative prior distributions

for all model parameters. We initially discarded the first 50,000 iterations as “burn-in” and base

inferences on an additional 50,000 iterations using three chains. Convergence of chains was

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assessed visually using trace plots. Furthermore, for any network where there were “loops” in

evidence, we empirically compared the direct and indirect estimates to assess if the NMA

consistency assumption is violated using a node-splitting approach.

139

As there was no evidence of inconsistency, we present the full NMA results in the report. All

analyses were conducted using the IndiRect NMA platform (CRG-EVERSANA, 2020™) or R.

Supplemental NMA Results

We provide three network diagrams that represents the NMAs in the report (Figures D2, D3, and

D4). To interpret the network figures, note that the lines indicate the presence of a trial directly

assessing the connecting interventions, with the thickness of the line corresponding to the number

of trials. The location of treatments and the distances between them do not have any meaning.

The medications are depicted in blue, and the trial names are depicted in orange.

Figure D2. Network of Studies Included in the NMAs of Medications for Obesity, Mean Percentage

Weight Loss, Change in SBP from Baseline to One Year and Categorical Weight Loss

B/N: bupropion/naltrexone, LIR: liraglutide, LSM: lifestyle modification, PBO: placebo, P/T: phentermine/

topiramate, SEM: semaglutide

SEM + LSM

LIR +

LSM

B/N + LSM

P/T + LSM

PBO +

LSM

STEP 1

STEP 5

STEP 8

COR-I

COR-II

SCALE

(Maintenance)

SCALE

(Obesity &

Pre-Diabetes)

STEP 8

EQUIP

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Figure D3. Network of Studies Included in the NMA of Medications for the Management of

Obesity with Diabetes Mellitus, Mean Percentage Weight Loss and Mean Change in SBP from

Baseline to One Year

B/N:

bupropion/naltrexone, LIR: liraglutide, LSM: lifestyle modification, PBO: placebo, P/T: phentermine/ topiramate,

SEM: semaglutide

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Figure D4. Network of Studies Included in the NMAs of Medications for Obesity, Discontinuation

Due to Adverse Events

B/N: bupropion/naltrexone, LIR: liraglutide, LSM: lifestyle modification, PBO: placebo, P/T: phentermine/

topiramate, SEM: semaglutide

Results of Categorical Weight Loss

We conducted NMAs of trials including participants with obesity alone separately from trials of

participants with obesity and diabetes, and excluded trials that included IBT as an adjunct to

medication. Categorical weight loss NMAs (proportion of patients achieving at least 5% or 10%

weight loss) are reported below.

Participants with Obesity Alone

For the trials of the medications conducted in participants with obesity without diabetes that

included standard diet and exercise counseling and reported proportion of patients who achieved

at least 5% or 10% weight loss at one year, we present the results of the baseline risk-adjusted

random effects model, given its better fit for the model compared to the unadjusted model in

Tables D4 and D5. All medications, in combination with diet and exercise counseling, showed

statistically significantly greater odds of achieving at least 5% weight loss at one year. Compared to

SEM + LSM

LIR +

LSM

B/N + LSM

P/T + LSM

PBO +

LSM

STEP 1

STEP 3

STEP 5

STEP 8

COR-I

COR-II

COR-BMOD

SCALE

(Maintenance)

SCALE

(Obesity &

Pre-Diabetes)

STEP 8

SCALE IBT

EQUIP

EQUATE

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placebo, the interventions demonstrated 4.3-17.3 times the odds of 5% weight loss and 3.6-22.4

times the odds of 10% weight loss. Semaglutide demonstrated the greatest odds of achieving 5%

and 10% weight loss at one year and was superior to all other medications in our review for this

outcome. Phentermine/topiramate (high dose) demonstrated greater odds than liraglutide and

bupropion/naltrexone, however this difference was not statistically significant for the outcome of

5% weight loss. Liraglutide was not statistically more effective in demonstrating at least 5% or 10%

weight loss than bupropion/naltrexone (Tables D4 and D5).

Table D4. NMA Results of Medications for the Management of Obesity, Odds Ratio of Likelihood

of Achieving at Least 5% Weight Loss at One Year (95% CI)

Semaglutide

2.0 (0.5 to 10.0)

Phentermine/

Topiramate*

4.0 (2.4 to 8.0) 2.0 (0.6 to 7.1) Liraglutide

4.0 (1.01 to 20.6) 2.0 (0.9 to 4.4) 1.0 (0.3 to 3.4)

Bupropion/

Naltrexone

17.3 (8.9 to 38.3) 8.6 (3.3 to 22.0) 4.3 (2.5 to 6.7) 4.3 (1.7 to 10.2) Placebo

Legend: Each box represents estimated odds ratio of achieving 5% weight loss and 95% credible interval for the

combined direct and indirect comparisons between two medications or one medication and placebo. Estimates in

bold indicate the 95% credible interval does not contain 1.

*High dose.

Table D5. NMA Results of Medications for the Management of Obesity, Odds Ratio of Likelihood

of Achieving at Least 10% Weight Loss at One Year (95% CI)

Semaglutide

2.6 (0.95 to 6.2)

Phentermine/

Topiramate*

5.3 (3.5 to 9.6) 2.1 (1.04 to 5.6) Liraglutide

6.3 (2.4 to 15.9) 2.5 (1.2 to 5.3) 1.2 (0.5 to 2.4)

Bupropion/

Naltrexone

22.4 (13.6 to 36.2) 8.8 (4.7 to 18.1) 4.2 (2.6 to 5.7) 3.6 (2.0 to 6.8) Placebo

Legend: Each box represents estimated odds ratio of achieving 10% weight loss and 95% credible interval for the

combined direct and indirect comparisons between two medications or one medication and placebo. Estimates in

bold indicate the 95% credible interval does not contain 1.

*High dose.

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Participants with Obesity and Diabetes Mellitus

For the trials of the medications conducted in participants with obesity and diabetes mellitus that

included standard diet and exercise counseling and reported proportion of patients who achieved

at least 5% or 10% weight loss at one year, we present the results of the unadjusted random effects

model, given its better fit for the model compared to the baseline-adjusted model in Tables D6 and

D7. Data on categorical weight loss in patients with diabetes mellitus was not available for

phentermine/topiramate and was therefore not included in the NMA. All medications, in

combination with diet and exercise counseling, showed greater odds of achieving at least 5% or

10% weight loss at one year, however, this difference was only statistically significant for liraglutide

for the 5% weight loss outcome and semaglutide and liraglutide for the 10% weight loss outcome.

Compared to placebo, the interventions demonstrated 2.2-2.7 times the odds of 5% weight loss and

3.3-6.1 times the odds of 10% weight loss. Semaglutide demonstrated the greatest odds of

achieving 5% or 10% weight loss at one year, followed by liraglutide.

Table D6. NMA Results of Medications for the Management of Obesity and Diabetes Mellitus,

Odds Ratio of Likelihood of Achieving at Least 5% Weight Loss at One Year (95% CI)

Semaglutide

1.2 (0.4 to 2.9) Liraglutide

1.2 (0.4 to 4.8) 1.1 (0.4 to 4.2)

Bupropion/

Naltrexone

2.7 (0.9 to 4.1) 2.4 (1.0 to 3.6) 2.2 (0.6 to 3.9) Placebo

Legend: Each box represents estimated odds ratio of achieving 5% weight loss and 95% credible interval for the

combined direct and indirect comparisons between two medications or one medication and placebo. Estimates in

bold indicate the 95% credible interval does not contain 1.

Table D7. NMA Results of Medications for the Management of Obesity and Diabetes Mellitus,

Odds Ratio of Likelihood of Achieving at Least 10% Weight Loss at One Year (95% CI)

Semaglutide

1.6 (0.3 to 6.8) Liraglutide

1.8 (0.3 to 12.2) 1.1 (0.2 to 8.1)

Bupropion/

Naltrexone

6.1 (1.3 to 12.8) 3.7 (1.1 to 8.9) 3.3 (0.5 to 10.8) Placebo

Each box represents estimated odds ratio of achieving 10% weight loss and 95% credible interval for the combined

direct and indirect comparisons between two medications or one medication and placebo. Estimates in bold

indicate the 95% credible interval does not contain 1.

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D2. Additional Clinical Evidence

Evidence Base

Semaglutide versus Placebo

The Report discusses the primary sources of data to inform our review of semaglutide for the

management of obesity with and without diabetes mellitus: STEP 1, STEP 2, STEP 3, STEP 5, and

STEP 8 trials. STEP 4 and STEP 6 are two additional trials from the STEP clinical trial program that

were not included in the Report due to study design (STEP 4) and differences in population (STEP 6).

Both studies were multi-center Phase III studies and evaluated subcutaneous semaglutide 2.4 mg

plus lifestyle intervention versus placebo plus lifestyle intervention.

140-142

STEP 6 also evaluated

subcutaneous semaglutide 1.7 mg, but we only reviewed evidence for the subcutaneous

semaglutide 2.4 mg arm as that is the approved dose for obesity treatment.

STEP 4 reported data regarding weight regain, in addition to other outcomes of interest.

Participants included in this trial were adults with BMI ≥30 kg/m

or ≥27 kg/m

with at least one

weight-related comorbid condition.

140,141

Participants with diabetes mellitus (HbA1C ≥6.5%) were

excluded. The study design included a 20-week run-in period with all participants receiving a dose

escalation of subcutaneous semaglutide starting at 0.25 mg and increased every four weeks to the

maintenance dose of 2.4 mg at week 16. At week 20, subjects were randomized to either continue

semaglutide 2.4 mg or switch to placebo. Due to the withdrawal study design, baseline weight for

these participants was different compared to the STEP trials included in the main review. The

baseline weight and BMI for all participants prior to the run-in period was 107.2 kg and 38.4 kg/m

At randomization (week 20) baseline weight was 96.5 kg in the semaglutide arm versus 95.4 kg in

the placebo arm and baseline BMI was 34.5 kg/m

in the semaglutide arm versus 34.1 kg/m

in the

placebo arm (Table D8).

STEP 6 was conducted in Japan and South Korea, with 100% of their participants of Asian

ethnicity.

142

Baseline BMI, body weight, and waist circumference of participants in the STEP 6 trial

were lower than that of the other STEP trials. Additionally, due to differences in guidelines, the

inclusion criteria were slightly different with STEP 6 requiring eligible participants to be adults aged

≥18 in South Korea and ≥20 in Japan with a BMI of at least 27 kg/m

with two or more treated or

untreated weight-related comorbidities, or a BMI of at least 35 kg/m

with one or more treated or

untreated weight-related comorbidities, according to the Japan Society for the Study of Obesity

(JASSO) guidelines. STEP 6 did not exclude individuals with diabetes mellitus, and at baseline, 25%

of participants in each arm had diabetes mellitus. Outcomes were assessed at week 68 for both

STEP 4 and STEP 6. Baseline characteristics are outlined in Table D8.

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Liraglutide versus Placebo

The Report discusses the primary sources of data to inform our review of semaglutide for the

management of obesity with and without diabetes mellitus: the SCALE clinical trial program

(Maintenance, Obesity & Pre-Diabetes, Sleep Apnea, Type 2 DM, Insulin, and IBT) trials. LOSEIT was

a single-center Phase III trial based at the Parker Institute in Denmark, which evaluated

subcutaneous liraglutide 3.0 mg plus lifestyle intervention versus placebo plus lifestyle

intervention.

143

Participants included in this trial were adults aged 18 to 74 with BMI ≥27 kg/m

with symptomatic knee osteoarthritis and were excluded if they were currently using medications

for weight loss or gain, participating in an ongoing weight loss program, or on radiography for end-

stage knee osteoarthritis. Prior to randomization, participants engaged in a dietary intervention

period for eight weeks and were randomized to liraglutide or placebo if they had achieved at least

5% weight-loss during that eight-week period. Baseline characteristics for BMI, weight, and waist

circumference were lower for participants in LOSEIT than those included in the main review.

Primary outcomes for this trial were also slightly different from those included in the main review,

with absolute changes in body weight and Knee Injury and Osteoarthritis Outcome Score (KOOS) as

the co-primary outcomes. The study captured categorical weight loss (≥5% and ≥10%) as well as

change in BMI and waist circumference. Outcomes were assessed at week 52. Baseline

characteristics are outlined in Table D8.

Table D8. Overview of Additional Trials of Semaglutide and Liraglutide for the Management of

Obesity

140-143

STEP 4

STEP 6

LOSEIT

Study Arms

Run-in

PBO*

SEM*

PBO

SEM

PBO

LIR

803

268

535

101

199

Lifestyle Intervention

Monthly counseling, reduced-

calorie diet, and increased

physical activity

Monthly counseling,

reduced-calorie

diet, and increased

physical activity

Low-calorie run-in with

weekly counseling then

reduced-calorie diet, and bi-

weekly counseling for 8

weeks

Mean Age, Years

59.3

59.2

Female Gender, %

76.5

80.2

25.7

42.7

Baseline

Weight, kg

107.2 95.4 96.5 90.2 86.9 90.8 96.3

Baseline Weight Loss, %

-10.6†

N/A

Baseline

BMI, kg/m

38.4 34.1 34.5 31.9 32 31.3 32.8

Race, White, %

83.7

84.3

83.4

Pre-Diabetes, %

kg: kilogram, LIR: liraglutide, m: meter, N/A: not applicable, N: total number, NR: not reported, PBO: placebo, SEM:

semaglutide

*Baseline data measured at Week 20.

†Change from baseline data measured at Week 20.

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Phentermine/Topiramate versus Placebo

The Report discusses the primary source of data to inform our review of phentermine/topiramate

for the management of obesity: the EQUIP and EQUATE trials. OB-204 was a single-center, double-

blind, parallel-group, placebo-controlled, Phase I/II trial that randomized adults with overweight or

obesity and moderate-to-severe obstructive sleep apnea syndrome to receive phentermine 15

mg/topiramate 92 mg (n=22), or placebo (n=23) (Table D9).

144

All participants in each treatment

group also received standardized lifestyle modification counseling. Participants were eligible to

participate if they were between the ages of 30-65 years, had a BMI of 30-40 kg/m

, a diagnosis of

moderate-to-severe obstructive sleep apnea syndrome, an apnea-hypopnea index ≥15, and were

unable to comply with CPAP treatment. Participants were excluded if they had a sleep disorder

other than obstructive sleep apnea syndrome, unstable angina or heart failure, history of

myocardial infarction, coronary revascularization, cholecystitis or cholelithiasis, glaucoma, or

seizures, used any prescription central nervous system stimulant, experienced a weight change >5

kg, had previous surgery for obesity, had a psychiatric disorder, or were pregnant or breastfeeding.

Participants in the OB-204 trial had a mean age of 52 years, and 47% were female. The majority

(91%) of participants were White and 9% were Black. The average weight of participants in this trial

was 105 kg and mean BMI was 36 kg/m

at baseline. See Table D9 for detailed baseline

characteristics.

Bupropion/Naltrexone versus Placebo

The Report discusses the primary sources of data to inform our review of bupropion/naltrexone for

the management of obesity: COR-I, COR-II and COR-BMOD. CVOT Light was a multi-center, Phase

IIIb trial that randomized participants with overweight or obesity at an increased risk of adverse

cardiovascular outcomes to receive bupropion 360 mg/naltrexone 32 mg or placebo.

145,146

All

participants in each treatment arm were also encouraged to participate in an Internet-based weight

management program that included resources on healthy eating such as a low-calorie mean plan,

exercise, behavioral modifications, weekly lessons, and access to a personal coach. Participants

were eligible to participate if they were women over 50 years old, or men over 45 years old, had a

BMI of 27-50 kg/m

, a waist circumference of ≥88 cm for women or ≥102 cm for men, and

demonstrated an increased risk of adverse cardiovascular outcomes, such as confirmed or high

likelihood of cardiovascular disease, or had type 2 diabetes mellitus and at least two of the

following: hypertension, dyslipidemia requiring pharmacotherapy, low high-density lipoprotein

cholesterol, or were currently smoking tobacco. Participants were excluded if they had a

myocardial infarction within four months, severe angina pectoris, NYHA class III or IV heart failure,

history of stoke or SBP ≥145 mmHg or diastolic blood pressure ≥95 mmHg, weight change >3%

within three months, had surgery for obesity, or history of seizures, mania, psychosis, bulimia, or

anorexia nervosa. Participants in CVOT Light had a mean age of 61 years, and 55% were female.

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The majority (84%) of participants were White and 15% were Black. The average weight of

participants in this trial was 106 kg and mean BMI was 37 kg/m

at baseline (Table D9).

Ignite was a multi-center, open-label, Phase IIIb trial that randomized participants for the first 26

weeks to receive bupropion 360 mg/naltrexone 32 mg or usual care.

147

Participants in the

treatment arm were additionally required to participate in a comprehensive lifestyle intervention,

which consisted of a progressive nutrition and exercise program with personalized goal-setting and

tracking tools with a coach or dietitian, while participants in the usual care arm were instructed to

follow an exercise prescription and a hypocaloric diet. From 26 weeks through 78 weeks,

participants in the bupropion/naltrexone group continued on the medication, while participants in

usual care arm were switched to bupropion/naltrexone in addition to the comprehensive lifestyle

intervention. For the purposes of our review, we are evaluating efficacy data only up to 26 weeks

because of the lack of comparative data beyond that timepoint. Participants were eligible to

participate if they were between the ages of 18-60 years, had either a BMI of 30-45 kg/m

or a BMI

27-45 kg/m

with dyslipidemia and/or controlled hypertension. Participants were excluded if they

had type 1 or type 2 diabetes mellitus, myocardial infarction within six months, angina pectoris

grade III/IV, history of strokes, seizures, bulimia, anorexia nervosa, had surgery for obesity, or had a

psychiatric illness including mania, psychosis, or depression. Participants in this trial had a mean

age of 47 years and were predominantly female (84%). The majority (76%) of participants were

White and 23% were Black. The average weight of participants in this trial was 101 kg and mean

BMI was 36 kg/m

at baseline. See Table D9 for detailed baseline characteristics.

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Table D9. Overview of Additional Trials of Phentermine/Topiramate and Bupropion/Naltrexone

for the Management of Obesity

144-149

OB-204

CVOT Light

Ignite

Study Arms

PBO

P/T (high)

PBO

B/N

PBO

B/N

4,450

4,455

153

Lifestyle

Intervention

LSM counseling,

reduced-calorie diet,

and increased physical

activity

LSM counseling,

reduced-calorie diet,

and increased physical

activity

LSM counseling,

reduced-calorie

diet, and

increased physical

activity

CLI with progressive

nutrition and an

exercise program,

and personalized

goal-setting

Mean Age,

Years

51.4 53.4 60.9 61.1 47 46.1

Female

Gender, %

34.8 59.1 54.4 54.7 86.5 81.7

Baseline

Weight, kg

106.9 103.7 106.3 105.6 100.2 101.4

Baseline

BMI, kg/m

35.3 36 37.4 37.2 36.3 36.3

Race,

White, %

91.3 90.9 83.1 83.9 71.9 81

Pre-

Diabetes, %

NR NR NR NR NR NR

B/N: bupropion/naltrexone, CLI: comprehensive lifestyle intervention, kg: kilogram, LSM: lifestyle modification, m:

meter, N: total number, NR: not reported, PBO: placebo, P/T: phentermine/topiramate

Results

For each medication, secondary outcomes from trials in the Report are summarized first, followed

by primary outcomes for the additional trials summarized in the supplement. Weight loss

outcomes are summarized first, followed by other outcomes (e.g., waist circumference, blood

glucose, and LDL cholesterol), where relevant. HRQoL is summarized for all drugs at the end of this

section. For each medication, results of trials conducted in patients with obesity are presented first,

followed by trials conducted in patients with obesity and diabetes mellitus.

Semaglutide versus Placebo

The efficacy of semaglutide compared with placebo for the management of obesity in patients

without diabetes mellitus was evaluated in three Phase III trials (STEP 1, 3, and 5). We were able to

obtain percent weight loss at six months through digitizing published graphical data. Participants in

the subcutaneous semaglutide 2.4 mg arm achieved greater percent weight loss at six months

(-11.7%, -15.4%, and -13.2% respectively) compared to placebo (-2.9%, -7.9%, and -2.6%,

respectively).

29,31,34-38,143

Similarly, at one year, the proportion of participants who achieved at least

15% weight loss and at least 20% weight loss, a greater proportion of participants in the

semaglutide arm achieved these categorical outcomes compared to participants in the placebo.

Treatment with semaglutide in STEP 1, 3, and 5 trials also resulted in additional clinical benefits in

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waist circumference, blood glucose, and LDL cholesterol compared to placebo. Outcomes related

to changes in LDL were reported as absolute change from baseline for STEP 3 and as ratio of LDL

from baseline for STEP 1 and 5. See Table D10 for detailed results.

Additionally, in an extension trial of STEP 1, participants went off semaglutide treatment at week 68

and were evaluated through the end of the trial at week 120. At that timepoint, participants who

were initially taking semaglutide, but went off-treatment, regained 14.8% of their weight from

week 68, and participants who were initially on placebo regained 2.1% of their weight.

In the

initial semaglutide arm, nearly two-thirds of the weight participants lost from baseline was regained

in about a year. Similarly, metabolic parameters, such as blood pressure and HbA1C, returned to

baseline values at the end of the trial. See Tables D26-D29 for detailed results.

The efficacy of semaglutide for the management of obesity and type 2 diabetes mellitus was

evaluated through one Phase III trial (STEP 2). We were able to obtain percent weight loss at six

months through digitizing published graphical data. Participants in the subcutaneous semaglutide

2.4 mg arm achieved greater percent weight loss at six months (-8.7%) compared to placebo

(-2.7%) (Table D12).

Similarly, at one year, the proportion of participants who achieved at least

15% weight loss and at least 20% weight loss, a greater proportion of participants in the

semaglutide arm ([15% WL: 25.8%]; [20% WL: 13.1%]) achieved these categorical outcomes

compared to participants in the placebo arm ([15% WL: 3.2%]; [20% WL: 1.6%]). Treatment with

subcutaneous semaglutide 2.4 mg was also associated with greater improvements in waist

circumference (-9.4 cm) compared to placebo (-4.5 cm). There were no clinical differences between

the subcutaneous semaglutide 2.4 mg arm and placebo arm in blood glucose and LDL cholesterol.

STEP 4, which had a crossover design including a 20-week run-in semaglutide dose escalation prior

to randomization to either continue subcutaneous semaglutide 2.4 mg or switch to placebo,

assessed the efficacy of semaglutide compared with placebo for the management of obesity.

140,141

Prior to randomization, all participants achieved a mean weight loss of -10.6% in the 20-week run-in

period. After randomization, at one year, participants in the subcutaneous semaglutide 2.4 mg arm

achieved additional weight loss (-7.9%) compared to participants in the placebo arm who

experienced weight regain (6.9%). More participants who switched to placebo experienced weight

regain (81.2%) compared to those who continued on semaglutide (12.3%). Overall percent weight

loss at one year from week 0 (including semaglutide run-in) was -17.8% in the semaglutide arm

compared to -5.4% in the placebo arm. For the co-primary outcomes of proportion of participants

who achieved at least 5%, 10%, 15%, or 20% weight loss at one year, a greater proportion of

participants in the semaglutide arm (88.7%, 79%, 63.7%, and 39.6%, respectively) achieved each

categorical outcome compared to participants in the placebo arm (47.6%, 20.4%, 9.2%, and 4.8%,

respectively). These categorical outcome data are digitized from published graphical data. See

Table D13 for detailed results.

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STEP 6 evaluated the efficacy of semaglutide compared with placebo for the management of

obesity in patients with or without diabetes mellitus. Participants in the subcutaneous semaglutide

2.4 mg arm achieved greater percent weight loss at one year (-13.2%) compared to placebo

(-2.1%) (Table D13).

142

Similarly, for the co-primary outcomes of proportion of participants who

achieved at least 5%, 10%, 15%, or 20% weight loss at one year, a greater proportion of participants

in the semaglutide arm (83%, 61%, 41%, and 20%, respectively) achieved each categorical outcome

compared to participants in the placebo arm (21%, 5%, 3%, and 2%, respectively).

Semaglutide versus Liraglutide

The efficacy of subcutaneous semaglutide versus subcutaneous liraglutide with a placebo

comparator for the management of obesity was evaluated in one Phase III trial (STEP 8).

We were

able to obtain percent weight loss at six months for the semaglutide and liraglutide arms by

digitizing published graphical data. Data on weight loss at six months were not available for the

placebo arm. Participants in the semaglutide arm achieved greater percent weight loss at six

months (-13.3%) compared to participants in the liraglutide arm (-6.8%). Treatment with

semaglutide also resulted in additional clinical benefits in waist circumference, blood glucose, and

LDL cholesterol compared to both liraglutide and placebo. Treatment with liraglutide resulted in

additional clinical benefits in waist circumference and blood glucose compared to placebo;

however, participants in the liraglutide arm experienced an increase in LDL cholesterol from

baseline (0.9 mg/dL) compared to semaglutide (-6.5 mg/dL) and placebo (-1.1 mg/dL), which both

had reduced LDL cholesterol from baseline. See Table D10 for detailed results.

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Table D10. Secondary Outcomes of Key Trials of Semaglutide for the Management of

Obesity

29,31,33-38

STEP 1

STEP 3

STEP 5

STEP 8

Study Arms

PBO

SEM

PBO

SEM

PBO

SEM

PBO

SEM

LIR

577

1,212

189

373

129

149

117

% Weight Loss from

Baseline to 6 Months,

Mean (SE)

-2.9*

(0.2)

-11.7*

(0.2)

-7.9

(0.5)†

-15.4*

(0.3)†

-2.6

(NR)

-13.2

(NR)

-13.3*

(NR)

-6.8*

(NR)

Participants with 15%

Weight loss, n (%)

(4.9)

612

(50.5)

(13.2)

208

(55.8)

7 (5.4)

(52.3)

5 (6.4)

(55.6)

(12)

Participants with 20%

Weight loss, n (%)

(1.7)

388

(32)

(3.7)

133

(35.7)

3 (2.3)

(34.9)

2 (2.6)

(38.5)

7 (6)

Change in Waist

Circumference, cm,

Mean (SE)

-4.1

(NR)

-13.5

(NR)

-6.3

(NR)

-14.6

(NR)

-4.5

(0.6)†

-14.3

(0.8)†

-2

(1.1)†

-13.2

(0.9)†

-6.6

(0.9)†

Change in Fasting

Blood Glucose, mg/dL,

Mean (SE)

-0.5

(NR)

-8.4

(NR)

-0.7

(NR)

-6.7

(NR)

1.6§

(NR)

-7.6§

(NR)

3.3

(1.4)†

-8.3

(1.1)†

-4.3

(1.2)†

Change in LDL

Cholesterol, mg/dL,

Mean (SD)

1.1*‡

(NR)

-3.3*‡

(NR)

2.6*

(NR)

-4.7

(NR)

-1.1‡

(NR)

-7.8‡

(NR)

-1.1*

(5.6)†

-6.5*

(3.1)†

0.9*

(2.8)†

cm: centimeter, dL: deciliter, LDL: low-density lipoprotein, LIR: liraglutide, mg: milligram, n: number, N: total

number, NR: not reported, PBO: placebo, SBP: systolic blood pressure, SD: standard deviation, SE: standard error,

SEM: semaglutide

*The number of patients for this outcome may differ from the primary analysis population.

†SE manually derived from standard deviation or 95% CIs.

‡Change in LDL cholesterol was calculated using ratio of LDL and respective baseline LDL.

§Timepoint for this outcome is at Week 104.

Liraglutide versus Placebo

The efficacy of liraglutide compared with placebo for the management of obesity was evaluated in

four Phase III trials in the SCALE clinical trial program (Maintenance, Sleep Apnea, Obesity & Pre-

Diabetes, IBT). We were able to obtain percent weight loss at six months by digitizing published

graphical data. Participants in the liraglutide arms achieved greater percent weight loss at six

months (-7.7%, -5.7%, -8.2%, and -8.4%) compared to participants in the placebo arm (-1%, -1.6%, -

2.9%, and -5.4%).

40,41,43,44,48-51

Data for the co-primary outcome of proportion of participants who

achieved at least 15% weight loss at one year were only available for SCALE (IBT), in which a greater

proportion of participants in the liraglutide arm (18.1%) achieved the outcome compared to the

placebo arm (8.9%). Treatment with liraglutide resulted in additional benefits in waist

circumference and blood glucose compared to placebo. Treatment with liraglutide resulted in

additional benefits in LDL cholesterol in the Obesity & Pre-Diabetes (-3 mg/dL) and IBT (-1.5 mg/dL)

trials compared to placebo (-1 mg/dL and 1.5 mg/dL, respectively). In the Maintenance trial,

participants in both the liraglutide and placebo arms experienced an increase in LDL cholesterol

from baseline (7.7 mg/dL and 11.6 mg/dL, respectively), although there was a greater increase in

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Evidence Report – Medications for Obesity Management Return to Table of Contents

the placebo arm. Data on LDL cholesterol were not available for the Sleep Apnea trial. See Table

D11 for detailed results.

The efficacy of subcutaneous liraglutide 3.0 mg compared with placebo for the management of

obesity with diabetes mellitus was evaluated in two Phase III trials in the SCALE clinical trial program

(Type 2 Diabetes, Insulin).

42,45,52

We were able to obtain percent weight loss at six months through

digitizing published graphical data. Participants in the liraglutide arms achieved greater percent

weight loss at six months (-6% and -6.4%, respectively) compared to participants in the placebo arm

(-2.7% and -2.1%, respectively) (Table D12). Categorical data for proportion of participants who

achieved at least 15% weight loss at one year were not available for either study. Treatment with

liraglutide resulted in additional benefits in waist circumference and blood glucose compared to

placebo. In the Type 2 Diabetes trial, participants in both the liraglutide and placebo arms

experienced an increase in LDL cholesterol from baseline (0.6 mg/dL and 5 mg/dL, respectively).

Participants receiving liraglutide in the Insulin trial improved in LDL cholesterol from baseline (-2.8

mg/dL) compared to participants in the placebo arm, who experienced an increase in LDL

cholesterol (0.9 mg/dL).

LOSEIT evaluated the efficacy of liraglutide compared with placebo for the management of obesity

in patients with or without diabetes mellitus. Data for percent weight loss at one year were not

available. For the co-primary outcomes of proportion of participants who achieved at least 5%

weight loss and at least 10% weight loss at one year, a great proportion of participants in the

liraglutide arm achieved each categorical outcome (35% and 21.3%, respectively) compared to

participants in the placebo arm (17.1% and 9.6%, respectively).

143

See Table D13 for detailed

results.

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Table D11. Secondary Outcomes of Key Trials of Liraglutide for the Management of

Obesity

40,41,43,44,48-51

SCALE

Maintenance

SCALE

Sleep Apnea‡

SCALE Obesity &

Pre-Diabetes

SCALE IBT

Study Arms

PBO

LIR

PBO

LIR

PBO

LIR

PBO

LIR

206

207

178

175

1,225

2,437

130

141

% Weight Loss from

Baseline to 6

Months, Mean (SE)

-1* (0.5)

-7.7*

(0.5)

-1.6

(0.3)

-5.7

(0.4)

-2.9

(0.3)

-8.2

(0.2)

-5.4*

(0.5)

-8.4*

(0.6)

Participants with

15% Weight loss, n

(%)

NR NR NR NR NR NR 12 (8.9)

(18.1)

Change in Waist

Circumference, cm,

Mean (SE)

-1.2

(0.4)†

-4.7

(0.5)†

-3.1

(0.5)

-6.4

(0.5)

-3.9

(0.2)†

-8.2

(0.1)†

-6.7

(NR)

-9.4

(NR)

Change in Fasting

Blood Glucose,

mg/dL, Mean (SE)

-3.6

(0.9)†

-9.0

(0.8)†

3.6 (1.8)

-3.6

(1.8)

0.1

(0.3)†

-7.1

(0.2)†

0.2 (NR)

-4.1

(NR)

Change in LDL

Cholesterol, mg/dL,

Mean (SD)

11.6

(1.6)†

7.7

(1.6)†

NR NR -1 (NR) -3 (NR) 1.5 (NR)

-1.5

(NR)

cm: centimeter, dL: deciliter, LDL: low-density lipoprotein, LIR: liraglutide, mg: milligram, n: number, N: total

number, NR: not reported, PBO: placebo, SBP: systolic blood pressure, SD: standard deviation, SE: standard error

*The number of patients for this outcome may differ from the primary analysis population.

†SE manually derived from standard deviation or 95% CIs.

‡Timepoint for all outcomes except percent weight loss is at week 32.

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Table D12. Secondary Outcomes of Key Trials of Semaglutide and Liraglutide for the Management

of Obesity with Diabetes Mellitus

30,42,45,52

STEP 2

SCALE

Type 2 Diabetes

SCALE

Insulin

Study Arms

PBO

SEM

PBO

LIR

PBO

LIR

376

388

211

412

193

191

% Weight Loss from

Baseline to 6 Months,

Mean (SE)

-2.7* (0.2) -8.7* (0.3) -2.7* (0.3)‡ -6* (0.3)‡

-2.1*

(0.4)

-6.4* (0.4)

Participants with 15%

Weight loss, n (%)

12 (3.2) 100 (25.8) NR NR NR NR

Participants with 20%

Weight loss, n (%)

6 (1.6) 51 (13.1) NR NR NR NR

Change in Waist

Circumference, cm,

Mean (SE)

-4.5 (0.4) -9.4 (0.4) -2.7 (0.4)‡ -6.1 (0.3)‡ -2.6 (NR) -5.3 (NR)

Change in Fasting Blood

Glucose, mg/dL, Mean

(SE)

-0.1 (1.8) -2.1 (1.8) -0.2 (2.5)‡ -34.3 (1.9)‡

-11.5

(NR)

-18.4 (NR)

Change in LDL

Cholesterol, mg/dL,

Mean (SD)

0* (NR)† 0* (NR)† 5 (NR) 0.6* (NR)

0.9*

(NR)†

-2.8*

(NR)†

cm: centimeter, dL: deciliter, LDL: low-density lipoprotein, mg: milligram, n: number, N: total number, NR: not

reported, PBO: placebo, SBP: systolic blood pressure, SD: standard deviation, SE: standard error, SEM: semaglutide

*The number of patients for this outcome may differ from the primary analysis population.

†Change in LDL cholesterol was calculated using ratio of LDL and respective baseline LDL.

‡SE manually derived from standard deviation or 95% CIs.

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Table D13. Results of Additional Trials of Semaglutide and Liraglutide for the Management of

Obesity

140-143

STEP 4

STEP 6

LOSEIT

Study Arms

PBO

SEM

PBO

SEM

PBO

LIR

250

520

100

193

% Weight Loss from

Baseline to One Year, Mean

(SE)

6.9*‡

(0.5)†

-7.9*‡ (4)† -2.1 (0.8) -13.2 (0.5) NR NR

Participants with at Least

5% Weight Loss, n (%)

119§

(47.6)

461§ (88.7) 21 (21) 160 (83) 13 (17.1) 28 (35)

Participants with at Least

10% Weight Loss, n (%)

51§

(20.4)

411§ (79) 5 (5) 117 (61) 7 (9.6) 17 (21.3)

Participants with at Least

15% Weight Loss, n (%)

23§ (9.2) 331§ (63.7) 3 (3) 79 (41) NR NR

Participants with at Least

20% Weight Loss, n (%)

12§ (4.8) 206§ (39.6) 2 (2) 38 (20) NR NR

LIR: liraglutide, n: number, N: total number, NR: not reported, PBO: placebo, SEM: semaglutide

*The number of patients for this outcome may differ from the primary analysis population.

†SE manually derived from standard deviation or 95% CIs.

‡Timepoint for this outcome is Weeks 20-68.

§Timepoint for this outcome is Weeks 0-68.

Phentermine/Topiramate versus Placebo

The Report discusses the primary outcome of percentage weight loss at one year and proportion of

participants achieving 5% and 10% weight loss in the EQUIP trial. In the EQUIP trial, data on weight

loss at six months were not available. For the categorical outcome of at least 15% weight loss at

one year, more participants in the phentermine 15 mg/topiramate 92 mg arm achieved this

outcome (32%) compared to those in placebo (3%)

54-57

(Table D14). In EQUATE, at six months,

participants in the high-dose phentermine/topiramate arm experienced the greatest percent

weight loss from baseline (-9.2%), followed by the low-dose intervention arm (-8.5%), and placebo

(-1.7%). Categorical weight loss of at least 15% at one year was not assessed in the EQUATE trial.

Treatment with phentermine/topiramate in both EQUIP and EQUATE was associated with

additional clinical benefits in terms of reductions in waist circumference, blood glucose, and LDL

cholesterol at one year. In the EQUIP trial, mean reduction in waist circumference was greater in

the treatment arm than placebo (-10.9 cm vs. -3.1cm, respectively).

54-57

Mean reduction in waist

circumference in the high-dose and low-dose intervention arms in EQUATE was also greater than

placebo (-8.7 cm and -8.8 cm, versus -3.1cm, respectively). In the EQUIP trial, participants receiving

phentermine/topiramate experienced a small improvement in their blood glucose levels (-0.6

mg/dL), while participants receiving placebo experienced a slight elevation in blood glucose on

average (1.9 mg/dL). Participants in both arms improved LDL cholesterol levels, but the effect was

greater in the phentermine/topiramate arm (-8.4 vs. -5.5 mg/dL, respectively). In the EQUATE trial,

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mean change from baseline in blood glucose levels in both arms was negligible (-1 to 0 mg/dL

change). See Table D14 for detailed results.

In the diabetes mellitus subgroup of the CONQUER trial, data on secondary outcomes such as

weight loss at six months, categorical weight loss of at least 15%, and change in waist circumference

were not available. All reported outcomes here are from the one-year timepoint. Participants in

the diabetes subgroup receiving high-dose and low-dose phentermine/topiramate experienced a

greater improvement in their blood glucose levels than participants in the placebo group (-12.6 and

-9 vs. -5.4 mg/dL, respectively).

53,58

Similar trends were observed for LDL cholesterol; high and low-

dose phentermine/topiramate was associated with greater improvements in LDL compared to

placebo (-2.8 and -3.6 vs. -2.3 mg/dL, respectively). See Table D15 for detailed results.

In the Phase I/II OB-204 trial, efficacy outcomes were assessed at 28 weeks. At that timepoint,

participants in the phentermine/topiramate arm achieved a greater percent weight loss (-10.3%)

compared to participants in the placebo arm (-4.2%).

144

Similarly, more participants receiving the

intervention achieved target weight loss of at least 5% and 10% body weight than participants

receiving placebo. See Table D16 for detailed results.

Bupropion/Naltrexone versus Placebo

Weight loss data at six months were not available in the COR-I trial. In COR-II and COR-BMOD,

participants in the bupropion/naltrexone arms experienced greater weight loss than participants in

the placebo arms at six months (-6.5% and -9.4% vs. -1.9% and -5.6%, respectively) (Table D14).

Similarly, for all three trials, more participants in the treatment arms achieved at least 15%

bodyweight at one year compared to the placebo arms.

63-66

At the one-year timepoint, participants receiving bupropion/naltrexone in the COR-I, COR-II, and

COR-BMOD trials experienced greater improvement in waist circumference (-6.2, -6.7, and -10 cm,

respectively) than participants receiving placebo (-2.5, -2.1, and -6.8, respectively).

61-66

Similarly,

participants receiving bupropion/naltrexone achieved greater improvements in blood glucose levels

(-3.2, -2.8, and -2.4 mg/dL) versus placebo (-1.3, -1.3, and -1.1, respectively). In COR-I and COR-II,

participants in the intervention arms experienced a greater improvement from baseline in their LDL

cholesterol (-4.4 and -6.2 mg/dL, respectively), compared to placebo (-3.3 and -2.1 mg/dL,

respectively). However, in the COR-BMOD trial, both arms experienced an increase in their LDL

cholesterol, with participants in the placebo arm experiencing a greater increase (8.1 mg/dL) than

participants in the bupropion/naltrexone arm (5.4 mg/dL). See Table D14 for detailed results.

In the COR Diabetes trial of bupropion/naltrexone for the management of obesity with diabetes

mellitus, participants in the intervention arm experienced a greater percent change in their weight

at six months (-5.1%) compared to those in the placebo arm (-2%).

59,60

Categorical weight loss of at

least 15% at one year was not available in this trial. At the one-year timepoint, participants in the

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treatment arm experienced greater improvements in waist circumference compared to placebo (-5

cm vs. -2.9 cm, respectively), change in blood glucose (-11.9 mg/dL vs. -4 mg/dL, respectively) and

change in LDL cholesterol (-1.4 mg/dL vs. 0 mg/dL, respectively). See Table D15 for detailed results.

In CVOT Light, participants in the bupropion 360 mg/naltrexone 32 mg arm achieved greater weight

loss at one year (-4.6%) than participants in the placebo arm (-1.8%) (Table D16).

145,146

The

categorical weight loss outcomes of at least 5% and 10% were not assessed in this trial.

In the Ignite trial, since all participants were either switched or continued on open-label

bupropion/naltrexone treatment at 26 weeks, we evaluated efficacy outcomes only up to that

timepoint.

147,149

Similar to CVOT Light, participants in the intervention arm achieved a greater

weight improvement at week 26 (-9.5%) compared to participants in the usual care arm (-0.9%).

For the endpoint of proportion of participants who lost at least 5% of and 10% of their weight, more

participants in the bupropion/naltrexone treatment arm achieved these outcomes compared to

participants in the usual care group. See Table D16 for detailed results.

Table D14. Secondary Outcomes of Key Trials of Phentermine/Topiramate and

Bupropion/Naltrexone for the Management of Obesity

54-57,61-66,85

EQUIP

EQUATE

COR-I

COR-II

COR BMOD

Study Arms PBO

P/T

(high)

PBO

P/T

(low)

P/T

(high)

PBO B/N PBO B/N PBO B/N

498

103

511

471

456

702

193

482

% Weight Loss

from Baseline to

6 Months, Mean

(SE)

NR NR

-1.7

(0.6)

-8.5

(0.6)

-9.2

(0.6)

NR NR

-1.9*

(0.3)

-6.5*

(0.2)

-5.6*

(0.5)

-9.4*

(0.4)

Participants with

15% Weight loss,

n (%)

(3.4)

161

(32.3)

NR NR NR 10 (2)

(12)

(2.4)

(13.5)

(10.9)

140

(29.1)

Change in Waist

Circumference,

cm, Mean (SE)

-3.1

(0.5)†

-10.9

(0.5)†

-3.3

(0.7)

-8.8*

(0.7)

-8.7

(0.7)

-2.5

(0.4)

-6.2

(0.4)

-2.1

(0.5)

-6.7

(0.3)

-6.8

(0.8)

-10

(0.5)

Change in

Fasting Blood

Glucose, mg/dL,

Mean (SE)

1.9

(0.5)†

-0.6

(0.5)†

-0.1*

(0.1)

-0.1*

(0.1)

-1.3

(0.6)

-3.2

(0.6)

-1.3

(0.6)

-2.8

(0.5)

-1.1

(1)

-2.4

(0.6)

Change in LDL

Cholesterol,

mg/dL, Mean

(SD)

-5.5*

(0.9)†

-8.4*

(0.9)†

NR NR NR

-3.3*

(1.2)

-4.4*

(1.2)

-2.1*

(1.3)

-6.2*

(0.9)

8.1*

(2.1)

5.4*

(1.4)

B/N: bupropion/naltrexone, cm: centimeter, dL: deciliter, LDL: low-density lipoprotein, LIR: liraglutide, mg:

milligram, n: number, N: total number, NR: not reported, PBO: placebo, P/T: phentermine/topiramate, SBP:

systolic blood pressure, SD: standard deviation, SE: standard error

*The number of patients for this outcome may differ from the primary analysis population.

†SE manually derived from standard deviation or 95% CIs.

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Table D15. Secondary Outcomes of Key Trials of Phentermine/Topiramate and

Bupropion/Naltrexone for the Management of Obesity and Obesity with Diabetes

53,58-60

CONQUER (Diabetes Subgroup)

COR Diabetes

Study Arms

PBO

P/T (low)

P/T (high)

PBO

B/N

157

164

159

265

% Weight Loss from

Baseline to 6 Months, Mean

(SE)

NR NR NR -2* (0.4) -5.1* (0.3)

Participants with 15%

Weight loss, n (%)

NR NR NR NR NR

Change in Waist

Circumference, cm, Mean

(SE)

NR NR NR -2.9 (0.6) -5 (0.5)

Change in Fasting Blood

Glucose, mg/dL, Mean (SE)

-5.4 (1.8)† -9 (3.6)† -12.6 (1.8)† -4 (3.4) -11.9 (2.7)

Change in LDL Cholesterol,

mg/dL, Mean (SD)

-2.3* (2.1) -3.6* (3.2) -2.8* (2) 0* (2.4) -1.4* (1.9)

B/N: bupropion/naltrexone, cm: centimeter, dL: deciliter, LDL: low-density lipoprotein, LIR: liraglutide, mg:

milligram, n: number, N: total number, NR: not reported, PBO: placebo, P/T: phentermine/topiramate, SBP:

systolic blood pressure, SD: standard deviation, SE: standard error

*The number of patients for this outcome may differ from the primary analysis population.

†SE manually derived from standard deviation or 95% CIs.

Table D16. Results of Additional Trials of Phentermine/Topiramate and Bupropion/Naltrexone for

the Management of Obesity

144-149

OB-204†

CVOT Light

Ignite‡

Study Arms PBO

P/T

(high)

PBO B/N PBO B/N

4450

4455

% Weight Loss

from Baseline to

One Year, Mean

(SE)

-4.2 (1.2)

-10.3

(1.2)

-1.8* (NR) -4.6* (NR) -0.9 (0.5) -9.5 (0.5)

Participants with

5% Weight Loss, n

(%)

11 (47.8) 16 (72.7) NR NR 10 (12.2) 60 (84.5)

Participants with

10% Weight Loss,

n (%)

3 (13) 12 (54.5) NR NR 3 (3.7) 30 (42.3)

B/N: bupropion/naltrexone, n: number, N: total number, NR: not reported, PBO: placebo, P/T:

phentermine/topiramate, SE: standard error

*The number of patients for this outcome may differ from the primary analysis population.

†Timepoint for all outcomes is at week 28.

‡Timepoint of interest for all outcomes for this trial is at week 26.

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HRQoL

As discussed in the Report, HRQoL was assessed using a variety of instruments, including SF-36v2,

IWQOL-Lite, PHQ-9, and IDS-SR. SF-36v2 consists of 36 questions across eight domains, including

physical functioning. Additionally, SF-36v2 provides two aggregated scores: the physical

component summary (PCS) and mental component summary (MCS). For the SF-36v2 and IWQOL-

Lite-CT instruments, an increase in score is representative of an improvement in health status

(positive is better). The PHQ-9 and IDS-SR and reflect depressive symptom severity; a decrease in

score in these measures indicates an improvement in depressive symptoms (lower is better).

For each medication, HRQoL data for additional studies included in the Supplement are described in

the text below. Additional HRQoL data beyond physical functioning and mental scores for studies

from the Report are also discussed in the text below. The Report outlines physical function and

mental HRQoL data for studies included in our primary analysis. Data from the Report for physical

function and mental HRQoL are outlined in Tables D17 and D18 below.

Semaglutide

HRQoL in STEP 4 was assessed using the SF-36v2 physical function score. During the 20-week run-in

period, participants experienced an average score improvement of 2.2 from baseline score. After

randomization, from weeks 20 to 68, participants who continued semaglutide experienced a further

improvement in physical functioning score (1.0) compared to a decreased score for those who

switched to placebo (-1.5). Additionally, improvements were seen in the semaglutide arm for the

SF-36v2 Physical Component Summary (0.8) and Mental Component Summary (0.1) compared to

decreased scores for both in the placebo arm (-0.9 and -3.4, respectively).

140

(Table D30).

Patient reported outcomes for STEP 6 included SF-36v2 physical functioning scores and the IWQOL-

Lite-CT physical function score. Participants in the semaglutide arm experienced improvement from

baseline in SF-36v2 physical functioning score (0.8) compared to placebo which resulted in a

decrease in score (-0.3) (higher is better). Improvement in the IWQOL-Lite-CT physical function

score was higher in the semaglutide arm (4.2) compared to placebo (0.8) (higher is better).

142

See

Table D30 for detailed results.

Liraglutide

The SCALE (Sleep Apnea) trial discussed in the Report also assessed patient-reported outcomes

related to sleep health using two instruments: Epworth Sleepiness Scale (ESS) and Functional

Outcomes of Sleep Questionnaire (FOSQ). For the FOSQ instrument, a higher score indicates less

functional impairment. The ESS assesses daytime sleepiness, with a lower score indicating a lower

propensity for daytime sleepiness. The change from baseline for both the ESS and FOSQ

instruments did not differ significantly between the semaglutide (-2.5 and 1.3, respectively) and

placebo arms (-2.3 and 1.1, respectively) (Table D31).

41,50

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The LOSEIT trial assessed patient-reported outcomes related to knee pain using the KOOS

instrument, with higher scores (scale 0-100) indicating improved disease status (positive is better).

At week 52, participants in the liraglutide arm reported improvement on the KOOS pain instrument

(0.4) compared to placebo arm, which reported a decreased score (-0.6) from baseline.

Additionally, participants in the liraglutide arm reported greater improvement in function in

activities of daily living (1.4) and knee-related quality of life (3.1) compared to those in the placebo

arm (-1.6 and 0.7, respectively). Conversely, change in symptoms had a decreased score in the

liraglutide arm (-1.2) compared to placebo (0.3). Overall, there were no significant differences in

change from baseline score for the KOOS instrument and its subsections observed between the

liraglutide and placebo arms.

143

Phentermine/Topiramate

HRQoL was assessed using the SF-36 instrument, the ESS, and the Pittsburgh Sleep Quality Index in

OB-204. Participants in the phentermine/topiramate group demonstrated greater improvement in

the SF-36 physical functioning subscale compared to placebo.

144,148

Additionally, participants

receiving phentermine/topiramate had a greater improvement compared to participants receiving

placebo in their sleep quality, measured by the ESS (-1.9% vs. -1.8%, respectively), and the PSQI (-

3.1% vs. -0.9%, respectively) (Tables D30 and D31).

Bupropion/Naltrexone

In the Ignite trial, HRQoL was assessed with the IWQOL-Lite total score. Participants receiving the

intervention had a significant improvement in their quality of life (16.4), while participants receiving

usual care slightly decreased in their reported quality of life (-1) (Table D30).

147,149

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Table D17. Physical Component HRQoL Outcomes of Key Trials

29-31,34,35,41-45,48,50-52,63-66

Study Name Arms

SF-36v2 Physical

Functioning Score,

Mean Change from

Baseline (SE)

SF-36v2 Physical

Component Score,

Mean Change from

Baseline (SE)

IWQOL-Lite-CT Physical

Function Score, Mean

Change from Baseline

(SE)

Semaglutide

STEP 1

PBO

0.4 (NR)

0.2† (0.3)*

5.3 (NR)

SEM

2.2 (NR)

2.4† (0.2)*

14.7 (NR)

STEP 2

PBO

1† (0.4)

5.3 (1.1)

SEM

2.5† (0.4)

10.1 (1)

STEP 3

PBO

1.6 (NR)

2.3 (NR)

SEM

2.4 (NR)

3 (NR)

Liraglutide

SCALE (Sleep

Apnea)

PBO

1.9 (0.5)

LIR

3 (0.6)

SCALE (Obesity &

Pre-Diabetes)

PBO

2.1 (0.2)*

LIR

3.6 (0.1)*

SCALE (IBT)

PBO

3.8 (NR)

3.8 (0.6)*

14.1 (NR)

LIR

4 (NR)

3.4 (0.6)*

14.9 (NR)

SCALE (Type 2

Diabetes)

PBO

8.9 (1.1)*

LIR

15.2 (0.9)*

SCALE (Insulin)

PBO

2.6 (0.5)*

2.2 (0.5)*

5.7 (NR)

LIR

2.5 (0.6)*

2.7 (0.5)*

8.2 (NR)

Bupropion/Naltrexone

COR-II

PBO

8.2 (0.8)

B/N

14.1 (0.6)

COR-BMOD

PBO

12 (0.8)

B/N

16.5 (0.5)

B/N: bupropion/naltrexone, IWQOL-Lite-CT: Quality of Life-Lite Clinical Trials Version, LIR: liraglutide, NR: not

reported, PBO: placebo, SE: standard error, SEM: semaglutide, SF-36v2: Short Form 36v2 Health Survey

Note: Greyed-out boxes indicate that the HRQoL instrument was not used for any trials within that intervention

group.

*SE manually derived from standard deviation or 95% CIs.

†The number of patients for this outcome may differ from the primary analysis population.

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Table D18. Mental Component HRQoL Outcomes of Key Trials

31,35,41,43,48,50,53-66

Study Name Arms

SF-36v2 MCS, Mean Change from

Baseline (SE)

Depression Score, Mean

Change from Baseline (SE)*

Semaglutide

STEP 1

PBO

-2.1‡ (0.3)†

SEM

-1.5‡ (0.2)†

STEP 3

PBO

-2.9 (NR)

SEM

-0.8 (NR)

Liraglutide

SCALE (Sleep Apnea)

PBO

0.9 (0.6)

LIR

1.4 (0.6)

SCALE (Obesity & Pre-

Diabetes)

PBO

-0.9 (0.3)†

LIR

0.2 (0.2)†

SCALE (IBT)

PBO

-2.2 (0.7)†

LIR

-1.2 (0.7)†

SCALE (Insulin)

PBO

-1.7 (0.5)†

LIR

-1.9 (0.6)†

Phentermine/Topiramate

EQUIP

PBO

-1.3 (0.2)†

P/T (low)

-1.2 (0.2)†

P/T (high)

-1.5 (0.1)†

EQUATE

PBO

-0.5 (0.4)†

P/T (low)

-1.3 (0.2)†

P/T (high)

-1.1 (0.4)†

CONQUER

PBO

P/T (low)

P/T (high)

Bupropion/Naltrexone

COR-I

PBO

-0.7 (0.2)

B/N

-0.3‡ (0.2)

COR-II

PBO

-0.5 (0.3)

B/N

-0.3 (0.2)

COR-BMOD

PBO

0‡ (0.4)

B/N

0.1‡ (0.2)

COR-Diabetes

PBO

-1.6 (0.4)

B/N

0 (0.3)

B/N: bupropion/naltrexone, IDS-SR: Inventory of Depressive Symptomology (Self-Report), LIR: liraglutide, MCS:

mental component summary, mg: milligram, NR: not reported, PBO: placebo, PHQ-9: Patient Health

Questionnaire, P/T: phentermine/topiramate, SE: standard error, SEM: semaglutide, SF-36v2: Short Form 36v2

Health Survey

Note: Greyed-out boxes indicate that the HRQoL instrument was not used for any trials within that intervention

group.

*Phentermine/topiramate studies utilized PHQ-9 for depression score, bupropion/naltrexone utilized IDS-SR for

depression score.

†SE manually derived from standard deviation or 95% CIs.

‡The number of patients for this outcome may differ from the primary analysis population.

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Harms

Semaglutide versus Placebo

The most frequent adverse events in the STEP 4 and 6 trials for semaglutide were gastrointestinal-

related symptoms, including nausea, constipation, and diarrhea.

140-142

Beyond gastrointestinal

events, semaglutide appeared relatively well-tolerated. Participants in the semaglutide arms of the

STEP 4 and 6 trials experienced more adverse events (81.3% and 86%, respectively) compared to

those in the placebo arms (75% and 79%, respectively). Similarly for STEP 4, participants in the

semaglutide arm experienced more serious adverse events (SAEs) (7.7%) compared to participants

in the placebo arm (5.6%).

140,141

However, STEP 6 reported a higher rate of serious adverse events

in the placebo arm (7%) compared to the semaglutide arm (5%).

142

One death was reported in each

treatment group for STEP 4, but both were determined to be unrelated to study treatment. There

were no deaths reported in STEP 6. Notable serious adverse events that occurred included one

occurrence of cholecystitis in the STEP 4 intervention arm, five occurrences of cholelithiasis in the

STEP 4 intervention arm (two occurrences in the placebo arm) and two occurrences in the STEP 6

intervention arm, one occurrence of nephrolithiasis in the STEP 4 intervention arm, and one

occurrence of ureterolithiasis in the STEP 4 intervention arm and one occurrence in the STEP 6

intervention arm (one occurrence in the placebo arm). Rates of discontinuation due to adverse

events were higher in the semaglutide arms for both STEP 4 and STEP 6 (2.4% and 3%, respectively)

compared to placebo arm (2.2% and 1%, respectively). Gastrointestinal events were the most

common reported reason for discontinuing due to adverse events. See D19 for detailed harms

results.

Liraglutide versus Placebo

The most common adverse events reported in LOSEIT included gastrointestinal events, with a total

of 264 events in the liraglutide arm versus 144 events in the placebo arm.

143

Participants in the

liraglutide arm experienced more adverse events (96%) compared to those in the placebo arm

(93%). Rates of serious adverse events were similar between both the liraglutide (9%) and placebo

arms (8%) (Table D19). Gastrointestinal serious adverse events occurred in one participant from

the liraglutide arm (ileus leading to surgery) and one participant from the placebo arm

(cholecystitis). There were no deaths reported in the trial. Rates of discontinuation due to adverse

events were higher in the liraglutide arm (10 patients) compared to placebo arm (four patients).

Gastrointestinal events were the most common reported reason for discontinuing due to adverse

events.

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Table D19. Harms in Additional Trials of Semaglutide and Liraglutide for the Management of

Obesity

140-143

STEP 4

STEP 6

LOSEIT

Study Arms

Run-in*

PBO†

SEM†

PBO

SEM

PBO

LIR

902

268

535

101

199

Any AE, n (%)

760

(84.3)

201 (75) 435 (81.3) 80 (79) 171 (86) 71 (93) 77 (96)

SAE, n (%)

21 (2.3)

15 (5.6)

41 (7.7)

7 (7)

10 (5)

6 (8)

7 (9)

AEs Leading to

Discontinuation, n (%)

48 (5.3) 6 (2.2) 13 (2.4) 1 (1) 5 (3) 4 (5.3) 10 (12.5)

GI Disorders Leading to

Discontinuation, n (%)

NR NR NR 0 (0) 4 (2) 2 (2.6) 8 (10)

Nausea, n (%)

13 (4.9)

75 (14)

4 (4)

35 (18)

Constipation, n (%)

17 (6.3)

62 (11.6)

3 (3)

52 (26)

Diarrhea, n (%)

19 (7.1)

77 (14.4)

6 (6)

32 (16)

AE: adverse event, GI: gastrointestinal, LIR: liraglutide, n: number, N: total number, NR: not reported, PBO:

placebo, SAE: serious adverse event, SEM: semaglutide

*Timepoint for harms is at Weeks 0-20.

†Timepoint for harms is at Weeks 20-68.

Phentermine/Topiramate versus Placebo

In OB-204, most treatment-emergent adverse events were mild to moderate in severity, and the

incidence of any adverse events was higher in the phentermine/topiramate arm (91%) than in the

placebo arm (78%).

144,148

Adverse reactions that occurred more frequently in the intervention arm

than in the placebo arm included dry mouth (50% vs. 0%), dysgeusia (27% vs. 0%), and sinusitis

(23% vs. 0%). Serious adverse events were rare and were experienced by no participants in the

phentermine/topiramate group, compared to one participant in the placebo group. Over twice

many participants in the intervention arm discontinued due to adverse events (9.1%) compared to

participants in the intervention arm (4.4%). See Table D20 for detailed harms results.

Bupropion/Naltrexone versus Placebo

In CVOT Light, over twice as many participants in the bupropion/naltrexone arm experienced any

adverse events (36%) compared to participants in the placebo arm (15%).

145,146

Rates of serious

adverse events were similar and relatively low across the two arms (9-10%) (Table D20). More

participants in the bupropion/naltrexone arm discontinued due to adverse events (28%) than in the

placebo arm (9%). The most common adverse events that led to discontinuation of the drug in both

the treatment arm and the placebo arm included gastrointestinal adverse reactions (14% and 2%,

respectively), which included nausea, constipation, and vomiting, and central nervous system

reactions (5% and 1%, respectively), which including tremor, dizziness, and headache. Psychiatric

disorders, such as insomnia, anxiety, and depression, leading to discontinuation were infrequently

observed in both arms (3% vs. 1%, respectively).

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In the Ignite trial, serious adverse events during the controlled treatment period (up to 26 weeks)

were low, with one participant in the intervention arm versus zero in the placebo arm experiencing

a serious adverse reaction (Table D20)

147,149

. Through the entire study period at 78 weeks, rates of

serious adverse events were low in both arms, occurring in two patients who continued on

bupropion/naltrexone and zero patients in the placebo arm who switched to the treatment. These

two serious adverse events were considered to be unrelated to the study drug.

At 26 weeks, in the Ignite trial, discontinuations due to adverse events occurred at a higher rate in

the bupropion/naltrexone arm (23%) than in the placebo arm (1.1%).

147,149

Throughout the entire

study period (78 weeks), adverse events that led to discontinuation were observed in 24% of

patients who were randomized to and continued open-label bupropion/naltrexone treatment, and

in 16% of patients who were initially in placebo, but switched to open-label treatment. The most

frequent adverse reactions leading to discontinuation of the treatment for both groups included

nausea (7%), anxiety (2.1%), headache (1.7%), dizziness (1.2%), and insomnia (1.2%). See Table D20

for detailed harms results.

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Table D20. Harms in Additional Trials of Phentermine/Topiramate and Bupropion/Naltrexone for

the Management of Obesity and Obesity with Diabetes Mellitus

144-149

OB-204

CVOT Light

Ignite

Study Arms PBO

P/T

(high)

PBO B/N PBO* B/N*

PBO



B/N‡

B/N



B/N‡

4450

4455

153

Any AE, n (%) 18 (78.2) 20 (90.9) 668 (15) 1620 (36.4) 0

(17.6)

NR NR

SAE, n (%)

1 (4.4)

386 (8.7)

463 (10.4)

1 (0.7)

2 (1.3)

AE Leading to

Disc., n (%)

1 (4.4) 2 (9.1) 388 (8.7) 1253 (28.1) 1 (1.1)

(22.9)

(15.7)

(24.2)

Gastrointestinal

Disorders

NR NR 84 (1.9)† (2)† NR NR NR NR

Nausea 1 (4.4) 2 (9.1) 21 (0.5)† 333 (7.5)†

(10.5)

0 NR NR

Dry Mouth

11 (50)

2 (0.04)

21 (0.5)

Nervous System

Disorders

NR NR 52 (1.2)† 226 (5.1)† NR NR NR NR

Headache

14 (0.3)†

51 (1.1)†

2 (1.3)

Dizziness

1 (4.6)

7 (0.2)†

62 (1.4)†

1 (0.7)

Dysgeusia

6 (27)

16 (0.4)

Infection

Sinusitis

5 (23)

1 (0.02)

Psychiatric

Disorders

NR NR 39 (0.9)† 136 (3.1)† NR NR NR NR

Anxiety

8 (0.2)†

26 (0.6)†

5 (3.3)

Insomnia

16 (0.4)†

35 (0.8)†

2 (1.3)

AE: adverse event, B/N: bupropion/naltrexone, disc.: discontinuation, n: number, N: total number, NR: not

reported, PBO: placebo, P/T: phentermine/topiramate, SAE: serious adverse event

*Timepoint up to 26 weeks.

†Rates of AEs leading to discontinuation.

‡Timepoint up to 78 weeks.

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D3. Evidence Tables

Table D21. UPSTF Study Quality

BMI: body mass index, CFB: change from baseline, IBT: intensive behavioral therapy, imp: imputation, ITT: intention to treat, PRO: patient-reported outcome, QoL: quality of life,

T2DM: type 2 diabetes mellitus, USPSTF: United States Preventive Services Task Force

*No publication; the sources for this trial are a conference presentation and ClinicalTrials.gov.

†This was an open-label randomized trial.

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Table D22. Study Design

Study Name & Type Intervention(s)

Lifestyle

Intervention

Description

Inclusions Exclusions

Study

Location

Outcomes Available and

Timepoint

Semaglutide

STEP 1

29,32,34,72

Phase III, MC, PBO-

controlled monotherapy

PBO + LI

(n=655)

Counseling

sessions every 4

wks; reduced-

calorie diet and

increase physical

activity; daily diary

to record diet and

exercise

Adults with BMI ≥30

kg/m

or ≥27 kg/m

with at least 1

weight-related

comorbid condition

DM; uncontrolled

thyroid disease; CVD;

treatment with GLP-1;

5 kg weigh loss within

90 days

129 sites in

16 countries

in Asia,

Europe, and

N/S America

Week 68 & Weeks 68-

120 (for extension trial):

% Δ in body weight,

absolute weight loss,

body weight reduction of

5%, 10%, 15%; waist

circ., SBP, LDL, A1C,

fasting FBG, hsCRP, SF-

36, IWQOL

SC SEM 2.4 mg

+ LI (n=1306)

Extension trial

(Wks 68-120)

-PBO + LI→ Off

treatment

(n=99)

-SC SEM 2.4

mg + LI→ Off

treatment

(n=228)

STEP 2

Phase III, MC, PBO-

controlled monotherapy

PBO + LI

(n=403)

Counseling

sessions every 4

wks; reduced-

calorie diet and

increase physical

activity; daily dairy

to record diet and

exercise

Adults with BMI of

≥27 kg/m², HbA1C

of 7-10%, and

diagnosed

with type 2 DM

Uncontrolled thyroid

disease; treatment

with GLP-1;

previous/planned

treatment with

surgery; 5 kg weight

loss within 90 days

149 sites in

12 countries

in Europe,

N/S America,

Middle East,

Africa, and

Asia

Week 68:

% Δ in body weight,

absolute weight loss;

body weight reduction of

5%, 10%, 15%, waist

circ., SBP, LDL, AIC,

fasting FBG, hsCRP, SF-

36, IWQOL, Δ in DM

medication

SC SEM 1.0 mg

+ LI (n=403)

SC SEM 2.4 mg

+ LI (n=404)

STEP 3

31,35,39

PBO + IBT

(n=204)

Low-calorie meal

replacement diet

Adults with BMI ≥30

kg/m

or ≥27 kg/m2

41 sites in US Week 68:

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Study Name & Type Intervention(s)

Lifestyle

Intervention

Description

Inclusions Exclusions

Study

Location

Outcomes Available and

Timepoint

Phase III, MC, PBO-

controlled monotherapy

[Nutrisystem] for 8

wks and IBT during

68 wks. IBT:

reduced calorie

diet + physical

activity (100

min/wk increased

by 25 min every 4

wks to reach 200

min/wk) + 30 IBT

visits

with at least 1

weight-related

comorbid condition

DM; prior weight loss

surgery; 5 kg weight

loss within 90 days

% Δ in body weight;

absolute weight loss;

body weight reduction of

5%, 10%, 15%; waist

circ.; SF-36

(68 weeks)

SC SEM 2.4 mg

+ IBT (n=407)

STEP 4

39,140,141

Phase III, MC, PBO-

controlled monotherapy

(Wks 0-20)

Run-in period

(n=803)

Monthly

counseling,

reduced-calorie

diet (500 kcal/d

deficit), increased

physical activity

(150 min/wk),

recorded daily by

participants and

reviewed during

counseling visits

Adults with BMI ≥30

kg/m

or ≥27 kg/m

with at least 1

weight-related

comorbid condition

HbA1C ≥6.5%; 5 kg

weight loss within 90

days

73 sites in 10

countries in

Europe,

North

America (US),

Middle East

(Israel),

Africa (South

Africa)

Weeks 20-68:

% Δ in body weight;

waist circ., SBP, SF-36

(Wks 20-68)

From run-in

with SEM→

PBO + LI

(n=268)

(Wks 20-68)

From run-in

with SEM→

SC SEM 2.4 mg

+ LI (n=535)

STEP 5

36-38

Phase III, MC, PBO-

controlled monotherapy

PBO + LI (n=

152)

Reduced calorie

diet and increased

physical activity

Adults with BMI ≥30

kg/m

or ≥27 kg/m

with at least 1

weight-related

comorbid condition

HbA1C ≥6.5%; 5 kg

weight loss within 90

days

41 sites in 5

countries

(North

America,

Europe)

Weeks 52 and 104:

% Δ from baseline in

body weight; body

weight reduction of 10%,

15%; waist circ.; SBP

SC SEM 2.4 mg

+ LI (n=152)

STEP 6

142

PBO + LI

(n=101)

Counseling every 4

wks; reduced

Adults (≥18 in South

Korea, ≥20 in Japan)

5 kg weight loss within

90 days; previous

22 sites in

Japan and 6

Week 68:

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Study Name & Type Intervention(s)

Lifestyle

Intervention

Description

Inclusions Exclusions

Study

Location

Outcomes Available and

Timepoint

Phase III, MC, PBO-

controlled monotherapy

SC SEM 1.7 mg

+ LI (n=101)

caloric intake (500

kcal/d); physical

activity ≥150

min/wk

with BMI ≥35 kg/m

with at least 1

weight-related

comorbid condition

OR BMI ≥27 kg/m

with 2 or more

weight-related

comorbid

conditions

obesity treatment

with surgery or taking

any medication for

indication of obesity

sites in South

Korea

% Δ from baseline to

week 68 in body weight;

body weight reduction of

10%, 15%; waist circ.;

SBP; A1C

SC SEM 2.4 mg

+ LI (n=199)

Semaglutide vs. Liraglutide

STEP 8

Phase III, MC, open-label,

PBO-controlled

monotherapy

PBO +LI (n=85)

Counseling

sessions every 4-6

wks; diet of 500

kcal/d deficit

relative to

baseline; physical

activity ≥150

mins/wk

Adults with BMI ≥30

kg/m

or ≥27 kg/m

with at least 1

weight-related

comorbid condition

DM, HbA1C ≥6.5%, 5

kg weight loss in last

90 days

19 sites in

the US

Week 68:

% Δ in body weight; body

weight reduction of 10%,

15%, 20%

SC SEM 2.4 mg

+ LI (n=126)

SC LIR 3.0 mg +

LI (n=127)

Liraglutide

SCALE (Maintenance)

40,49

Phase III, MC, PBO-

controlled monotherapy

PBO + LI

(n=210)

Low-calorie diet

run-in with weekly

counseling (4-12

wks) then

counseling weekly

during drug

escalation, then

every 4 wks; 500

kcal/day deficit

relative to

baseline; 150+

min/wk

Lost ≥5% initial

bodyweight during

run-in diet (4-12

wks); adults with

BMI ≥30 kg/m

≥27 kg/m

with

comorbidities of

treated/untreated

dyslipidemia or HTN

Diagnosis, type 1/2

DM; treatment with

GLP-1 or medications

causing significant

weight loss/gain;

bariatric surgery;

history of pancreatitis

36 sites in

the US and

Canada

Week 56:

% Δ body weight; weight

reduction 5%, 10%; waist

circ.; BMI; SBP; LDL;

HbA1C; FPG

SC LIR 3.0 mg +

LI (n=212)

SCALE (Sleep Apnea)

41,50

PBO + LI

(n=179)

Counseling

sessions every 4

Adults 18-64 years;

BMI ≥30 kg/m

;

>5% Δ in body weight

during previous 3

Week 32:

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Study Name & Type Intervention(s)

Lifestyle

Intervention

Description

Inclusions Exclusions

Study

Location

Outcomes Available and

Timepoint

Phase III, MC, PBO-

controlled monotherapy SC LIR 3.0 mg +

LI (n=180)

wks; 500 kcal/day

deficit relative to

baseline; 150+

min/wk

moderate-severe

OSA and

unable/unwilling to

use CPAP

months; central sleep

apnea; T1/2 DM

40 sites in

North

America

Δ in AHI; Δ in body

weight; Δ in FPG; Δ in

HbA1C; FOSQ; ESS

SCALE (Type 2

Diabetes)

42,52

Phase III, MC, PBO-

controlled monotherapy

PBO + LI

(n=212)

500 kcal/day

deficit relative to

baseline; 150+

min/wk

Adults ≥18;

overweight or

obese (BMI ≥27

kg/m

); T2DM

treated w/ diet and

exercise alone or 1-

3 OHA (metformin,

TZD, sulfonylurea)

≥5 kg weight loss in

last 90 days; previous

surgical treatment;

treatment with GLP-1

or DDP-4 or insulin

within last 3 months

126 sites in 9

countries

(France,

Germany,

Israel, South

Africa, Spain,

Sweden,

Turkey, UK)

Weeks 56:

% Δ body weight; weight

reduction 5%, 10%;

HbA1C; waist circ.

Week 68:

68 weeks: % Δ body

weight; waist circ.

Weeks 56-68:

% Δ body weight; waist

circ.

1.8mg SC LIR +

LI (n=211)

SC LIR 3.0 mg +

LI (n=423)

SCALE (Obesity & Pre-

Diabetes)

43,48

Phase III, MC, PBO-

controlled monotherapy

PBO + LI

(n=1244)

Monthly

counseling; 500

kcal/day deficit

relative to

baseline; 150+

min/wk

Adults ≥18; BMI ≥30

kg/m

or ≥27 kg/m

with untreated

dyslipidemia/HTN

T1/2 DM; history of

pancreatitis; previous

bariatric surgery

191 sites in

27 countries

(Europe, N/S

America,

Asia, Africa,

Australia)

Week 56:

Weight Δ; weight

reduction 5%, 10%; Δ in

BMI, waist circ., glycemic

control variables

SC LIR 3.0 mg +

LI (n=2487)

SCALE (IBT)

44,51

Phase III, MC, PBO-

controlled monotherapy

PBO + IBT

(n=140)

IBT, comprising

behavioral

counseling,

hypocaloric diet,

physical activity

(100-250 min/wk)

Adults ≥18; BMI ≥30

kg/m

≥5 kg weight loss in

last 90 days; T1/2 DM;

use of medications

known to induce

weight loss/gain;

history CVD

17 sites in US

Week 56:

Δ in % body weight;

weight reduction 5%,

10%, 15%; Δ in waist

circ., LDL, SBP, HbA1C;

SC LIR 3.0 mg +

IBT (n=142)

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Study Name & Type Intervention(s)

Lifestyle

Intervention

Description

Inclusions Exclusions

Study

Location

Outcomes Available and

Timepoint

SCALE (Insulin)

Phase III, MC, PBO-

controlled monotherapy

PBO + IBT

(n=198)

Hypocaloric diet,

increased physical

activity, behavioral

therapy delivered

in frequent

counseling

sessions

Adults ≥18; BMI ≥27

kg/m

; T2DM;

receiving stable

treatment with any

basal insulin and ≤2

OADs

T1DM; ≥5 kg weight

loss in last 90 days;

treatment with GLP-1

or DDP-4 or insulin

within last 3 months;

use of medications

known to induce

significant weight

change in last 90 days

53 sites

globally

Week 56:

% Δ in body weight;

weight reduction 5%,

10%; Δ in waist circ.,

FPG, SBP

SC LIR 3.0 mg +

IBT (n=198)

LOSEIT (KOA)

143

Phase III, single-center,

PBO-controlled

monotherapy

PBO + LI (n=

76)

8 wk lead-in low-

calorie diet (800-

1,000 kcal/day)

with meal

bars/powders and

wkly dietician

consults; 1,200

kcal/day wks 0-8

and 1,500 kcal/day

wks 8-52; dietary

group sessions

every 2 wks in first

8 wks

Adults aged 18-74;

BMI ≥27 kg/m

;

symptomatic KOA;

stable body weight

Current use weight

loss/gain medications;

recent/ongoing

participation in

organized weight loss

program; end-stage

KOA on radiography

1 site in the

Week 52:

Δ in body weight; HrQoL;

weight reduction 5%,

10%; Δ in BMI, waist circ.

SC LIR 3.0 mg +

LI (n= 80)

Phentermine/Topiramate

EQUIP

56,57

PBO +LI

(n=514)

Provided with

standardized

lifestyle

counseling, (LEARN

Adults 18-70 years,

BMI ≥35 kg/m

triglycerides ≤200

mg/dl with

Weight gain/loss >5 kg

in 3 months; eating

disorders, bariatric

surgery, glaucoma,

91 sites in

the U.S.

Week 56:

%/kg Δ in body weight;

body weight reduction of

5%, 10%, 15%; waist

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Study Name & Type Intervention(s)

Lifestyle

Intervention

Description

Inclusions Exclusions

Study

Location

Outcomes Available and

Timepoint

Phase III, MC, PBO-

controlled combination

therapy

PT 3.75 mg/23

mg + LI

(n=241)

Manual), advised

to follow 500-kcal

diet deficit,

increase water

consumption,

increase physical

activity

treatment of 0-1

lipid lowering med,

BP ≤140/90 mm Hg

with treatment of

0-2 anti-HTN

medications, and

fasting serum FBG

level ≤110

and nephrolithiasis;

thyroid dysfunction;

current substantial

depression, stroke,

MI, HF, DM

circ.; blood pressure,

heart rate, FBG,

triglycerides, HDL, LDL,

depression

PT 15 mg/92

mg + LI

(n=512)

EQUATE

54,55

Phase III, MC, PBO-

controlled combination

therapy

PBO +LI

(n=109)

LEARN Manual

(Lifestyle, Exercise,

Attitude,

Relationships,

Nutrition,

counseling to

reduce energy

intake by 500

kcal/day, food

diary, increase

physical activity;

brief monthly visits

to discuss progress

Adults 18-70 years

and BMI 30-45

kg/m

Use of phentermine or

topiramate within past

3 months, weight

gain/loss of >5 kg, use

of a very low calorie

diet, use of

pharmacotherapy for

weight loss, DM,

stroke, participation in

formal weight loss

program within past 3

months, surgery

34 sites in US

Week 28:

%/kg Δ in body weight;

body weight reduction of

5%, 10%; waist circ.;

blood pressure, heart

rate, FBG, HbA1C,

insulin, inflammatory

biomarkers, concomitant

med use, RBANS,

depression (PHQ-9 & C-

SSRS)

Phentermine

7.5 mg +LI

(n=109)

Topiramate 46

mg +LI (n=108)

PT 7.5 mg/46

mg + LI

(n=107)

Phentermine

15 mg + LI

(n=108)

Topiramate 92

mg +LI (n=107)

PT 15 mg/92

mg + LI

(n=108)

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Study Name & Type Intervention(s)

Lifestyle

Intervention

Description

Inclusions Exclusions

Study

Location

Outcomes Available and

Timepoint

CONQUER

53,58

Phase III, MC, PBO-

controlled combination

therapy

PBO +LI

(n=994)

Provided with

LEARN manual,

advised to

implement

lifestyle changes,

and instructions to

reduce caloric diet

by 500 kcal/day,

monthly check-in

with study staff on

progress

Adults (18-70 years)

with overweight/

obesity, BMI 27-45

kg/m² and 2+

comorbidities: SBP

140-160 mm Hg,

DBP 90-100 mm Hg

(no BMI limit and

diff SBP/DBP

criteria for

diabetic), 2+ anti-

HTN drugs;

concentration of

triglycerides 2.26-

4.52 mmol/L or 2+

lipid-lowering

drugs;

concentration FBG

>5.55 mmol/L,

blood FBG >7.77

mmol/L at 2hr,

T2DM; waist circ.

≥102 cm for men or

≥88 cm for women

Blood pressure

>160/100 mm Hg,

concentration fasting

FBG >13.32 mmol/L or

triglycerides >4.52

mmol/L, T1DM,

antidiabetic drugs

besides metformin,

nephrolithiasis, and

current depressive

symptoms (PHQ 21

total score ≥10),

surgery

93 sites in US

Week 56:

%/kg Δ in body weight;

body weight reduction of

5%, 10%; waist circ.;

BMI, blood pressure,

triglycerides, LDL, HDL,

FBG, insulin, biomarkers,

concomitant drugs,

progression to DM (for

non-diabetic), body

composition

PT 7.5 mg/46

mg + LI

(n=498)

PT 15 mg/92

mg + LI

(n=995)

OB-204

(Winslow 2012)

144,148

PBO + LI (n=23)

Lifestyle

modification

counseling (LEARN

behavioral weight

loss and

Adults 30-65 years,

BMI between 30-40

kg/m

, diagnosis of

moderate to severe

Other sleep disorder,

limb movement

arousal index >10,

uncontrolled blood

pressure, unstable

1 site in US

Week 28:

Δ in AHI, OSA

parameters (apnea

index, respiratory

disturbance, oxygen

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Study Name & Type Intervention(s)

Lifestyle

Intervention

Description

Inclusions Exclusions

Study

Location

Outcomes Available and

Timepoint

Phase I/II, single-center

PBO-controlled

combination therapy

PT 15 mg/92

mg + LI (n=22)

management

program)

OSA syndrome, and

AHI ≥15

angina, surgery,

cardiac arrythmia, HF,

valvulopathy, MI

saturation index, arousal

index), PSQI, ESS, SF-36,

change in blood

pressure, heart rate, lipid

profile, glycemic

variables, % Δ weight

loss, body weight

reduction of 5%, 10%

Bupropion/Naltrexone

COR-I

61,62

Phase III, MC, PBO-

controlled combination

therapy

PBO + LI

(n=581)

Hypocaloric diet

(500 kcal

deficit/day),

dietary counseling

and weight

management

booklets, advice

on lifestyle

modification

(instructions,

increase physical

activity)

Adults aged 18-65

years with had BMI

30–45 kg/m² and

uncomplicated

obesity, or BMI 27-

45 kg/m² and

controlled HTN or

dyslipidemia, or

both

DM; vascular, hepatic,

or renal disease;

surgical/device for

obesity; or loss/gain

>4 kg within 3 months,

additional weight loss

drugs

34 sites in US

Week 56:

% Δ in body weight; body

weight reduction of 5%,

10%, 15%; waist circ.;

triglycerides, LDL, HDL,

FBG, insulin, HOMA-IR;

and hsCRP; COEQ; IW-

QOL-Lite; FCI; SBP; DBP;

IDS-SR

BN 360 mg/16

mg + LI

(n=578)

BN 360 mg/32

mg + LI

(n=583)

COR-II

63,64

Phase III, MC, PBO-

controlled combination

therapy

PBO + LI

(n=495)

Instructions to

follow hypocaloric

diet (500 kcal

deficit/day),

increase physical

activity, and

behavioral

modification

Adults aged 18-65

years with had BMI

30-45 kg/m² and

uncomplicated

obesity, or BMI 27-

45 kg/m² and

controlled HTN or

dyslipidemia, or

both

DM; vascular, hepatic,

or renal disease;

surgical/device for

obesity; or loss/gain

>4 kg within 3 months,

additional weight loss

drugs

36 sites in US

Week 56:

%/kg Δ in body weight;

body weight reduction of

5%, 10%, 15%; waist

circ.; triglycerides, LDL,

HDL, FBG, insulin,

HOMA-IR; and hsCRP;

COEQ; IW-QOL-Lite; SBP;

DBP; IDS-SR

BN 360 mg/32

mg + LI

(n=1001)

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Study Name & Type Intervention(s)

Lifestyle

Intervention

Description

Inclusions Exclusions

Study

Location

Outcomes Available and

Timepoint

COR-BMOD

65,66

Phase III, MC, PBO-

controlled combination

therapy

PBO + BMOD

(n=202)

Intensive

behavioral group

modification:

group counseling

(wks 1-16: wkly,

wks 16-28:

biweekly, after wk

28: monthly),

deficit diet (varies

depending on

weight), exercise

gradually

increased to 180

min/wk, diary

entry

Adults 18-65 years

of age, with a BMI

of 30–45 kg/m

, or

a BMI of 27-45

kg/m

in presence

of controlled HTN

and/or dyslipidemia

DM; sig.

cerebrovascular, CV,

hepatic, or renal

disease; treatment

with bupropion/

naltrexone,

surgical/device

intervention; >4 kg

loss/gain within 3

months

9 sites in US

Week 56:

% Δ in body weight; body

weight reduction of 5%,

10%, 15%; waist circ.;

triglycerides, LDL, HDL,

FBG, insulin, and hsCRP;

IWQOL-Lite; FCI; SBP;

DBP; IDS-SR

BN 360 mg/32

mg + BMOD

(n=591)

COR Diabetes

59,60

Phase III, MC, PBO-

controlled combination

therapy

PBO + LI

(n=159)

Hypocaloric diet

(500 kcal

deficit/day),

dietary counseling

and weight

management

booklets, advice

on behavioral

modification

(instructions,

increase physical

activity [walking at

least 30 min most

days])

Adults aged 18-70

years, with T2DM,

BMI ≥27 and I ≥45

kg/m

, HbA1C 7-

10% (53-86

mmol/mol), and

FBG 270 mg/dL

T1DM or “brittle-DM”

or hospitalization/ER

visit due to poor

diabetic control, DM

secondary to

pancreatitis or

pancreatectomy,

loss/gain >5 kg within

3 months, surgical/

device for obesity, tx

with bupropion or

naltrexone, weight

loss program within 1

month, pregnant/

breastfeeding

53 sites in US

Week 56:

% Δ in body weight; body

weight reduction of 5%,

10%; waist circ.;

triglycerides, LDL, HDL,

FBG, insulin, SBP; DBP;

HOMA-IR, hsCRP;

HbA1C; OADs; HbA1C

<7% and <6.5%; rescue

med use for DM; d/c due

to poor glycemic control;

IDS-SR

BN 360 mg/32

mg + LI

(n=265)

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Study Name & Type Intervention(s)

Lifestyle

Intervention

Description

Inclusions Exclusions

Study

Location

Outcomes Available and

Timepoint

CVOT (Light Study)

145,146

Phase IIIb, MC, PBO-

controlled combination

therapy

PBO + LI

(n=4450)

Internet-based

weight

management

program

(resources on

healthy eating,

exercise,

behavioral

modifications,

weekly

lessons/emails),

access to personal

weight loss coach,

program to track

weight, meals,

physical activity,

and low-fat, low-

calorie meal plan

>50 years (women)

or >45 years (men),

BMI between 27-50

kg/m

, waist circ. of

>88 cm (women) or

>102 cm (men), and

have characteristics

associated with an

increased risk of

adverse CV

outcomes; and/or

T2DM and at least 2

comorbidities (HTN,

etc.)

MI, angina pectoris,

NYHA class III or IV,

HF, history of stroke,

blood pressure

>145/95 mm Hg,

weight gain/loss of

>3% within 3 months,

bariatric or cardiac

surgery

266 sites in

Week 52:

Time from

randomization to first

occurrence of a MACE,

time to first occurrence

of a MACE/

hospitalization for

unstable angina, stroke,

or MI, Δ in body weight,

BMI, waist circ., SBP,

DBP, heart rate

BN 360 mg/32

mg + LI

(n=4455)

Ignite

147,149

Phase IIIb, MC, controlled

combination therapy

Usual care

(including LI)

(n=89)

-CLI: Phone/

internet-based

progressive

nutrition and

exercise program

with

dietician/coach

with individualized

goal setting and

tracking tools

-Usual care: Site-

based LI program,

exercise and

hypocaloric diet

(500 kcal deficit),

Adults age 18-60

years, with either

obesity (BMI 30-45

kg/m

) or

overweight (BMI

27-45 kg/m

) with

dyslipidemia and/or

controlled HTN

DM; MI within 6

months; angina

pectoris grade

III/IV; clinical history

of strokes, seizures,

cranial trauma,

bulimia, anorexia

nervosa

15 sites in US

Weeks 26* and 78:

%/kg Δ in body weight;

body weight reduction of

5%, 10%, 15%; waist

circ.; triglycerides, LDL,

HDL, FBG, insulin, heart

rate; HOMA-IR; ASEX,

BES Total Score; IWQOL-

Lite; SBP; DBP

BN 360 mg/32

mg + CLI

(n=153)

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Study Name & Type Intervention(s)

Lifestyle

Intervention

Description

Inclusions Exclusions

Study

Location

Outcomes Available and

Timepoint

nutrition tracker,

pedometer,

literature

AHI: apnea-hypopnea index, A1C: glycated hemoglobin, ASEX: Arizona Sexual Experience Scale, BES: Binge Eating Scale, BMI: body-mass index, BMOD:

behavioral modification, BN: bupropion/naltrexone, BP: blood pressure, cm: centimeter, CLI: comprehensive lifestyle intervention, COEQ: Control of Eating

Questionnaire, CPAP: continuous positive airway pressure, hsCRP: C-reactive protein, C-SSRS: Columbia Suicide Severity Rating Scale, CVD: cardiovascular

disease, d: day, DBP: diastolic blood pressure, dL: deciliter, DM: diabetes mellitus, ER: emergency room, ESS: Epworth Sleepiness Scale, FCI: Food Craving

Inventory, FBG: fasting blood glucose, FOSQ: Functional Outcomes of Sleep Questionnaire, GLP-1: glucagon-like peptide-1, HbA1C: glycated hemoglobin, HDL:

high-density lipoprotein, HOMA-IR: Homeostasis Model Assessment for Insulin Resistance, HRQol: health-related quality of life, HTN: hypertension, IBT:

intensive behavioral therapy, IDS-SR: Inventory of Depressive Symptomatology (Self-Report), IWQOL-Lite: Impact of Weight on Quality of Life-Lite, kcal: calorie,

kg: kilogram, KOA: knee osteoarthritis, L: liter, LDL: low-density lipoprotein, LEARN: lifestyle, exercise, attitudes, relationships, and nutrition, LI: lifestyle

intervention, LIR: liraglutide, m: meter, MACE: major adverse cardiovascular events, MC: multi-center, mg: milligram, min: minute, mmHg: milliliter of mercury,

mmol: millimole, n: number, NYHA: New York Heart Association, OAD: oral antidiabetic drug, OHA: oral hypoglycemic agents, OSA: obstructive sleep apnea,

PBO: placebo, PHQ-9: Patient Health Questionnaire, PSQI: Pittsburgh Sleep Quality Index, PT: phentermine/topiramate, RBANS: Repeatable Battery for the

Assessment of Neuropsychological Status, SBP: systolic blood pressure, SC: subcutaneous, SEM: semaglutide, SF-36: Short Form Health Survey, TZD:

thiazolidinediones, U.K.: United Kingdom, U.S.: United States, vs.: versus

*We focus on the 26-week timepoint, during the randomized period of the trial.

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Table D23. Baseline Characteristics I

29-45,48-66,72,140-149

Study Name Intervention(s)

Age, Years

Female

Sex, %

Race/Ethnicity, %

BMI, kg/m

Baseline

Weight, kg

Mean

Semaglutide

STEP 1

PBO + LI (n=655) 47 12 76

76% White, 12% Asian, 6% Black, 6% other; 13%

Latinx

38 6.5 105.2 21.5

SC SEM 2.4 mg + LI (n=1306) 46 13 73.1

75% White, 14% Asian, 6% Black, 6% other; 12%

Latinx

37.8 6.7 105.4 22.1

STEP 1

(Extension)†

PBO→ Off Treatment (n=99) 50 11 67.7

75% White, 23% Asian, 1% Black, 1% Other; 1%

Hispanic/Latinx

37.7 8 105.4 25.6

SC SEM 2.4 mg + LI→

Off Treatment (n=228)

48 12 66.7

76% White, 19% Asian, 4% Black, <1% Other, 2%

Hispanic/Latinx

37.6 7 105.6 21.8

STEP 2

PBO + LI (n=403) 55 11 47.1

60% White, 27% Asian, 9% Black, 4% other; 12%

Latinx

35.9 6.5 100.5 20.9

SC SEM 1.0 mg + LI (n=403) 56 10 50.4

68% White, 24% Asian, 7% Black, 2% other; 15%

Latinx

35.3 5.9 99 21.1

SC SEM 2.4 mg + LI (n=404) 55 11 55.2

59% White, 28% Asian, 9% Black, 5% other; 12%

Latinx

35.9 6.4 99.9 22.5

STEP 3

PBO + IBT (n=204) 46 13 88.2

78% White, 3% Asian, 18% Black, 2% other; 23%

Latinx

37.8 6.9 103.7 22.9

SC SEM 2.4 mg + IBT (n=407) 46 13 77.4

75% White, 1% Asian, 20% Black, 3% other; 18%

Latinx

38.1 6.7 106.9 22.8

STEP 4

Run-in period (n=803) 46 12 79

84% White, 2% Asian, 13% Black, 1% Other; 8%

LatinX

38.4 6.9 107.2 22.7

From run-in with SEM→

PBO + LI (n=268)*

46 12 76.5

84% White, 2% Asian, 13% Black, 1% Other; 8%

LatinX

34.1 7.1 95.4 22.7

From run-in with SEM→

SC SEM 2.4 mg + LI (n=535)*

47 12 80.2

83% White, 3% Asian, 13% Black, <1% other; 8%

LatinX

34.5 6.9 96.5 22.5

STEP 5

PBO + LI (n=152) 47 10 74.3

93% White, 0% Asian, 3% Black, 1% American

Indian/Alaskan Native, 3% other; 14% Latinx

38.5 6.9 106 NR

SC SEM 2.4 mg + LI (n=152) 47 12 80.9

93% White, 1% Asian, 5% Black, 0% other, 1%

American Indian/Alaskan Native; 12% Latinx

STEP 6

PBO + LI (n=101)

25.7

100% Asian

31.9

4.2

90.2

15.1

SC SEM 1.7 mg + LI (n=101)

36.6

100% Asian

31.6

3.7

86.1

11.9

SC SEM 2.4 mg + LI (n=199)

42.7

100% Asian

4.6

86.9

16.5

Semaglutide vs. Liraglutide

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Study Name Intervention(s)

Age, Years

Female

Sex, %

Race/Ethnicity, %

BMI, kg/m

Baseline

Weight, kg

Mean

STEP 8

PBO + LI (n=85) 51 12 77.6

71% White, 4% Asian, 22% Black, 4% other; 8%

Latinx

38.8 6.5 108.8 23.1

SC SEM 2.4 mg + LI (n=126) 48 14 81

75% White, 3% Asian, 20% Black, 2% other; 12%

Latinx

37 7.4 102.5 25.3

SC LIR 3.0 mg + LI (n=127) 49 13 76.4

75% White, 5% Asian, 16% Black, 5% other; 13%

Latinx

37.2 6.4 103.7 22.5

Liraglutide

SCALE

(Maintenance)

PBO + LI (n=210) 46.5 11 79

88% White, 11% Black, 0% Asian, 0% Native

Hawaiian/Pacific Islander

35.2 5.9 98.7 21.2

SC LIR 3.0 mg + LI (n=212) 45.9 11.9 84

80% White, 15% Black, 1% Asian, 1% Native

Hawaiian/Pacific Islander

36 5.9 100.4 20.8

SCALE

(Sleep Apnea)

PBO + LI (n=179) 48.4 9.5 27.9

75% White, 2% Asian, 20% Black, 1% Native

Hawaiian/Pacific Islander, 2% other; 13% Latinx

39.4 7.4 118.7 25.4

SC LIR 3.0 mg + LI (n=180) 48.6 9.9 28.3

72% White, 7% Asian, 18% Black, 1% Native

Hawaiian/Pacific Islander, 2% other; 11% Latinx

38.9 6.4 116.5 23

SCALE

(Type 2

Diabetes)

PBO + LI (n=212) 54.7 9.8 54.2

83% White, 2% Asian, 13% Black, 2% other; 11%

Latinx

37.4 7.1 106.5 21.3

1.8 mg SC LIR + LI (n=211) 54.9 10.7 48.8

84% White, 2% Asian, 13% Black, 1% other; 8%

Latinx

37 6.9 105.8 21

SC LIR 3.0 mg + LI (n=423) 55 10.8 48

84% White, 3% Asian, 10% Black, 3% other; 11%

Latinx

37.1 6.5 105.7 21.9

SCALE (Obesity

& Pre-

Diabetes)

PBO + LI (n=1244) 45 12 78.1

85% White, 4% Asian, 9% Black, <1% American

Indian/Alaska Native, <1% Native Hawaiian/Pacific

Islander, 1% other; 11% Latinx

38.3 6.3 106.2 21.7

SC LIR 3.0 mg + LI (n=2487) 45.2 12.1 78.7

85% White, 4% Asian, 10% Black, <1% American

Indian/Alaska Native, <1% Native Hawaiian/Pacific

Islander, 2% other; 10% Latinx

38.3 6.4 106.2 21.2

SCALE (IBT)

PBO + IBT (n=140)

11.2

82.9

82% White, 2% Asian, 16% Black; 6% Latinx

38.7

7.2

106.7

SC LIR 3.0 mg + IBT (n=142)

45.4

11.6

83.8

79% White, 1% Asian, 19% Black; 17% Latinx

39.3

6.8

108.5

22.1

SCALE (Insulin)

PBO + IBT (n=198)

57.6

10.4

91% White, 3% Asian, 6% Black; 15% Latinx

35.3

5.8

98.9

19.9

SC LIR 3.0 mg + IBT (n=198)

55.9

11.3

44.5

88% White, 2% Asian, 9% Black; 22% Latinx

35.9

6.5

100.6

20.8

LOSEIT (KOA)

PBO + LI (n=76)

59.3

9.7

31.3

90.8

14.3

SC LIR 3.0 mg + LI (n=80) 59.2 10.8 65 NR 32.8 5.5 96.3 18.2

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Study Name Intervention(s)

Age, Years

Female

Sex, %

Race/Ethnicity, %

BMI, kg/m

Baseline

Weight, kg

Mean

Phentermine/Topiramate

EQUIP

PBO + LI (n=514) 43 11.8 82.7

80% White, 18% Black, 1% American Indian/Alaskan

Native, <1% Asian, <1% Native Hawaiian/Pacific

Islander, <1% other

42 6.2 115.8 21.5

P/T 3.75 mg/23 mg + LI

(n=241)

43 11 83.4

80% White, 16% Black, <1% American

Indian/Alaskan Native, <1% Asian, <1% Native

Hawaiian/Pacific Islander, 2% other

42.6 6.5 118.5 21.9

P/T 15 mg/92 mg + LI (n=512) 41.9 12.2 82.8

80% White, 18% Black, 1% American Indian/Alaskan

Native, <1% Asian, <1% Native Hawaiian/Pacific

Islander, 1% other

41.9 6 115.2 20.7

EQUATE

PBO + LI (n=109)

11.4

78.9

76% White, 23% Black, 0% Asian, 1% other

36.2

3.9

100

Phentermine 7.5 mg + LI

(n=109)

46.4 11.6 78.9 74% White, 24% Black, 2% Asian, 2% other 36.3 4 101 15.1

Topiramate 46 mg + LI (n=108)

46.9

12.6

79.6

88% White, 10% Black, 2% Asian, 2% other

36.1

4.1

100.7

16.3

P/T 7.5 mg/46 mg + LI (n=107)

44.6

11.1

79.4

75% White, 24% Black, 0% Asian, 1% other

36.6

3.9

102.2

16.5

Phentermine 15 mg + LI

(n=108)

45.7 12.4 79.6 83% White, 13% Black, 1% Asian, 3% other 36.2 4.2 101.4 16.4

Topiramate 92 mg +LI (n=107)

45.8

11.2

79.4

77% White, 21% Black, 2% Asian, 2% other

4.3

104.5

15.6

P/T 15 mg/92 mg + LI (n=108)

44.6

12.8

78.7

82% White, 15% Black, 2% Asian, 3% other

35.9

3.9

99.3

15.6

CONQUER

(Diabetes

subgroup)

PBO +LI (n=157) 52.6 9.8 71.3

85% White, 12% Black, 2% Asian, 2% other

29% Hispanic/Latinx, 71% not Hispanic/Latinx

36.2 5.2 99.3 18.6

P/T 7.5 mg/46 mg + LI (n=67) 52.5 9.3 65.6

94% White, 5% Black, 0% Asian, 2% other

31% Hispanic/Latinx, 69% not Hispanic/Latinx

35.3 4.3 97.2 16.1

P/T 15 mg/92 mg + LI (n=164) 52.1 10.1 62.1

83% White, 14% Black, 2% Asian, 3% other

31% Hispanic/Latinx, 69% not Hispanic/Latinx

37.1 5.2 103.2 20.1

OB-204

(Winslow

2012)

PBO + LI (n=23) 51.4 5.7 34.8

91% White, 9% Black, 4% Hispanic/Latinx, 96% not

Hispanic/Latinx

35.3 3.1 106.9 16.7

P/T 15 mg/92 mg + LI (n=22) 53.4 7 59.1

91% White, 9% Black, 0% Hispanic/Latinx, 100% not

Hispanic/Latinx

36 3.1 103.7 14.6

Bupropion/Naltrexone

COR-I

PBO + LI (n=581)

43.7

11.1

76% White, 19% Black, 5% other

36.2

99.5

14.3

B/N 360 mg/16 mg + LI

(n=578)

44.4 11.3 85 74% White, 21% Black, 5% other 36.2 4.3 99.5 14.8

B/N 360 mg/32 mg + LI

(n=583)

44.4 11.1 85 75% White, 18% Black, 6% other 36.1 4.4 99.7 15.9

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Study Name Intervention(s)

Age, Years

Female

Sex, %

Race/Ethnicity, %

BMI, kg/m

Baseline

Weight, kg

Mean

COR-II

PBO + LI (n=495)

44.4

11.4

84.8

84% White, 15% Black, 2% other

36.1

4.3

99.2

15.9

B/N 360 mg/32 mg + LI

(n=1001)

44.3 11.2 84.6 83% White, 13% Black, 3% other 36.2 4.5 100.3 16.6

COR-BMOD

PBO + BMOD (n=202)

45.6

11.4

91.6

74% White, 22% African American, 5% other

4.2

101.9

B/N 360 mg/32 mg + BMOD

(n=591)

45.9 10.4 89.3 69% White, 25% African American, 7% other 36.3 4.2 100.2 15.4

COR Diabetes

PBO + LI (n=159)

53.8

9.7

52.8

83% White, 11% Black, 6% other

36.3

4.5

105

17.1

B/N 360 mg/32 mg + LI

(n=265)

53.9 9.2 54.3 78% White, 19% Black, 3% other 36.7 4.8 106.3 19.1

CVOT (Light

Study)

PBO + LI (n=4450) 60.9 7.4 54.4

83% White, 15% Black/African American, <1% Asian,

<1% American Indian/Alaskan Native, <1% Native

Hawaiian/Pacific Islander

93% non-Hispanic/Latinx, 7% Hispanic/Latinx

37.4 5.4 106.3 19.2

B/N 360 mg/32 mg + LI

(n=4455)

61.1 7.3 54.7

84% White, 15% Black/African American, <1% Asian,

<1% American Indian/Alaskan Native, <1% Native

Hawaiian/Pacific Islander

94% non-Hispanic/Latinx, 6% Hispanic/Latinx

37.2 5.3 105.6 19.1

Ignite

Usual care (including LI) (n=89) 47 10 86.5

72% White, 27% Black/African American, 0% Asian,

1% American Indian/Alaskan Native

6% Hispanic/LatinX, 94% not Hispanic/Latinx

36.3 4.4 100.2 16.6

B/N 360 mg/32 mg + CLI

(n=153)

46.1 9.7 81.7

81% White, 18% Black/African American, 1% Asian,

0% American Indian/Alaskan Native

3% Hispanic/LatinX, 97% not Hispanic/Latinx

36.3 4.2 101.4 15.1

BMI: body-mass index, BMOD: behavioral modification, B/N: bupropion/naltrexone, CLI: comprehensive lifestyle intervention, IBT: intensive behavioral therapy, kg:

kilogram, KOA: knee osteoarthritis, LI: lifestyle intervention, LIR: liraglutide, m: meter, mg: milligram, n: number, NR: not reported, PBO: placebo, P/T:

phentermine/topiramate, SC: subcutaneous, SD: standard deviation, SEM: semaglutide, vs.: versus

*Baseline data measured at Week 20.

†Baseline data measured at Week 68.

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Table D24. Baseline Characteristics II

29-45,48-66,72,140-149

Study Name Intervention(s)

Waist

Circumference,

A1C, Mean %

Diabetes

Pre-

Diabetes,

SBP, mm HG LDL, mg/dL

Fasting Blood

Glucose,

mg/dL

Mean

Semaglutide

STEP 1

PBO + LI (n=655)

114.8

14.4

5.7

0.3

40.2

127

112.5

29.8

94.7

10.5

SC SEM 2.4 mg + LI

(n=1306)

114.6 14.8 5.7 0.3 0 45.4 126 14 110.3 31.6 95.4 10.7

STEP 1

(Extension)#

PBO→ Off Treatment

(n=99)

NR NR 5.7 0.3 0 53.5 130 15 113.7 NR NR NR

SC SEM 2.4 mg + LI→

Off Treatment

(n=228)

NR NR 5.7 0.3 0 62.3 129 14 113.4 29.4 NR NR

STEP 2

PBO + LI (n=403)

115.5

13.9

8.1

0.8

100

130

89*

158.4*

41.4

SC SEM 1.0 mg + LI

(n=403)

113.9 14 8.1 0.8 100 0 130 14 89* NR 154.8* 41.4

SC SEM 2.4 mg + LI

(n=404)

114.5 14.3 8.1 0.8 100 0 130 13 89* NR 153* 41.4

STEP 3

PBO + IBT (n=204)

111.8

16.2

5.8

0.3

52.9

124

111.8*

31.2

94*

9.8

SC SEM 2.4 mg + IBT

(n=407)

113.6 15.1 5.7 0.3 0 48.2 124 15 107.7* 30.3 93.9* 9.4

STEP 4

Run-in period (n=803) 115.3 15.5 5.7 0.3 0 NR 127 14 116.6*

IQR:

97.3-

138.6

97 10.7

From run-in with

SEM→ PBO + LI

(n=268)§

104.7 16.9 5.4 0.3 0 42.5 121 13 112.5

IQR:

93.6-

130.9

86.9 7.6

From run-in with

SEM→ SC SEM 2.4 mg

+ LI (n=535)§

105.5 15.9 5.4 0.3 0 49 121 13 110.4

IQR:

91.1-

130.9

87.9 7.7

STEP 5

PBO + LI (n=152)

115.7 14.8 5.7 0.3

46.4 125.5 14.5 112.1 NR 95.4 10.8

SC SEM 2.4 mg + LI

(n=152)

STEP 6

PBO + LI (n=101)

103.8

9.9

6.4

1.1

133

123.7

113.5

28.8

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Study Name Intervention(s)

Waist

Circumference,

A1C, Mean %

Diabetes

Pre-

Diabetes,

SBP, mm HG LDL, mg/dL

Fasting Blood

Glucose,

mg/dL

Mean

SC SEM 1.7 mg + LI

(n=101)

101.4 8.8 6.4 1.1 25 21 135 13 119.9 NR 111.7 27

SC SEM 2.4 mg + LI

(n=199)

103.8 11.8 6.4 1.2 25 22 133 14 116 NR 111.7 27

Semaglutide vs. Liraglutide

STEP 8

PBO + LI (n=85)

115.4

15.1

5.6

0.4

123

105.2

97.6

12.2

SC SEM 2.4 mg + LI

(n=126)

111.8 16.3 5.5 0.3 0 34.1 125 14 106.4 NR 96.1 10.2

SC LIR 3.0 mg + LI

(n=127)

113.5 15 5.5 0.3 0 35.4 126 16 108.1 NR 95.2 8.5

Liraglutide

SCALE

(Maintenance)

PBO + LI (n=210)

107.8

15.2

5.6

0.4

117.8

10.8

104.4

30.9

10.8

SC LIR 3.0 mg + LI

(n=212)

109.4 15.3 5.6 0.4 0 NR 116.6 12.5 100.5 27.1 97.2 9

SCALE (Sleep

Apnea)

PBO + LI (n=179)

122.7

14.9

5.6

0.4

62.6

127.1

12.3

111.4

26.8

97.2

16.2

SC LIR 3.0 mg + LI

(n=180)

122.3 14.5 5.7 0.4 0 63.9 125.8 11.5 111.6 28.9 97.2 10.8

SCALE (Type 2

Diabetes)

PBO + LI (n=212)

117.3

7.9

0.8

100

129.2

13.6

85.2

39.3

155.5

1.8 mg SC LIR + LI

(n=211)

117.5 14.7 8 0.8 100 0 130.5 14.5 91.5 38.5 160.4 35.1

SC LIR 3.0 mg + LI

(n=423)

118 14.4 7.9 0.8 100 0 128.9 13.6 86.4 35.5 158.4 32.8

SCALE (Obesity

& Pre-

Diabetes)

PBO + LI (n=1244)

114.5

14.3

5.6

0.4

60.9

123.2

12.8

112.2

27.6

95.5

9.8

SC LIR 3.0 mg + LI

(n=2,487)

115 14.4 5.6 0.4 0 61.4 123 12.9 111.6 27.9 95.9 10.6

SCALE (IBT)

PBO + IBT (n=140)

115

15.6

5.5

0.4

127

119.9

34.8

97.2

10.5

SC LIR 3.0 mg + IBT

(n=142)

116 14.4 5.5 0.4 0 NR 125 15 112.1 30.9 97.2 9

SCALE (Insulin)

PBO + IBT (n=198)

114.2

13.2

100

132

164

SC LIR 3.0 mg + IBT

(n=198)

114.8 13.7 7.9 1.1 100 0 129 14 94 33 141 40

LOSEIT (KOA)

PBO + LI (n=76)

101.8

11.1

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Study Name Intervention(s)

Waist

Circumference,

A1C, Mean %

Diabetes

Pre-

Diabetes,

SBP, mm HG LDL, mg/dL

Fasting Blood

Glucose,

mg/dL

Mean

SC LIR 3.0 mg + LI

(n=80)

105.5 13.9 NR NR NR NR NR NR NR NR NR NR

Phentermine/Topiramate

EQUIP

PBO +LI (n=514)

120.5

13.9

121.8

11.5

121.3

8.7

P/T 3.75 mg/23 mg +

LI (n=241)

121.7 15.2 NR NR 0 NR 122.5 11.1 122.5 33 93.8 9.11

P/T 15 mg/92 mg + LI

(n=512)

120.1 14.6 NR NR 0 NR 122 11.6 119.8 30.1 93 9.47

EQUATE

PBO +LI (n=109)

110.7

9.5

5.4*

0.41

120.6

14.1

5.3*

0.59

Phentermine 7.5 mg

+LI (n=109)

111.7 10.8 5.5* 0.4 0 NR 122.3 12.9 NR NR 5.2* 0.53

Topiramate 46 mg +

LI (n=108)

110.6 11.5 5.5* 0.43 0 NR 123.4 13.7 NR NR 5.2* 0.55

P/T 7.5 mg/46 mg + LI

(n=107)

111.7 12.9 5.4* 0.42 0 NR 123.4 12.2 NR NR 5.2* 0.55

Phentermine 15 mg +

LI (n=108)

111.2 11.3 5.4* 0.37 0 NR 120.5 13.4 NR NR 5.2* 0.53

Topiramate 92 mg +

LI (n=107)

112.6 11.3 5.5* 0.38 0 NR 123.2 14.1 NR NR 5.3* 0.5

P/T 15 mg/92 mg + LI

(n=108)

109.5 10.5 5.5* 0.43 0 NR 121.2 12.4 NR NR 5.3* 0.55

CONQUER

(Diabetes

Subgroup)

PBO + LI (n=157)

112.7

12.5

6.9

1.3

100

125.7

13.9

0.9

P/T 7.5 mg/46 mg + LI

(n=67)

111.4 10.8 6.8 1.2 100 NR 127 12.1 2.8 0.9 NR NR

P/T 15 mg/92 mg + LI

(n=164)

114.1 12.8 6.8 1.1 100 NR 126 14 3 1 NR NR

OB-204

(Winslow

2012)

PBO + LI (n=23)

138.4

13.5

121.5

36.2

109.2

46.6

P/T 15 mg/92 mg + LI

(n=22)

NR NR NR NR NR NR 137.5 12.1 131.6 35.5 110.2 30.1

Bupropion/Naltrexone

COR-I

PBO + LI (n=581)

110

12.2

119

9.8

3.1

0.9

93.6

10.8

B/N 360 mg/16 mg +

LI (n=578)

109.8 11.2 NR NR 0 NR 119.5 9.9 3.2 0.8 95.4 10.8

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Study Name Intervention(s)

Waist

Circumference,

A1C, Mean %

Diabetes

Pre-

Diabetes,

SBP, mm HG LDL, mg/dL

Fasting Blood

Glucose,

mg/dL

Mean

B/N 360 mg/32 mg +

LI (n=583)

108.8 11.3 NR NR 0 NR 118.9 9.9 3.1 0.8 93.6 12.6

COR-II

PBO + LI (n=495)

108.9*

11.7

118.2*

10.5

117.1*

32.6

94.2*

10.4

B/N 360 mg/32 mg +

LI (n=1,001)

109.3* 11.9 NR NR 0 NR 118.1* 10 119.8* 30.2 94.8* 11.2

COR-BMOD

PBO + BMOD (n=202)

109

11.8

116.7

10.9

109.2

27.3

94.1

20.1

B/N 360 mg/32 mg +

BMOD (n=591)

109.3 11.4 NR NR 0 NR 116.6 10.1 109.5 27.5 92.4 10.7

COR Diabetes

PBO + LI (n=159)

114.3

12.4

0.9

100

124.5

9.6

101

33.9

163.9

44.5

B/N 360 mg/32 mg +

LI (n=265)

115.6 12.6 8 0.8 100 NR 125 11 100.2 34.2 160 41.3

CVOT (Light

Study)

PBO + LI (n=4,450) 118.5†

IQR:

110-

128

7.1‡

IQR:

6.4-

8.2

85.5 NR 125.5 12.6 82†

IQR:

65-

106

NR NR

B/N 360 mg/32 mg +

LI (n=4,455)

118†

IQR:

110-

128

7‡

IQR:

6.1-

8.1

84.9 NR 125.9 12.5 82†

IQR:

64-

105

NR NR

Ignite

Usual care (including

LI) (n=89)

111.9 11.9 NR NR 0 NR 120.6 11.4 118* 26.2 92.4* 11.5

B/N 360 mg/32 mg +

CLI (n=153)

112.2 11.2 NR NR 0 NR 123.7 9.5 115.5* 27.6 89.7* 10.6

A1C: glycated hemoglobin, BMOD: behavioral modification, B/N: bupropion/naltrexone, CLI: comprehensive lifestyle intervention, cm: centimeter, dL: deciliter,

IBT: intensive behavioral therapy, IQR: interquartile range, KOA: knee osteoarthritis, LDL: low-density lipoprotein, LI: lifestyle intervention, LIR: liraglutide, mg:

milligram, mm Hg: millimeter of mercury, n: number, NR: not reported, PBO: placebo, P/T: phentermine/topiramate, SBP: systolic blood pressure, SC:

subcutaneous, SD: standard deviation, SEM: semaglutide, vs.: versus

*The number of patients for this characteristic may differ from the randomized population.

†Median.

‡Measured only in patients who had diabetes mellitus.

§Baseline data measured at Week 20.

#Baseline data measured at Week 68.

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Table D25. Baseline Characteristics III

29-35,39-43,45,48-50,52-66,72,140-142,145,146

Study Name

Intervention(s)

Pre-Existing Conditions

Medications

Semaglutide

STEP 1

PBO + LI (n=655)

Dyslipidemia (35%), HTN (36%), knee arthritis (16%),

sleep apnea (11%), asthma/COPD (12%), NAFLD (10%),

PCOS (7%), CAD (3%)

Antihypertensive; lipid lowering

SC SEM 2.4 mg + LI

(n=1306)

Dyslipidemia (38%), HTN (36%), knee arthritis (13%),

sleep apnea (12%), asthma/COPD (11%), NAFLD (7%),

PCOS (7%), CAD (3%)

STEP 1

(Extension)†

PBO→ Off Treatment

(n=99)

Dyslipidemia (40%), HTN (38%), KOA (19%), OSA (10%),

asthma/COPD (10%), NAFLD (16%), PCOS (10%), CAD

(2%)

GLP-1 (4%)

SC SEM 2.4 mg + LI→

Off Treatment

(n=228)

Dyslipidemia (42%), HTN (40%), KOA (11%), OSA (8%),

asthma/COPD (16%), NAFLD (9%), PCOS (13%), CAD (3%)

GLP-1 (6%)

STEP 2

PBO + LI (n=403)

CAD (8%), Dyslipidemia (71%), HTN (71%), knee arthritis

(17%), OSP (13%), NAFLD (23%), PCOS (5%),

asthma/COPD (8%)

Biguaindes (90%), Sulfonylureas (25%), SGLT2i

(26%), TZDs (5%), DDP4i (<1%), GLP-1 (<1%)

SC SEM 1.0 mg + LI

(n=403)

CAD (10%), Dyslipidemia (71%), HTN (71%), knee

arthritis (14%), OSP (13%), NAFLD (20%), PCOS (4%),

asthma/COPD (12%)

Biguaindes (94%), Sulfonylureas (25%), SGLT2i

(24%), TZDs (4%), DDP4i (<1%), GLP-1 (<1%)

SC SEM 2.4 mg + LI

(n=404)

CAD (6%), Dyslipidemia (66%), HTN (68%), knee arthritis

(18%), OSP (17%), NAFLD (21%), PCOS (3%),

asthma/COPD (9%)

Biguaindes (92%), Sulfonylureas (27%), SGLT2i

(25%), TZDs (5%), DDP4i (<1%), GLP-1 (<1%)

STEP 3

PBO + IBT (n=204)

Dyslipidemia (33%), HTN (33%), knee arthritis (15%),

asthma/COPD (12%), OSP (9%), NAFLD (6%), PCOS (6%),

CAD (2%)

SC SEM 2.4 mg + IBT

(n=407)

Dyslipidemia (36%), HTN (36%), knee arthritis (19%),

asthma/COPD (17%), OSP (14%), NAFLD (6%), PCOS

(5%), CAD (2%)

STEP 4

Run-in period (n=803)

Dyslipidemia (36%), HTN (37%), knee arthritis (12%),

OSA (12%), asthma/COPD (12%), NAFLD (7%), PCOS

(4%), CAD (<1%)

From run-in with

SEM→ PBO + LI

(n=268)*

Dyslipidemia (37%), HTN (37%), knee arthritis (10%),

OSA (12%), asthma/COPD (13%), NAFLD (7%), PCOS

(5%), CAD (1%)

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Study Name

Intervention(s)

Pre-Existing Conditions

Medications

From run-in with

SEM→ SC SEM 2.4 mg

+ LI (n=535)*

Dyslipidemia (35%), HTN (37%), knee arthritis (14%),

OSA (11%), asthma/COPD (11%), NAFLD (7%), PCOS

(4%), CAD (<1%)

STEP 5

PBO + LI (n=152)

SC SEM 2.4 mg + LI

(n=152)

NR NR

STEP 6

PBO + LI (n=101)

Dyslipidemia (79%), HTN (72%), NAFLD (46%), kidney

disease (13%), OSA (10%), knee arthritis (9%)

Biguanides (72%), SGLT2 inhibitors (52%),

Sulfonylureas (32%), Thiazolidinediones (12%)

SC SEM 1.7 mg + LI

(n=101)

Dyslipidemia (87%), HTN (73%), NAFLD (40%), kidney

disease (15%), OSP (13%), knee arthritis (9%)

Biguanides (60%), SGLT2 inhibitors (44%),

Sulfonylureas (24%), Thiazolidinediones (16%)

SC SEM 2.4 mg + LI

(n=199)

Dyslipidemia (90%), HTN (76%), NAFLD (47%), kidney

disease (14%), OSP (9%), knee arthritis (11%)

Biguanides (53%), SGLT2 inhibitors (41%),

Sulfonylureas (14%), Thiazolidinediones (16%)

Semaglutide vs. Liraglutide

STEP 8

PBO +LI (n=85)

Dyslipidemia (42%), HTN (46%), knee arthritis (26%),

OSA (22%), asthma/copd (15%), NAFLD (8%), PCOS (2%),

CAD (5%)

SC 2.4 mg + LI (n=126)

Dyslipidemia (48%), HTN (38%), knee arthritis (18%),

OSA (19%), asthma/copd (14%), NAFLD (4%), PCOS (5%),

CAD (3%)

SC LIR 3.0 mg + LI

(n=127)

Dyslipidemia (51%), HTN (43%), knee arthritis (13%),

OSA (14%), asthma/copd (14%), NAFLD (9%), PCOS (6%),

CAD (2%)

Liraglutide

SCALE

(Maintenance)

PBO + LI (n=210)

Dyslipidemia (31%), HTN (29%)

SC LIR 3.0 mg + LI

(n=212)

Dyslipidemia (28%), HTN (33%) NR

SCALE (Sleep

Apnea)

PBO + LI (n=179)

Dyslipidemia (31%), HTN (43%)

SC LIR 3.0 mg + LI

(n=180)

Dyslipidemia (36%), HTN (42%)

SCALE (Type 2

Diabetes)

PBO + LI (n=212)

Dyslipidemia (59%), HTN (68%)

Metformin, glitazone, sulfonylurea

1.8mg SC LIR + LI

(n=211)

Dyslipidemia (68%), HTN (70%)

SC LIR 3.0 mg + LI

(n=423)

Dyslipidemia (70%), HTN (69%)

PBO + LI (n=1244)

Dyslipidemia (29%), HTN (36%)

Anti-hypertensives (33%), lipid-lowering drugs (15%)

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Study Name

Intervention(s)

Pre-Existing Conditions

Medications

SCALE (Obesity

& Pre-Diabetes)

SC LIR 3.0 mg + LI

(n=2487)

Dyslipidemia (39%), HTN (34%) Anti-hypertensives (31%), lipid-lowering drugs (16%)

SCALE (IBT)

PBO + IBT (n=140)

SC LIR 3.0 mg + IBT

(n=142)

NR NR

SCALE (Insulin)

PBO + IBT (n=198)

biguanides, sulfonylureas, SGLT2i, TZDs

SC LIR 3.0 mg + IBT

(n=198)

LOSEIT (KOA)

PBO + LI (n=76)

SC LIR 3.0 mg + LI

(n=80)

NR NR

EQUIP

PBO +LI (n=514)

Depression (16%)

Antidepressants (13%)

P/T 3.75 mg/23 mg +

LI (n=241)

Depression (20%) Antidepressants (15%)

P/T 15 mg/92 mg + LI

(n=512)

Depression (15%) Antidepressants (13%)

EQUATE

PBO + LI (n=109)

HTN (33%) & dyslipidemia (22%)

SSRIs (9%)

Phentermine 7.5 mg +

LI (n=109)

HTN (32%) & dyslipidemia (26%) SSRIs (13%)

Topiramate 46 mg +

LI (n=108)

HTN (23%) & dyslipidemia (31%) SSRIs (13%)

P/T 7.5 mg/46 mg + LI

(n=107)

HTN (24%) & dyslipidemia (17%) SSRIs (12%)

Phentermine 15 mg +

LI (n=108)

HTN (34%) & dyslipidemia (35%) SSRIs (13%)

Topiramate 92 mg +

LI (n=107)

HTN (27%) & dyslipidemia (27%) SSRIs (10%)

P/T 15 mg/92 mg + LI

(n=108)

HTN (30%) & dyslipidemia (24%) SSRIs (10%)

CONQUER

(Diabetes

Subgroup)

PBO +LI (n=157)

Dyslipidemia (32%) & HTN (52%)

P/T 7.5 mg/46 mg + LI

(n=67)

Dyslipidemia (40%) & HTN (60%) NR

P/T 15 mg/92 mg + LI

(n=164)

Dyslipidemia (32%) & HTN (55%) NR

PBO + LI (n=23)

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Study Name

Intervention(s)

Pre-Existing Conditions

Medications

OB-204

(Winslow 2012)

P/T 15 mg/92 mg + LI

(n=22)

NR NR

COR-I

PBO + LI (n=581)

HTN (19%) and dyslipidemia (50%)

B/N 360 mg/16 mg +

LI (n=578)

HTN (20%) and dyslipidemia (50%) NR

B/N 360 mg/32 mg +

LI (n=583)

HTN (22%) and dyslipidemia (49%) NR

COR-II

PBO + LI (n=495)

HTN (21%) and dyslipidemia (53%)

B/N 360 mg/32 mg +

LI (n=1001)

HTN (21%) and dyslipidemia (56%) NR

COR-BMOD

PBO + BMOD (n=202)

HTN (NR) and dyslipidemia (NR) NR

B/N 360 mg/32 mg +

BMOD (n=591)

COR Diabetes

PBO + LI (n=159)

Dyslipidemia (86%)

Sulfonylurea (49%), TZDs (31%), Metformin (77%)

B/N 360 mg/32 mg +

LI (n=265)

Dyslipidemia (83%) Sulfonylurea (49%), TZDs (31%), Metformin (80%)

CVOT (Light

Study)

PBO + LI (n=4450)

CVD (33%), diabetes (86%), CVD & diabetes (18%), HTN

(93%), dyslipidemia (92%)

Statin (79%), Insulin (23%), Metformin (57%), B-

Blocker (38%), Diuretic (32%), ACE inhibitor/ARB

(77%), Calcium channel blocker (19%)

B/N 360 mg/32 mg +

LI (n=4455)

CVD (32%), diabetes (85%), CVD & diabetes (17%), HTN

(93%), dyslipidemia (92%)

Statin (79%), Insulin (23%), Metformin (57%), B-

Blocker (40%), Diuretic (33%), ACE inhibitor/ARB

(77%), Calcium channel blocker (20%)

Ignite

Usual care (including

LI) (n=89)

NR NR

B/N 360 mg/32 mg +

CLI (n=153)

NR NR

ACE: angiotensin-converting enzyme, ARB: angiotensin II receptor blocker, BMOD: behavioral modification, B/N: bupropion/naltrexone, CAD: coronary artery

disease, CLI: comprehensive lifestyle intervention, COPD: chronic obstructive pulmonary disease, CVD: cardiovascular disease, DDp4i:

dipeptidyl peptidase-4,

GLP-1:

glucagon-like peptide-1, HTN: hypertension, IBT: intensive behavioral therapy, KOA: knee osteoarthritis, LI: lifestyle intervention, LIR: liraglutide, mg:

milligram, n: number, NAFLD: nonalcoholic fatty liver disease, NR: not reported, OSA: obstructive sleep apnea, OSP: oral sodium phosphate, PBO: placebo,

PCOS: polycystic ovarian syndrome, P/T: phentermine/topiramate, SC: subcutaneous, SEM: semaglutide, SGLT2: sodium-glucose cotransporter-2, TZD:

thiazolidinediones, vs.: versus

*Baseline data measured at Week 20.

†Baseline data measured at Week 68.

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Table D26. Efficacy: Weight Loss Outcomes I

29-38,40-45,48-67,72,140-149

Study Name Arms N

Change in Body Weight from

Baseline, Mean kg

Weight Loss from Baseline

to Six Months, Mean %

Weight Loss from Baseline

to One Year, Mean %

Mean

Semaglutide

STEP 1

PBO + LI

655

577

-2.6

592

-2.9

0.2

577

-2.8

0.3*

SC SEM 2.4 mg + LI

1306

1212

-15.3

1232

-11.7

0.2

1212

-15.6

0.3*

STEP 1

(Extension)#

PBO→ Off Treatment

0.5

2.1

0.5

SC SEM 2.4 mg + LI→

Off Treatment

197 197 12 0.6 NR NR NR 197 14.8 0.8

STEP 2

PBO + LI

403

376

-3.5

0.4

381

-2.7

0.2

376

-3.4

0.4

SC SEM 1.0 mg + LI

403

380

-6.9

0.4

378

-6.6

0.3

380

-7

0.4

SC SEM 2.4 mg + LI

404

388

-9.7

0.4

386

-8.7

0.3

388

-9.6

0.4

STEP 3

PBO + IBT

204

-6.2

189

-7.9

0.5*

189

-5.8

0.4*

SC SEM 2.4 mg + IBT

407

-16.8

380

-15.4

0.3*

373

-16.5

0.5*

STEP 4

Run-in period†

803

-11.1

0.2*

803

-10.6

0.2*

From run-in with SEM→

PBO + LI‡

268 250 6.1 0.5* 265 -9.6 0.3* 268 6.9 0.5*

From run-in with SEM→ SC

SEM 2.4 mg + LI‡

535 520 -7.1 0.3* 531 -13.2 0.3* 535 -7.9 0.4*

STEP 5

PBO + LI

152

129

-3.5

0.7*

129

-2.6

129

-3.3

0.6*

SC SEM 2.4 mg + LI

152

149

-16.7

0.8*

149

-12

149

-15.8

0.8*

STEP 6

PBO + LI

101

100

-1.7

0.7

100

-2.4

0.4

101

-2.1

0.8

SC SEM 1.7 mg + LI

101

-8.2

0.7

-8.3

0.6

-9.6

0.8

SC SEM 2.4 mg + LI

199

193

-11.3

0.5

197

-10.1

0.4

193

-13.2

0.5

Semaglutide vs. Liraglutide

STEP 8

PBO + LI

-1.6

1.2*

-1.9

1.1*

SC SEM 2.4 mg + LI

126

-15.3

1.0*

-13.3

117

-15.8

0.9*

SC LIR 3.0 mg

127

-6.8

1.0*

-6.8

117

-6.4

0.9*

Liraglutide

SCALE

(Maintenance)

PBO + LI

206

-0.1

0.5*

168

-1

0.5

144

-0.2

0.5*

SC LIR 3.0 mg + LI

207

-6

0.5*

181

-7.7

0.5

156

-6.2

0.5*

SCALE (Sleep

Apnea)§

PBO + LI

178

-1.9

0.4

178

-1.6

0.3

SC LIR 3.0 mg + LI

175

-6.7

0.5

175

-5.7

0.4

PBO + LI

211

116

-3.1

0.5*

137

-2.7

0.3*

211

-2

0.3*

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Study Name Arms N

Change in Body Weight from

Baseline, Mean kg

Weight Loss from Baseline

to Six Months, Mean %

Weight Loss from Baseline

to One Year, Mean %

Mean

SCALE (Type 2

Diabetes)

SC LIR 1.8 mg + LI

204

158

-5.2

0.5*

172

-4.9

0.3*

204

-4.6

0.4*

SC LIR 3.0 mg + LI

412

317

-7

0.3*

337

-6

0.3*

412

-5.9

0.3*

SCALE (Obesity

& Pre-

Diabetes)

PBO + LI

1225

-2.8

6.5

1225

-2.9

0.3

1220

-2.6

0.2*

SC LIR 3.0 mg + LI 2437 2437 -8.4 7.3 2437 -8.2 0.2 2432 -8 0.1*

SCALE (IBT)

PBO + IBT

140

128

-5.4

0.5

130

-4

0.6*

SC LIR 3.0 mg + IBT

142

137

-8.4

0.6

141

-7.4

0.7*

SCALE (Insulin)

PBO + IBT

198

183

-2.1

0.4

193

-1.5

0.4

SC LIR 3.0 mg + IBT

198

188

-6.4

0.4

191

-5.8

0.4

LOSEIT

PBO + LI

1.2

1.2*

SC LIR 3.0 mg + LI

-2.8

1.3*

Phentermine/Topiramate

EQUIP

PBO + LI

498

-1.6

0.4

P/T 3.75 mg/23 mg + LI

234

-5.1

0.5

P/T 15 mg/92 mg + LI

498

-10.9

0.4

EQUATE

PBO + LI

103

-1.5

103

-1.7

0.6

Phentermine 7.5 mg + LI

104

-5.3

104

-5.5

0.6

Topiramate 46 mg + LI

102

-4.7

102

-5.1

0.6

P/T 7.5 mg/46 mg + LI

103

-8.3

103

-8.5

0.6

Phentermine 15 mg + LI

106

-6

106

-6.1

0.6

Topiramate 92 mg + LI

105

-6.4

105

-6.4

0.6

P/T 15 mg/92 mg + LI

103

-9

103

-9.2

0.6

CONQUER

(Diabetes

Subgroup)

PBO +LI

157

-1.9

0.6*

P/T 7.5 mg/46 mg + LI

-6.8

0.9*

P/T 15 mg/92 mg + LI

164

-8.8

0.6*

OB-204

(Winslow

2012)

PBO + LI

-4.7

1.2

-4.2

1.2

P/T 15 mg/92 mg + LI 22 22 -11 1.2 22 -10.3 1.2 NR NR NR

Bupropion/Naltrexone

COR-I

PBO + LI

511

-1.4

0.3

511

-1.3

0.3

B/N 360 mg/16 mg + LI

471

-4.9

0.3

471

-5

0.3

B/N 360 mg/32 mg + LI

471

-6.1

0.3

471

-6.1

0.3

COR-II

PBO + LI

456

-1.3

0.3

456

-1.9

0.3

456

-1.2

0.3

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Study Name Arms N

Change in Body Weight from

Baseline, Mean kg

Weight Loss from Baseline

to Six Months, Mean %

Weight Loss from Baseline

to One Year, Mean %

Mean

B/N 360 mg/32 mg + LI

702

-6.2

0.2

825

-6.5

0.2

702

-6.4

0.3

COR-BMOD

PBO + BMOD

202

-5.6

0.5

193

-5.1

0.6

B/N 360 mg/32 mg +

BMOD

591 NR NR NR NR -9.4 0.4 482 -9.3 0.4

COR-Diabetes

PBO + LI

159

-2

0.4

159

-1.8

0.4

B/N 360 mg/32 mg + LI

265

-5.1

0.3

265

-5

0.3

CVOT (Light

Study)

PBO + LI

4450

2848

-1.9

0.1*

3297

-1.7

2848

-1.8

B/N 360 mg/32 mg + LI

4455

2995

-4.9

0.1*

3404

-4.5

2995

-4.6

Ignite

Usual care (including LI)

-1

0.5

-0.9

0.5

B/N 360 mg/32 mg + CLI

-9.5

0.6

-9.5

0.5

BMOD: behavioral modification, B/N: bupropion/naltrexone, CLI: comprehensive lifestyle intervention, IBT: intensive behavioral therapy, KOA: knee

osteoarthritis, kg: kilogram, LI: lifestyle intervention, LIR: liraglutide, mg: milligram, N: total number, NR: not reported, PBO: placebo, P/T:

phentermine/topiramate, SC: subcutaneous, SE: standard error, SEM: semaglutide, vs.: versus

*SE manually derived from standard deviation or 95% CIs.

†Timepoint for outcomes is at Week 20.

‡Timepoint for outcomes is Week 20-68.

§Timepoint for all outcomes is at Week 32.

#Timepoint for all outcomes is Week 68-120.

©Institute for Clinical and Economic Review, 2022 Page D66

Evidence Report – Medications for Obesity Management Return to Table of Contents

Table D27. Efficacy: Weight Loss Outcomes II

29-38,40-45,48-52,54-57,59-67,72,140-144,147-149

Study Name Arms N

% Participants with 5% Body

Weight Loss

% Participants with 10% Body

Weight Loss

% Participants with 15% Body

Weight Loss

Semaglutide

STEP 1

PBO + LI

655

31.5

182

577

4.9

577

SC SEM 2.4 mg + LI

1306

86.4

1047

1212

69.1

838

1212

50.5

612

1212

STEP 1

(Extension)‡

PBO→ Off Treatment

22.6

SC SEM 2.4 mg + LI→

Off Treatment

197 48.2 95 197 NR NR NR NR NR NR

STEP 2

PBO + LI

403

28.5

107

376

8.2

376

3.2

376

SC SEM 1.0 mg + LI

403

57.1

217

380

28.7

109

380

13.7

380

SC SEM 2.4 mg + LI

404

68.8

267

388

45.6

177

388

25.8

100

388

STEP 3

PBO + IBT

204

47.6

189

13.2

189

SC SEM 2.4 mg + IBT

407

86.6

323

373

75.3

281

373

55.8

208

373

STEP 4

Run-in period

803

From run-in with SEM→

PBO + LI*

268 47.6 119 250 20.4 51 250 9.2 23 250

From run-in with SEM→

SC SEM 2.4 mg + LI*

535 88.7 461 520 79 411 520 63.7 331 520

STEP 5

PBO + LI

152

29.5

129

13.2

129

5.4

129

SC SEM 2.4 mg + LI

152

88.6

132

149

68.5

102

149

52.3

149

STEP 6

PBO

101

100

SC SEM 1.7 mg + LI

101

SC SEM 2.4 mg + LI

199

160

193

117

193

Semaglutide vs. Liraglutide

STEP 8

PBO +LI

29.5

15.4

6.4

SC SEM 2.4 mg + LI

126

87.2

102

117

70.9

117

55.6

117

SC LIR 3.0 mg

127

58.1

117

25.6

117

Liraglutide

SCALE

(Maintenance)

PBO + LI

206

21.8

188

6.3

188

SC LIR 3.0 mg + LI

207

50.5

194

26.1

194

SCALE (Sleep

Apnea)†

PBO + LI

178

18.5

178

1.7

178

SC LIR 3.0 mg + LI

175

46.3

175

23.4

175

PBO + LI

211

21.4

211

6.7

211

©Institute for Clinical and Economic Review, 2022 Page D67

Evidence Report – Medications for Obesity Management Return to Table of Contents

Study Name Arms N

% Participants with 5% Body

Weight Loss

% Participants with 10% Body

Weight Loss

% Participants with 15% Body

Weight Loss

SCALE (Type 2

Diabetes)

SC LIR 1.8 mg + LI

204

40.4

204

15.9

204

SC LIR 3.0 mg + LI

412

54.3

224

412

25.2

104

412

SCALE (Obesity

& Pre-

Diabetes)

PBO + LI

1225

27.1

331

1220

10.6

129

1220

SC LIR 3.0 mg + LI 2437 63.2 1537 2432 33.1 805 2432 NR NR NR

SCALE (IBT)

PBO + IBT

140

38.8

130

19.8

130

8.9

130

SC LIR 3.0 mg + IBT

142

61.5

141

30.5

141

18.1

141

SCALE (Insulin)

PBO + IBT

198

193

6.6

193

SC LIR 3.0 mg + IBT

198

51.8

100

191

22.8

191

LOSEIT

PBO + LI

17.1

9.6

SC LIR 3.0 mg + LI

21.3

Phentermine/Topiramate

EQUIP

PBO +LI

498

17.3

498

7.4

498

3.4

498

P/T 3.75 mg/23 mg + LI

234

44.9

105

234

18.8

234

7.3

234

P/T 15 mg/92 mg + LI

498

66.7

332

498

47.2

235

498

32.3

161

498

EQUATE

PBO + LI

103

15.5

103

6.8

103

Phentermine 7.5 mg + LI

104

43.3

104

12.5

104

Topiramate 46 mg + LI

102

39.2

102

18.6

102

P/T 7.5 mg/46 mg + LI

103

62.1

103

38.8

103

Phentermine 15 mg + LI

106

46.2

106

20.8

106

Topiramate 92 mg + LI

105

48.6

105

23.8

105

P/T 15 mg/92 mg + LI

103

40.8

103

CONQUER

(Diabetes

subgroup)

PBO + LI

157

P/T 7.5 mg/46 mg + LI

P/T 15 mg/92 mg + LI

164

OB-204

(Winslow

2012)

PBO + LI

47.8

P/T 15 mg/92 mg + LI 22 72.7 16 22 54.5 12 22 NR NR NR

Bupropion/Naltrexone

COR-I

PBO + LI

511

B/N 360 mg/16 mg + LI

471

186

471

B/N 360 mg/32 mg + LI

471

226

471

116

471

COR-II

PBO + LI

456

17.1

456

5.7

456

2.4

456

Evidence Report – Medications for Obesity Management Return to Table of Contents

Study Name Arms N

% Participants with 5% Body

Weight Loss

% Participants with 10% Body

Weight Loss

% Participants with 15% Body

Weight Loss

B/N 360 mg/32 mg + LI

702

50.5

354

702

28.3

199

702

13.5

702

COR-BMOD

PBO + BMOD

202

42.5

193

20.2

193

10.9

193

B/N 360 mg/32 mg +

BMOD

591 66.4 320 482 41.5 200 482 29.1 140 482

COR-Diabetes

PBO + LI

159

18.9

159

5.7

159

B/N 360 mg/32 mg + LI

265

44.5

118

265

18.5

265

CVOT (Light

Study)

PBO + LI

4450

B/N 360 mg/32 mg + LI

4455

Ignite

Usual care (including LI)

12.2

3.7

B/N 360 mg/32 mg + CLI

84.5

42.3

12.7

BMOD: behavioral modification, B/N: bupropion/naltrexone, CLI: comprehensive lifestyle intervention, IBT: intensive behavioral therapy, KOA: knee

osteoarthritis, kg: kilogram, LI: lifestyle intervention, LIR: liraglutide, mg: milligram, n: number, N: total number, NR: not reported, PBO: placebo, P/T:

phentermine/topiramate, SC: subcutaneous, SEM: semaglutide, vs.: versus

*Timepoint for outcomes is Weeks 0-68.

†Timepoint for all outcomes is at Week 32.

‡Timepoint for all outcomes is Week 68-120.

Evidence Report – Medications for Obesity Management Return to Table of Contents

Table D28. Efficacy: Secondary Outcomes I

29-38,40-45,48-67,72,140-149

Study Name Arms N

Change in A1C from Baseline, Mean %

Change in SBP from Baseline,

Mean mm Hg

Change in Waist

Circumference from

Baseline, cm

Mean

Semaglutide

STEP 1

PBO + LI

655

563

-0.15

0.01*

577

-1.1

0.5*

-4.1

SC SEM 2.4 mg + LI

1306

1197

-0.45

0.01*

1212

-6.2

0.4*

-13.5

STEP 1

(Extension)¤

PBO→ Off Treatment

0.1

0.03

1.6

SC SEM 2.4 mg + LI→

Off Treatment

197 195 0.4 0.02 197 9 1.0 NR NR

STEP 2

PBO + LI

403

374

-0.4

0.1

376

-0.5

0.8

-4.5

0.4

SC SEM 1.0 mg + LI

403

376

-0.4

0.1

379

-2.9

0.9

-6.7

0.4

SC SEM 2.4 mg + LI

404

381

-0.4

0.1

387

-3.9

0.7

-9.4

0.4

STEP 3

PBO + IBT

204

-0.27

0.01*

188

-1.6

1.1*

-6.3

SC SEM 2.4 mg + IBT

407

-0.51

0.02*

372

-5.6

0.7*

-14.6

STEP 4

Run-in period†

803

-0.4

0.01*

803

-5.7

0.5*

-10.1

0.2*

From run-in with

SEM→ PBO + LI‡

268 246 0.1 0* 248 4.4 0.8* 3.3 0.5*

From run-in with

SEM→ SC SEM 2.4 mg

+ LI‡

535 515 -0.1 0.03* 518 0.5 0.6* -6.4 0.4*

STEP 5

PBO + LI

152

129

-0.2

0.02*

129

-1

1.2*

-4.5

0.6*

SC SEM 2.4 mg + LI

152

149

-0.5

0.03*

149

-7

1.1*

-14.3

0.8*

STEP 6

PBO + LI

101

100

-0.03

0.07

100

-5.3

1.2

-1.8

0.7

SC SEM 1.7 mg + LI

101

-0.89

0.07

-10.8

1.3

-7.7

0.7

SC SEM 2.4 mg + LI

199

193

-0.93

0.05

193

-10.8

0.9

-11.1

0.5

Semaglutide vs. Liraglutide

STEP 8

PBO + LI

0.1

0.02*

3.2

1.5*

-2

1.1*

SC SEM 2.4 mg + LI

126

113

-0.2

0.03*

114

-5.7

1.2*

-13.2

0.9*

SC LIR 3.0 mg

127

107

-0.1

0.03*

112

-2.9

1.2*

-6.6

0.9*

Liraglutide

SCALE

(Maintenance)

PBO + LI

206

0.1

0.03*

206

2.8

0.7*

-1.2

0.4*

SC LIR 3.0 mg + LI

207

-0.1

0.03*

207

0.2

0.8*

-4.7

0.5*

SCALE (Sleep

Apnea)§

PBO + LI

178

171

-0.2

179

-3.1

0.5

SC LIR 3.0 mg + LI

175

174

-0.4

178

-3.4

0.9

-6.4

0.5

PBO + LI

211

-0.3

0.06*

211

-0.4

0.9*

-2.7

0.4*

Evidence Report – Medications for Obesity Management Return to Table of Contents

Study Name Arms N

Change in A1C from Baseline, Mean %

Change in SBP from Baseline,

Mean mm Hg

Change in Waist

Circumference from

Baseline, cm

Mean

SCALE (Type 2

Diabetes)

SC LIR 1.8 mg + LI

204

-1.1

0.07*

204

-3.5

0.9*

-4.8

0.4*

SC LIR 3.0 mg + LI

412

411

-1.3

0.04*

411

-2.8

0.7*

-6.1

0.3*

SCALE (Obesity

& Pre-Diabetes)

PBO + LI

1225

-0.06

0.01*

1225

-1.5

0.4*

-3.9

0.2*

SC LIR 3.0 mg + LI

2437

-0.3

0.01*

2437

-4.2

0.3*

-8.2

0.1*

SCALE (IBT)

PBO + IBT

140

-0.06

0.02*

130

-0.6

-6.7

SC LIR 3.0 mg + IBT

142

-0.16

0.03*

141

-2.8

-9.4

SCALE (Insulin)

PBO + IBT

198

188

-0.6

198

-1.6

0.9

-2.6

SC LIR 3.0 mg + IBT

198

187

-1.1

198

-5.6

0.9

-5.3

LOSEIT

PBO + LI

0.9

1.1*

SC LIR 3.0 mg + LI

-1.4

1.1*

Phentermine/Topiramate

EQUIP

PBO + LI

498

0.9

0.6*

-3.1

0.5*

P/T 3.75 mg/23 mg + LI

234

-1.8

0.8*

-5.6

0.6*

P/T 15 mg/92 mg + LI

498

-2.9

0.6*

-10.9

0.5*

EQUATE

PBO + LI

103

0.1

0.02

103

-1.8

-3.3

0.7

Phentermine 7.5 mg +

104 89 0.1 0.02 104 -3.3 NR -6.4 0.7

Topiramate 46 mg + LI

102

0.1

0.02

102

-6.8

-5.4

0.7

P/T 7.5 mg/46 mg + LI

103

0.02

102

-7

-8.8#

0.7

Phentermine 15 mg +

106 90 0.1 0.02 104 -3.5 NR -6.6 0.7

Topiramate 92 mg + LI

105

0.02

105

-6.4

-6.2

0.7

P/T 15 mg/92 mg + LI

103

0.02

103

-5.2

-8.7

0.7

CONQUER

(Diabetes

subgroup)

PBO +LI

157

144

-0.1

0.05

157

-2.1

1.1

P/T 7.5 mg/46 mg + LI

-0.4

1.5*

-2.9

1.6

P/T 15 mg/92 mg + LI

164

150

-0.4

0.6*

153

-4.2

OB-204

(Winslow 2012)

PBO + LI

-7.3

2.6

P/T 15 mg/92 mg + LI 22 NR NR NR 22 -15 2.6 NR NR

Bupropion/Naltrexone

COR-I

PBO + LI

511

-1.9

0.4

-2.5

0.4

B/N 360 mg/16 mg + LI

471

0.3

0.4

-5

0.4

B/N 360 mg/32 mg + LI

471

-0.1

0.4

-6.2

0.4

Evidence Report – Medications for Obesity Management Return to Table of Contents

Study Name Arms N

Change in A1C from Baseline, Mean %

Change in SBP from Baseline,

Mean mm Hg

Change in Waist

Circumference from

Baseline, cm

Mean

COR-II

PBO + LI

456

-0.5

0.4

-2.1

0.5

B/N 360 mg/32 mg + LI

702

0.6

0.3

-6.7

0.3

COR-BMOD

PBO + BMOD

202

193

-3.9

0.7

-6.8

0.8*

B/N 360 mg/32 mg +

BMOD

591 NR NR NR 482 -1.3 0.5 -10 0.5*

COR-Diabetes

PBO + LI

159

137

-0.14

0.09

159

-1.1

0.9

-2.9

0.6

B/N 360 mg/32 mg + LI

265

222

-0.63

0.07

265

0.7

-5

0.5

CVOT (Light

Study)

PBO + LI

4450

2850

0.3*

-0.8

0.1*

B/N 360 mg/32 mg + LI

4455

2997

1.2

0.3*

-2.1

0.2*

Ignite

Usual care (including

LI)

82 NR NR NR 82 -2.8 1 -1.6 0.7

B/N 360 mg/32 mg +

CLI

71 NR NR NR 71 -4.8 1.1 -7 0.7

A1C: glycated hemoglobin, BMOD: behavioral modification, B/N: bupropion/naltrexone, CLI: comprehensive lifestyle intervention, cm: centimeter, IBT: intensive

behavioral therapy, KOA: knee osteoarthritis, kg: kilogram, LI: lifestyle intervention, LIR: liraglutide, mg: milligram, N: total number, NR: not reported, PBO: placebo,

P/T: phentermine/topiramate, SBP: systolic blood pressure, SC: subcutaneous, SE: standard error, SEM: semaglutide, vs.: versus

*SE manually derived from standard deviation or 95% CIs.

†Timepoint for outcomes is at Week 20.

‡Timepoint for outcomes is Week 20-68.

§Timepoint for all outcomes is at Week 32.

#The number of patients for this outcome may differ from the primary analysis population.

¤Timepoint for all outcomes is Week 68-120.

Evidence Report – Medications for Obesity Management Return to Table of Contents

Table D29. Efficacy: Secondary Outcomes II

29-38,40-45,48-67,72,140-149

Study Name Arms N

Change in LDL from Baseline,

mg/dL

Ratio of LDL from Baseline

Change in Blood

Glucose, mg/dL

Change in BMI, kg/m2

Mean

Semaglutide

STEP 1

PBO + LI

655

561

1.1

561

1.01

-0.5

-0.9

SC SEM 2.4 mg + LI

1306

1194

-3.3

1194

0.97

-8.4

-5.5

STEP 1

(Extension)††

PBO→ Off Treatment

0.95

0.7

0.2

SC SEM 2.4 mg + LI→

Off Treatment

197 NR NR NR 194 1.01 NR NR NR 4.3 0.2

STEP 2

PBO + LI

403

374

1.00

-0.1

1.8

-1.3

0.1

SC SEM 1.0 mg + LI

403

376

-0.9

376

0.99

-1.8

1.8

-2.5

0.1

SC SEM 2.4 mg + LI

404

382

1.00

-2.1

1.8

-3.5

0.1

STEP 3

PBO + IBT

204

2.6

-0.7

-2.2

SC SEM 2.4 mg + IBT

407

-4.7

-6.7

-6.0

STEP 4

Run-in period† 803 NR NR NR 798 1

IQR:

0.8-1.1

-9.5 0.4* -4.0 0.1*

From run-in with

SEM→ PBO + LI‡

268 245 8 1.3* NR NR NR 6.7 0.9* 2.2 0.2*

From run-in with

SEM→ SC SEM 2.4 mg

+ LI‡

535 517 1 1.0* NR NR NR -0.8 0.5* -2.6 0.1*

STEP 5

PBO + LI

152

129

-1.1

129

0.99

1.6*

-1.3

0.2*

SC SEM 2.4 mg + LI

152

149

-7.8

149

0.93

-7.6*

-6

0.3*

STEP 6

PBO

101

0.96

2.2

1.6

-0.6

0.2

SC SEM 1.7 mg+ LI

101

0.90

-17.8

1.8

-3.1

0.2

SC SEM 2.4 mg+ LI

199

193

0.85

-19.6

1.3

-4.2

0.2

Semaglutide vs. Liraglutide

STEP 8

PBO +LI

-1.1

5.6*

3.3

1.4*

SC SEM 2.4 mg + LI

126

112

-6.5

3.1*

-8.3

1.1*

SC LIR 3.0 mg

127

107

0.9

2.8*

-4.3

1.2*

Liraglutide

SCALE

(Maintenance)

PBO + LI

206

11.6

1.6*

-3.6

0.9*

0.2*

SC LIR 3.0 mg + LI

207

7.7

1.6*

-9.0

0.8*

-2.1

0.2*

SCALE (Sleep

Apnea)§

PBO + LI

178

3.6

1.8

-0.6

0.1

SC LIR 3.0 mg + LI

175

-3.6

1.8

-2.2

0.2

SCALE (Type 2

Diabetes)

PBO + LI

211

-0.2

2.6*

-0.8

0.1*

SC LIR 1.8 mg + LI

204

-3.1

-26.8

3.5*

-1.7

0.1*

SC LIR 3.0 mg + LI

412

411

0.6

-34.3

1.9*

-2.2

0.1*

Evidence Report – Medications for Obesity Management Return to Table of Contents

Study Name Arms N

Change in LDL from Baseline,

mg/dL

Ratio of LDL from Baseline

Change in Blood

Glucose, mg/dL

Change in BMI, kg/m2

Mean

SCALE (Obesity

& Pre-Diabetes)

PBO + LI

1225

-1

0.1

0.3*

-1.0

0.1*

SC LIR 3.0 mg + LI

2437

-3

-7.1

0.2*

-3.0

0.1*

SCALE (IBT)

PBO + IBT

140

130

1.5

0.2

SC LIR 3.0 mg + IBT

142

141

-1.5

-4.1

SCALE (Insulin)

PBO + IBT

198

190

0.9

190

1.01

-11.5

SC LIR 3.0 mg + IBT

198

186

-2.8

186

0.97

-18.4

LOSEIT

PBO + LI

0.3

0.4*

SC LIR 3.0 mg + LI

-1.0

0.4*

Phentermine/Topiramate

EQUIP

PBO +LI

498

478

-5.5¤

0.9*

1.9

0.5*

P/T 3.75 mg/23 mg +

234 230 -7.7¤ 1.3* NR NR NR 0.8 0.7* NR NR

P/T 15 mg/92 mg + LI

498

486

-8.4¤

0.9*

-0.6

0.5*

EQUATE

PBO + LI

103

-0.1**

0.1

Phentermine 7.5 mg +

104 NR NR NR NR NR NR 0.0** 0.1 NR NR

Topiramate 46 mg + LI

102

0.0**

0.1

P/T 7.5 mg/46 mg + LI

103

0.0**

0.1

Phentermine 15 mg +

106 NR NR NR NR NR NR -0.1** 0.1 NR NR

Topiramate 92 mg + LI

105

0.0**

0.1

P/T 15 mg/92 mg + LI

103

-0.1**

0.1

CONQUER

(Diabetes

Subgroup)

PBO + LI

157

152

-2.3

2.1

-5.4

1.8*

P/T 7.5 mg/46 mg + LI

-3.6

3.2

-9

3.6*

P/T 15 mg/92 mg + LI

164

158

-2.8

-12.6

1.8*

OB-204

(Winslow 2012)

PBO + LI

-1.6

5.6

-5.6

5.9

P/T 15 mg/92 mg + LI

-11

-8.9

6.1

Bupropion/Naltrexone

COR-I

PBO + LI

511

345

-3.3

1.2

-1.3

0.6

B/N 360 mg/16 mg +

471 332 -3.7 1.2 NR NR NR -2.4 0.6 NR NR

B/N 360 mg/32 mg +

471 358 -4.4 1.2 NR NR NR -3.2 0.6 NR NR

COR-II

PBO + LI

456

-2.1

1.3

-1.3

0.6

B/N 360 mg/32 mg +

702 702 -6.2 0.9 NR NR NR -2.8 0.5 NR NR

COR-BMOD

PBO + BMOD

202

143

8.1

2.1

-1.1

1.0

Evidence Report – Medications for Obesity Management Return to Table of Contents

Study Name Arms N

Change in LDL from Baseline,

mg/dL

Ratio of LDL from Baseline

Change in Blood

Glucose, mg/dL

Change in BMI, kg/m2

Mean

B/N 360 mg/32 mg +

BMOD

591 392 5.4 1.4 NR NR NR -2.4 0.6 NR NR

COR-Diabetes

PBO + LI

159

134

2.4

-4

3.4

B/N 360 mg/32 mg +

265 220 -1.4 1.9 NR NR NR -11.9 2.7 NR NR

CVOT (Light

Study)

PBO + LI

4450

B/N 360 mg/32 mg +

4455 NR NR NR NR NR NR NR NR NR NR

Ignite

Usual care (including

LI)

82 82 -1.9 2.1 NR NR NR 1.6 1.0 NR NR

B/N 360 mg/32 mg +

CLI

71 71 -2 2.2 NR NR NR -2.9 1.0 NR NR

BMI: body-mass index, BMOD: behavioral modification, B/N: bupropion/naltrexone, CLI: comprehensive lifestyle intervention, IBT: intensive behavioral therapy, IQR:

interquartile range, kg: kilogram, KOA: knee osteoarthritis, kg: kilogram, LDL: low-density lipoprotein, LI: lifestyle intervention, LIR: liraglutide, m: meter, mg: milligram, N: total

number, NR: not reported, PBO: placebo, P/T: phentermine/topiramate, SC: subcutaneous, SE: standard error, SEM: semaglutide, vs.: versus

*SE manually derived from standard deviation or 95% CIs.

†Timepoint for outcomes is at Week 20.

‡Timepoint for outcomes is Week 20-68.

§Timepoint for all outcomes is at Week 32.

#Timepoint for this outcome is at Week 104.

¤Percent change.

**The number of patients for this outcome may differ from the primary analysis population.

††Timepoint for all outcomes is Week 68-120.

Evidence Report – Medications for Obesity Management Return to Table of Contents

Table D30. Patient-Reported Outcomes

29-32,34,35,41-45,48,50-52,54-57,59-67,140-142,144,147-149

Study Name Arms N

SF-36, Change from Baseline

IWQOL-Lite-CT, Change from

Baseline

Depression

Score, Change

from Baseline

Physical

Functioning

Score

Physical

Component

Score

Mental

Component

Score

Physical

Function

Score

Total Score

Mean

Semaglutide

STEP 1

PBO + LI

655

0.4

0.2*

0.3†

-2.1*

0.3†

5.3

SC SEM 2.4 mg + LI

1306

2.2

2.4*

0.2†

-1.5*

0.2†

14.7

STEP 2

PBO + LI

403

0.4

5.3

1.1

SC SEM 2.4 mg + LI

404

2.5*

0.4

10.1

STEP 3

PBO + IBT

204

1.6

2.3

-2.9

SC SEM 2.4 mg + IBT

407

2.4

-0.8

STEP 4

Run-in period#

803

2.2

5.1†

From run-in with SEM→

PBO + LI¤

268 -1.5 0.4† -0.9 0.5† -3.4 0.5† NR NR NR NR NR NR

From run-in with SEM→

SC SEM 2.4 mg + LI¤

535 1 0.2† 0.8 0.3† 0.1 0.3† NR NR NR NR NR NR

STEP 5

PBO + LI

SC SEM 2.4 mg + LI

STEP 6

PBO + LI

101

-0.3

0.4

0.8

1.4

SC SEM 1.7 mg + LI

101

-0.1

0.5

2.8

1.5

SC SEM 2.4 mg + LI

199

0.8

0.3

4.2

1.1

Semaglutide vs. Liraglutide

STEP 8

PBO + LI

SC SEM 2.4 mg + LI

SC LIR 3.0 mg

Liraglutide

SCALE

(Maintenance)

PBO + LI

SC LIR 3.0 mg + LI

SCALE (Sleep

Apnea)**

PBO + LI

171

1.9

0.5

0.9

0.6

SC LIR 3.0 mg + LI

174

0.6

1.4

0.6

SCALE (Type 2

Diabetes)

PBO + LI

211

8.9

1.1†

7.6

0.9†

SC LIR 1.8 mg + LI

204

12.5

1.2†

9.1

1.0†

Evidence Report – Medications for Obesity Management Return to Table of Contents

Study Name Arms N

SF-36, Change from Baseline

IWQOL-Lite-CT, Change from

Baseline

Depression

Score, Change

from Baseline

Physical

Functioning

Score

Physical

Component

Score

Mental

Component

Score

Physical

Function

Score

Total Score

Mean

SC LIR 3.0 mg + LI

411

15.2

0.9†

11.7

0.7†

SCALE (Obesity

& Pre-Diabetes)

PBO + LI

1225

2.1

0.2†

-0.9

0.3†

7.7

0.4†

SC LIR 3.0 mg + LI

2437

3.6

0.1†

0.2

0.2†

10.6

0.3†

SCALE (IBT)

PBO + IBT

140

3.8

0.6†

-2.2

0.7†

14.1†

12.8

1.7†

SC LIR 3.0 mg + IBT

142

3.4

0.6†

-1.2

0.7†

14.9†

13.2

1.6†

SCALE (Insulin)

PBO + IBT

198

2.6

0.5†

2.2

0.5†

-1.7

0.5†

5.7†

4.8

1.2†

SC LIR 3.0 mg + IBT

198

2.5

0.6†

2.7

0.5†

-1.9

0.6†

8.2†

5.7

1.3†

LOSEIT

PBO + LI

SC LIR 3.0 mg + LI

Phentermine/Topiramate

EQUIP

PBO + LI

498

-1.3*‡

0.2†

P/T 3.75 mg/23 mg + LI

234

-1.2*‡

0.2†

P/T 15 mg/92 mg + LI

498

-1.5*‡

0.1†

EQUATE

PBO + LI

101

-0.5*‡

0.4†

Phentermine 7.5 mg + LI

103

-1.1*‡

0.3†

Topiramate 46 mg + LI

102

-1.1*‡

0.3†

P/T 7.5 mg/46 mg + LI

-1.3*‡

0.2†

Phentermine 15 mg + LI

104

-1.4*‡

0.4†

Topiramate 92 mg + LI

103

-1.7*‡

0.3†

P/T 15 mg/92 mg + LI

103

-1.1*‡

0.4†

CONQUER

(Diabetes

Subgroup)

PBO + LI

P/T 7.5 mg/46 mg + LI

P/T 15 mg/92 mg + LI

OB-204

(Winslow 2012)

PBO + LI

4.5

2.9

P/T 15 mg/92 mg + LI

9.2

2.9

Bupropion/Naltrexone

COR-I

PBO + LI

511

8.6*

0.5

-0.7*§

0.2

B/N 360 mg/16 mg + LI

471

11.7*

0.5

0*§

0.2

B/N 360 mg/32 mg + LI

471

12.7*

0.5

-0.3*§

0.2

COR-II

PBO + LI

456

8.2

0.8

6.4

0.6

-0.5*§

0.3

Evidence Report – Medications for Obesity Management Return to Table of Contents

Study Name Arms N

SF-36, Change from Baseline

IWQOL-Lite-CT, Change from

Baseline

Depression

Score, Change

from Baseline

Physical

Functioning

Score

Physical

Component

Score

Mental

Component

Score

Physical

Function

Score

Total Score

Mean

B/N 360 mg/32 mg + LI

702

14.1

0.6

10.9

0.5

-0.3*§

0.2

COR-BMOD

PBO + BMOD

202

0.8

10.3*

0.9

0*§

0.4

B/N 360 mg/32 mg +

BMOD

591 NR NR NR NR NR NR 16.5 0.5 13.4* 0.6 0.1*§ 0.2

COR-Diabetes

PBO + LI

159

7.9*

0.9

-1.6*§

0.4

B/N 360 mg/32 mg + LI

265

9.3*

0.7

0*§

0.3

CVOT (Light

Study)

PBO + LI

4450

B/N 360 mg/32 mg + LI

4455

Ignite

Usual care (including LI)

-1

1.4

B/N 360 mg/32 mg + CLI

16.4

1.5

BMOD: behavioral modification, B/N: bupropion/naltrexone, CLI: comprehensive lifestyle intervention, IBT: intensive behavioral therapy, IWQOL-Lite: Impact

of Weight on Quality of Life-Lite, KOA: knee osteoarthritis, kg: kilogram, LI: lifestyle intervention, LIR: liraglutide, mg: milligram, N: total number, NR: not

reported, PBO: placebo, P/T: phentermine/topiramate, SC: subcutaneous, SE: standard error, SEM: semaglutide, SF-36: Short Form Health Survey, vs.: versus

*The number of patients for this outcome may differ from the primary analysis population.

†SE manually derived from standard deviation or 95% CIs.

‡Depression for this trial is measured by the PHQ-9.

§Depression for this trial is measured by the IDS-SR.

#Timepoint for outcomes is at week 20.

¤Timepoint for outcomes is week 20-68.

**Timepoint for all outcomes is at week 32.

Evidence Report – Medications for Obesity Management Return to Table of Contents

Table D31. Patient-Reported Outcomes of Sleep Apnea Studies

41,50,144,148

Study Name Arms N

ESS

FOSQ

PSQI

Mean

Liraglutide

SCALE (Sleep Apnea)

PBO + LI

171

-2.3

0.3

1.1

0.1

SC LIR 3.0 mg + LI

174

-2.5

0.3

1.3

0.2

Phentermine/Topiramate

OB-204 (Winslow 2012)

PBO + LI

-1.8

0.8

-0.9

0.7

P/T 15 mg/92 mg + LI

-1.9

0.8

-3.1

0.7

ESS: Epworth Sleepiness Scale, FOSQ: Functional Outcomes of Sleep Questionnaire, LI: lifestyle intervention, LIR: liraglutide, mg: milligram, N: total number,

NR: not reported, PBO: placebo, PSQI: Pittsburgh Sleep Quality Index, P/T: phentermine/topiramate, SC: subcutaneous, SE: standard error

Evidence Report – Medications for Obesity Management Return to Table of Contents

Table D32. Safety

29-38,40-45,48-66,140-149

Study Name Arms N

Any Adverse Events Serious Adverse Events

Adverse Events Leading to

Discontinuation

Semaglutide

STEP 1

PBO + LI

655

566

86.4

6.4

3.1

SC SEM 2.4 mg + LI

1306

1171

89.7

128

9.8

STEP 2

PBO + LI

402

309

76.9

9.2

3.5

SC SEM 2.4 mg + LI

403

353

87.6

9.9

6.2

STEP 3

PBO + IBT

204

196

96.1

2.9

SC SEM 2.4 mg + IBT

407

390

95.8

9.1

5.9

STEP 4

Run-in period†

902

760

84.3

2.3

5.3

From run-in with SEM→

PBO + LI‡

268 201 75 15 5.6 6 2.2

From run-in with SEM→

SC SEM 2.4 mg + LI‡

535 435 81.3 41 7.7 13 2.4

STEP 5

PBO + LI

152

136

89.5

11.8

4.6

SC SEM 2.4 mg + LI

152

146

96.1

7.9

5.9

STEP 6

PBO + LI

101

SC SEM 1.7 mg + LI

100

SC SEM 2.4 mg + LI

199

171

Semaglutide vs. Liraglutide

STEP 8

PBO + LI

95.3

7.1

3.5

SC SEM 2.4 mg + LI

126

120

95.2

7.9

3.2

SC LIR 3.0 mg

127

122

96.1

12.6

Liraglutide

SCALE

(Maintenance)

PBO + LI

210

186

88.6

2.4

8.6

SC LIR 3.0 mg + LI

212

194

91.5

4.3

8.5

SCALE (Sleep

Apnea)

PBO + LI

179

124

69.3

3.4

SC LIR 3.0 mg + LI

176

141

80.1

3.4

SCALE (Type 2

Diabetes)

PBO + LI

212

182

85.8

9.9

3.3

SC LIR 1.8 mg + LI

210

190

90.5

13.8

8.6

SC LIR 3.0 mg + LI

422

392

92.9

12.3

9.2

SCALE (Obesity &

Pre-Diabetes)

PBO + LI

1242

786

63.3

3.8

SC LIR 3.0 mg + LI

2481

1992

80.3

154

6.2

240*

9.7

Evidence Report – Medications for Obesity Management Return to Table of Contents

Study Name Arms N

Any Adverse Events Serious Adverse Events

Adverse Events Leading to

Discontinuation

SCALE (IBT)

PBO + IBT

140

124

88.6

1.4

4.3

SC LIR 3.0 mg + IBT

142

136

95.8

4.2

8.5

SCALE (Insulin)

PBO + IBT

197

175

88.8

9.6

SC LIR 3.0 mg + IBT

195

180

92.3

8.2

7.7

LOSEIT

PBO + LI

5.3

SC LIR 3.0 mg + LI

12.5

Phentermine/Topiramate

EQUIP

PBO + LI

513

374

72.9

2.5

8.4

P/T 3.75 mg/23 mg + LI

240

192

2.5

11.3

P/T 15 mg/92 mg + LI

511

432

84.5

2.5

EQUATE

PBO + LI

109

79.8

7.3

Phentermine 7.5 mg + LI

109

79.8

1.8

9.2

Topiramate 46 mg + LI

106

84.9

7.4

P/T 7.5 mg/46 mg + LI

106

80.2

0.9

15.1

Phentermine 15 mg + LI

108

82.4

0.9

10.2

Topiramate 92 mg + LI

107

79.4

0.9

16.8

P/T 15 mg/92 mg + LI

108

83.3

1.9

21.3

CONQUER

(Diabetes

subgroup)

PBO + LI

157

125

79.6

3.2

8.3

P/T 7.5 mg/46 mg + LI

80.6

P/T 15 mg/92 mg + LI

164

141

3.7

18.9

OB-204 (Winslow

2012)

PBO + LI

78.2

4.4

4.3

P/T 15 mg/92 mg + LI

90.9

9.1

Bupropion/Naltrexone

COR-I

PBO + LI

569

390

68.5

1.4

9.8

B/N 360 mg/16 mg + LI

569

455

1.6

122

21.4

B/N 360 mg/32 mg + LI

573

476

83.1

1.6

112

19.5

COR-II

PBO + LI

492

370

75.2

1.4

13.8

B/N 360 mg/32 mg + LI

992

852

85.9

2.1

241

24.3

COR-BMOD

PBO + BMOD

200

133

66.5

0.5

25*

12.4

B/N 360 mg/32 mg + BMOD

584

487

83.4

3.8

150*

25.4

COR-Diabetes

PBO + LI

169

144

85.2

4.7

15.4

B/N 360 mg/32 mg + LI

333

301

90.4

3.9

29.4

PBO + LI

4450

668

386

8.7

388

8.7

Evidence Report – Medications for Obesity Management Return to Table of Contents

Study Name Arms N

Any Adverse Events Serious Adverse Events

Adverse Events Leading to

Discontinuation

CVOT (Light

Study)

B/N 360 mg/32 mg + LI 4455 1620 36.4 463 10.4 1253 28.1

Ignite

Usual care (including LI)§

1.1

B/N 360 mg/32 mg + CLI§

153

0.7

22.9

Usual care (including LI)→B/N

360 mg/32 mg + CLI‡

89 NR NR 0 0 14 15.7

B/N 360 mg/32 mg + CLI

(continued)‡

153 NR NR 2 1.3 37 24.2

BMOD: behavioral modification, B/N: bupropion/naltrexone, CLI: comprehensive lifestyle intervention, IBT: intensive behavioral therapy, KOA: knee osteoarthritis, LI: lifestyle

intervention, LIR: liraglutide, mg: milligram,

n: number, N: total number, NR: not reported, PBO: placebo, P/T: phentermine/topiramate, SC: subcutaneous, SEM: semaglutide,

vs.: versus

*The number of patients for this outcome may differ from the safety analysis population.

†Timepoint for outcomes is at week 20.

‡Timepoint for outcomes is week 20-68.

§Timepoint for all outcomes is at week 26.

‡Timepoint for all outcomes is at week 78.

Evidence Report – Medications for Obesity Management Return to Table of Contents

Table D33. Safety Focus Areas for STEP Trials of Semaglutide

29-31,33-38,68

STEP 1

STEP 2*

STEP 3

STEP 5

STEP 8

Study Arms

PBO

SEM

PBO

SEM

PBO

SEM

PBO

SEM

PBO

SEM

LIR

655

1306

402

403

204

407

152

126

127

GI Disorders,

n (%)

314

(47.9)

969

(74.2)

138

(34.3)

256

(63.5)

129

(63.2)

337

(82.8)

82 (53.9)

125

(82.2)

47 (55.3)

106

(84.1)

105

(82.7)

Gallbladder-

Disorders, n (%)

8 (1.2) 34 (2.6) 3 (0.7) 1 (0.2) 3 (1.5) 20 (4.9) 2 (1.3) 4 (2.6) 1 (1.2) 1 (0.8) 4 (3.1)

Hepatic

Disorders, n (%)

20 (3.1) 31 (2.4) 14 (3.5) 10 (2.5) 4 (2) 8 (2) 3 (2) 3 (2) 3 (3.5) 2 (1.6) 1 (0.8)

Acute

Pancreatitis,

n (%)

0 (0) 3 (0.2) 1 (0.2) 1 (0.2) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (0.8)

CV Disorders,

n (%)

75 (11.5) 107 (8.2) 5 (1.2) 6 (1.5) 22 (10.8) 40 (9.8) 30 (19.7) 17 (11.2) 9 (10.6) 16 (12.7) 18 (14.2)

Psychiatric

Disorders, n (%)

83 (12.7) 124 (9.5) 15 (3.7) 24 (6) 24 (11.8) 60 (14.7) 25 (16.4) 26 (17.1) 9 (10.6) 7 (5.6) 19 (15)

Acute Renal

Failure, n (%)

2 (0.3) 3 (0.2) 2 (0.5) 4 (1) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.2) 1 (0.8) 0 (0)

Retinal

Disorders, n (%)

NR (NR) NR (NR) 17 (4.2) 28 (6.9) NR (NR) NR (NR) NR (NR) NR (NR) NR (NR) NR (NR) NR (NR)

CV: cardiovascular, GI: gastrointestinal, LIR: liraglutide, n: number, N: total number, NR: not reported, PBO: placebo

*Trial conducted in individuals with obesity and type 2 diabetes mellitus.

Evidence Report – Medications for Obesity Management Return to Table of Contents

D4. Ongoing Studies

Table D34. Ongoing Studies

Title/Trial Sponsor Study Design Treatment Arms Patient Population Primary Outcome(s)

Estimated

Completion

Date

Semaglutide

Semaglutide Effects

on Heart Disease and

Stroke in Patients

With Overweight or

Obesity (SELECT)

Novo Nordisk

NCT03574597

Phase III

MC, QB, PC,

RCT

N~17,500

Semaglutide 2.4 mg

Placebo

Inclusion Criteria

• Male or female, age ≥45 years

• BMI ≥27 kg/m

• Have established CV disease with ≥1 of following:

prior MI; prior stroke; or symptomatic PAD, or

peripheral arterial revascularization procedure, or

amputation due to atherosclerotic disease

Exclusion Criteria

• MI, stroke, hospitalization for unstable angina

pectoris or transient ischemic attack within past 60

days

• HbA1C≥ 48 mmol/mol (6.5%)

• History of T1DM or T2DM (history of gestational

diabetes is allowed)

• Time to first

occurrence of a

composite

endpoint

consisting of: CV

death, non-fatal

MI, or non-fatal

stroke [0-59

months]

September

2023

Research Study to

Investigate How Well

Semaglutide Works in

People Living With

Heart Failure and

Obesity (STEP-HFpEF)

Novo Nordisk

NCT04788511

Phase III

MC, DB, PC,

RCT

N~516

Semaglutide 2.4 mg

Placebo

Inclusion Criteria

• Male or female, age ≥18 years

• BMI ≥30.0 kg/m

• NYHA Class II-IV

• LVEF ≥45%

Exclusion Criteria

• Change in body weight >5 kg (11 lbs) within 90 days

• HbA1C ≥6.5% (48 mmol/mol)

• Change in KCCQ

clinical summary

score [week 0-

52]

• Change in body

weight [week 0-

52]

March 2023

Research Study to

Look at How Well

Semaglutide Works in

People Living With

Heart Failure, Obesity

and Type 2 Diabetes

(STEP HFpEF DM)

Phase III

MC, QB, PC,

RCT

N~610

Semaglutide 2.4 mg

Placebo

Inclusion Criteria

• Male or female, age ≥18 years

• BMI ≥30.0 kg/m

• NYHA Class II-IV

• LVEF ≥45%

• Diagnosed with T2DM

• HbA1C ≤10%

• Change in KCCQ

clinical summary

score [week 0-

52]

• Change in body

weight [week 0-

52]

June 2023

Evidence Report – Medications for Obesity Management Return to Table of Contents

Title/Trial Sponsor Study Design Treatment Arms Patient Population Primary Outcome(s)

Estimated

Completion

Date

Novo Nordisk

NCT04916470

Exclusion Criteria

• Change in body weight >5 kg (11 lbs) within 90 days

• Uncontrolled and potentially unstable diabetic

retinopathy or maculopathy

Research Study of

How Well

Semaglutide Works in

People Living With

Overweight or

Obesity (STEP 7)

Novo Nordisk

NCT04251156

Phase III

MC, QB, PC,

RCT

N~375

Semaglutide 2.4 mg

Placebo

Inclusion Criteria

• Male or female, age ≥18 years

• History of ≥1 unsuccessful dietary effort to lose

body weight

• For subjects without T2DM: BMI ≥30 kg/m

or ≥27

kg/m

with the ≥1 weight-related comorbidity

(treated or untreated): HTN, dyslipidemia, OSA, or

CVD

• For subjects with T2DM: Treated with either diet

and exercise alone OR stable treatment ≥60 days

with up to 3 oral antidiabetic medications

(metformin, α-glucosidase inhibitor, SU, glinides,

SGLT2i or glitazone), HbA1C 7.0-10.0% (53-86

mmol/mol), BMI ≥27 kg/m

Exclusion Criteria

• Change in body weight >5 kg (11 lbs) within 90 days

• For subjects without T2DM at screening: HbA1C

≥6.5% (48 mmol/mol)

• For subjects with T2DM at screening: Renal

impairment measured as eGFR <30 mL/min/1.73

(<60 mL/min/1.73 m

in subjects treated with

SGLT2i)

• Uncontrolled and potentially unstable diabetic

retinopathy or maculopathy

• Change in body

weight [week 0-

44]

• Subjects who

achieve body

weight reduction

equal to or above

5% [week 0-44]

August 2022

Research Study

Looking at How Well

Semaglutide Works in

People Living With

Obesity and

Prediabetes (STEP 10)

Novo Nordisk

Phase III

MC, QB, PC,

RCT

N~201

Semaglutide 2.4 mg

Placebo

Inclusion Criteria

• Male or female aged ≥18 years

• BMI ≥30.0 kg/m

• Prediabetes defined as at least one of following:

HbA1C 6-6.4% (42-47 mmol/mol) or FBG 5.5-6.9

mmol/L (99-125 mg/dL)

Exclusion Criteria

•

History of T1DM or T2DM

•

Change in body

weight [week 0-

52]

• Change to

normoglycemia

(normoglycemia

defined as having

both

January

2023

Evidence Report – Medications for Obesity Management Return to Table of Contents

Title/Trial Sponsor Study Design Treatment Arms Patient Population Primary Outcome(s)

Estimated

Completion

Date

NCT05040971

• Treatment with glucose-lowering agent(s) within 90

days

• HbA1C ≥6.5% (≥48 mmol/mol)

• FPG ≥7.0mmol/L (126 mg/dL)

• Change in body weight >5 kg (11 lbs) within 90 days

• Treatment with any obesity medication within 90

days

HbA1C<6.0%

(<42 mmol/mol)

and FPG <5.5

mmol/L (<99

mg/dL) [week 0-

52]

Research Study

Investigating How

Well Semaglutide

Works in People From

Thailand and South

Korea Living With

Obesity

Novo Nordisk

NCT04998136

Phase III

MC, QB, PC,

RCT

N~150

Semaglutide 2.4 mg

Placebo

Inclusion Criteria:

• Male or female aged ≥18 years

• BMI ≥25 kg/m

• Both parents of Asian descent

• History of at least 1 unsuccessful dietary effort to

lose body weight

Exclusion Criteria

• HbA1C at least 48 mmol/mol (6.5%)

• History of T1DM or T2DM

• Change in body weight >5 kg (11 lbs) within 90 days

• Renal impairment with estimated eGFR <15

mL/min/1.73 m

at screening

• Change in body

weight [week 0-

44]

• At least 5% body

weight reduction

(yes/no) [week 0-

44]

April 2023

Research Study

Looking at How Well

Semaglutide Works in

People Suffering

From Obesity and

Knee Osteoarthritis

Novo Nordisk

NCT05064735

Phase III

MC, TB, PC,

RCT

N~375

Semaglutide 2.4 mg

Placebo

Inclusion Criteria

• Male or female, age ≥18 years

• BMI ≥30.0 kg/m

• Clinical diagnosis of knee OA with moderate

radiographic changes KL grades 2 or 3 as per

central reading) in target (most symptomatic) knee

• Pain due to knee OA

Exclusion Criteria

• Joint replacement in target knee

• Arthroscopy or injections into target knee within

last 3 months prior to enrolment

• Any other joint disease in target knee

• Change in body

weight [week 0-

68]

• Change in

WOMAC pain

score [week 0-

68]

April 2023

Latino Semaglutide

Study (LSS)

Phase III

single-

center, TB,

PC, RCT

Semaglutide 2.4 mg

Placebo

Inclusion Criteria

• Self-identify as being of Hispanic/Latino ethnicity

• BMI >30 kg/m

• Age 18-75 years old

• Change from

baseline in

weight loss

[week 0-final

August 2023

Evidence Report – Medications for Obesity Management Return to Table of Contents

Title/Trial Sponsor Study Design Treatment Arms Patient Population Primary Outcome(s)

Estimated

Completion

Date

Loma Linda University

& Novo Nordisk

NCT05087342

N~375

Exclusion Criteria

• Current cancer treatment

• Diabetes, T1 or T2

• Eating disorders

• Medication use targeting GPL-1 system

• In last 30 days, attempted to lose weight by LSM

alone or with use of anti-obesity medications

resulting in >5 lbs weight loss

• History of bariatric surgery

• Use of obesogenic medications (including but not

limited to steroids, haloperidol, clozapine,

risperidone, olanzapine, amitriptyline, imipramine,

paroxetine, and lithium), which cannot be

substituted or stopped

• Pregnant or planning to become pregnant in next 8

months

• Any contraindication to semaglutide 2.4 mg

including personal or family history of medullary

thyroid carcinoma or multiple endocrine neoplasia

syndrome type 2, hypersensitivity to semaglutide

2.4 mg or any product components

study visit and 7

months post

baseline]

Liraglutide

The Efficacy and

Safety of Liraglutide

on Body Weight Loss

in Obese and

Overweight Patients

Shanghai Zhongshan

Hospital

NCT04605861

Phase III

single-

center, DB,

PC, RCT

N=414

Liraglutide 3 mg

Placebo

Inclusion Criteria

• Aged 18-70 years old

• Failed to control body weight in previous diet

therapy

• Stable body weight (patient reported body weight

change <5 kg) in last 3 months

• BMI ≥30 kg/m

(obesity) or BMI ≥27 kg/m

(overweight) with ≥1 related metabolic abnormality

(HTN, dyslipidemia, T2DM)

• Those with T2DM: Receiving diet and exercise

therapy alone, or receiving metformin,

sulfonylureas, glycosidase inhibitors and glinides

alone or in combination on basis of diet and

exercise therapy, with their treatment remaining

• % of body weight

loss [week 0-32]

• Proportion of

body weight loss

≥5% [week 0-32]

July 2022

Evidence Report – Medications for Obesity Management Return to Table of Contents

Title/Trial Sponsor Study Design Treatment Arms Patient Population Primary Outcome(s)

Estimated

Completion

Date

stable, HbA1C 7.0-10.0%, and FBG <13.3 mmol/L

(240 mg/dL)

Exclusion Criteria

• T1DM or secondary DM, acute metabolic

complications; 2 or more severe hypoglycemia

events, binge-eating disorder, hyperthyroidism,

pancreatic cancer, acute gallbladder disease,

psychological disorders, CV and cerebrovascular

diseases, MTC, AIDS, syphilis, proliferative

retinopathy or maculopathy, malignancy

• Receiving GLP-1, DPP-4 inhibitors, SGLT-2 inhibitor,

insulin therapy, OTC weight-loss drugs or appetite

inhibitors, prescription weight-loss drugs, lipid

dissolving infections

• Obesity caused by endocrine diseases

• Taking drugs that can significantly increase weight

in the 3 months

• Previous or planned surgery for obesity

• History of heart valve replacement

• SBP ≥160 mmHg or DBP ≥100 mmHg

• AST or ALT >3.0-fold ULN, or total bilirubin >2.0-

fold ULN

• eGFR <60 mL/min/1.73 m

• History of drug abuse

•

Pregnant or breastfeeding

Liraglutide, Phentermine/Topiramate, and Bupropion/Naltrexone

Individualized Obesity

Pharmacotherapy

Mayo Clinic

NCT03374956

Phase III

TB, parallel

assignment,

RCT

N=200

Phenotype-guided

therapy (intervention):

• Phen. 7.5mg/top.

46 mg

• Liraglutide 3 mg

• Bup. 360 mg/nalt.

32 mg

Randomly assigned

therapy (control):

Inclusion Criteria

• Adults with obesity (BMI >30 kg/m

)

• No unstable psychiatric disease and controlled

comorbidities or other diseases

• Men or women of childbearing potential with

negative pregnancy tests

Exclusion Criteria

• Abdominal bariatric surgery

• Positive history of chronic GI diseases, or systemic

disease that could affect GI motility, or use of

Total body weight loss

[12 weeks]

July 2022

Evidence Report – Medications for Obesity Management Return to Table of Contents

Title/Trial Sponsor Study Design Treatment Arms Patient Population Primary Outcome(s)

Estimated

Completion

Date

• Phen. 7.5 mg/top.

46 mg

• Liraglutide 3 mg

• Bup. 360 mg/nalt.

32 mg

• Phen. 15-37.5 mg

medications that may alter GI motility, appetite, or

absorption

• Significant untreated psychiatric dysfunction based

on Hospital Anxiety and Depression Inventory, and

the Questionnaire on Eating and Weight Patterns

(binge eating disorders and bulimia), with anxiety

or depression score >11

AIDS: acquired immunodeficiency syndrome, ALT: alanine aminotransferase, AST: aspartate aminotransferase, BMI: body mass index, CV: cardiovascular, CVD:

cardiovascular disease, DB: double-blind, DBP: diastolic blood pressure, DDP-4: dipeptidyl peptidase 4, dL: deciliter, DM: diabetes mellitus, eGFR: estimated glomerular

filtration rate, FBG: fasting blood glucose, GI: gastrointestinal, GLP-1: glucagon-like peptide 1, HbA1C: glycated hemoglobin, HTN: hypertension, KCCQ: Kansas City

Cardiomyopathy Questionnaire, kg: kilogram, KL: Kellgren and Lawrence, lb: pound, LSM: lifestyle modification, LVEF: left ventricular ejection fraction, m: meter, MC:

multicenter, mg: milligram, MI: myocardial infarction, min: minute, mmol/mol: millimoles per mole, mmol/L: millimoles per liter, mL: milliliter, MTC: medullary thyroid

cancer, N: total number, NYHA: New York Heart Association, OA: osteoarthritis, OSA: obstructive sleep apnea, OTC: over the counter, PAD: peripheral artery disease,

PC: placebo-controlled, QB: quadruple blind, RCT: randomized controlled trial, SBP: systolic blood pressure, SGLT2: sodium-glucose co-transporter-2, SU: sulphonylurea,

TB: triple-blind, ULN: upper limits of normal, WOMAC: Western Ontario and McMaster Universities Osteoarthritis Index

Source: www.ClinicalTrials.gov

(NOTE: studies listed on site include both clinical trials and observational studies).

Evidence Report – Medications for Obesity Management Return to Table of Contents

D5. Previous Systematic Reviews and Technology Assessments

We identified 15 systematic literature reviews or meta-analyses evaluating therapies for weight-loss

treatment in adults with overweight or obesity, two of which are summarized below.

Shi, Q., et al. (2022). “Pharmacotherapy for Adults with Overweight and Obesity: A Systematic

Review and Network Meta-Analysis of Randomised Controlled Trials”

This systematic review and network meta-analysis evaluated the comparative efficacy and safety of

several medications for adults with overweight and obesity who were seeking weight-loss

management. The interventions assessed included semaglutide, liraglutide,

phentermine/topiramate, bupropion/naltrexone, metformin, orlistat, exenatide, pramlintide,

dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, ipragliflozin/metformin/pioglitazone, and

sibutramine/levocarnitine. Inclusion criteria included randomized controlled trials evaluating a

candidate weight-lowering drug in comparison to placebo, lifestyle modification, or an alternative

drug. Studies were excluded if their outcomes did not focus on weight loss or quality of life

measures and if they recruited patients with psychological disorders and eating disorders. Search

terms for PubMed, Embase, and Cochrane Library searches included “weight loss,” “weight-loss

drugs,” and “RCTs.” By March 2021, investigators identified 143 randomized controlled trials

(N=49,810) for inclusion. Median age was 47, the proportion of females was 75%, median BMI was

35.3, and median duration of follow-up was 24 weeks. Data on the GLP-1 receptor agonists

(semaglutide, liraglutide, and exenatide) were presented together.

Phentermine/topiramate (MD: -7.97; 95% CI: -9.28 to -6.66) and the GLP-1 receptor agonists (MD:

5.76; 95% CI: -6.30 to -5.21) were the most effective at helping participants achieve percentage and

absolute body weight change from baseline, and all drugs except levocarnitine were associated with

a reduction in body weight. For the categorical outcome of weight loss of at least 5% or 10% body

weight, phentermine/topiramate, GLP-1 receptor agonists, and bupropion/naltrexone were the

most effective at helping participants achieve these categorical outcomes, and more than doubled

the proportion of participants receiving these interventions losing at least 5% or 10% body weight

compared to participants who were receiving lifestyle modification alone. In post-hoc analyses,

semaglutide (separate from the other GLP-1 agonists) demonstrated the largest percent weight loss

(MD: -11.41; 95% CI: -12.54 to -10.27) and had the highest likelihood of achieving target weight loss

of at least 5% and 10%. In terms of subgroup effects, participants receiving GLP-1 receptor agonists

achieved a greater amount of weight loss if they were non-diabetic, compared to participants who

had diabetes. However, this has low credibility due to inconsistency across studies.

Quality-of-life outcomes were available in 15 trials that looked at health-related quality of life

scores, and in seven trials that assessed depression, and included the drugs

phentermine/topiramate, bupropion/naltrexone, GLP-1 receptor agonists, and orlistat. All drugs in

this network except orlistat helped improve quality of life, improvements in depression scores from

Evidence Report – Medications for Obesity Management Return to Table of Contents

baseline were not statistically significant. For secondary outcomes, GLP-1 receptor agonists

significantly reduced HbA1C levels when compared to lifestyle modification alone, and orlistat

significantly reduced LDL cholesterol compared to lifestyle modification. GLP-1 receptor agonists

and phentermine/topiramate were associated with the largest reductions in systolic blood pressure.

With regards to safety, phentermine/topiramate, bupropion/naltrexone, GLP-1 receptor agonists,

and orlistat were associated with an increased risk of participants discontinuing due to adverse

events. Between the drugs, bupropion/naltrexone and phentermine/topiramate were found to

have the most discontinuations due to adverse events.

Investigators concluded that phentermine/topiramate and GLP-1 receptor agonists were most

effective for weight loss, with high to moderate certainty of evidence, and demonstrated small

benefits on quality-of-life outcomes. Evidence on other secondary outcomes were of low to very

low certainty. Limitations included the lack of individual patient data pooling, which prevented

more precise subgroup analyses, and heterogeneity in participant baseline characteristics and

duration of follow-up.

Arastu, N., et al. (2022). “Efficacy of Subcutaneous Semaglutide Compared to Placebo for Weight

Loss in Obese, Non-Diabetic Adults: A Systematic Review & Meta-Analysis”

150

Investigators conducted a systematic review and meta-analysis evaluating the efficacy of

subcutaneous semaglutide in treating obesity in adults with overweight or obesity without

diabetes, compared to placebo. Randomized controlled trials of adult participants with a BMI ≥27

kg/m

were included, and studies that included participants who were under 18 years of age or had

type 1 or type 2 diabetes mellitus were excluded. EBSCOhost (including CINAHL Complete,

Academic search Premier, MEDLINE, and Cochrane Central Register of Controlled Trials) was used

for the literature search and included search terms such as “semaglutide,” “Wegovy,” “obesity,”

and “overweight.” By August 31, 2021, investigators identified four studies (N=2,882) that met

eligibility criteria and were included in quantitative synthesis. The mean age was 46 years. All

studies were determined to have low risks of bias.

For the primary outcome of mean body weight loss, the mean difference of weight loss in

participants receiving semaglutide versus placebo was -11.62 kg (95% CI: -13.03 to -10.21;

p<0.00001), indicating that semaglutide demonstrated a statistically significant reduction in weight

loss compared to placebo. Additionally, the proportion of participants receiving semaglutide, who

achieved weight loss of at least 5% was higher in all trials compared to placebo (p<0.001).

Semaglutide was also associated with a statistically significant reduction in waist circumference

(MD: -9.16 cm; 95% CI: -9.91 to -8.40; p<0.00001), and BMI (MD: -4.33 kg/m2; 95% CI: -4.88 to -

3.78; p<0.00001). Subgroup analyses between the semaglutide 2.4 mg dose and the 0.4 mg dose

indicated no significant differences between the treatment doses.

Evidence Report – Medications for Obesity Management Return to Table of Contents

While semaglutide was shown to be superior to placebo in helping reduce body weight in

participants with overweight or obesity, investigators identified several potential limitations,

including the limited number of studies, variability in type of lifestyle modification, and lack of long-

term data on semaglutide.

Evidence Report – Medications for Obesity Management Return to Table of Contents

E. Long-Term Cost-Effectiveness: Supplemental

Information

E1. Methods

Rationale for Not Including Certain Health States in the Base Case

We did not include cancer, osteoarthritis, joint surgery, or sleep apnea as separate Markov states in

our model because: 1) the causal association between weight reduction and decreasing the

incidence of cancer or osteoarthritis is uncertain, 2) any benefits of modest weight loss on cancer

and osteoarthritis are estimated to be small relative to the cardiovascular benefits being assessed,

3) the impact of any improvement on cardiovascular outcomes from improvements in sleep apnea

associated with weight loss would be captured from the changes in weight loss- and blood

pressure-related cardiovascular disease and mortality, 4) the cost of treating sleep apnea, such as a

continuous positive airway pressure machine, would have a negligible impact on the incremental

cost, 5) the short-term impact of weight loss on quality of life due to sleep apnea is inherently

included as a utility gain associated with weight loss, measured directly in clinical trials but not

explicitly stated as resulting from changes to sleep apnea, and 6) there is no known evidence from

semaglutide trials or other pharmacotherapy clinical trials demonstrating that these therapies

directly reduce the risk of or morbidity associated with weight-related comorbidities.

Impact Inventory

Consistent with the recommendations from the Second Panel on Cost Effectiveness in Health and

Medicine, the impact inventory of what was included in the base case and scenario analyses from

the health care sector and societal perspectives, respectively, is shown in Table E1.

151

Evidence Report – Medications for Obesity Management Return to Table of Contents

Table E1. Impact Inventory

Sector

Type of Impact (Add Additional

Domains, as Relevant)

Included in This Analysis

from […] Perspective?

Notes on Sources (if

Quantified), Likely Magnitude

& Impact (if Not)

Health Care

Sector

Societal

Formal Health Care Sector

Health

Outcomes

Longevity effects

HRQoL effects

Adverse events  

Evaluated, but did not include

AEs. Expected that AEs would

lead to treatment disc. early in

therapy and not to significant

costs or disutility.

Medical Costs

Paid by third-party payers

Paid by patients out-of-pocket Possibly Possibly

Sources used for cost estimates

provided comprehensive

descriptions for what medical

costs were included, but did not

include whether out-of-pocket

costs were included in

estimates.

Future related medical costs

Future unrelated medical costs



Informal Health Care Sector

Health-Related

Costs

Patient time costs

N/A



Unpaid caregiver-time costs

N/A



Transportation costs

N/A



Non-Health Care Sector

Productivity

Labor market earnings lost

N/A

Cost of unpaid lost productivity

due to illness

N/A X

Cost of uncompensated

household production

N/A



Consumption

Future consumption unrelated to

health

N/A 

Social Services

Cost of social services as part of

intervention

N/A



Legal/Criminal

Justice

Number of crimes related to

intervention

N/A 

Cost of crimes related to

intervention

N/A 

Education

Impact of intervention on

educational achievement of

population

N/A 

Housing

Cost of home improvements,

remediation

N/A 

Environment

Production of toxic waste

pollution by intervention

N/A 

Other

Other impacts (if relevant)

N/A



AE: adverse event, N/A: not applicable

Adapted from Sanders et al.

151

Evidence Report – Medications for Obesity Management Return to Table of Contents

Description of evLY Calculations

The evLY considers any extension of life at the same “weight” no matter what treatment is being

evaluated or what population is being modeled. Below are the stepwise calculations used to

calculate the evLY.

1) First, we attribute a utility of 0.851, the age- and sex-adjusted utility of the general

population in the US that are considered healthy.

152

2) We calculate the evLY for each model cycle.

3) Within a model cycle, if using the intervention results in additional life years versus the

primary comparator, we multiply the general population utility of 0.851 with the

additional life years gained (ΔLY gained) within the cycle.

4) The life years shared between the intervention and the comparator use the

conventional utility estimate for those life years within the cycle.

5) The total evLY for a cycle is calculated by summing steps 3 and 4.

6) The evLY for the comparator arm is equivalent to the QALY for each model cycle.

7) The total evLYs are then calculated as the sum of evLYs across all model cycles over the

time horizon.

Finally, the evLYs gained is the incremental difference in evLYs between the intervention and the

comparator arm.

Target Population

Model inputs were chosen based upon patient characteristics in clinical trials. Patient age, BMI,

gender, SBP, smoking status, and presence of hypertension and diabetes mellitus were required

inputs for calculating mortality and cardiovascular risk. Consistent with clinical trials and real-world

evidence on users of medications for weight management, patients were 80% female with average

age of 45 years, BMI of 38 kg/m

, SBP of 125 mmHg, and HbA1C of 5.5% at model entry.

33,43,53,56,61,83

The base-case model cohort characteristics are shown in Table E2.

Table E2. Base-Case Model Cohort Characteristics

Value

Primary Sources

Mean Age

45 years

CONQUER, EQUIP, COR-I, SCALE,

STEP 1, STEP 8

33,43,53,56,61,83

Mean BMI

38 kg/m

Female

80.0%

Mean SBP

125 mmHg

Diagnosis of Hypertension

(Actively Treated)

35.0%

Diagnosis of Diabetes Mellitus

Assumption for base case

Smoking

12.5%

CDC

153

CDC: Centers for Disease Control and Prevention, BMI: body mass index, kg: kilogram, m: meter, mmHg: millimeter

of mercury, SBP: systolic blood pressure

Evidence Report – Medications for Obesity Management Return to Table of Contents

Treatment Strategies

• Semaglutide

o Titration: 0.25 mg administered subcutaneously once weekly for the first four

weeks, with the dose increased every four weeks to reach the maintenance dose of

2.4 mg by week 16

o Maintenance dose: 2.4 mg administered subcutaneously once a week

• Liraglutide

o Titration: Starting at a dose of 0.6 mg with weekly 0.6-mg increments to 3.0 mg

o Maintenance dose: 3.0 mg administered subcutaneously once daily

• Phentermine/topiramate extended-release

o Loading dose: 3.75 mg/23 mg (phentermine 3.75 mg/topiramate 23 mg ER) daily for

14 days; then increase to the maintenance dose 1 and 2. Maintenance dose 2 is the

target regimen of our study.

o Maintenance dose 1: 7.5 mg/46 mg daily

o Maintenance dose 2: 15 mg/92 mg daily

• Bupropion/naltrexone ER

o Titration: Starting at a dose of 8 mg/90 mg once a day for a week, with weekly

increases in 8 mg/90 mg increments until dose of 16 mg/180 mg twice daily is

achieved at week four

o Maintenance dose: 16 mg/180 mg twice daily (32 mg/360 mg per day)

E2. Model Inputs and Assumptions

Key model assumptions and rationales are presented in Table 4.1 of the Report. Additional model

assumptions/rationales are listed in Table E3 below.

Evidence Report – Medications for Obesity Management Return to Table of Contents

Table E3. Model Assumptions

Assumption

Rationale

Proportion of smokers does

not vary over time

Smoking behavior has not been convincingly shown to be influenced by

FDA-approved anti-obesity interventions. However, we do acknowledge

that despite it not being a comparator or intervention in the base-case

analysis, bupropion alone (Zyban®, GlaxoSmithKline) is approved for

smoking cessation. This assumption may therefore result in an

underestimation of bupropion’s effect on cardiovascular events.

Inclusion of adverse events in

the model would add

significant complexity without

providing much improvement

in cost-effectiveness

estimation or face validity to

the model

Adverse events reported with these four medications occur early, are

generally not severe in nature, and would normally not lead to appreciable

treatment discontinuation as compared to inadequate weight loss

response. However, we adjusted the cost of treatment by the probability

of discontinuation to estimate the impact of early treatment

discontinuation due to adverse events or lack of effectiveness.

Once patients develop diabetes

mellitus, their diabetes care

and associated diabetes

outcomes is similar between

those who are on weight

management and those who

are not

Although liraglutide and semaglutide affect blood glucose, the treatment

pathways for diabetes mellitus in those who will have access to liraglutide

and semaglutide would also include access to these treatments for

diabetes mellitus, albeit potentially at a different dose. We assumed that

diabetes treatment outcomes would not differ in patients with treatments

that affect HbA1C versus those that did not.

FDA: Food and Drug Administration, HbA1C: glycated hemoglobin, SBP: systolic blood pressure

Model Inputs

Clinical Inputs

The key model inputs are listed in Table 4.2 of the Report. Those inputs, plus additional inputs, are

listed in Table E4 below.

Evidence Report – Medications for Obesity Management Return to Table of Contents

Table E4. Key Model Inputs

Parameter

Input

Source

Clinical Inputs

Absolute Difference in % Weight Change, SEM vs. LSM

-13.7%

ICER NMA, Table 3.11

Absolute Difference in HbA1C Change, SEM vs. LSM

-0.30

STEP 1

Absolute Difference in % Weight Change, LIR vs. LSM

-5.0%

ICER NMA, Table 3.11

Absolute Difference in HbA1C Change, LIR vs. LSM

-0.20

SCALE (Maintenance)

Absolute Difference in % Weight Change, P/T vs. LSM

-9.1%

ICER NMA, Table 3.11

Absolute Difference in HbA1C Change, P/T vs. LSM

0.00

EQUIP

53,56

Absolute Difference in % Weight Change, B/N vs. LSM

-4.6%

ICER NMA, Table 3.11

Absolute Difference in HbA1C Change, B/N vs. LSM

0.00

61,65

Treatment Discontinuation, SEM

0.042

ICER NMA, Table 3.19

Treatment Discontinuation, LIR

0.058

ICER NMA, Table 3.19

Treatment Discontinuation, P/T

0.058

ICER NMA, Table 3.19

Treatment Discontinuation, B/N

0.053

ICER NMA, Table 3.19

Treatment Discontinuation, LSM

0.025

STEP 1, STEP 2, STEP 4, STEP 6

Baseline Risk of CV Event, Female Non-Smoker without Treated

HTN

0.04

Framingham Risk Calculation

Coefficient

Baseline Risk of CV Event, Male Smoker with Treated HTN

0.23

Multiplier for Probability of MI from CV Risk

0.22

Multiplier for Probability of Stroke from CV Risk

0.23

Multiplier for Probability of Other CVD from CV Risk

0.55

Probability of Mortality Following Acute MI

0.08

OECD Statistics

154

Probability of Mortality Following Acute Stroke

0.08

Relative Risk of Annual Mortality Post-MI

1.58

Majed 2015

Relative Risk of Annual Mortality Post-Stroke

3.13

Relative Risk of Annual Mortality with Other CVD

1.9

Pande 2011

Relative Risk of Annual Mortality Post-HF

1.82

Ødegaard 2020

Relative Risk of Annual Mortality Post-DM

1.15

Tancredi 2015

Annual Probability of Recurrent MI in Male

0.0813

Peters 2021

155

Annual Probability of Recurrent MI in Female

0.0723

Annual Probability of Recurrent Stroke

0.12

Kolmos 2021

156

Proportion of Male Patients with Hypertension, BMI <25

0.14

Wang 2004

157

Proportion of Female Patients with Hypertension, BMI <25

0.164

Proportion of Male Patients with Hypertension, BMI ≥25 to 30

0.268

Proportion of Female Patients with Hypertension, BMI ≥25 to 30

0.292

Proportion of Male Patients with Hypertension, BMI ≥30

0.431

Proportion of Female Patients with Hypertension, BMI ≥30

0.42

Probability of Developing HF from Acute MI, Age 25-54

0.0994

Sulo 2016

Probability of Developing HF from Acute MI, Age 55-74

0.1648

Probability of Developing HF from Acute MI, Age 75-85

0.268

Annual probability of Developing HF Post MI, Age 25-54

0.012

Annual probability of Developing HF Post MI, Age 55-74

0.031

Annual probability of Developing HF Post MI, Age 75-85

0.080

Comorbidity Cost Inputs

Cost Other CVD

$14,279

Scully 2017

Cost Acute Stroke

$17,316

HCUP

Cost Post Stroke

$6,500

Kazi 2019

Cost Acute MI

$26,034

HCUP

Cost Post MI

$3,117

Kazi 2016

100

Cost HF, First Year

$27,030

Patel 2021

101

; Urbich 2020

102

Cost HF, Second Year or Later

$15,605

Patel 2021

101

Evidence Report – Medications for Obesity Management Return to Table of Contents

Parameter

Input

Source

Cost DM

$11,425

ADA 2018

103

Risk Equations

Onset of Cardiovascular Condition, 10-Year Risk

Office-Based Non-Laboratory Prediction Model

Baseline and Beta Coefficient

Women

Men

So(10)

0.94833

0.8843

Log of Age

2.72107

3.113

BMI

0.51125

0.7928

Log of SBP if not treated

2.81291

1.8551

Log of SBP if treated

2.88267

1.9267

Smoking

0.61868

0.7095

Diabetes

0.77763

0.5316

Framingham Risk Calculation

Coefficient

Onset of Diabetes, Annual Risk

1.46×10

-6

exp (1.87×HbA1C) × 1.97×10

-2

exp (0.101×BMI)

Exponential regression from

Edelman et al.

BMI: body mass index, B/N: bupropion/naltrexone, CV: cardiovascular, CVD: cardiovascular disease, DM: diabetes

mellitus, HbA1C: glycated hemoglobin, HF: heart failure, HTN: hypertension, ICER: Institute for Clinical and Economic

Review, LIR: liraglutide, LSM: lifestyle modification, NMA: network meta-analysis, P/T: phentermine/topiramate, SEM:

semaglutide

Clinical Probabilities/Response to Treatment

Response to treatment was determined from clinical trials evaluating drug treatments plus lifestyle

modification versus lifestyle modification alone or compared with other treatments, where such

studies existed.

33,53,56,61,83,84

The primary outcome evaluated for this model was weight change

relative to the comparator, evaluated using the NMA depicted in Table 3.11 of the Report. Patients

would achieve the maximum weight reduction before the end of year one and maintained the

maximum efficacy while the initial treatment is maintained. A secondary outcome, needed for

determining the proportion of people developing diabetes mellitus each cycle, was mean reduction

in HbA1C.

Mortality

For patients without pre-existing comorbidities, mortality was estimated from age- and gender-

adjusted mortality rates in the general population, using all-cause mortality from the Human

Mortality Database US-specific tables.

This mortality probability was multiplied by the relative risk

for mortality for each post-event state, specifically post-myocardial infarction, post-stroke, other

cardiovascular disease, and heart failure.

79-82

In addition, mortality from the acute myocardial

infarction and acute stroke events was also factored into the model.

154

Evidence Report – Medications for Obesity Management Return to Table of Contents

Adverse Events

Adverse events were not considered in the model, as adverse events of weight loss medications

were unlikely to generate measurable health care costs or health utility losses. However, in

calculating average treatment effect, patients who discontinue the treatment due to an adverse

event were assumed to be a part of the study cohort. Cost of treatment was adjusted for the

proportion of patients who continue treatment where the treatment discontinuation was assumed

to incur at the very beginning of the first model cycle. Discontinuation rates were calculated from

the NMA results. (Table 3.19)

Economic Inputs

Administration and Monitoring Costs

Administration costs were determined to be nominal for these injectable and oral products, which

are administered at home. The injectable products, semaglutide and liraglutide, are dispensed as

single-use subcutaneous injection pens. Monitoring costs were also determined to be nominal and

were not included in the model. Table E5 presents the dose, frequency, and route of administration

as well as monitoring and administration utilization of each intervention.

Table E5. Dose, Frequency of Administration, and Annual Monitoring and Administration

Utilization

Intervention

Route

Dose

Frequency of Administration

Semaglutide

Subcutaneous

2.4 mg

Weekly

Liraglutide

Subcutaneous

3 mg

Daily

Phentermine/

Topiramate

Oral 15 mg/92 mg

Daily

Bupropion/

Naltrexone

Oral 32 mg/360 mg Daily

mg: milligram

Evidence Report – Medications for Obesity Management Return to Table of Contents

E3. Results

Cost-Effectiveness Plane

Figure E1 presents the cost-effectiveness plane. The x-axis represents therapy benefit and the y-

axis represents cost. Each point in the plane represents the estimated cost and effectiveness in the

base-case result for a particular therapy option added to lifestyle modification.

Figure E1. Cost-Effectiveness Plane

B/N: bupropion/naltrexone, LIR: liraglutide, LSM: lifestyle management, P/T: phentermine/topiramate, QALY:

quality-adjusted life year, SEM: semaglutide, USD: United States Dollar

SEM

LIR

P/T

B/N

LSM

$100,000

$200,000

$300,000

$400,000

$500,000

16.50 17.00 17.50 18.00

Discounted Cost (USD)

Discounted QALY gained

Evidence Report – Medications for Obesity Management Return to Table of Contents

Undiscounted Base-Case Results

Discounted base-case results and incremental results are presented in Report Tables 4.4 and 4.5.

The undiscounted base-case results are presented in Table E6. The undiscounted incremental

results compared to lifestyle modification are shown in Table E7.

Table E6. Undiscounted Base-Case Results

Treatment Drug Cost Non-Drug Cost Total Cost

Life

Years

QALYs evLYs

Semaglutide

$463,900

$213,800

$677,700

34.14

28.73

28.76

Liraglutide

$390,100

$267,300

$657,400

33.64

27.73

27.76

Phentermine/Topiramate

$64,100

$281,400

$345,500

33.62

27.78

27.81

Bupropion/Naltrexone

$84,000

$302,700

$386,600

33.40

27.35

27.36

Lifestyle Modification*

$18,300

$324,200

$342,400

33.19

26.91

evLY: equal-value life year, QALY: quality-adjusted life year

*Reference for evLY calculation for all active treatments.

Table E7. Undiscounted Incremental Results for the Base Case

Incremental Values vs. Lifestyle Modification

Treatment Drug Cost

Non-Drug

Cost

Total Cost

Life

Years

QALYs evLYs

Semaglutide

$445,600

-$110,400

$335,300

0.95

1.82

1.85

Liraglutide

$371,800

-$56,900

$315,000

0.45

0.82

0.85

Phentermine/Topiramate

$45,800

-$42,800

$3,100

0.42

0.88

0.90

Bupropion/Naltrexone

$65,700

-$21,500

$44,200

0.21

0.44

0.45

Lifestyle Modification*

evLY: equal-value life year, QALY: quality-adjusted life year

*Reference for incremental calculation for all active treatments.

Key incremental cost per QALY ratios over the lifetime horizon are shown in Table 4.6 of the Report

for each of the treatment strategies. All calculated incremental ratios over the lifetime horizon

between treatment options included in our model are show in Table E8.

Evidence Report – Medications for Obesity Management Return to Table of Contents

Table E8. Incremental Cost-Effectiveness Ratios for the Base Case, Results from Discounted and

Undiscounted Outcomes

Treatment Comparator

Cost per Life

Year Gained

Cost per QALY

Gained

Cost per evLY

Gained

Discounted Results

Semaglutide

Lifestyle modification

$624,000

$238,000

$235,000

Liraglutide

Lifestyle modification

$1,210,000

$485,000

$475,000

Phentermine/Topiramate

Lifestyle modification

$22,000

$8,000

$7,000

Bupropion/Naltrexone

Lifestyle modification

$359,000

$124,000

$121,000

Semaglutide

Liraglutide

$85,000

$31,000

Phentermine/topiramate

$1,128,000

$472,000

$468,000

Bupropion/naltrexone

$703,000

$277,000

$274,000

Liraglutide

Phentermine/topiramate $23,837,000

P/T less costly,

more effective

P/T less costly,

more effective

Bupropion/naltrexone

$1,991,000

$941,000

$921,000

Phentermine/Topiramate Bupropion/naltrexone

P/T less costly,

more effective

P/T less costly,

more effective

P/T less costly,

more effective

Undiscounted Results

Semaglutide

Lifestyle modification

$352,000

$184,000

$181,000

Liraglutide

Lifestyle modification

$702,000

$382,000

$371,000

Phentermine/Topiramate

Lifestyle modification

$7,000

$4,000

$3,000

Bupropion/Naltrexone

Lifestyle modification

$209,000

$101,000

$98,000

Semaglutide

Liraglutide

$40,000

$20,000

Phentermine/topiramate

$630,000

$352,000

$348,000

Bupropion/naltrexone

$394,000

$211,000

$208,000

Liraglutide

Phentermine/topiramate

$12,807,000

P/T less costly,

more effective

P/T less costly,

more effective

Bupropion/naltrexone

$1,145,000

$702,000

$681,000

Phentermine/Topiramate Bupropion/naltrexone

P/T less costly,

more effective

P/T less costly,

more effective

P/T less costly,

more effective

evLY: equal-value life year, PT: phentermine/topiramate, QALY: quality-adjusted life year

Cumulative Incidence of Cardiovascular Conditions and Mortality

Average life expectancy in patients receiving semaglutide and lifestyle modification was 34.14 and

33.19 years, respectively. The respective cumulative incidence of any major cardiovascular

condition through the end of the model time horizon was 52.06% and 59.51%. Figures E2 and E3

present the overall survival estimates and cumulative incidence of cardiovascular conditions across

the five treatment arms.

Evidence Report – Medications for Obesity Management Return to Table of Contents

Figure E2. Cumulative Incidence of Any Major Cardiovascular Comorbidity

B/N: bupropion/naltrexone, LIR: liraglutide, LSM: lifestyle modification, P/T: phentermine/topiramate, SEM:

semaglutide

Figure E3. Overall Survival

B/N: bupropion/naltrexone, LIR: liraglutide, LSM: lifestyle modification, P/T: phentermine/topiramate, SEM:

semaglutide

20%

40%

60%

80%

100%

45 50 55 60 65 70 75 80 85 90 95 100

Cumulative Incidence

Age (year)

SEM

LIR

P/T

B/N

LSM

20%

40%

60%

80%

100%

45 50 55 60 65 70 75 80 85 90 95 100

Overall Survival

Age (year)

SEM

LIR

P/T

B/N

LSM

Evidence Report – Medications for Obesity Management Return to Table of Contents

E4. Sensitivity Analyses

One-Way Sensitivity Analysis

The model was sensitive to several inputs, including the disutility per BMI change, baseline HbA1C,

cost of diabetes mellitus management, baseline BMI, weight-lowering effect of treatment

compared to lifestyle management, and change in HbA1C with treatment. The one-way sensitivity

analysis results and tornado diagrams for each treatment option are presented in Table E9 on the

following page.

Evidence Report – Medications for Obesity Management Return to Table of Contents

Table E9. Tornado Diagram Inputs and Results for One-Way Sensitivity Analyses (by Incremental Cost-Effectiveness Ratio)†

SEM vs. LSM

Input Variable

Lower Input

Higher Input

Lower Input ICER

Higher Input ICER

Disutility per BMI change

-0.00555

-0.00111

$197,000

$301,000

Baseline HbA1C

5.1

5.85

$230,000

$325,000

Cost of DM

$7,501

$17,418

$206,000

$259,000

Baseline BMI

$222,000

$272,000

Difference in % Weight Change, SEM vs. LSM

-0.14974

-0.12466

$221,000

$258,000

Difference in HbA1C between SEM and LSM

-0.33018

-0.26982

$231,000

$246,000

Relative Risk of Mortality for Other CVD

1.3

2.8

$231,000

$244,000

Relative Risk of Mortality for Stroke

1.98

4.92

$233,000

$244,000

SEM Treatment Discontinuation Rate

0.032

0.054

$234,000

$241,000

Age-Related Disutility

-0.0009

-0.0005

$235,000

$241,000

Probability of Stroke Occurring in Those with CV

0.18793

0.274094

$236,000

$240,000

Relative Risk of Mortality for MI

1.18

2.12

$236,000

$240,000

Relative Risk of Mortality for DM

1.14

1.16

$236,000

$240,000

Proportion Female

0.741

0.817504

$236,000

$239,000

Cost of Other CVD

$10,056

$18,498

$237,000

$239,000

Probability of Mortality for Acute MI

0.05274

0.098482

$237,000

$239,000

Annual Weight Gain

0.004

$238,000

$240,000

Probability of Mortality for Acute Stroke

0.05605

0.102826

$237,000

$239,000

Proportion of CV Events that are MIs

0.18032

0.265386

$237,000

$239,000

Cost of HF, Second Year or Later

$10,098

$24,115

$237,000

$238,000

LRG vs. LSM

Input Variable

Lower Input

Higher Input

Lower Input ICER

Higher Input ICER

Disutility per BMI change

-0.00555

-0.00111

$419,000

$576,000

Baseline HbA1C

5.1

5.85

$484,000

$628,000

Difference in % Weight Change, LIR vs. LSM

-0.061

-0.039

$423,000

$567,000

Difference in HbA1C between LIR and LSM

-0.23018

-0.16982

$453,000

$522,000

Baseline BMI

$469,000

$531,000

Cost of DM

$7,501

$17,418

$448,000

$510,000

Relative Risk of Mortality for Other CVD

1.3

2.8

$470,000

$499,000

Relative Risk of Mortality for Stroke

1.98

4.92

$473,000

$499,000

Age-Related Disutility

-0.0009

-0.0005

$479,000

$493,000

Annual Weight Gain

0.004

$485,000

$499,000

LIR Treatment Discontinuation Rate

0.049

0.067

$479,000

$491,000

Probability of Stroke Occurring in Those with CV

0.18793

0.274094

$481,000

$490,000

Relative Risk of Mortality for MI

1.18

2.12

$481,000

$490,000

Relative Risk of Mortality for DM

1.14

1.16

$482,000

$489,000

Proportion Female

0.741

0.817504

$481,000

$487,000

Probability of Mortality for Acute MI

0.05274

0.098482

$484,000

$487,000

Probability of Mortality for Acute Stroke

0.05605

0.102826

$484,000

$487,000

Baseline Age

44.4246

45.57539

$485,000

$487,000

Proportion of CV events that are MIs

0.18032

0.265386

$484,000

$487,000

Cost of Other CVD

$10,056

$18,498

$484,000

$487,000

$175,000 $200,000 $225,000 $250,000 $275,000 $300,000 $325,000

$400,000 $450,000 $500,000 $550,000 $600,000 $650,000

Evidence Report – Medications for Obesity Management Return to Table of Contents

P/T vs. LSM

Input Variable

Lower Input

Higher Input

Lower Input ICER

Higher Input ICER

Cost of DM

$7,501

$17,418

$24,000

-$17,000

Difference in % Weight Change, P/T vs. LSM

-0.111

-0.0715

-$3,000

$24,000

Baseline HbA1C

5.1

5.85

$26,000

$7,000

Baseline BMI

$16,000

$4,000

Difference in HbA1C between B/N and LSM

-0.030184

0.030184

$1,000

$9,000

Disutility per BMI Change

-0.00555

-0.00111

$6,000

$11,000

P/T Treatment Discontinuation Rate

0.040

0.081

$9,000

$5,000

Cost of Other CVD

$10,056

$18,498

$9,000

$6,000

Annual Weight Gain

0.004

$8,000

$9,000

Cost of HF, Second Year or Later

$10,098

$24,115

$7,000

$8,000

Relative Risk of Mortality for Other CVD

1.3

2.8

$8,000

$7,000

Relative Risk of Mortality for Stroke

1.98

4.92

$7,000

$8,000

Cost of Acute MI

$16,462

$41,171

$8,000

$7,000

Cost of Acute Stroke

$11,153

$26,886

$8,000

$7,000

Proportion of CV Events that are Strokes

0.188

0.274

$7,000

$8,000

LSM Treatment Discontinuation Rate

0.017

0.035

$7,000

$8,000

Cost of Post Stroke

$5,418

$7,801

$8,000

$7,000

Proportion Female

0.741

0.818

$7,000

$8,000

Relative Risk of Mortality for MI

1.18

2.12

$7,000

$8,000

Age-Related Disutility

-0.0009

-0.0005

$8,000

$7,000

B/N vs. LSM

Input Variable

Lower Input

Higher Input

Lower Input ICER

Higher Input ICER

Difference in % Weight Change, B/N vs. LSM

-0.0604

-0.0311

$81,000

$210,000

Disutility per BMI Change

-0.00555

-0.00111

$97,000

$172,000

Cost of DM

$7,501

$17,418

$140,000

$99,000

Baseline HbA1C

5.1

5.85

$153,000

$125,000

Difference in HbA1C between B/N and LSM

-0.13872

-0.11128

$100,000

$129,000

Baseline BMI

$142,000

$116,000

B/N Treatment Discontinuation Rate

0.036

0.073

$128,000

$119,000

Relative Risk of Mortality for Other CVD

1.3

2.8

$127,000

$120,000

Relative Risk of Mortality for Stroke

1.98

4.92

$127,000

$121,000

Annual weight gain

0.004

$124,000

$129,000

Age-Related Disutility

-0.0009

-0.0005

$126,000

$122,000

Cost of Other CVD

$10,056

$18,498

$125,000

$122,000

Probability of Stroke Occurring in Those with CV

0.18793

0.274094

$125,000

$123,000

Relative Risk of Mortality for MI

1.18

2.12

$125,000

$123,000

Proportion Female

0.741

0.818

$122,000

$124,000

Relative Risk of Mortality for DM

1.14

1.16

$124,000

$123,000

Cost of HF, Second Year or Later

$10,098

$24,115

$124,000

$123,000

LSM Treatment Discontinuation Rate

0.017

0.027

$123,000

$124,000

Relative Risk of Mortality for MI

1.18

2.12

$124,000

$123,000

Baseline Age

44.4246

45.57539

$124,000

$123,000

BMI: body mass index, B/N: bupropion/naltrexone, CV: cardiovascular, CVD: cardiovascular disease, DM: diabetes mellitus, Hb: hemoglobin, HF: heart failure, ICER: incremental cost-effectiveness ratio, LIR: liraglutide, LSM: lifestyle modification, MI: myocardial

infarction, P/T: phentermine/topiramate, SEM: semaglutide

*Note lower input may reflect either upper or lower ICER value depending on the direction that the input has on the ICER output. †In the tornado diagram, blue bars denote effects from low input estimates, while green bars denote effects from high input estimates.

-$20,000 -$10,000 $0 $10,000 $20,000 $30,000

$50,000 $100,000 $150,000 $200,000 $250,000

Evidence Report – Medications for Obesity Management Return to Table of Contents

Probabilistic Sensitivity Analysis

Probabilistic sensitivity analysis results are presented in the Report. Additional results, including

incremental cost-effectiveness scatterplots and acceptability curves are presented in Figure E4.

Figure E4. Results of Probabilistic Sensitivity Analysis, Incremental Cost-Effectiveness Scatterplots

and Acceptability Curve

Incremental Cost-Effectiveness Scatterplot

Y-axis: Incremental Cost (USD)

X-axis: Incremental Effectiveness (QALY Gained)

Acceptability Curve

Y-axis: Probability Cost Effective

X-axis: Cost-Effectiveness Threshold (USD/QALY)

Semaglutide v. Lifestyle Modif

ication

Liraglutide v. Lifestyle Modification

$50,000

$100,000

$150,000

$200,000

$250,000

$300,000

$350,000

$400,000

-0.5 0 0.5 1 1.5 2

20%

40%

60%

80%

100%

$0 $100,000 $200,000 $300,000

$50,000

$100,000

$150,000

$200,000

$250,000

$300,000

$350,000

-0.2 0 0.2 0.4 0.6 0.8

Incremental Effectiveness (QALY gained)

20%

40%

60%

80%

100%

$0 $100,000 $200,000 $300,000

Evidence Report – Medications for Obesity Management Return to Table of Contents

Incremental Cost-Effectiveness Scatterplot

Y-axis: Incremental Cost (USD)

X-axis: Incremental Effectiveness (QALY Gained)

Acceptability Curve

Y-axis: Probability Cost Effective

X-axis: Cost-Effectiveness Threshold (USD/QALY)

Phentermine/Topiramate v. Lifestyle Modification

Naltrexone/Bupropion v. Lifestyle Modification

-$40,000

-$30,000

-$20,000

-$10,000

$10,000

$20,000

$30,000

$40,000

-0.5 0 0.5 1

20%

40%

60%

80%

100%

$0 $100,000 $200,000 $300,000

$10,000

$20,000

$30,000

$40,000

$50,000

$60,000

-0.2 0 0.2 0.4 0.6

20%

40%

60%

80%

100%

$0 $100,000 $200,000 $300,000

Evidence Report – Medications for Obesity Management Return to Table of Contents

Incremental Cost-Effectiveness Scatterplot

Y-axis: Incremental Cost (USD)

X-axis: Incremental Effectiveness (QALY Gained)

Acceptability Curve

Y-axis: Probability Cost Effective

X-axis: Cost-Effectiveness Threshold (USD/QALY)

Sema

glutide v. Phentermine/Topiramate

Semaglutide v. Bupropion/Naltrexone

$50,000

$100,000

$150,000

$200,000

$250,000

$300,000

$350,000

-0.2 0 0.2 0.4 0.6 0.8

20%

40%

60%

80%

100%

$0 $100,000 $200,000 $300,000

$50,000

$100,000

$150,000

$200,000

$250,000

$300,000

$350,000

-0.5 0 0.5 1 1.5

20%

40%

60%

80%

100%

$0 $100,000 $200,000 $300,000

Evidence Report – Medications for Obesity Management Return to Table of Contents

E5. Scenario Analyses

Key scenario analysis results are presented in the Report. Indirect costs of each cardiovascular

conditions were calculated from published research and public data (Table E11). Additional results

for the societal perspective scenario analyses are presented by incremental cost per outcome

gained in Table E12. Changes to inputs for Comorbidity X scenarios are presented in Table E13

whereas cost per life year, QALY, and evLY gained results of the Comorbidity X scenarios are

presented in Tables E14 and E15, respectively. In scenario analyses, we explored how cost

effectiveness is impacted by the average BMI prior to initiating treatment and for a population of

patients with an equal male to female ratio. Cost per life year, QALY, and evLY gained results of the

class III obesity scenarios and similar male-female ratio scenario are presented in Tables E16-E18.

Table E11. Societal Perspective Indirect Cost* Inputs

Parameter

Input

Source

Indirect Cost of Type 2 Diabetes $3,245

American Diabetes

Association 2018

103

Indirect Cost of Myocardial Infarction Management $3,467

American Heart

Association/American

Stroke Association

158

Indirect Cost of Stroke Management $5,271

American Heart

Association/American

Stroke Association

158

Indirect Cost of Other Cardiovascular Conditions $7,340

American Heart

Association/American

Stroke Association

158

Indirect Cost of Heart Failure

$10,403

Cook 2014

108

*Annual productivity loss calculated from the ratio of direct vs. indirect burden of each chronic condition

management.

Table E12. Societal Perspective Incremental Cost-Effectiveness Ratios

Treatment Comparator

Cost per Life

Year Gained

Cost per QALY

Gained

Cost per

evLY Gained

Semaglutide

Lifestyle modification

$568,000

$217,000

$214,000

Liraglutide

Lifestyle modification

$1,149,000

$461,000

$451,000

Phentermine/Topiramate

Lifestyle modification

P/T less costly, more effective

Bupropion/Naltrexone

Lifestyle modification

$307,000

$106,000

$104,000

Semaglutide

Liraglutide

$34,000

$12,000

Phentermine/topiramate

$1,068,000

$447,000

$443,000

Bupropion/naltrexone

$646,000

$254,000

$252,000

Liraglutide

Phentermine/topiramate $23,592,000

P/T less costly,

more effective

P/T less

costly, more

effective

Bupropion/naltrexone

$1,921,000

$908,000

$889,000

Phentermine/Topiramate

Bupropion/naltrexone

P/T less costly, more effective

evLY: equal-value life year, P/T: phentermine/topiramate, QALY: quality-adjusted life year, SEM: semaglutide

Evidence Report – Medications for Obesity Management Return to Table of Contents

Table E13. Inputs for Comorbidity X Scenarios

Parameter

Input

Source

Cancer Inputs

Annual Incidence of Cancer for Ages 40-49 years

0.28%

White 2014

159

Annual Incidence of Cancer for Ages 50-59 years

0.68%

Annual Incidence of Cancer for Ages 60-69 years

1.39%

Annual Incidence of Cancer for Ages 70-79 years

1.95%

Annual Incidence of Cancer for Ages ≥80 years

1.83%

Relative Risk of Cancer per One Unit Increase in BMI

1.04

Munsell 2014

160

Relative Risk of Death with Cancer

3.73

Kim 2022

105

Annual Cost of Cancer

$15,756

CKD Inputs

Annual Incidence of CKD for BMI Range 25-30

0.32%

Mohammedi 2018

161

Annual Incidence of CKD for BMI Range 30-35

0.37%

Annual Incidence of CKD for BMI Range 35-40

0.51%

Annual Incidence of CKD for BMI Range 40-45

0.79%

Relative Risk of Death with CKD

2.48

USRDS 2015

162

Annual Cost of CKD

$12,497

USRDS 2021

163

BMI: body mass index, CKD: chronic kidney disease

Table E14. Comorbidity X Scenario Analysis (Cancer)

Treatment Comparator

Cost per Life

Year Gained

Cost per QALY

Gained

Cost per

evLY Gained

Semaglutide

Lifestyle modification

$480,000

$215,000

$211,000

Liraglutide

Lifestyle modification

$976,000

$447,000

$434,000

Phentermine/Topiramate

Lifestyle modification

$14,000

$6,000

Bupropion/Naltrexone

Lifestyle modification

$242,000

$106,000

$102,000

Semaglutide

Liraglutide

$65,000

$29,000

$28,000

Phentermine/topiramate

$968,000

$447,000

$441,000

Bupropion/naltrexone

$564,000

$255,000

$251,000

Liraglutide

Phentermine/topiramate

P/T less costly, more effective

Bupropion/naltrexone

$1,945,000

$953,000

$926,000

Phentermine/Topiramate

Bupropion/naltrexone

P/T less costly, more effective

BMI: body mass index, CKD: chronic kidney disease, P/T: phentermine/topiramate

Evidence Report – Medications for Obesity Management Return to Table of Contents

Table E15. Comorbidity X Scenario Analysis (Chronic Kidney Disease)

Treatment Comparator

Cost per Life

Year Gained

Cost per QALY

Gained

Cost per

evLY Gained

Semaglutide

Lifestyle modification

$504,000

$213,000

$209,000

Liraglutide

Lifestyle modification

$997,000

$439,000

$426,000

Phentermine/Topiramate

Lifestyle modification

$9,000

$4,000

$3,000

Bupropion/Naltrexone

Lifestyle modification

$242,000

$100,000

$97,000

Semaglutide

Liraglutide

$66,000

$27,000

Phentermine/topiramate

$1,056,000

$460,000

$455,000

Bupropion/naltrexone

$601,000

$256,000

$252,000

Liraglutide

Phentermine/topiramate

P/T less costly, more effective

Bupropion/naltrexone

$2,003,000

$965,000

$939,000

Phentermine/Topiramate

Bupropion/naltrexone

P/T less costly, more effective

BMI: body mass index, CKD: chronic kidney disease, QALY: quality-adjusted life year

Table E16. Class III Obesity Scenario 1, Baseline BMI of 40-45 m

/kg (Average BMI of 42.5)

Treatment Comparator

Cost per Life

Year Gained

Cost per QALY

Gained

Cost per

evLY Gained

Semaglutide

Lifestyle modification

$557,000

$209,000

$205,000

Liraglutide

Lifestyle modification

$1,203,000

$464,000

$451,000

Phentermine/Topiramate

Lifestyle modification

$5,000

$2,000

Bupropion/Naltrexone

Lifestyle modification

$334,000

$111,000

$108,000

Semaglutide

Liraglutide

$44,000

$16,000

Phentermine/topiramate

$1,001,000

$415,000

$408,000

Bupropion/naltrexone

$620,000

$241,000

$237,000

Liraglutide

Phentermine/topiramate

P/T less costly, more effective

Bupropion/naltrexone

$2,059,000

$941,000

$913,000

Phentermine/Topiramate

Bupropion/naltrexone

P/T less costly, more effective

evLY: equal-value life year, P/T: phentermine/topiramate, QALY: quality-adjusted life year, SEM: semaglutide

Table E17. Class III Obesity Scenario 2, Baseline BMI of 45-50 m

/kg (Average BMI of 47.5)

Treatment Comparator

Cost per Life

Year Gained

Cost per QALY

Gained

Cost per

evLY Gained

Semaglutide

Lifestyle modification

$573,000

$205,000

$200,000

Liraglutide

Lifestyle modification

$1,414,000

$501,000

$486,000

Phentermine/Topiramate

Lifestyle modification

$11,000

$3,000

Bupropion/Naltrexone

Lifestyle modification

$370,000

$115,000

$111,000

Semaglutide

Liraglutide

$25,000

$9,000

Phentermine/topiramate

$1,014,000

$403,000

$394,000

Bupropion/naltrexone

$628,000

$234,000

$228,000

Liraglutide

Phentermine/topiramate

P/T less costly, more effective

Bupropion/naltrexone

$2,630,000

$1,118,000

$1,079,000

Phentermine/Topiramate

Bupropion/naltrexone

P/T less costly, more effective

evLY: equal-value life year, P/T: phentermine/topiramate, QALY: quality-adjusted life year, SEM: semaglutide

Evidence Report – Medications for Obesity Management Return to Table of Contents

Table E18. Similar Proportion of Male and Female (50:50) Scenario

Treatment Comparator

Cost per Life

Year Gained

Cost per QALY

Gained

Cost per

evLY Gained

Semaglutide

Lifestyle modification

$535,000

$228,000

$225,000

Liraglutide

Lifestyle modification

$1,043,000

$466,000

$455,000

Phentermine/Topiramate

Lifestyle modification

$17,000

$7,000

$6,000

Bupropion/Naltrexone

Lifestyle modification

$296,000

$116,000

$114,000

Semaglutide

Liraglutide

$74,000

$30,000

Phentermine/topiramate

$992,000

$457,000

$453,000

Bupropion/naltrexone

$609,000

$267,000

$264,000

Liraglutide

Phentermine/topiramate

$70,143,000

P/T less costly, more effective

Bupropion/naltrexone

$1,781,000

$917,000

$896,000

Phentermine/Topiramate

Bupropion/naltrexone

P/T less costly, more effective

evLY: equal-value life year, P/T: phentermine/topiramate, QALY: quality-adjusted life year, SEM: semaglutide

E6. Heterogeneity and Subgroups

There are patient or cohort-specific factors that may affect treatment response in patients with

overweight or obesity. Our model was not specifically designed to test the cost effectiveness of

weight-management in patients with diabetes mellitus.

We explored how the cost effectiveness is impacted by the average BMI prior to initiating

treatment and male to female ratio. Incremental cost-effectiveness ratios for the patients with

class III obesity and population consisting of similar proportion of male and female are presented in

Table E19.

Table E19. Analysis to Address Potential Heterogeneity Effect Across Subpopulations: Class III

Obesity or Similar Male and Female Proportions (50:50), Incremental Cost-Effectiveness (QALY)

Ratios

Treatment Comparator

BMI 40-45 m

/kg

(Average: 42.5)

BMI 45-50 m

/kg

(Average: 47.5)

Male:

Female

50:50

Semaglutide

Lifestyle modification

$209,000

$205,000

$228,000

Liraglutide

Lifestyle modification

$464,000

$501,000

$466,000

Phentermine/Topiramate

Lifestyle modification

$2,000

$3,000

$7,000

Buproprion/Naltrexone

Lifestyle modification

$111,000

$115,000

$116,000

Semaglutide

Liraglutide

$16,000

$9,000

$30,000

Phentermine/topiramate

$415,000

$403,000

$457,000

Buproprion/naltrexone

$241,000

$234,000

$267,000

Liraglutide

Phentermine/topiramate

Phentermine/topiramate less costly, more effective

Buproprion/naltrexone

$941,000

$1,118,000

$917,000

Phentermine/Topiramate

Buproprion/naltrexone

Phentermine/topiramate less costly, more effective

BMI: body mass index

Evidence Report – Medications for Obesity Management Return to Table of Contents

E7. Prior Economic Models

Our study adapted structurally-advanced prior economic models that focused on causal

associations between BMI and cardiovascular comorbidities. Borisenko et al. developed a bariatric

surgery Markov model in which the natural course of weight-related cardiovascular conditions was

included as separate Markov states.

90,91,164-166

A recently developed model linked BMI and glucose

intolerance with the onset of diabetes mellitus and cardiovascular complications.

167

Similar to our

model, both models incorporated the Framingham risk equation as a predictor of cardiovascular

comorbidity onset. Due to ongoing uncertainty around the causal association between weight loss

and non-cardiovascular comorbidities, the bariatric surgery Markov model excluded cancer,

osteoarthritis, sleep apnea, and chronic kidney disease. In our model, we tested the potential

influence of the non-cardiovascular conditions on the cost effectiveness using an add-on

Comorbidity X state. This structural adaptation to the model, with the inclusion of conditions not

evaluated in the base case, could be considered as an advanced method of scenario analysis in

situations with limited evidence regarding exposure-outcome association.

Additionally, we critically evaluated economic models involving GLP-1 receptor agonists in the US

health care setting. Lee at al. analyzed the cost effectiveness of medication-assisted weight loss

options using treatment cost and BMI-dependent quality of life without including comorbid states

in the model.

168

Similar to our findings, this study concluded that 1) phentermine/topiramate was

the most cost-effective strategy; 2) patients on semaglutide gained the largest clinical and QALY

benefits; 3) liraglutide was dominated by phentermine/topiramate and semaglutide. These

conclusions regarding semaglutide and liraglutide were supported by a recent analysis of four GLP-1

receptor agonists.

169

A more detailed comparison of findings could not be made because the

structure of the two previous models notably differed from our model.

Another recent publication analyzed the cost effectiveness of medication-assisted weight loss

treatment strategies compared to lifestyle modification.

105

The study adapted a model to evaluate

the cost effectiveness of semaglutide 2.4 mg for the treatment of adult patients with overweight or

obesity. The Markov model examined semaglutide compared to no treatment, diet and exercise

alone, and standard-of-care therapy options (liraglutide 3 mg, phentermine/topiramate, and

bupropion/naltrexone) from the US third-party payer’s perspective over a 30-year time horizon.

Treatment duration with any therapy (aside from diet and exercise) did not exceed two years, after

which a gradual weight regain to baseline was applied to address natural weight gain until the end

of the time horizon. In the model, patients could transition between no comorbidity, single

comorbidity, dual comorbidity, multi-comorbidity, and death. Comorbidities included in the model

were post-myocardial infarction, type 2 diabetes mellitus, post-stroke, obstructive sleep apnea, and

cancer. Patients could experience acute events of bariatric surgery, acute coronary syndrome,

stroke/transient ischemic attack, and knee replacements. In this study, the base-case incremental

cost-effectiveness ratios (cost per QALY) from this model for semaglutide 2.4 mg compared to

Evidence Report – Medications for Obesity Management Return to Table of Contents

liraglutide 3 mg, phentermine/topiramate, bupropion/naltrexone, diet and exercise, and no

treatment were $23,556, $144,296, $127,518, $122,549, and $27,113, respectively. Liraglutide 3

mg, phentermine/topiramate, and bupropion/naltrexone compared to diet and exercise resulted in

incremental cost-effectiveness ratios of $439,200, $32,700, and $86,500. In an exercise assessing

how our model results compared with those of this published model, we edited our model to

include a two-year treatment, 30-year time horizon, and used disutilities for cardiovascular events

and diabetes mellitus reported in this study.

105

The resulting incremental cost-effectiveness ratio

estimates for semaglutide compared with lifestyle modification from our model were

approximately $10,000 per QALY gained less than the same comparison reported by Kim N et al.

This remaining difference is explained by structural differences, higher mortality leading to lower

QALY gains, and other differences in inputs not modeled in our validation exercise. Due to concerns

associated with attributing long-term benefits to a short-term (i.e., two-year) treatment and the

likely poor performance of the ACC/AHA models in predicting cardiovascular risk after

discontinuation of short-term treatment as well as the potential risks of weight cycling, we chose to

focus solely on evaluating the cost effectiveness of lifetime treatment.

170,171

Additional differences noted between these two models included the incorporation of certain

cancers, sleep apnea, and the acute events of bariatric surgery and knee replacements.

105

evaluated the potential impact of cancers and chronic kidney disease in scenario analyses. In our

Comorbidity X scenarios, we determined that conditions other than cardiovascular conditions likely

have a nominal impact on incremental cost-effectiveness ratios. Additionally, we were unable to

assess differences in the application of risk equations to models. For example, Kim et al. utilized

Framingham Recurring Coronary Heart Disease and United Kingdom Prospective Diabetes Study risk

equations within their model structure, whereas we used the ACC/AHA risk equation model, which

incorporates updated estimates from Framingham but not changes in cardiovascular risk due to

HbA1C. Finally, treatment efficacy inputs were derived directly from clinical trials in this published

analysis, whereas our analysis involved conducting an NMA to derive the primary effectiveness

inputs.

Evidence Report – Medications for Obesity Management Return to Table of Contents

F. Potential Budget Impact: Supplemental

Information

Methods

The primary aim of the potential budgetary impact analysis is to document the percentage of

patients who could be treated at selected semaglutide prices without crossing a potential budget

impact threshold that is aligned with overall growth in the US economy. For 2022-2023, the five-

year annualized potential budget impact threshold that should trigger policy actions to manage

access and affordability is calculated to be approximately $777 million per year

for a novel

prescription drug therapy.

Potential budget impact was defined as the total differential cost of using semaglutide rather than

relevant existing therapy (alone) for the treated population, calculated as differential health care

costs (including drug costs) minus any offsets in these costs (for instance, due to offsets in major

adverse cardiovascular events). All costs were undiscounted and estimated over one- and five-year-

time horizons. The five-year timeframe was of primary interest, given the potential for cost offsets

to accrue over time and to allow a more realistic impact on the number of patients treated with the

new therapy. This longer-term budget impact horizon of five years is aligned with the durable

treatment persistence assumption key to our underlying cost-effectiveness analytic approach.

To estimate the size of the potential candidate populations for treatment, we use the US adult

population size and prevalence of obesity and overweight in conjunction specific weight-related

comorbidities or biomarkers for such. Specifically, we utilize deidentified and merged patient

records from the National Health and Nutrition Examination Survey (NHANES) over the 2017-2018

and 2019-March 2020 data collection cycles for estimates of prevalence.

NHANES is a program

combining interviews and physical examinations to assess health and nutritional status among US

adults and children.

To determine size of the salient cohort with overweight and with weight-

related comorbidities specifically, we use the following patient-level data as captured within

NHANES, where patient records must have evidence of one or more of the following in addition to

reporting with overweight (defined as 27.0 kg/m

≤BMI<30 kg/m

): 1) Ever told you have high blood

pressure, 2) Ever told you have high cholesterol, 3) Ever told you have prediabetes, 4) HbA1C ≥6.5%,

5) Ever told you have diabetes, 6) Insulin level ≥23 microunits/mL, and 7) Stop breathing three or

more nights a week. Accordingly, we estimate a combined prevalence value for US adults with BMI

≥30 or 27.0 kg/m

≤BMI<30 kg/m

with one or more weight-related comorbidities at 53.53% (41.96%

with obesity, 11.57% with overweight and one or more weight-related comorbidities). Semaglutide

captures market share proportionally from all modeled comparators (liraglutide,

phentermine/topiramate, bupropion/naltrexone, lifestyle modification alone), with semaglutide

Evidence Report – Medications for Obesity Management Return to Table of Contents

achieving 100% market share by year five. This is a key modeling assumption aimed at

understanding the proportion of the total population that can be treated without crossing the

annual budget impact threshold.

Results

Table F1 describes the per-patient budget impact calculations in more detail, based on WAC

($17,597.48 per year), discounted WAC ($13,618.22 per year), and the prices to reach $150,000,

$100,000, and $50,000 per QALY ($9,700, $7,500, and $5,300 per year, respectively) compared

lifestyle modification alone. Similarly, Figure F1 visualizes semaglutide’s cumulative net budget

impact per treated patient per year at its calculated net price, assuming an incremental 20% uptake

per year.

Table F1. Per-Patient Budget Impact Calculations Over a Five-Year Time Horizon

Average Annual Per Patient Budget Impact

WAC

Discounted

WAC

$150,000/QALY $100,000/QALY $50,000/QALY

Semaglutide

$13,300

$9,400

$5,700

$3,500

$1,400

QALY: quality-adjusted life year, WAC: wholesale acquisition cost

Figure F1. Cumulative Per-Patient Budget Impact Calculations Over a Five-Year Time Horizon at

Semaglutide Net Price

$9,700

$19,300

$28,700

$37,900

$47,000

$5,000

$10,000

$15,000

$20,000

$25,000

$30,000

$35,000

$40,000

$45,000

$50,000

Year 1 Year 2 Year 3 Year 4 Year 5

Cumulative Annual Budget Impact Per

Treated Patient