Postgraduate Medicine

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Efficacy and safety of semaglutide for weight

management: evidence from the STEP program

Anastassia Amaro, Danny Sugimoto & Sean Wharton

To cite this article: Anastassia Amaro, Danny Sugimoto & Sean Wharton (2022) Efficacy and
safety of semaglutide for weight management: evidence from the STEP program, Postgraduate
Medicine, 134:sup1, 5-17, DOI: 10.1080/00325481.2022.2147326

To link to this article: https://doi.org/10.1080/00325481.2022.2147326

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POSTGRADUATE MEDICINE
2022, VOL. 134, NO. S1, 5–17
https://doi.org/10.1080/00325481.2022.2147326

SUPPLEMENT: SEMAGLUTIDE FOR WEIGHT MANAGEMENT – AN INTRODUCTION

FOR PRIMARY CARE

Efficacy and safety of semaglutide for weight management: evidence from the STEP
program
a b c
Anastassia Amaro , Danny Sugimoto and Sean Wharton
a
Penn Metabolic Medicine, Division of Endocrinology, University of Pennsylvania, Philadelphia, PA, USA; bCedar Crosse Research Center, Chicago,
IL, USA; cYork University, McMaster University and Wharton Weight Management Clinic, Toronto, Ontario, Canada

ABSTRACT ARTICLE HISTORY

Obesity is a global health challenge. It is a multifactorial, complex, and progressive disease associated Received 15 September
with various health complications and increased mortality. Lifestyle modifications are central to weight 2022
management but may be insufficient to maintain clinically meaningful weight loss. Pharmacotherapies Accepted 10 November
are recommended as an adjunct to lifestyle interventions to induce and sustain clinically meaningful 2022
weight loss and reduce the risk of comorbidities in appropriate patients. Glucagon-like peptide-1 is an KEYWORDS
incretin metabolic hormone responsible for a range of physiological effects, including glucose and Obesity; glucagon-like
appetite regulation. Several glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been approved peptide-1 receptor agonist;
for the treatment of type 2 diabetes since 2005 including exenatide (short- and extended-release), semaglutide; primary care
lixisenatide, liraglutide, dulaglutide, albiglutide, and semaglutide. Of these, semaglutide (subcuta­
neous) and liraglutide are currently US Food and Drug Administration (FDA)-approved for chronic
weight management in patients with or without diabetes. The phase 3 Semaglutide Treatment Effect in
People with obesity (STEP) program was designed to investigate the effect of semaglutide versus
placebo on weight loss, safety, and tolerability in adults with overweight or obesity. Following the
submission of the results of the STEP 1–4 trials, the FDA approved once-weekly subcutaneous
semaglutide 2.4 mg for chronic weight management in people with overweight or obesity in
April 2021. Data from the program demonstrated that semaglutide (2.4 mg once weekly) achieved
significant and sustained weight loss, together with improvements in cardiometabolic risk factors
compared with placebo, and was generally well tolerated, with a safety profile consistent with other
GLP-1RAs. The most common adverse events reported in STEP 1–5 were gastrointestinal events, which
were transient, mild-to-moderate in severity, and typically resolved without permanent treatment
discontinuation. This article reviews the data from STEP 1–5 and highlights clinically relevant findings
for primary care providers.

1. Introduction As an adjunct to lifestyle interventions, appropriate use

Obesity is a chronic, progressive disease with a complex
pathophysiology and a multifactorial origin, including
genetic, metabolic, behavioral, sociocultural, and environ­
mental factors [1,2]. Obesity is a global pandemic, with the
worldwide prevalence nearly tripling since 1975 [3]. In 2016,
39% of adults aged 18 years and older were overweight
(defined as body mass index [BMI] ≥25 kg/m2) and 13%
were living with obesity (defined as BMI ≥30 kg/m2) [3].
Furthermore, in the US, 42.4% of adults were living with
obesity from 2017 to 2018 [4].
Obesity is associated with a decrease in life expectancy and
the development of clinical complications, including cardio­
vascular diseases (CVDs), metabolic diseases (type 2 diabetes
[T2D]), mechanical dysfunction (musculoskeletal disorders
such as osteoarthritis), sleep apnea, and some malignancies
[2,5]. Although weight loss can improve complications arising
from obesity, the magnitude of weight loss achieved with the
lifestyle changes of diet and physical activity can be limited
and difficult to maintain [6,7].
of pharmacotherapies for weight management can help
people with overweight or obesity achieve greater magni­
tudes of weight loss and maintain weight loss [8,9].
Historically, pharmacotherapy options have been limited,
with a need for treatment options that can induce and
sustain clinically meaningful weight loss and improve asso­
ciated complications such as T2D and CVD [2,10]. Several
agents for weight management have been approved or are
currently being investigated. The glucagon-like peptide-1
(GLP-1) receptor agonist (GLP-1RA) semaglutide, which was
initially approved for the treatment of T2D, has been shown
to improve cardiovascular outcomes in these patients
[11,12], and was approved in 2021 for chronic weight man­
agement in people with overweight or obesity. This manu­
script discusses recently published results from the
Semaglutide Treatment Effect in People with obesity
(STEP) 1–5 trials and considers the clinical implications of
these findings for the treatment of patients with obesity.

CONTACT Anastassia Amaro Anastassia.Amaro@pennmedicine.upenn.edu Penn Metabolic Medicine, 3737 Market Street, Philadelphia, PA 19104, USA
© 2023 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
6 A. AMARO ET AL.
Article overview and relevance to clinical practice
● Obesity is a chronic, complex disease associated with
cardiometabolic and other complications.
● As an adjunct to lifestyle interventions, pharmacotherapy
can aid weight management in patients with overweight
or obesity.
● This supplement explores the clinical profile of the
once-weekly GLP-1RA semaglutide 2.4 mg for chronic
weight management, based on results from the phase
3 STEP clinical trial program, and provides practical
guidance on integrating once-weekly semaglutide
2.4 mg into clinical practice in primary care.
● In this first article in the supplement, we:
● Review the mechanism of action of GLP-1RAs in obesity;
● Introduce semaglutide and summarize the design
of the STEP 1–5 trials;
● Explore the efficacy and safety profile of semaglu­
tide 2.4 mg in the STEP 1–5 trials;
● Discuss other potential safety considerations for
GLP-1RAs.
2. Mechanism of action of glucagon-like peptide-1
receptor agonists in patients with obesity
GLP-1 is an incretin (metabolic hormone) secreted from L-cells
in the small and large intestine, and cells in the central ner­
vous system, predominantly in the brainstem [13]. Native
GLP-1 mediates many physiological effects via GLP-1 receptors
found in various tissues in the body, including the brain,
cardiovascular system, kidneys, lung, and gastrointestinal (GI)
system [14–17] (Figure 1).
Eating food triggers the release of endogenous GLP-1 within
minutes. This hormone has several effects on the body, including
inhibiting glucagon secretion while enhancing insulin production,
both in a glucose-dependent manner [13,14,23], and encouraging
feelings of fullness (satiety) through central effects on neural
GLP-1 is synthesized and secreted by:
Neurons in
hindbrain
L-cells
of the gut
GLP-1R is not expressed in the liver
Figure 1. Location of GLP-1 synthesis and secretion, and GLP-1 receptor expression [13,14].
GLP-1 is secreted from two main sites in the body: L-cells in the gut and specialized cells in the nucleus tractus solitarius of the hindbrain. Native GLP-1 mediates its effects via GLP-1
receptors expressed in a broad range of tissues. GLP-1 facilitates a multitude of physiological actions to increase satiety, reduce appetite, and slow gastric emptying [14–22].
AV, atrioventricular; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor.
pathways [23,24]. These effects lower blood glucose by increasing
the storage of excess glucose in muscles and fat, and decrease
appetite and further food (energy) consumption [13,14]. Insulin is
released in response to stimulation by GLP-1 when glucose levels
are elevated, therefore plasma glucose levels are lowered in
a glucose-dependent manner and hypoglycemia is unlikely [25].
Endogenous GLP-1 has a short half-life in plasma (approxi­
mately 1.5 to 2 minutes) owing to its rapid degradation by the
enzyme dipeptidyl peptidase-4 (DPP-4) [26]; therefore, research
efforts have focused on the development of longer-acting
GLP-1RAs for the management of obesity and diabetes, including
semaglutide.
The first GLP-1RA approved in the US was twice-daily exena­
tide for the treatment of T2D in 2005. Since then, several other
GLP-1RAs have been approved, also for the treatment of T2D,
including once-daily analogs, lixisenatide and liraglutide and
once-weekly molecules exenatide extended-release, dulaglutide,
albiglutide, and semaglutide [27–33]. All of these GLP-1RAs are
administered as a subcutaneous injection, although a daily oral
preparation of semaglutide has also been recently approved [34].
Of these, only subcutaneous semaglutide and liraglutide are
currently US Food and Drug Administration (FDA)-approved for
chronic weight management (semaglutide at 2.4 mg once weekly
and liraglutide at 3.0 mg once daily) and for glucose control in
T2D (semaglutide at 0.5 mg, 1.0 mg, and 2.0 mg once weekly and
liraglutide at 1.2 mg and 1.8 mg once daily) [30,33,35,36].
Key clinical take-home points: Mechanism of action
of GLP-1RAs in patients with obesity
● GLP-1 is an incretin hormone with multiple physiological
effects, including glucose-dependent enhancement of
insulin production and suppression of glucagon secre­
tion, and effects on control of appetite.
● Through central effects, GLP-1 receptor agonism
decreases appetite, encourages feelings of satiety,
and decreases energy intake.
GLP-1R is expressed in:
Body weight
Brain Appetite
Lungs Satiety
Heart (AV node)
Glucose production
Gastric emptying
Pancreas Glucagon secretion
Apoptosis
Kidney
Natriuresis
Diuresis
GI tract Insulin secretion
& bio-synthesis
Muscle
 POSTGRADUATE MEDICINE 7

Amino acid substitution at position 8

(Ala to Aib) protects against DPP-4 cleavage

8
His Aib Glu Gly Thr Phe Thr Ser Asp
Val

COOH
Spacer Ser
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Glu
Acetylation at position 26 with C18 fatty di-acid provides 26
strong binding to albumin Phe 34
Ile Ala Trp Leu Val Arg Gly Arg Gly

Amino acid substitution at position 34

(Lys to Arg) enables site-specific C18 fatty acid binding at position 26

Figure 2. Semaglutide key modifications from native GLP-1 [38–41].

Semaglutide is a close analog of native GLP-1, a 31-amino acid protein. Three important structural modifications have been made to the semaglutide molecule that extend its half-life to
approximately 1 week [38–41]. DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1.

3. Semaglutide The American Heart Association listed the STEP program as

Semaglutide is a human GLP-1 analog with 94% amino acid
homology to native GLP-1 and it has a half-life of approxi­
mately 1 week [37–39] (Figure 2).
Clinical studies in people with obesity have shown that
semaglutide affects body weight through multiple mechan­
isms that together lead to decreased energy intake and sub­
sequent weight loss [42,43].
Once-weekly subcutaneous semaglutide 2.4 mg is
approved in the US as an adjunct to a reduced calorie diet
and increased physical activity for chronic weight manage­
ment in adults with overweight (BMI ≥27 kg/m2) with at
least one weight-related comorbidity (e.g. hypertension, T2D,
or dyslipidemia), or obesity (BMI ≥30 kg/m2) [33].
Key clinical take-home points: Semaglutide
● Semaglutide is a GLP-1 analog that is approved as an
adjunct to a reduced calorie diet and increased phy­
sical activity for chronic weight management as
a once-weekly subcutaneous 2.4 mg dose in adults
with:
2
● Overweight (BMI ≥27 kg/m ) with at least one
weight-related comorbidity;
2 hemoglobin levels of ≥6.5%, or who had received treatment
● Obesity (BMI ≥30 kg/m ).
4. The Semaglutide Treatment Effect in People with
obesity trials
As demonstrated in the STEP clinical development program,
semaglutide produces clinically meaningful and durable
weight loss [2,44–48]. Here, we discuss the STEP 1 to 5 trials:
the phase 3, double-blinded, randomized, multinational trials
(STEP 3 was US only) that assessed once-weekly subcutaneous
semaglutide 2.4 mg versus placebo for weight management in
adults with obesity or overweight and with and without T2D.
one of the most pivotal scientific developments of 2021 [49].
4.1. Eligibility
Eligibility criteria for the STEP 1 to 5 trials included adults
(≥18 years of age) with a stable body weight (≤5 kg weight
change within 90 days before screening) and a history of at
least one self-reported unsuccessful dietary effort to lose
weight [2,44–48]. In addition, for the STEP 1, 3, 4, and 5 trials,
participants were required to have a BMI of either ≥30 kg/m2,
or ≥27 kg/m2 combined with at least one weight-related
comorbidity which could be dyslipidemia, obstructive sleep
apnea, hypertension, or CVD. In the STEP 2 trial, participants
were required to have a BMI of ≥27 kg/m2, a diagnosis of T2D
at least 180 days before screening, glycated hemoglobin levels
of 7% to 10%, and to be managed with diet and exercise alone
or treated with up to three oral glucose-lowering drugs for at
least 90 days before screening [44].
In the STEP 1, 3, 4, and 5 trials, patients were excluded if
they had renal impairment measured as an estimated glomer­
ular filtration rate value of <15 mL/min/1.73 m2 [45–48].
Additionally, participants with diabetes (type 1 or 2), glycated
with either glucose-lowering agents or anti-obesity medica­
tions within the prior 90 days were excluded [45–48]. In
STEP 2, patients were excluded if they had an estimated glo­
merular filtration rate value of <30 mL/min/1.73 m2 (<60 mL/
min/1.73 m2 in patients treated with sodium-glucose co-
transporter-2 inhibitors) [44]. In the STEP 1 to 5 trials, additional
exclusion criteria included participants with a history or pre­
sence of chronic pancreatitis or with acute pancreatitis within
the past 180 days [2], those who had a personal or first-degree
relative history of medullary thyroid cancer or multiple endo­
crine neoplasia type 2 [44–48], and participants classified as
being in New York Heart Association Class IV [2].
8 A. AMARO ET AL.

4.2. Trial design
A total of 4,988 participants across the STEP 1 to 5 trials were
randomized to receive either semaglutide or placebo. To miti­
gate side effects, the trials in the STEP program were designed
to slowly escalate the dose of semaglutide over a 16-week
period. Therefore, once-weekly subcutaneous semaglutide
was initiated at a dose of 0.25 mg and escalated every
4 weeks to the subsequent dosing levels of 0.5 mg, 1.0 mg,
and 1.7 mg, until reaching the target dose of 2.4 mg. STEP 2
included a semaglutide 1.0 mg treatment arm where patients
were escalated every 4 weeks, from 0.25 mg to 0.5 mg, and
then to the target dose of 1.0 mg [2,44–48]. In STEP 1, 2, 4, and
5, participants received treatment as an adjunct to lifestyle
intervention (monthly counseling on a −500-kcal/day diet
relative to estimated energy expenditure at week 0 and
a recommended 150 minutes/week of physical activity). In
STEP 3, patients received treatment as an adjunct to intensive
behavioral therapy (IBT; defined as 30 individual dietitian vis­
its) including an initial 8-week low-calorie diet with partial
meal replacement followed by a hypocaloric diet for
60 weeks, together with physical activity (increasing gradually
from 100 minutes/week to 200 minutes/week).
The trials included a 68-week treatment period
(104-week treatment period for STEP 5 only) followed by
a 7-week off-treatment follow-up period [2]. STEP 4
included a 20-week run-in period where all participants
received once-weekly subcutaneous semaglutide 0.25 mg
at week 0 and escalated dose every 4 weeks until reaching
the target of 2.4 mg. At week 20, after 4 weeks of treat­
ment at the target dose of semaglutide, STEP 4 partici­
pants were randomized to continue once-weekly
subcutaneous semaglutide 2.4 mg or switch to placebo
[2,45]. The STEP 1 trial had an off-treatment extension
phase, where 327 participants were followed for an addi­
tional 45 weeks (a total of 52 weeks off-treatment) until
the end-of-trial visit at week 120 [50].
A primary endpoint for all trials was percentage change
from baseline (at randomization) to end of treatment in body
weight (Table 1), where baseline was week 0 in STEP 1–3, and
5, and week 20 in STEP 4. In addition, STEP 1–3 and 5 included
the proportion of participants achieving weight loss of ≥5%
from baseline at end of treatment as a co-primary endpoint
(Table 1). For efficacy analyses, the results described in this
article are based on analyses that assessed treatment effects
regardless of adherence to treatment or the use of rescue
medications (anti-obesity medications or bariatric surgery)
[2,44–48]. This analysis approach is referred to as the ‘treat­
ment policy estimand’ in the original STEP trial results pub­
lications (for further information on estimands in
contemporary reporting of clinical trial results in weight man­
agement, see Wharton et al. [51]) [2,44–48].
Statistical analysis for continuous endpoints were
achieved using an analysis of covariance model with ran­
domized treatment, stratification groups, and the interac­
tion between stratification groups as factors and baseline
endpoint value as covariate. Missing data were imputed
and the results were combined using Rubin’s rules.
Categorical endpoints were analyzed by logistical regres­
sion [44].
Participants were mostly white (62.1% to 93.1%), had
a mean age of 46.2 to 55.3 years, were mostly female (50.9%
to 81.0%), had a mean BMI of 35.7 to 38.5 kg/m2, and a mean
waist circumference of 113.0 to 115.7 cm [2,44–48].
A summary of the trial details and key outcomes are shown
in Table 2. In the subsequent sections, we summarize the main
findings.

Table 1. Key endpoints of the STEP trials [2,44–48].

STEP 2 STEP 3 STEP 4 STEP 5
STEP 1 Weight management Weight management Sustained weight Long-term weight
Weight management in T2D with IBT (US only) managementc management
Primary/co-primary endpoints
For once-weekly subcutaneous semaglutide 2.4 mg vs placebo
% change in body weighta ✓ ✓ ✓ ✓ ✓
Achievement of ≥5% body weight ✓ ✓ ✓ ✓
lossb
Confirmatory secondary endpoints
For once-weekly subcutaneous semaglutide 2.4 mg vs placebo
Achievement of ≥10% body weight ✓ ✓ ✓ ✓
lossb
Achievement of ≥15% body weight ✓ ✓ ✓ ✓
lossb
a
Change in waist circumference ✓ ✓ ✓ ✓ ✓
Change in systolic blood pressurea ✓ ✓ ✓ ✓ ✓
Change in SF-36 Physical Functioning ✓ ✓ ✓ ✓
a
score
Change in IWQOL-Lite-CT Physical ✓ ✓
Function scorea
Change in HbA1ca ✓
For once-weekly subcutaneous semaglutide 2.4 mg vs once-weekly subcutaneous semaglutide 1.0 mg
a
% change in body weight ✓
a
Assessed as change from baseline (randomization) to end of treatment at week 68 (STEP 1–4) or week 104 (STEP 5). bAssessed from baseline (randomization) at
week 68 (STEP 1–4) or at week 104 (STEP 5). cSTEP 4 primary and confirmatory secondary endpoints were assessed from randomization (week 20) to week 68.
HbA1c, glycated hemoglobin; IBT, intensive behavioral therapy; IWQOL-Lite-CT, Impact of Weight on Quality of Life-Lite Clinical Trials; SF-36, 36-Item Short Form
Health Survey; T2D, type 2 diabetes.
Table 2. Trial details and key outcomes of the STEP 1 to 5 trials [2,44–48].
STEP 3 STEP 4 STEP 5
STEP 1 STEP 2 Weight management Sustained weight Long-term weight
Weight management, Weight management with IBTc (US only), management management
without T2Da in T2Db without T2Da without T2Da without T2Da
Trial length (weeks) 68 68 68 68 104
Participants 1,961 1,210 611 Run-in period: 902 304
Randomized: 803
Trial objectives To show superiority of To show superiority of To maximize the effect To maintain the effect of To show superiority of
semaglutide 2.4 mg OW semaglutide 2.4 mg vs placebo and of semaglutide 2.4 semaglutide 2.4 mg vs semaglutide 2.4 mg vs
vs placebo on WL semaglutide 1.0 mg OW on WL mg vs placebo on placebo on WL from placebo on WL and to
To assess safety and To assess safety and tolerability WL randomization to EOT compare safety and
tolerability and baseline (week tolerability in adults
20) to EOT with obesity or
To compare safety in overweight after 2
adults with obesity or years of treatment
overweight who
reached the target
dose of semaglutide
during 20-week run-in
Interventions Lifestyle interventiond Lifestyle interventiond plus: IBTc plus: Lifestyle interventiond Lifestyle interventiond
plus: Semaglutide 2.4 mg OW Semaglutide 2.4 mg plus: plus:
Semaglutide 2.4 mg OW or OW Run-in period (weeks 0– Semaglutide 2.4 mg OW
or Semaglutide 1.0 mg OW or 20) or
Placebo or Placebo Semaglutide OW (target Placebo
(randomized 2:1) Placebo (randomized 2:1) dose of 2.4 mg) (randomized 1:1)
(randomized 1:1:1) From week 20
Semaglutide 2.4 mg OW
or
Placebo (randomized 2:1)
Key results
Semaglutide Placebo Semaglutide Semaglutide Placebo Semaglutide Placebo Semaglutide Placebo Semaglutide Placebo
2.4 mg 2.4 mg 1.0 mg 2.4 mg 2.4 mg 2.4 mg
Mean body weight change from baselinee,f, % –14.9 –2.4 –9.6 –7.0 –3.4 –16.0 –5.7 –7.9 6.9 –15.2 –2.6
Participants with ≥5% body weight lossg,h, % 86.4 31.5 68.8 57.1 28.5 86.6 47.6 88.7 47.6 77.1 34.4
g,h
Participants with ≥10% body weight loss , % 69.1 12.0 45.6 28.7 8.2 75.3 27.0 79.0 20.4 61.8 13.3
Improvements in trial endpoints with semaglutide 2.4 mg vs placebo ● Waist circumference ● Waist circumference ● Waist circumference ● Waist circumference ● Waist circumference
● BMI ● BMI ● BMI ● BMI ● BMI
● Blood pressure ● Systolic blood pressure ● Blood pressure ● Systolic blood ● Blood pressure
● HbA1c level ● HbA1c level ● HbA1c level pressure ● HbA1c
● Fasting plasma glucose ● Fasting plasma glucose levels ● Fasting plasma glu­ ● HbA1c level ● Lipid profile
i
levels ● Lipid profile cose levels ● Lipid profile ● Fasting plasma glucose
● Lipid profile ● C-reactive protein levels ● Lipid profile ● Fasting plasma glu­ levels
● C-reactive protein levels ● SF-36 Physical Functioning score ● C-reactive protein cose levels ● C-reactive protein level
● SF-36 Physical ● IWQOL-Lite-CT Physical Function level ● SF-36 Physical ● A greater proportion of
Functioning score score ● SF-36 Mental Functioning score, and participants with predia­
● IWQOL-Lite-CT Physical ● Urine albumin-to-creatinine ratio Component Physical and Mental betes at baseline had
Function score ● Liver parameters Summary score Component Summary normoglycemia at
● A greater proportion of scores week 104
participants with pre­
diabetes at baseline had
normoglycemia at
week 68
POSTGRADUATE MEDICINE
9
 10
A. AMARO ET AL.

a
Adults with overweight or obesity (BMI ≥30.0 kg/m2 or ≥27.0 kg/m2) with at least one comorbidity, and without diabetes. bAdults with overweight or obesity and T2D, with HbA1c levels of 7.0% to 10.0%. cIBT, including initial 8-week low-
calorie diet followed by a hypocaloric diet for 60 weeks, 30 counseling sessions, and 100 minutes/week of physical activity increased by 25 minutes/week every 4 weeks until 200 minutes/week. dParticipants received treatment as an adjunct
to lifestyle intervention (monthly counseling on a −500-kcal/day diet relative to estimated energy expenditure at week 0, and a recommended 150 minutes/week of physical activity). eAssessed as change from baseline (randomization) to
end of treatment at week 68 (STEP 1–4) or week 104 (STEP 5). fAnalyses assessed treatment effects regardless of adherence to treatment or the use of rescue medications (anti-obesity medications or bariatric surgery) (treatment policy
estimand data). gAssessed from baseline (randomization) at week 68 (STEP 1–4) or at week 104 (STEP 5). hIn-trial data, defined as the time from randomization to last contact with trial site, irrespective of treatment discontinuation or rescue
intervention. iFor patients who maintained semaglutide versus those who switched to placebo over weeks 20 to 68, a non-significant difference was observed for the high-density lipoprotein cholesterol and free-fatty acids lipid values.
BMI, body mass index; EOT, end of trial; HbA1c, glycated hemoglobin; IBT, intensive behavioral therapy; IWQOL-Lite-CT, Impact of Weight on Quality of Life-Lite Clinical Trials Version; OW, once weekly; T2D, type 2 diabetes;
SF-36, 36-Item Short-Form Health Survey; WL, weight loss.

Key clinical take-home points: The Semaglutide
Treatment Effect in People with obesity trials
● The STEP 1–5 trials were phase 3, double-blind, ran­
domized trials that assessed once-weekly subcuta­
neous semaglutide 2.4 mg versus placebo for weight
management in adults with obesity or overweight.
● Trials included patients with T2D (STEP 2) and without
T2D (STEP 1 and 3–5).
● STEP 1–3 comprised 68-weeks’ treatment. Patients in
STEP 1 were also followed for an additional 45 weeks
(a total of 52 weeks off-treatment) until the end-of-
trial visit at week 120.
● STEP 4 included an initial 20-week semaglutide run-in
period, followed by randomization to continued sema­
glutide 2.4 mg or switch to placebo for the remaining
48 weeks.
● STEP 5 comprised 104-weeks’ treatment.
● All trials used a gradual dose escalation over the initial
16-week period to mitigate potential side effects.
● Trial participants also received lifestyle intervention
(counseling on diet and physical activity) or IBT
(STEP 3 only; including 30 therapy sessions, physical
activity, and an initial 8-week low-calorie diet with
partial meal replacement followed by a hypocaloric
diet).
● STEP 1–5 trial endpoints assessed changes in body
weight and cardiometabolic parameters. Changes in
self-reported physical functioning were also assessed
in STEP 1–4.
4.3. Efficacy of semaglutide in the STEP 1 to 5 trials
4.3.1. STEP 1
In STEP 1, in adults with overweight or obesity without T2D
receiving semaglutide (n = 1,306) or placebo (n = 655), once-
weekly subcutaneous semaglutide plus lifestyle intervention
from baseline to week 68 was associated with substantial, sus­
tained, clinically relevant mean weight loss of 14.9% versus 2.4%
for placebo, with an estimated treatment difference (ETD) of
−12.4 percentage points (95% confidence interval [CI]: −13.4,
−11.5; P < 0.001). Consistent with this finding, a greater propor­
tion of participants achieved the co-primary endpoint of ≥5%
weight loss with semaglutide (86.4%) versus placebo (31.5%;
P < 0.001 for odds). Semaglutide was also associated with
greater improvements compared with placebo in cardiometa­
bolic risk factors, including reductions in waist circumference,
blood pressure, glycated hemoglobin levels, and lipid levels [47].
These endpoints are discussed in Article 2 in the supplement by
Amaro et al.
In the 52-week off-treatment extension phase of STEP 1
(n = 327), there was weight regain in both treatment arms
resulting in net weight loss of 5.6% with semaglutide 2.4 mg
and 0.1% with placebo over the full 120-week period [50]. In
addition, the improvements in cardiometabolic risk factors
observed from baseline to week 68 reverted toward baseline
at week 120 for most endpoints [50]. These results highlight
POSTGRADUATE MEDICINE 11
the importance of recognizing obesity as a chronic disease
requiring long-term treatment to maintain beneficial thera­
peutic effects.
4.3.2. STEP 2
STEP 2 demonstrated that in patients with T2D and over­
weight or obesity, once-weekly subcutaneous semaglutide
2.4 mg (n = 404) plus lifestyle intervention led to greater
reductions in body weight than placebo (n = 403) or semaglu­
tide 1.0 mg (n = 403). The mean weight loss in the semaglu­
tide 2.4 mg group was 9.6% versus 7.0% for the semaglutide
1.0 mg group and 3.4% for the placebo group. The ETD for
semaglutide 2.4 mg versus placebo was −6.2 percentage
points (95% CI: −7.3, −5.2%; P < 0.0001), whereas it was
−2.7 percentage points (95% CI: −3.7%, −1.6; P < 0.0001) for
semaglutide 2.4 mg versus semaglutide 1.0 mg. A greater
proportion of participants achieved ≥5% weight loss with
semaglutide 2.4 mg (68.8%) versus placebo (28.5%;
P < 0.0001 for odds) and versus semaglutide 1.0 mg (57.1%
[statistical significance not tested]). Semaglutide 2.4 mg also
resulted in improvement in cardiometabolic risk factors com­
pared with placebo [44].
4.3.3. STEP 3
When used as an adjunct to IBT and an initial low-calorie diet,
once-weekly subcutaneous semaglutide 2.4 mg (n = 407) pro­
duced significantly greater weight loss than placebo (n = 204)
(16.0% vs 5.7%; treatment difference of −10.3 percentage
points [95% CI: −12.0, −8.6]; P < 0.001) at 68 weeks in adults
with overweight or obesity without T2D [46].
Interpreting the findings of STEP 3 (placebo-subtracted
weight loss of 10.3%) in the context of STEP 1 (placebo-
subtracted weight loss of 12.4%), the inclusion of an intensive
lifestyle intervention (including a partial meal replacement
program and 30 treatment sessions) provided only a modest
contribution to additional weight loss beyond that achieved
with semaglutide and less intensive lifestyle intervention. It
should be noted, however, that definitive conclusions about
the contributions of IBT and less intensive lifestyle interven­
tion cannot be made [46].
4.3.4. STEP 4
Among adults with overweight or obesity completing a 20-week
run-in period on subcutaneous semaglutide 2.4 mg (n = 535;
mean change in body weight –10.6%), maintaining treatment
with semaglutide compared with switching to placebo (n = 268)
resulted in continued weight loss; the mean weight loss from
week 20 to 68 in the semaglutide group was 7.9%, compared
with a weight gain of 6.9% in the placebo group, with a treatment
difference of −14.8 percentage points (95% CI: −16.0, −13.5;
P < 0.001) [45].
4.3.5. STEP 5
In STEP 5, once-weekly subcutaneous semaglutide 2.4 mg
(n = 152) resulted in substantial initial body weight reductions
that were then maintained over 104 weeks compared to pla­
cebo (n = 152) [48]. There was no additional weight loss
12 A. AMARO ET AL.
between weeks 52–104; weight loss was maintained during this
period [48]. The mean weight loss in the semaglutide group
was –15.2%, compared to –2.6% in the placebo group (ETD:
−12.6 percentage points [95% CI: –15.3, −9.8] P < 0.0001).
Similar to the results of the STEP 1–3 trials, a greater proportion
of participants achieved ≥5% weight loss with semaglutide
2.4 mg versus placebo (77.1% vs 34.4%; P < 0.0001 for odds).
Treatment with semaglutide also improved cardiometabolic risk
factors compared with placebo, indicating a favorable benefit-
risk profile of semaglutide 2.4 mg for the long-term manage­
ment of weight. The effects of semaglutide 2.4 mg on cardio­
metabolic parameters and other outcomes in STEP 1–5 are
discussed in subsequent articles in this supplement.
Key clinical take-home points: Efficacy of semaglutide
in the STEP 1 to 5 trials
● The STEP 1–3 68-week trials show that significant
weight loss of 15% to 16% in participants without
T2D, and 9.6% in those with T2D, can be achieved
with once-weekly subcutaneous semaglutide 2.4 mg
in adults with overweight or obesity.
● In STEP 4, switching to placebo after a 20-week run-in
period on semaglutide 2.4 mg resulted in weight
regain, while continuing treatment with semaglutide
2.4 mg resulted in further substantial weight loss after
48 weeks.
● Improvements in weight loss were maintained over
a longer term of 104 weeks in STEP 5.
● Results from the STEP 4 and 5 trials highlight the
chronicity of obesity and the importance of longer-
term treatment to achieve and maintain clinically
meaningful weight loss.
● Substantially more patients achieved clinically mean­
ingful weight losses of ≥5% with semaglutide 2.4 mg
in the STEP 1–5 trials than with placebo.
5. Overall safety profile of semaglutide 2.4 mg in
the STEP 1 to 5 trials
Semaglutide 2.4 mg once weekly was generally well tolerated
in adults with obesity, or overweight with comorbidities, with­
out T2D (STEP 1, 3, 4, and 5), and in adults with T2D and
overweight or obesity (STEP 2) [44–48]. Table 3 gives
a summary of the safety profile of semaglutide 2.4 mg in the
STEP 1 to 5 trials.
The most common adverse events (AEs) among people
treated with semaglutide 2.4 mg were GI events (most com­
monly nausea, diarrhea, vomiting, and constipation) [44–47].
Most GI AEs in STEP 1 to 5 were mild-to-moderate in severity
and resolved without permanent treatment discontinuation
[42–46]. These GI AEs were transient, with median durations
with semaglutide 2.4 mg lasting up to 8 days for nausea,
5 days for diarrhea, 2 days for vomiting, and 55 days for
constipation [44–48]. Nausea was typically most prevalent
during the initial dose-escalation periods, and the proportion
of participants with nausea declined thereafter [44,46–48].
More participants discontinued treatment with semaglutide
2.4 mg than placebo due to GI AEs in STEP 1–3 and 5, but
overall few participants discontinued treatment due to such
AEs [44–48]. In STEP 4, most GI AEs occurred during the run-in
period, during which semaglutide was escalated to the target
maintenance dose of 2.4 mg once weekly in all participants
who entered the randomized period. After the 20-week run-in
period, the proportion of participants discontinuing treatment
due to any AE was low among those randomized to continued
semaglutide 2.4 mg treatment and was similar to the rate in
those who switched to placebo [45].
GI side effects, which are common to all GLP-1RAs, may
affect patient adherence [52]. However, such GI effects are
typically mild-to-moderate in severity and decline in preva­
lence after initial dose-escalation, particularly for nausea, and
a gradual dose escalation schedule may help alleviate or pre­
vent GI side effects [52,53]. Recommendations for the manage­
ment of GI side effects with GLP-1RAs in clinical practice
suggest an approach described as ‘the three Es: Education
and explanation, Escalation to an appropriate dose, and
Effective management of GI side effects’ [53]. As part of the
Education and explanation approach, patients should be
counseled on the potential for GI side effects and their usual
mild-to-moderate nature, alongside recommendations for
dietary modifications and management of current GI symp­
toms. Gradual escalation to an appropriate dose is detailed in
the prescribing information for many GLP-1RAs and should
therefore be the standard approach when initiating treatment;
however, for patients reporting challenges with GI symptoms
during the first weeks of treatment, a slower dose escalation is
recommended as part of ‘the three Es.’ Finally, effective man­
agement of GI side effects is essential, and a stepwise, sever­
ity-based approach is recommended, including dietary
modifications for mild side effects, identifying/ruling out any
underlying GI disorders, GLP-1RA dose adjustment, considera­
tion of pharmacological treatment, and switching to an alter­
native to GLP-1RAs [53]. Further information on such practical
considerations for GLP-1RA use is provided by Kyrillos et al. in
the final article in this supplement.
GLP-1RAs have a glucose-dependent mechanism of action,
therefore there is no expectation of symptomatic hypoglyce­
mia and there were no concerns identified in the STEP trials
[23]. In STEP 1, hypoglycemia was reported as an AE in 0.6% of
participants in the semaglutide group versus 0.8% of partici­
pants in the placebo group [47]. In STEP 2, which included
participants with T2D, severe or blood-glucose symptomatic
hypoglycemia was reported in 5.7% and 5.5% of participants
in the 2.4 mg and 1.0 mg semaglutide groups, respectively,
versus 3.0% in the placebo group [44]. It is important to note
that during STEP 2, participants were permitted to receive
a stable dose of up to three oral glucose-lowering agents
[44]. In the total STEP 2 population, the most commonly
received agents were biguanides (92% of participants), sulfo­
nylureas (25% of participants), and sodium-glucose co-
transporter-2 inhibitors (25% of participants) [44]. In STEP 3,
0.5% of participants in the semaglutide group and none in the
placebo group reported hypoglycemia as an AE [46].
Hypoglycemia incidence was similarly low in STEP 4, with
Table 3. Summary of AEs from the STEP 1 to 5 trials [2,44–48].
STEP 3 STEP 5
STEP 1 STEP 2a Weight management STEP 4 Long-term
Weight management Weight management in T2D with IBT (US only) Sustained weight management weight management
Semaglutide
Run-in 2.4 mg
Semaglutide Semaglutide Semaglutide Semaglutide (semaglutide (randomized Placebo (randomized Semaglutide
2.4 mg Placebo 2.4 mg 1.0 mg Placebo 2.4 mg Placebo 2.4 mg) period) period) 2.4 mg Placebo
AEs, % 89.7 86.4 87.6 81.8 76.9 95.8 96.1 84.3 81.3 75 96.1 89.5
GI AEs, % 74.2 47.9 63.5 57.5 34.3 82.8 63.2 71.4 41.9 26.1 82.2 53.9
Nausea 4.2 17.4 33.7 32.1 9.2 58.2 22.1 46.8 14.0 4.9 53.3 21.7
Diarrhea 31.5 15.9 21.3 22.1 11.9 36.1 22.1 23.5 14.4 7.1 34.9 23.7
Constipation 23.4 9.5 17.4 12.7 5.5 36.9 24.5 22.2 11.6 6.3 30.9 11.2
Vomiting 24.8 6.6 21.8 13.4 2.7 27.3 10.8 15.5 10.3 3.0 30.3 4.6
Median duration of GI AEs, days
Nausea 8 6 8 10 6 5 5 NR NR NR 4 2
Diarrhea 3 3 5 4 4 3 3 NR NR NR 5 3
Constipation 35 25 55 51 21 27 16 NR NR NR 58 39
Vomiting 2 1 1 2 1 2 2 NR NR NR 2 2
SAEs, % 9.8 6.4 9.9 7.7 9.2 9.1 2.9 2.3 7.7 5.6 7.9 11.8
AEs leading to trial product 7.0 3.1 6.2 5.0 3.5 5.9 2.9 5.3 2.4 2.2 5.9 4.6
discontinuation, %
GI AEs leading to trial product 4.5 0.8 4.2 3.5 1.0 3.4 0 NR NR NR 3.9 0.7
discontinuation, %
a
STEP 2 was the only trial that enrolled patients with T2D.
AEs, adverse events; GI, gastrointestinal; IBT, intensive behavioral therapy; NR, not reported; SAEs, serious adverse events; T2D, type 2 diabetes.
POSTGRADUATE MEDICINE
13
14 A. AMARO ET AL.
hypoglycemia reported as an AE in 0.1% of participants during
the initial 20-week semaglutide run-in period, and thereafter
in 0.6% of participants continuing semaglutide 2.4 mg and in
1.1% of participants switching to placebo [45]. In STEP 5,
hypoglycemia was reported as an AE in 2.6% of participants
in the semaglutide group and none in the placebo group [48].
Key clinical take-home points: Overall safety profile
of semaglutide 2.4 mg in the STEP 1 to 5 trials
● Semaglutide 2.4 mg once weekly was generally well
tolerated in adults with overweight or obesity in the
STEP 1–5 trials.
● The safety profile of semaglutide was consistent with
the known profile of GLP-1RAs, with GI events the
most commonly reported AEs.
● Most GI events were transient, mild-to-moderate in
severity, and resolved without permanent treat­
ment discontinuation.
● Gradual dose-escalation may help alleviate or prevent
GI side effects – practical guidance on this and other
topics is discussed in more detail in the final article in
this supplement by Kyrillos et al.
6. Addressing other potential safety concerns
6.1. Pancreatitis
Cases of pancreatitis have been described in connection with
the use of GLP-1RAs, including exenatide and liraglutide, and
also with DPP-4 inhibitors such as sitagliptin [54,55]. However,
trials and a meta-analysis have shown that GLP-1RA treatment
does not appear to substantially increase pancreatic events
[52,56].
In the STEP 1 to 5 trials, participants with a history or
presence of chronic pancreatitis, or with acute pancreatitis
within the past 180 days, were excluded. In STEP 1–5, there
were very few reports of acute pancreatitis and no notable
difference in the incidences in semaglutide 2.4 mg groups
(0–0.2% of participants across trials) and placebo groups
(0–0.2% of participants across trials) [44–48].
Amylase and lipase are biomarkers of pancreatic inflam­
mation and are routinely measured in clinical trials of incre­
tin-based therapies as a regulatory requirement [57]. Both
GLP-1RAs and DPP-4 inhibitors have been linked to
increased levels of serum lipase and serum amylase [58].
Elevations in amylase and lipase have been described fol­
lowing treatment with GLP-1RAs and DPP-4 inhibitors, how­
ever little is known about amylase or lipase activity in
individuals with overweight or obesity without T2D, or
whether routinely monitoring these enzymes can predict
subsequent acute pancreatitis onset [57].
In STEP 3, increases in amylase were seen in one patient
treated with semaglutide, and one patient treated with sema­
glutide had increased lipase [46].
As with other GLP-1RAs and DDP-4 inhibitors, the prescribing
information for subcutaneous semaglutide in both T2D and
obesity includes warnings and precautions relating to pancrea­
titis [29–33,59–61].
A consensus statement by the American Association of
Clinical Endocrinologists and the American College of
Endocrinology on the management of T2D recommends that
GLP-1RAs should be used cautiously (if at all) in patients with
a history of pancreatitis (due to a lack of clinical trial data), and
that treatment should be discontinued if acute pancreatitis
develops [62].
6.2. Gallbladder disorders
Weight loss is known to increase the risk of cholelithiasis,
with new gallstone prevalence reaching 10% to 12% after 8
to 16 weeks of a low-calorie diet and reaching greater than
30% within 12 to 18 months after gastric bypass sur­
gery [63].
GLP-1RA treatment has been linked with an increase in
gallbladder AEs, including cholelithiasis and cholecystitis
[64–66]. In STEP 1, 3, and 5, gallbladder-related disorders
were reported in a higher proportion of participants in the
semaglutide 2.4 mg groups (2.6%, 4.9%, and 2.6%, respec­
tively) compared with the placebo groups (1.2%, 1.5%, and
1.3%, respectively). In STEP 2 and during maintenance dos­
ing in STEP 4 (week 20 onwards), slightly fewer participants
experienced gallbladder-related disorders in the semaglu­
tide 2.4 mg groups (0.2% and 2.8%, respectively) compared
with the placebo groups (0.7% and 3.7%, respectively)
[44–48].
It is important to note that the presence of gallstones
was not an exclusion criterion in any of the STEP trials [67].
6.3. Thyroid C-cell tumors
The prescribing information for semaglutide, as well as other
FDA-approved long-acting GLP-1RAs (albiglutide, dulaglutide,
extended-release exenatide, and liraglutide), state that they
have been reported to cause thyroid C-cell tumors in rodents,
including medullary thyroid carcinoma (MTC), while also not­
ing that the human relevance of this has not been determined
[29–33].
MTC is distinct from other types of thyroid cancers (derived
from thyroid follicular cells) as it originates from the parafolli­
cular C-cells of the thyroid gland [68]. Furthermore, the pre­
valence of MTC is very low, comprising 2% to 4% of all thyroid
cancers [68,69].
A meta-analysis of 11 cardiovascular outcomes studies of
GLP-1RAs including over 55,000 patients identified no
increased risk of MTC with GLP-1RAs [70].
No cases of MTC were reported in STEP 1 to 5.
Furthermore, there were no imbalances in calcitonin levels
between semaglutide 2.4 mg and the placebo group in
these studies (calcitonin is a marker for potential MTC)
[44–48].
Owing to contraindications of FDA-approved long-
acting GLP-1RAs, as noted earlier, participants with
a personal or first-degree relative history of MTC or multi­
ple endocrine neoplasia type 2 were excluded from STEP 1
to 5 [44–48].

Key clinical take-home points: Addressing other
potential safety concerns
● The prescribing information for semaglutide should be
referred to for information on contraindications, warn­
ings, and precautions relating to pancreatitis, gallbladder
disorders, and MTC.
● Participants with a history or presence of chronic
pancreatitis, or with acute pancreatitis within the
past 180 days, were excluded from the STEP trials.
● In STEP 1–5, there were very few reports of acute
pancreatitis and no notable difference in the inci­
dences between semaglutide 2.4 mg groups and
placebo groups.
● GLP-1RA treatment has been linked with an increase
in gallbladder AEs, including cholelithiasis and chole­
cystitis, and a slightly higher incidence of gallbladder-
related disorders was reported with semaglutide ver­
sus placebo in some STEP studies.
● No cases of MTC were reported in STEP 1 to 5.
7. Conclusions
The road to ideal pharmacological weight management has
been complex, and GLP-1RAs offer opportunities for effective
weight control alongside lifestyle interventions.
The primary goal of pharmacotherapies like semaglutide
when combined with lifestyle intervention for chronic weight
management is to achieve a clinically meaningful weight loss.
A secondary goal is to provide long-term weight management
and to minimize weight regain [71]. The phase 3 STEP 1 to 5
trials have shown that significant and sustained weight loss of
14% to 16% in participants without T2D, and 9.6% in those
with T2D, can be achieved with a once-weekly dose of sema­
glutide, offering clinicians a new tool to manage obesity and
associated complications.
In the STEP 1 to 5 trials, semaglutide 2.4 mg once weekly
was generally well tolerated with a safety profile consistent
with the GLP-1RA class. Mild-to-moderate and transient GI
events were the most common AEs and resolved without
permanent treatment discontinuation in most cases [44–48].
Obesity is being increasingly recognized as a chronic dis­
ease which requires long-term treatment. Results from the
STEP 4 and 5 trials support the need for continued therapy
with semaglutide to maintain weight loss [45,48], further
demonstrated by the STEP 1 extension phase in which parti­
cipants regained weight upon withdrawal of treatment [50].
Obesity is also a crucial contributor to CVD. The ongoing
Semaglutide Effects on Heart Disease and Stroke in Patients
with Overweight or Obesity (SELECT) study (NCT03574597) will
assess the effect of once-weekly subcutaneous semaglutide
2.4 mg treatment on CVD risk reduction in patients with over­
weight or obesity and established CVD without T2D.
Multiple agents for weight management, with varying
mechanisms of action, have been approved or are currently in
clinical development. For example, tirzepatide (a novel glucose-
dependent insulinotropic polypeptide and GLP-1RA) resulted in
substantial and sustained weight reduction in patients with
POSTGRADUATE MEDICINE 15
obesity in the SURMOUNT-1 clinical trial [72]. Currently, there
are no published head-to-head trials of weight management
agents, except for the STEP 8 trial which evaluated semaglutide
versus liraglutide in adults with overweight or obesity. STEP 8
showed that semaglutide resulted in significantly greater weight
loss at 68 weeks compared with liraglutide [73].
Obesity management continues to evolve. Ten years ago
there were very limited treatments for people living with obesity.
Today, we are at the stage where many individuals can receive
effective treatment for this chronic condition. The use of sema­
glutide in conjunction with lifestyle intervention provides sus­
tained, clinically relevant reductions in body weight and offers an
effective, pharmacotherapeutic option with a magnitude of
weight loss increasingly closing the gap to bariatric surgery
[74–77]. The future is much brighter for those living with obesity.
Abbreviations
AE, adverse event
AV, atrioventricular
BMI, body mass index
CI, confidence interval
CVD, cardiovascular disease
DPP-4, dipeptidyl peptidase-4
EOT, end of trial
ETD, estimated treatment difference
FDA, US Food and Drug Administration
GI, gastrointestinal
GLP-1, glucagon-like peptide-1
GLP-1RA, glucagon-like peptide-1 receptor agonist
HbA1c, glycated hemoglobin
IBT, intensive behavioral therapy
IWQOL-Lite-CT, Impact of Weight on Quality of Life-Lite Clinical Trials
MTC, medullary thyroid carcinoma
NR, not reported
OW, once weekly
SAEs, serious adverse events
SF-36, 36-Item Short Form Health Survey
STEP, Semaglutide Treatment Effect in People with obesity
T2D, type 2 diabetes
WL, weight loss
Acknowledgments
Medical writing support was provided by Laura Moore, PhD, of Axis,
a division of Spirit Medical Communications Group Limited, and Gemma
Hall, a contract writer working on behalf of Axis, and funded by Novo
Nordisk Inc., in accordance with Good Publication Practice 3 (GPP3) guide­
lines (www.ismpp.org/gpp3).
Funding
This peer-reviewed article was supported by Novo Nordisk Inc.; the com­
pany was provided with the opportunity to perform a medical accuracy
review.
Declaration of financial/other relationships
Anastassia Amaro: advisory boards and consultant – Medality Medical,
Novo Nordisk, and Pfizer, and research support – Altimmune, Eli Lilly,
Fractyl Health, and Novo Nordisk.
Danny Sugimoto: grants – AstraZeneca, Boehringer Ingelheim, Bristol
Myers Squibb, Lilly, Merck, and Novo Nordisk.
16 A. AMARO ET AL.
Sean Wharton: research funding, advisory/consulting fees, and/or
other support – AstraZeneca, Bausch Health Inc., Boehringer Ingelheim,
CIHR, Janssen, Lilly, and Novo Nordisk.
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
ORCID
Anastassia Amaro http://orcid.org/0000-0002-3132-5778
Danny Sugimoto http://orcid.org/0000-0002-7801-1231
Sean Wharton http://orcid.org/0000-0003-0111-1530
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