Efficacy and safety of semaglutide for weight management: evidence from the STEP program

1

ABSTRACT

Obesity is a global health challenge. It is a multifactorial, complex, and progressive disease associated with various health complications and increased mortality. Lifestyle modifications are central to weight management but may be insufficient to maintain clinically meaningful weight loss. Pharmacotherapies are recommended as an adjunct to lifestyle interventions to induce and sustain clinically meaningful weight loss and reduce the risk of comorbidities in appropriate patients. Glucagon-like peptide-1 is an incretin metabolic hormone responsible for a range of physiological effects, including glucose and appetite regulation. Several glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been approved for the treatment of type 2 diabetes since 2005 including exenatide (short- and extended-release), lixisenatide, liraglutide, dulaglutide, albiglutide, and semaglutide. Of these, semaglutide (subcutaneous) 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.

KEYWORDS:

• Obesity
• glucagon-like peptide-1 receptor agonist
• semaglutide
• primary care

1. Introduction

Video 1

Efficacy and Safety of Semaglutide for Weight Management

Obesity is a chronic, progressive disease with a complex pathophysiology and a multifactorial origin, including genetic, metabolic, behavioral, sociocultural, and environmental 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 cardiovascular 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].

As an adjunct to lifestyle interventions, appropriate use of pharmacotherapies for weight management can help people with overweight or obesity achieve greater magnitudes 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 associated 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 management in people with overweight or obesity. This manuscript 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.

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 semaglutide 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 nervous 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).

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.

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 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 (approximately 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 exenatide 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 secretion, and effects on control of appetite.

• Through central effects, GLP-1 receptor agonism decreases appetite, encourages feelings of satiety, and decreases energy intake.

3. Semaglutide

Semaglutide is a human GLP‑1 analog with 94% amino acid homology to native GLP‑1 and it has a half-life of approximately 1 week [37–39] (Figure 2).

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.

Clinical studies in people with obesity have shown that semaglutide affects body weight through multiple mechanisms that together lead to decreased energy intake and subsequent 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 management 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 physical activity for chronic weight management as a once-weekly subcutaneous 2.4 mg dose in adults with:

  • Overweight (BMI ≥27 kg/m²) with at least one weight-related comorbidity;

  • Obesity (BMI ≥30 kg/m²).

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. The American Heart Association listed the STEP program as 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 glomerular filtration rate value of <15 mL/min/1.73 m² [45–48]. Additionally, participants with diabetes (type 1 or 2), glycated hemoglobin levels of ≥6.5%, or who had received treatment with either glucose-lowering agents or anti-obesity medications within the prior 90 days were excluded [45–48]. In STEP 2, patients were excluded if they had an estimated glomerular 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 presence 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 endocrine neoplasia type 2 [44–48], and participants classified as being in New York Heart Association Class IV [2].

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 mitigate 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 visits) 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 treatment at the target dose of semaglutide, STEP 4 participants 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 additional 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 ‘treatment policy estimand’ in the original STEP trial results publications (for further information on estimands in contemporary reporting of clinical trial results in weight management, see Wharton et al. [51]) [2,44–48].

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

	STEP 1 Weight management	STEP 2 Weight management in T2D	STEP 3 Weight management with IBT (US only)	STEP 4 Sustained weight management^c	STEP 5 Long-term weight management
Primary/co-primary endpoints
For once-weekly subcutaneous semaglutide 2.4 mg vs placebo
% change in body weight^a	✓	✓	✓	✓	✓
Achievement of ≥5% body weight loss^b	✓	✓	✓		✓
Confirmatory secondary endpoints
For once-weekly subcutaneous semaglutide 2.4 mg vs placebo
Achievement of ≥10% body weight loss^b	✓	✓	✓		✓
Achievement of ≥15% body weight loss^b	✓	✓	✓		✓
Change in waist circumference^a	✓	✓	✓	✓	✓
Change in systolic blood pressure^a	✓	✓	✓	✓	✓
Change in SF-36 Physical Functioning score^a	✓	✓	✓	✓
Change in IWQOL-Lite-CT Physical Function score^a	✓	✓
Change in HbA1c^a		✓
For once-weekly subcutaneous semaglutide 2.4 mg vs once-weekly subcutaneous semaglutide 1.0 mg
% change in body weight^a		✓

^aAssessed 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.

HbA_1c, 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.

Statistical analysis for continuous endpoints were achieved using an analysis of covariance model with randomized treatment, stratification groups, and the interaction 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 regression [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 2. Trial details and key outcomes of the STEP 1 to 5 trials [2,44–48].

	STEP 1 Weight management, without T2D^a		STEP 2 Weight management in T2D^b			STEP 3 Weight management with IBT^c (US only), without T2D^a		STEP 4 Sustained weight management without T2D^a		STEP 5 Long-term weight management without T2D^a
Trial length (weeks)	68		68			68		68		104
Participants	1,961		1,210			611		Run-in period: 902 Randomized: 803		304
Trial objectives	To show superiority of semaglutide 2.4 mg OW vs placebo on WL To assess safety and tolerability		To show superiority of semaglutide 2.4 mg vs placebo and semaglutide 1.0 mg OW on WL To assess safety and tolerability			To maximize the effect of semaglutide 2.4 mg vs placebo on WL		To maintain the effect of semaglutide 2.4 mg vs placebo on WL from randomization to EOT and baseline (week 20) to EOT To compare safety in adults with obesity or overweight who reached the target dose of semaglutide during 20-week run-in		To show superiority of semaglutide 2.4 mg vs placebo on WL and to compare safety and tolerability in adults with obesity or overweight after 2 years of treatment
Interventions	Lifestyle intervention^d plus: Semaglutide 2.4 mg OW or Placebo (randomized 2:1)		Lifestyle intervention^d plus: Semaglutide 2.4 mg OW or Semaglutide 1.0 mg OW or Placebo (randomized 1:1:1)			IBT^c plus: Semaglutide 2.4 mg OW or Placebo (randomized 2:1)		Lifestyle intervention^d plus: Run-in period (weeks 0–20) Semaglutide OW (target dose of 2.4 mg) From week 20 Semaglutide 2.4 mg OW or Placebo (randomized 2:1)		Lifestyle intervention^d plus: Semaglutide 2.4 mg OW or Placebo (randomized 1:1)
Key results
	Semaglutide 2.4 mg	Placebo	Semaglutide 2.4 mg	Semaglutide 1.0 mg	Placebo	Semaglutide 2.4 mg	Placebo	Semaglutide 2.4 mg	Placebo	Semaglutide 2.4 mg	Placebo
Mean body weight change from baseline^e,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 loss^g,h, %	86.4	31.5	68.8	57.1	28.5	86.6	47.6	88.7	47.6	77.1	34.4
Participants with ≥10% body weight loss^g,h, %	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 BMI Blood pressure HbA1c level Fasting plasma glucose levels Lipid profile C-reactive protein levels SF-36 Physical Functioning score IWQOL-Lite-CT Physical Function score A greater proportion of participants with prediabetes at baseline had normoglycemia at week 68		Waist circumference BMI Systolic blood pressure HbA1c level Fasting plasma glucose levels Lipid profile C-reactive protein levels SF-36 Physical Functioning score IWQOL-Lite-CT Physical Function score Urine albumin-to-creatinine ratio Liver parameters			Waist circumference BMI Blood pressure HbA1c level Fasting plasma glucose levels Lipid profile C-reactive protein level SF-36 Mental Component Summary score		Waist circumference BMI Systolic blood pressure HbA1c level Lipid profile^i Fasting plasma glucose levels SF-36 Physical Functioning score, and Physical and Mental Component Summary scores		Waist circumference BMI Blood pressure HbA1c Lipid profile Fasting plasma glucose levels C-reactive protein level A greater proportion of participants with prediabetes at baseline had normoglycemia at week 104

^aAdults 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 HbA_1c 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; HbA_1c, 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, randomized trials that assessed once-weekly subcutaneous 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 semaglutide 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, sustained, 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 proportion 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 cardiometabolic 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 the importance of recognizing obesity as a chronic disease requiring long-term treatment to maintain beneficial therapeutic effects.

4.3.2. STEP 2

STEP 2 demonstrated that in patients with T2D and overweight 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 semaglutide 1.0 mg (n = 403). The mean weight loss in the semaglutide 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 compared 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) produced 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 intervention 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 placebo (n = 152) [48]. There was no additional weight loss 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 management of weight. The effects of semaglutide 2.4 mg on cardiometabolic 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 meaningful 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, without 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.

Table 3. Summary of AEs from the STEP 1 to 5 trials [2,44–48].

	STEP 1 Weight management		STEP 2^a Weight management in T2D			STEP 3 Weight management with IBT (US only)		STEP 4 Sustained weight management			STEP 5 Long-term weight management
	Semaglutide 2.4 mg	Placebo	Semaglutide 2.4 mg	Semaglutide 1.0 mg	Placebo	Semaglutide 2.4 mg	Placebo	Run-in (semaglutide 2.4 mg)	Semaglutide 2.4 mg (randomized period)	Placebo (randomized period)	Semaglutide 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  Diarrhea  Constipation  Vomiting	8 3 35 2	6 3 25 1	8 5 55 1	10 4 51 2	6 4 21 1	5 3 27 2	5 3 16 2	NR NR NR NR	NR NR NR NR	NR NR NR NR	4 5 58 2	2 3 39 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 discontinuation, %	7.0	3.1	6.2	5.0	3.5	5.9	2.9	5.3	2.4	2.2	5.9	4.6
GI AEs leading to trial product discontinuation, %	4.5	0.8	4.2	3.5	1.0	3.4	0	NR	NR	NR	3.9	0.7

^aSTEP 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.

The most common adverse events (AEs) among people treated with semaglutide 2.4 mg were GI events (most commonly 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 prevalence after initial dose-escalation, particularly for nausea, and a gradual dose escalation schedule may help alleviate or prevent GI side effects [52,53]. Recommendations for the management 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 symptoms. 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 management of GI side effects is essential, and a stepwise, severity-based approach is recommended, including dietary modifications for mild side effects, identifying/ruling out any underlying GI disorders, GLP-1RA dose adjustment, consideration of pharmacological treatment, and switching to an alternative 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 hypoglycemia 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 participants 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), sulfonylureas (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 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 treatment 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 inflammation and are routinely measured in clinical trials of incretin-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 following treatment with GLP-1RAs and DPP-4 inhibitors, however 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 semaglutide 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 pancreatitis [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 surgery [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%, respectively) compared with the placebo groups (1.2%, 1.5%, and 1.3%, respectively). In STEP 2 and during maintenance dosing in STEP 4 (week 20 onwards), slightly fewer participants experienced gallbladder-related disorders in the semaglutide 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 noting 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 parafollicular C-cells of the thyroid gland [68]. Furthermore, the prevalence 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 multiple 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, warnings, 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 incidences between semaglutide 2.4 mg groups and placebo groups.

• GLP-1RA treatment has been linked with an increase in gallbladder AEs, including cholelithiasis and cholecystitis, and a slightly higher incidence of gallbladder-related disorders was reported with semaglutide versus 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 semaglutide, 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 disease 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 participants 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 overweight 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 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 semaglutide in conjunction with lifestyle intervention provides sustained, 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

HbA_1c, 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

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.

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.

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) guidelines (www.ismpp.org/gpp3).

Additional information

Funding

This peer-reviewed article was supported by Novo Nordisk Inc.; the company was provided with the opportunity to perform a medical accuracy review.