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

Figures & data

Video 1

Efficacy and Safety of Semaglutide for Weight Management

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.

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.

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.

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.

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.

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