Behavioral strategies adjusting dietary habits and physical activity constitute the cornerstone of addressing overweight and obesity. Nonetheless, these approaches often fall short in achieving substantial and sustainable weight reduction. Hence, pharmacological intervention emerges as a supplementary measure for prolonged weight control in individuals with a body mass index (BMI) of 30 kg m–2 or higher, or 27 kg m–2 with obesity-related health issues.
Semaglutide, a mimic of glucagon-like peptide-1 (GLP-1), has garnered approval for managing type 2 diabetes (both orally and via subcutaneous injection) and for mitigating cardiovascular risks in those with type 2 diabetes and cardiovascular ailments (specifically through subcutaneous injection). Administered weekly at 2.4 mg subcutaneously, semaglutide has secured regulatory clearance in the United States, Europe, the United Kingdom, and Canada for weight management in adults grappling with overweight (BMI ≥ 27 kg m–2 alongside at least one obesity-related comorbidity) or obesity (BMI ≥ 30 kg m–2), backed by findings from the Semaglutide Treatment Effect in People with Obesity (STEP) clinical trial program. Across STEP 1 and 3 trials involving non-diabetic participants, semaglutide 2.4 mg exhibited average placebo-adjusted weight reductions of 12.4% and 10.3%, respectively, by week 68.
Earlier investigations within the STEP initiative were confined to durations not exceeding 68 weeks. The 2-year STEP 5 study discussed here aimed to assess the sustained impact of weekly subcutaneous semaglutide 2.4 mg, in conjunction with behavioral interventions, on body weight and cardiometabolic risks among non-diabetic adults grappling with obesity (BMI ≥ 30 kg m–2) or overweight (BMI ≥ 27 kg m–2 with at least one related comorbidity). This phase 3, double-blind, placebo-controlled trial conducted across multiple nations represents the lengthiest investigation into semaglutide's efficacy for weight management. Co-primary endpoints encompassed the percentage alteration in body weight from baseline to week 104 and the attainment of weight loss equivalent to or greater than 5% of baseline weight at week 104.
Findings
Participants and Intervention:
Between October 5, 2018, and February 1, 2019, 304 individuals were randomly assigned to either receive semaglutide 2.4 mg (n = 152) or placebo (n = 152) and were encompassed in the comprehensive analysis set (comprising all randomized individuals as per the intention-to-treat principle). The study involved both in-trial periods (irrespective of treatment discontinuation or rescue interventions) and on-treatment phases (with the trial product). Overall, out of 304 participants, 282 (92.8%) concluded the trial by attending the end-of-trial safety evaluation, 272 (89.5%) underwent body weight assessment at the week 104 end-of-treatment visit to determine the long term effects of semaglutide, and 243 (79.9%) adhered to the treatment protocol until the end-of-treatment visit (Fig. 1).
Procedures
Participants were administered subcutaneous semaglutide 2.4 mg or a placebo once a week for 104 weeks, alongside standard behavioral intervention, followed by a 7-week period without treatment. Semaglutide treatment commenced at 0.25 mg per week for the initial 4 weeks using a pre-filled pen injector, with a fixed-dose escalation every 4 weeks until reaching the maintenance dose of 2.4 mg by week 16 (lower maintenance doses allowed if 2.4 mg was intolerable for participants). Behavioral intervention involved counseling by a dietitian or equivalent healthcare professional every 4 weeks through in-person visits or telephone sessions, focusing on adhering to a reduced-calorie diet (500 kcal deficit per day compared to estimated energy expenditure at randomization) and increased physical activity (encouraging 150 minutes per week, such as walking), with daily recording (via diary, app, or other tools) reviewed during counseling sessions. Apart from these standardized behavioral intervention criteria, no further standardization was applied across study sites. Participants discontinuing treatment prematurely remained in the trial and were encouraged to attend scheduled visits, particularly those at weeks 104 and 111.
Measurements of body weight, waist circumference, and vital signs (systolic and diastolic blood pressure, and pulse) were taken at baseline and repeated every 4 weeks until week 20, followed by assessments every 8 weeks until week 100 and week 104 (within 3 days before or after the scheduled visit day). These parameters were also measured at the end-of-trial visit at week 111 (within 5 days before or after the scheduled visit day). Height was measured at screening. HbA1c, fasting plasma glucose, lipids, and C-reactive protein were measured at baseline and weeks 20, 52, 84, and 104; electrocardiograms were performed at these time points as well. Fasting serum insulin was measured at baseline and week 104. Physical examinations were conducted at screening and weeks 52 and 104. Hematology and biochemistry laboratory parameters were measured at screening and weeks 20, 52, 84, and 104. Adverse events were recorded at each visit. Control of eating was assessed in a subset of participants from the United States and Canada, with results to be presented separately.
Due to the emergence of COVID-19 in the second year of the study, trial visits were allowed to be conducted via telephone, during which counseling and safety-related information were provided; however, endpoint assessments were not conducted during telephone visits.
Assessment data were collected during the subsequent in-person visits.
Outcomes
The primary endpoints were the percentage change in body weight from baseline to week 104 and achieving weight loss of at least 5% of baseline weight at week 104. These were tested first, followed by secondary endpoints in a predefined order, including achieving weight loss of at least 10% or 15% at week 104, and changes in waist circumference and systolic blood pressure from baseline to week 104.
Additional secondary endpoints not included in the primary statistical testing hierarchy were also assessed, including achieving weight loss of ≥20% at week 104; changes in various parameters from baseline to week 104 and week 52; and achieving weight loss of ≥5%, ≥10%, ≥15%, and ≥20% at week 52.
Exploratory endpoints reported included changes from baseline to week 104 in glycemic category, antihypertensive medication use, and lipid-lowering medication use.
Safety endpoints included treatment-emergent adverse events and serious adverse events recorded between baseline and week 111, as well as changes from baseline to week 104 in pulse, amylase, lipase, and calcitonin. An independent external event adjudication committee reviewed cardiovascular events, acute pancreatitis, and deaths.
Statistical Analysis A sample size of 300 participants provided sufficient power for the primary and secondary endpoints. The two co-primary endpoints were analyzed independently, requiring statistical superiority for both to demonstrate a significant benefit of semaglutide versus placebo.
Efficacy and safety endpoints were analyzed using the full analysis set and the safety analysis set, respectively. Two estimands were employed to assess treatment efficacy, accounting for intercurrent events and missing data differently. The treatment policy estimand evaluated the treatment effect among all participants, regardless of treatment discontinuation or rescue intervention, while the trial product estimand addressed the average treatment effect in all participants assuming adherence to the treatment protocol. Statistical analyses were conducted using appropriate methods, and results were presented with 95% confidence intervals and corresponding p-values.
Conclusion
The STEP 5 trial evaluated the effectiveness and safety of weekly subcutaneous semaglutide 2.4 mg compared to placebo, both alongside behavioral intervention, for the long-term management of adults dealing with obesity or overweight along with at least one weight-related comorbidity, excluding diabetes. The primary goals were to assess the percentage change in body weight and the accomplishment of a weight loss of ≥5% by week 104. The study included all randomly assigned participants, regardless of any treatment discontinuations or rescue interventions. Between October 5, 2018, and February 1, 2019, 304 individuals were randomly allocated to receive either semaglutide 2.4 mg (n = 152) or placebo (n = 152), with a high trial completion rate of 92.8% (participants attending the end-of-trial safety visit). The majority of participants were female (77.6%) and white (93.1%), with an average age of 47.3 (standard deviation: 11.0) years, a body mass index of 38.5 (standard deviation: 6.9) kg m–2, and a weight of 106.0 (standard deviation: 22.0) kg. The mean reduction in body weight from baseline to week 104 was significantly higher in the semaglutide group (n = 152) compared to the placebo group (n = 152), with an estimated treatment difference of -12.6 percentage points (95% confidence interval: -15.3 to -9.8; P < 0.0001). A greater proportion of participants in the semaglutide group achieved a weight loss of ≥5% from baseline at week 104 (77.1% versus 34.4%; P < 0.0001). Gastrointestinal adverse events, predominantly mild-to-moderate in severity, were more frequently reported with semaglutide compared to placebo (82.2% versus 53.9%). In summary, in adults dealing with overweight or obesity (with at least one weight-related comorbidity), semaglutide treatment resulted in significant and sustained weight loss over the 104-week period compared to placebo.
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