[commentary] The STEP 5 trial assessed the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg versus placebo (both plus behavioral intervention) for long-term treatment of adults with obesity, or overweight with at least one weight-related comorbidity, without diabetes. The co-primary endpoints were the percentage change in body weight and achievement of weight loss of ≥5% at week 104. Efficacy was assessed among all randomized participants regardless of treatment discontinuation or rescue intervention.
From 5 October 2018–1 February 2019, 304 participants were randomly assigned to semaglutide 2.4 mg (n = 152) or placebo (n = 152), 92.8% of whom completed the trial (attended the end-of-trial safety visit). Most participants were female (236 (77.6%)) and white (283 (93.1%)), with a mean (s.d.) age of 47.3 (11.0) years, body mass index of 38.5 (6.9) kg m–2 and weight of 106.0 (22.0) kg.
The mean change in body weight from baseline to week 104 was −15.2% in the semaglutide group (n = 152) versus −2.6% with placebo (n = 152), for an estimated treatment difference of −12.6%-points (95% confidence interval, −15.3 to −9.8; p < 0.0001). More participants in the semaglutide group than in the placebo group achieved weight loss ≥5% from baseline at week 104 (77.1% versus 34.4%; p < 0.0001).
(b) Observed proportions of participants and OR for achieving weight loss of at least 5% from baseline at week 104 in the full analysis set during the in-trial observation period, based on the treatment policy estimand.
Estimated means in percent are from the primary analysis. The in-trial observation period was the time from random assignment to last contact with a trial site, regardless of treatment discontinuation or rescue intervention. The treatment policy estimand assesses treatment effect regardless of treatment discontinuation or rescue intervention; see Extended Data Figure 6 for corresponding data for the trial product estimand (which assesses treatment effect assuming all participants adhered to treatment and did not receive rescue intervention). The change in body weight analysis was conducted with the use of the analysis-of-covariance method, with randomized treatment as a factor and baseline body weight as a covariate. The achievement of at least 5% weight loss analysis was conducted with the use of logistic regression, with the same factor and covariate. A multiple imputation approach was used for missing data. The results were accompanied by two-sided 95% CIs and corresponding p-values (significance defined as p < 0.05). As co-primary endpoints, the analyses were controlled for multiple comparisons.
Gastrointestinal adverse events, mostly mild-to-moderate, were reported more often with semaglutide than with placebo (82.2% versus 53.9%). In summary, in adults with overweight (with at least one weight-related comorbidity) or obesity, semaglutide treatment led to substantial, sustained weight loss over 104 weeks versus placebo. Trial registration: NCT03693430.
…Semaglutide was associated with greater reductions from baseline to week 104 in waist circumference (–14.4 cm (0.9) with semaglutide versus −5.2 cm (1.2) with placebo; ETD −9.2 cm, 95% CI −12.2 to −6.2, p < 0.0001) and systolic blood pressure (–5.7 mmHg (1.1) with semaglutide versus −1.6 (1.2) with placebo; ETD −4.2 mmHg, 95% CI −7.3 to −1.0; p = 0.01) (both were confirmatory secondary endpoints; Table 2, Figure 2 & Extended Data Figure 4a, 4b). Compared with placebo, semaglutide also led to improvements in diastolic blood pressure, glycated hemoglobin (HbA1c), fasting plasma glucose, fasting serum insulin, C-reactive protein, total cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol and triglycerides (all were supportive secondary endpoints; Table 2 & Extended Data Figure 4c, 4d).
Of the participants with prediabetes at baseline who also had a glycemic status assessment at week 104, 59 (79.7%) of 74 treated with semaglutide reverted to normoglycaemia at week 104, compared with 20 (37.0%) of 54 participants on placebo (an exploratory endpoint; Table 2 & Extended Data Figure 5). Of the participants with normoglycaemia at baseline who also had a glycemic status assessment at week 104, one (1.4%) of 71 treated with semaglutide had prediabetes at week 104, compared with 10 (13.0%) of 77 participants on placebo. Among participants with a week 104 assessment, none in the semaglutide group and 3 in the placebo group had type 2 diabetes at week 104 (one had normoglycaemia at baseline and two had prediabetes at baseline). The proportion of participants with changes in the use of lipid-lowering and antihypertensive medication (among those receiving such medications during the trial) is reported in Table 2 (both were exploratory endpoints).