Weight Loss Maintenance With Once-Weekly Semaglutide 2.4 MG in Adults With Overweight or Obesity Reaching Maintenance Dose (STEP 4)

Abstract

Background: In people with overweight or obesity, long-term maintenance of weight loss is challenging. Subcutaneous (s.c.) semaglutide, a glucagon-like peptide-1 analogue, has shown clinically-relevant weight loss in a phase 2 trial in people with obesity. STEP 4 investigated the impact of continued semaglutide 2.4 mg treatment, vs switching to placebo, on maintenance of weight loss in participants who reached 2.4 mg of semaglutide during a run-in period. Methods: This was a 68-week withdrawal trial (NCT03548987) in 902 subjects aged ≥18 years with body mass index (BMI) ≥30 kg/m2 (or BMI ≥27 kg/m2 with ≥1 weight-related comorbidity), without diabetes. Following a 20 week run-in period, 803 subjects who reached the maintenance dose of once-weekly (OW) s.c. semaglutide 2.4 mg were randomized 2:1 to continue treatment with semaglutide 2.4 mg or switch to placebo for 48 weeks, both as adjunct to lifestyle intervention. The primary endpoint was percentage change in body weight between randomization (week 20) and week 68. Confirmatory secondary endpoints included change in waist circumference and systolic blood pressure. Two estimands were defined: treatment policy and trial product; results are presented for the treatment policy estimand, unless stated otherwise. Results: Mean body weight (±SD) was 107.2 ±22.7 kg at week 0 and 96.1 ±22.6 kg at randomization (week 20; mean change -10.6%). Randomized participants were mostly female (79%) and white (84%); mean age was 46 years and mean BMI was 34.4 kg/m2. Between weeks 20–68, estimated mean body weight change was −7.9% vs +6.9% for semaglutide 2.4 mg vs placebo (estimated treatment difference [ETD]: −14.8%; 95% confidence interval [CI]: −16.0, −13.5; p<0.0001), and -8.8% vs 6.5%, respectively, for the trial product estimand (ETD: -15.3%; 95% CI: -16.5, -14.1; p<0.0001). For participants randomized to continue semaglutide, the estimated change in body weight from week 0–68 was -17.4% (-18.2% for trial product estimand). Continued semaglutide treatment (weeks 20–68) led to clinically-relevant improvements in waist circumference, systolic blood pressure, BMI, HbA1c, FPG, and lipids (total cholesterol, LDL, VLDL, and triglycerides) vs switching to placebo (p<0.0001 for all). During the run-in period, 5.3% of participants discontinued treatment due to adverse events; during the randomized period, 2.4% (semaglutide) and 2.2% (placebo) discontinued. Nausea, diarrhea and constipation (mostly transient and mild-to-moderate) were the most frequent adverse events with semaglutide. Conclusion: In adults with overweight or obesity, continued treatment after dose escalation with OW s.c. semaglutide 2.4 mg until week 68 led to clinically-relevant weight loss, while switching to placebo led to significant weight regain; these data underscore the chronicity and relapsing nature of obesity, and the need for continued treatment.

The Antiobesity Effect and Safety of GLP-1 Receptor Agonist in Overweight/Obese Patients Without Diabetes: A Systematic Review and Meta-Analysis

“…The different half-life might explain the differences of GI events between liraglutide and exenatide treatments. Furthermore, according to the meta-analysis of 3 RCTs involving 2351 patients, our study also found that there were no significant differences of GI events between semaglutide and placebo 7 9 10 . Semaglutide, has a half-life of 183 hours, longer than liraglutide and exenatide, which may also explain why semaglutide appeared the least GI events than liraglutide and exenatide 6 .…”

“…The selected RCTs were published between 2008 and 2021. Besides, in the included studies, 23 RCTs reported weight loss 7 8 9 10 11 12 13 16 17 18 19 20 21 22 23 24 25 26 27 28 37 , 20 RCTs provided BMI and WC as efficacy parameters 5 6 7 8 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 , 14 RCTs showed total cholesterol (TC), triglyceride (TG), and low density lipoprotein cholesterol (LDL-C) 7 8 9 10 12 13 16 17 21 23 24 26 27 28 , 15 RCTs displayed high density lipid-cholesterol (HDL-C) 8 9 10 11 12 13…”

“…Seventeen RCTs had reported weight loss of GLP-1RAs in the overweight/obese patients without diabetes compared with placebo as presented in the forest plot of Fig. 2a 7 8 9 10 11 13 14 15 16 20 21 22 23 25 37 . Our meta-analysis showed that the weight loss effect of overweight/obese patients without diabetes treated with GLP-1RAs was more significant than patients treated with placebo, and the overall reduction weight was –5.39 kg [95% CI (–6.82, –3.96), I 2 =99.2%, p<0.001].…”

“…Thirteen RCTs had reported BMI reduction of GLP-1RAs in overweight/obese patients without diabetes 7 8 9 10 13 16 20 21 22 23 25 27 28 . As presented in Fig.…”

“…Semaglutide, with a longer half-life than liraglutide and exenatide, was administered once weekly 6 In 2018, O’Nei et al first compared the weight loss effect and safety of semaglutide and placebo in overweight/obese patients, suggesting that patients displayed an overall weight loss of –11.3% in semaglutide group and –2.3% in placebo group 7 . Additionally, Wadden et al 8 , Rubin et al 9 , Wilding et al 10 , and Blundell et al 37 have recently carried large-scale RCTs of semaglutide treatments in overweight/obese patients since 2021, their results all similarly displayed that semaglutide can reduce weight in the overweight/obese patients without diabetes. However, there were no systematic meta-analysis of antiobesity effect in semaglutide treatment for overweight/obese patients without diabetes, and there were also no studies comparing the antiobesity effect of liraglutide, exenatide and semaglutide.…”