Aims: Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has shown clinically relevant weight loss vs placebo in a phase 2 trial. Studies have shown additive effects of lifestyle interventions combined with weight loss medication.
Methods: This 68-week, randomised, double-blind, multicentre, placebo-controlled, phase 3 trial (NCT03611582) compared the effect on body weight of once-weekly subcutaneous semaglutide 2.4 mg vs placebo, both as adjunct to a low-calorie meal replacement diet for the first 8 weeks and intensive behavioural therapy (IBT; decreased energy intake, increased physical activity and counselling) for the trial duration in adults with overweight (body mass index [BMI] ≥27 kg/m2) plus ≥1 comorbidity, or obesity (BMI ≥30 kg/m2), without type 2 diabetes. Effects on cardiovascular disease (CVD) risk factors, glucose metabolism, patient-reported outcomes and safety/tolerability were also assessed.
Results: 611 randomised subjects (mean age 46 years, body weight 106 kg, BMI 38 kg/m2; 81% female) were included. At week 68, mean body weight decreased from baseline by 16.0% with semaglutide vs 5.7% with placebo (estimated treatment difference: –10.3; 95% CI: –12.0, –8.6; p<0.0001). More subjects achieved weight loss ≥5%, ≥10%, ≥15% and ≥20% with semaglutide vs placebo (87% vs 48%; 75% vs 27%; 56% vs 13%; 36% vs 4%, respectively; all p<0.0001). From baseline to week 68, the proportion of subjects with prediabetes decreased from 48% to 7% in the semaglutide group, and from 53% to 26% in the placebo group. Greater improvements were seen with semaglutide in waist circumference, BMI, blood pressure and lipids (total cholesterol, LDL, VLDL, FFA and triglycerides). Semaglutide was well tolerated; gastrointestinal adverse events were most common (semaglutide: 83%; placebo: 63%).
Conclusions: In adults with overweight or obesity, semaglutide 2.4 mg as an adjunct to IBT led to significantly greater weight loss and improvements in CVD risk factors and glucose metabolism vs placebo plus IBT.