Once-weekly semaglutide in adults with overweight or obesity
The search for an effective and safe weight loss–inducing drug has been an elusive goal in clinical medicine. For decades highly touted weight-loss agents have come into clinical use only to be removed because of serious adverse effects. These included fenfluramine/phentermine (valvular heart disease), sibutramine (cardiovascular disease), rimonabant (mood disorders), and lorcaserin (cancer). It is, therefore, not surprising that skepticism exists for new antiobesity agents.
Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue approved for the treatment of type 2 diabetes. It also has direct and indirect effects on the brain to induce early satiety and, as a result, limit caloric intake that confers weight loss. The STEP-1 (Semaglutide Treatment Effect in People with Obesity) trial evaluated the efficacy and safety of subcutaneous semaglutide dosed 2.4 mg once weekly as a weight-loss intervention.
This double-blind trial involved 1961 adults with a body mass index (BMI) ≥30 or with a BMI ≥27 and ≥1 weight-related coexisting condition, who did not have diabetes. Patients received lifestyle interventions and were randomly allocated (2:1 ratio) to receive semaglutide or placebo. The follow-up was 68 weeks and the coprimary endpoints were the percentage change in body weight and weight reduction ≥5% of total weight, which is considered clinically important.
The mean change in body weight at 68 weeks was -14.9% in the semaglutide group and -2.4% in the placebo group (treatment difference -12.4 percentage points; 95% CI, -13.4 to -11.5). There were statistically significant higher proportions of patients in the semaglutide group than in the placebo group with weight loss ≥5% (86.4% vs 31.5%), ≥10% (69.1% vs 12.0%), and ≥15% (50.5% vs 4.9%). The mean decrease in body weight from baseline was -15.3 kg in the semaglutide group and -2.6 kg in the placebo group. More patients in the semaglutide group than in the placebo group discontinued treatment due to gastrointestinal adverse effects: 59 (4.5%) versus 5 (0.8%).
The authors concluded that in patients with overweight or obesity, semaglutide at a dose 2.4 mg once weekly plus lifestyle interventions conferred sustained, clinically important weight loss. They further indicated that the observed 14.9% mean weight loss with semaglutide is greater than the 4% to 10% weight loss attained with other currently used antiobesity medications, including orlistat (malabsorptive agent) and liraglutide (another once-weekly subcutaneous GLP-1 analogue).
The Achilles heel of antiobesity treatments has been the limited duration of follow-up, which is clinically important given that weight loss recidivism is common. Although the follow-up duration in the STEP-1 trial (1.3 years) is longer than many weight loss trials, what is needed is long-term data assessing the efficacy and safety of semaglutide after 3 to 5 years of use. Semaglutide should be considered in selected patients (its use will be limited by its relatively high cost), but dietary and other lifestyle interventions should remain the cornerstone of antiobesity treatment. Ultimately, efforts should focus more on primary prevention, given the ongoing linked epidemics of obesity and type 2 diabetes.