Maintaining long-term weight loss is challenging, even with lifestyle interventions, such as diet and exercise. Clinical guidelines suggest the use of adjunctive drug therapy, especially in people who have a body mass index of 30 or higher; however, the use of these medications remains limited because of cost and safety concerns, among other reasons. A global phase 3 trial evaluated the efficacy and safety of semaglutide administered subcutaneously compared with placebo as an adjunct to lifestyle interventions for the management of overweight or obesity.

A total of 1,961 adults who are obese or overweight and who had one or more weight-related coexisting conditions, but not diabetes, were included in the study. They were randomly assigned to once-weekly treatment with 2.4 mg of subcutaneous semaglutide, a glucagon-like peptide-1 analogue used to manage type 2 diabetes, or placebo for 68 weeks, plus lifestyle intervention.

At week 68, the mean weight change was -14.9% among those who received semaglutide compared with -2.4% for those in the placebo group. Participants who received semaglutide were more likely than placebo recipients to lose 5% or more, 10% or more, or 15% or more of baseline body weight at week 68. Among the participants for whom data were available at week 68, 86.4% attained at least a 5% weight loss. Compared with those receiving placebo, participants who received semaglutide also had greater reductions from baseline in waist circumference and blood pressure. Benefits were also noted regarding changes in levels of glucose, C-reactive protein, and lipids, and in physical functioning scores.

Gastrointestinal disorders, the most common adverse events, occurred more often in the semaglutide group than in the placebo group. Most gastrointestinal events were mild to moderate and resolved without permanent discontinuation of treatment. More participants in the semaglutide group discontinued treatment because of adverse events.

Limitations of the trial included the preponderance of women and white participants, its relatively short duration, the exclusion of people with type 2 diabetes, and the possibility that participants who enrolled may have been more committed to weight loss than the general population.