Semaglutide for Obesity: A Randomized Trial

The prevalence of obesity in the United States has increased during the last decade. Complications associated with obesity include type 2 diabetes and heart disease. Although challenging, lifestyle modification through dietary change and exercise remains the cornerstone of treatment. The use of medication for weight loss has been hampered by lack of effect and high cost.

Semaglutide is a glucagon like peptide 1 (GLP1) analogue that is used in the management of diabetes. It works to decrease serum glucose levels by stimulating glucose-dependent insulin release from pancreatic islet cells.  Semaglutide has been shown to slow gastric emptying and reduce food intake that resulted in weight loss.

In the global phase 3, randomized, double blind, placebo-controlled Semaglutide Treatment Effect in People with Obesity (STEP1) trial, Wilding and colleagues evaluated whether semaglutide (2.4 mg once weekly) along with lifestyle intervention resulted in weight loss in participants with either a body mass index (BMI) ≥30 or BMI ≥27 and one or more weight-related condition. The coprimary end points were percentage change in body weight and weight reduction of at least 5%. After a follow up of 68 weeks, participants who received semaglutide had a mean reduction in body weight of 15.3 kg, compared with 2.6 kg with placebo.

Overall, the evidence from this study suggests that in participants with overweight or obesity, semaglutide was effective in achieving weight loss. Based on these results, the FDA approved the use of semaglutide for weight loss.

The following NEJM Journal Watch summary explains the study and results in further detail:

Allan S. Brett, MD, reviewing Wilding JPH et al. N Engl J Med 2021 Feb 10

One glucagon-like peptide-1 (GLP-1) agonist, liraglutide (Saxenda), is approved for treating obesity. Now, another GLP-1 agonist, semaglutide (marketed for diabetes as Ozempic), has been examined in an industry-supported obesity-treatment trial that involved nearly 1700 nondiabetic obese adults (mean body-mass index, 38 m/kg²; mean weight, 105 kg). Patients were randomized to receive either semaglutide or placebo, given once weekly by injection; an initial semaglutide dose of 0.25 mg was titrated during 4 months to a maximal dose of 2.4 mg if tolerated. (Note: the maximal weekly dose of injected semaglutide for diabetes treatment is 1.0 mg.)

At 68 weeks, mean reduction in body weight was significantly greater with semaglutide than with placebo (−15.3 vs. −2.6 kg). Weight loss exceeded 15% of baseline weight in half of semaglutide recipients. A difference between the semaglutide and placebo groups in mean weight loss was apparent within several weeks, and the difference increased steadily throughout the trial. Gastrointestinal side effects were significantly more common with semaglutide than with placebo: Differences between the two groups in the proportions of patients who had nausea, vomiting, and diarrhea were 27, 18, and 16 percentage points, respectively. Nevertheless, physical function scores favored the semaglutide group.

Comment: The weight reduction observed in this trial is impressive, but it's not the end of the story. The study duration was insufficient to assure safety — particularly for a condition that often is chronic. To address this concern, the manufacturer has initiated a 17,000-person trial (with estimated duration of 3–6 years) that focuses particularly on cardiovascular safety (SELECT). If semaglutide gets U.S. FDA approval for obesity treatment, cost surely will be an issue: The nondiscounted cost of injected semaglutide (at its current price and dose for diabetes treatment) is more than US$10,000 annually.

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Dr. Fernandes is an Endocrinologist at Rhode Island Hospital and Assistant Professor of Medicine at the Warren Alpert Medical School of Brown University. She was an NEJM editorial fellow from 2018-2019. She completed her fellowship in Endocrinology at the University of Vermont.