May 30, 2023 – Subcutaneous semaglutide plus behavioral therapy and a low-calorie diet increased weight loss compared with the same intensive lifestyle regimen with placebo in a phase 3 study of adults with overweight or obesity.

Thomas A. Wadden, PhD, of the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, and the STEP 3 Investigators reported their findings in the February 24, 2021, issue of the Journal of the American Medical Association.Semaglutide is a glucagon-like peptide 1 receptor agonist that is FDA approved for type 2 diabetes at dosages of 0.5 mg, 1 mg, or 2 mg weekly. In a prior phase 2 study, daily subcutaneous semaglutide with monthly behavioral therapy produced significant weight loss in patients with obesity. This study evaluated subcutaneous semaglutide 2.4 mg administered weekly and combined with intensive behavioral therapy and a low-calorie diet.

Adults with a history of prior weight loss efforts and either body mass index (BMI) greater than or equal to 30 kg/m2, or BMI greater than or equal to 27 kg/m2 with at least 1 obesity-related comorbidity (cardiovascular disease, dyslipidemia, hypertension, or obstructive sleep apnea) were included.

A total of 611 participants were randomized in a 2:1 ratio to receive either 2.4-mg subcutaneous semaglutide once weekly or placebo for 68 weeks. A total of 567 participants completed the trial. Both groups were simultaneously treated with a low-calorie diet (1000-1200 kcal/day) for 8 weeks followed by a hypocaloric diet (1200-1800 kcal/day) for the remainder of the study and underwent 30 sessions of behavioral therapy throughout the study course.

The coprimary endpoints were percentage change in body weight and the proportion of participants losing 5% or greater of their body weight.

At 68 weeks, participants treated with semaglutide lost significantly more weight compared with those receiving placebo (–16.0% vs –5.7%, P < .001). In addition, the proportion of patients losing 5% or more of their baseline body weight was greater in the semaglutide group compared with the placebo group (86.6% vs 47.6%, P < 0.001).

The rates of adverse events were high but similar between the study groups (95.8% for semaglutide and 96.1% for placebo). Gastrointestinal disorders were the most common adverse events, occurring more frequently in the semaglutide group (82.8% vs 63.2% for placebo), but were noted to be typically mild to moderate and of short duration (days to weeks).

Serious adverse events occurred in 9.1% of the semaglutide group and 2.9% of the placebo group. This included 20 participants with hepatobiliary disorders in the semaglutide group compared with 3 participants in the placebo group, and 3 participants with malignant neoplasms in the semaglutide group compared with 1 participant in the placebo group.

“The present findings suggest that the addition of semaglutide to intensive behavioral therapy may help patients achieve more than the average 5% to 10% reduction in body weight typically produced by behavioral interventions,” the authors concluded.

However, the authors noted that the amount of weight loss was similar to the earlier STEP 1 trial evaluating weekly subcutaneous semaglutide and a less intensive lifestyle intervention. They pointed out that “further study is needed of the optimal program of lifestyle modification required with semaglutide.”