Clinical Trial Results for Semaglutide Demonstrate Weight Loss Benefit as Add-On Therapy

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Intensive behavior therapy with a low-calorie diet and regular physical activity doesn't always lead to weight loss. In this featured clinical trial, physicians led by Thomas A. Wadden, PhD, of the University of Pennsylvania, examine the effect of once-weekly subcutaneous semaglutide as add-on therapy for weight loss.

Once-weekly subcutaneous semaglutide, when used as an adjunct to behavioral therapy and lifestyle changes, led to more weight loss during a 68-week treatment period compared with placebo, according to a study published in JAMA.

The late-stage, double-blind STEP 3 trial was conducted across 41 sites in the United States between 2018 and 2020. A total of 611 participants (mean age, 46 years) who were either overweight with ≥1 comorbidity or obese were randomly assigned to either 2.4 mg semaglutide (n=407) or placebo (n=204). Participants in both arms also received a low-calorie diet for the first 8 weeks as well as intensive behavioral therapy for the entire study.

Behavioral therapy consisted of 30 counseling visits with a registered dietitian who provided education and instruction on diet, physical activity, and behavioral strategies.

Co-primary endpoints included the percentage change in body weight and the loss of ≥5% of baseline weight by the 68-week follow up. Additional confirmatory secondary endpoints were the loss of ≥10% or ≥15% of baseline weight by follow up.

The mean baseline body mass index of the study population was 38.0, and the mean waist circumference was 113.0 cm. Approximately 78.8% of participants had ≥1 comorbidity at screening.

The estimated mean body weight change from baseline to week 68 was –16.0% for the semaglutide arm vs –5.7% for the placebo group (difference, −10.3 percentage points; 95% CI, −12.0 to −8.6; P <.001). A significantly greater proportion of participants who were treated with semaglutide lost ≥5 of baseline body weight by follow up (86.6% vs 47.6%; P <.001).

Additionally, treatment with semaglutide was associated with more participants who achieved weight loss of ≥10% or ≥15% vs treatment with placebo (75.3% vs 27.0% and 55.8% vs 13.2%, respectively; P <.001).

Participants who received semaglutide more frequently reported gastrointestinal (GI) adverse events (82.8% vs 63.2%). Treatment discontinuation due to gastrointestinal events was reported in 3.4% of participants who received semaglutide vs 0% of participants in the placebo group.

A limitation of this trial is the relatively short follow-up period. The researchers suggest that a longer follow-up trial, the STEP 5 trial, should help determine whether or not semaglutide provides sustained weight reduction.

The investigators indicate the findings are promising, especially for individuals who achieve weight reductions at 6 and 12 months, as “weight loss with behavioral therapy often plateaus at this level.”

Disclosure: This clinical trial was supported by Novo Nordisk A/S. Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Wadden TA, Bailey TS, Billings LK, et al. Effect of subcutaneous semaglutide vs placebo as an adjunct to intensive behavioral therapy on body weight in adults with overweight or obesity: The STEP 3 randomized clinical trial. Published online February 24, 2021. JAMA. doi:10.1001/jama.2021.1831