Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 18;384(11):989. doi: 10.1056/NEJMoa2032183. Epub 2021 Feb 10. (Original study)

BACKGROUND: Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

METHODS: In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (=27 in persons with =1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.

RESULTS: The mean change in body weight from baseline to week 68 was -14.9% in the semaglutide group as compared with -2.4% with placebo, for an estimated treatment difference of -12.4 percentage points (95% confidence interval [CI], -13.4 to -11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group as compared with -2.6 kg in the placebo group (estimated treatment difference, -12.7 kg; 95% CI, -13.7 to -11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).

CONCLUSIONS: In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 number, NCT03548935).

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Nurse rater

Given the prevalence of obesity and the correlation of obesity to the development of diabetes and cardiovascular disease, this STEP trial offers encouragement. While it is disappointing that the study demographics were heavily weighted towards white women, it was none the less good to see a strong complement of women in the study. I would encourage the study authors to consider a broader racial composition for future versions of the study as people of color to determine if the same results can be achieved across races.

Physician rater

This is a huge breakthrough if it is a safe drug that helps patients lose weight and reduces vascular and other associated obesity-related outcomes.

Physician rater

This is perhaps the first time I've been excited about a medication for weight loss. Definitely want to start thinking about how I could use this in my practice.

Physician rater

Although the results of weight loss with semaglutide are not surprising, this once-weekly GLP1R-agonist leads to much greater weight loss than the once-daily liraglutide, making it a better choice for this indication.

Physician rater

As a weight-loss drug, these results mirror the liraglutide data (ie, both drugs used at higher doses than approved for the treatment of diabetes). The amount of weight loss in this study is impressive.

Physician rater

If semaglutide gains FDA approval for weight loss management, as may be coming based on this study, patients needing rapid weight loss to be eligible for procedures such as elective arthroplasty will not need bariatric surgery. Patients with pre-existing gallbladder disease may not be good candidates for this therapy, though.

Physician rater

This is a well done RCT demonstrating benefit of IM semaglutide to treat obesity with an absolute 12% difference in body weight at 68 weeks. With a NNH of 27 at 68 weeks, semaglutide may become an important therapy in our toolbox to treat patients with obesity and obesity-associated chronic conditions. The study would have been strengthened by a cost-effective analysis as I worry cost will be a barrier for many patients.
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