Most patients had 5% weight loss with semaglutide
The STEP 1 trial enrolled 1,961 adults with a body mass index (BMI) of at least 30 kg/m2 or at least 27 with at least one weight-related coexisting condition, but without type 2 diabetes, at 129 sites in 16 countries in Asia, Europe, North America, and South America.
Participants were a mean age of 47 and three-quarters were women. Most participants were White (76%), followed by Asian (13%), Black or African American (6%), or other (5%).
On average, they had a BMI of 38 and weighed 105 kg. Three-quarters had one or more coexisting conditions.
Participants were randomized to receive semaglutide (1,306 patients) or placebo (655 patients), added to lifestyle intervention.
Everyone received 17 monthly individual counseling sessions during which they learned about adhering to a diet with a 500-calorie/day deficit, were encouraged to build up to walking 150 minutes each week, and recorded their daily diet and exercise (in a diary or using an app).
Semaglutide was administered with a prefilled pen injector at a dose of 0.25 mg/week for the first 4 weeks, escalated to 2.4 mg/week by week 16 (or lower if the patient had unacceptable side effects).
At 68 weeks, participants in the semaglutide versus placebo group had greater mean weight loss (14.9% vs. 2.4%, or 15.3 kg vs. 2.6 kg).
Participants in the semaglutide versus placebo group were much more likely to have lost at least 5% of their initial weight (86% vs. 31.5%) or at least 10% of their initial weight (69.1% vs. 12.0%), or at least 15% of their initial weight (50.5% vs. 4.9%; P < .001 for all three comparisons).
About 80% of participants adhered to the study treatment. A third of participants in the semaglutide group who completed the study lost at least 20% of their initial weight, which approaches the 20%-30% reported weight loss 1-3 years after sleeve gastrectomy, the researchers noted.
Participants in the semaglutide group also had greater improvements in waist circumference and levels of hemoglobin A1c, C-reactive protein (a marker of inflammation), and fasting lipids, as well as in physical function scores on SF-36 and IWQOL-Lite-CT questionnaires.
In their editorial, Dr. Ingelfinger and Dr. Rosen noted that “daily oral semaglutide [already approved in 7-mg and 14-mg doses for the treatment of type 2 diabetes as Rybelsus] might be more appealing to many people,” as a weight-loss medication than a once-weekly subcutaneous dose. Semaglutide is the first GLP-1 agonist available as an oral agent.
The ongoing Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity (SELECT) trial (with expected completion in 2023) will shed light on cardiovascular outcomes after 2.5-5 years.
GI disorders and ‘important limitations’
More participants in the semaglutide than the placebo group reported gastrointestinal disorders (typically nausea, diarrhea, vomiting, and constipation; 74.2% vs. 47.9%), which were mostly transient and mild to moderate in severity, but also led to more treatment discontinuation (7.0% vs. 3.1%).
More patients in the semaglutide versus placebo group had a gall bladder–related disorder (2.6% vs. 1.2%, mostly cholelithiasis) and mild acute pancreatitis (3 vs. 0 participants), but there were no between-group differences in neoplasms.
Dr. Wilding and colleagues acknowledge the limitations of the study, including the fact that it enrolled mainly women, mainly non-White participants, was relatively short, and excluded patients with type 2 diabetes.
Mean placebo-corrected weight loss with 2.4 mg/weekly subcutaneous semaglutide was greater than with 3.0 mg once-daily subcutaneous liraglutide (Saxenda, Novo Nordisk) – the only GLP-1 agonist approved for weight management – in the 56-week SCALE trial (12.4% vs. 4.5%); however, the two studies had different populations.
The study was supported by Novo Nordisk. Dr. Ingelfinger is a deputy editor and Dr. Rosen is an associate editor of the New England Journal of Medicine. Dr. Ingelfinger, Dr. Rosen, and Dr. Leurent have reported no relevant financial relationships. Dr. O’Rahilly has a current research collaboration with Novo Nordisk scientists in an unrelated area and has been a consultant for the company.
A version of this article first appeared on Medscape.com.