"Semaglutide in Adults with Overweight or Obesity". The New England Journal of Medicine. 2021.

Clinical Question

Does once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention lead to significant weight loss in adults with obesity or overweight?

Bottom Line

Once-weekly subcutaneous semaglutide at a dose of 2.4 mg plus lifestyle intervention resulted in a sustained and clinically relevant reduction in body weight compared with placebo in adults without diabetes who were overweight or obese.

Major Points

Obesity is a chronic disease and a major public health challenge that can lead to several complications and reduce life expectancy. While lifestyle interventions are the cornerstone for weight management, maintaining long-term weight loss is difficult. Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, has demonstrated weight loss capabilities, and its efficacy and safety as a weight management tool were evaluated in this study.

Guidelines

Existing clinical guidelines suggest the use of adjunctive pharmacotherapy for weight management, primarily for adults with a BMI of 30 or above, or 27 or above with weight-related conditions. However, current anti-obesity medications are often limited by modest efficacy, safety concerns, and cost.

Design

- Randomized, double-blind, placebo-controlled trial
- N=1,961 adults with recent MI and increased ventricular ectopy
- Intervention: Once-weekly semaglutide 2.4 mg subcutaneous injection (n=1,306)
- Comparison: Placebo (n=655)
- Duration: 68 weeks treatment plus 7-week follow-up without treatment
- The primary outcome: Percentage change in body weight and weight reduction of at least 5%

Population

- Adults (≥18 years) with overweight (BMI ≥27 with ≥1 weight-related condition) or obesity (BMI ≥30), without diabetes
- 74.1% female, 75.1% white, with a mean age of 46 years
- Exclusion criteria included diabetes, a history of chronic pancreatitis, previous surgery for obesity, and use of anti-obesity medication within 90 days prior to enrollment

Interventions

- Semaglutide administered subcutaneously with dosage gradually increased over 16 weeks to reach the maintenance dose of 2.4 mg weekly
- Adjunct lifestyle intervention including counseling sessions every 4 weeks to adhere to a reduced-calorie diet and increased physical activity

Outcomes

- Primary outcomes: Mean weight change from baseline to week 68 was -14.9% in the semaglutide group compared with -2.4% with placebo [estimated treatment difference of -12.4 percentage points (95% CI, -13.4 to -11.5; P<0.001)].
- Secondary outcomes: More participants achieved weight reductions of 5% or more (86.4% vs. 31.5%), 10% or more (69.1% vs. 12.0%), and 15% or more (50.5% vs. 4.9%) with semaglutide compared to placebo (P<0.001 for all comparisons).

Criticisms

- The majority of participants were female and white, limiting generalizability to other populations.
- The trial duration may not fully reflect long-term efficacy and safety.
- Participants in the trial may represent a subgroup more committed to weight-loss efforts compared to the general population.

Funding

Funded by Novo Nordisk.

Further Reading