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Original Investigation
January 11, 2022

Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial

Author Affiliations
  • 1Washington Center for Weight Management and Research, Arlington, Virginia
  • 2Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge
  • 3Novo Nordisk A/S, Søborg, Denmark
  • 4Weight Management Center, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston
  • 5Dallas Diabetes Research Center at Medical City, Dallas, Texas
  • 6Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 7Department of Nutrition Sciences, University of Alabama at Birmingham
JAMA. 2022;327(2):138-150. doi:10.1001/jama.2021.23619
Visual Abstract. Effect of Weekly Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes
Effect of Weekly Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes
Key Points

Question  Among adults with overweight or obesity without diabetes, what is the effect of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg, on weight loss when each is added to counseling for diet and physical activity?

Findings  In this randomized clinical trial that included 338 participants, mean body weight change from baseline to 68 weeks was –15.8% with semaglutide vs –6.4% with liraglutide, a statistically significant difference.

Meaning  Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide, compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity resulted in significantly greater weight loss at 68 weeks.

Abstract

Importance  Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management.

Objective  To compare the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg (both with diet and physical activity), in people with overweight or obesity.

Design, Setting, and Participants  Randomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment: September 11-November 26) to May 2021 (end of follow-up: May 11) in adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities, without diabetes (N = 338).

Interventions  Participants were randomized (3:1:3:1) to receive once-weekly subcutaneous semaglutide, 2.4 mg (16-week escalation; n = 126), or matching placebo, or once-daily subcutaneous liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical activity. Participants unable to tolerate 2.4 mg of semaglutide could receive 1.7 mg; participants unable to tolerate 3.0 mg of liraglutide discontinued treatment and could restart the 4-week titration. Placebo groups were pooled (n = 85).

Main Outcomes and Measures  The primary end point was percentage change in body weight, and confirmatory secondary end points were achievement of 10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide vs liraglutide at week 68. Semaglutide vs liraglutide comparisons were open-label, with active treatment groups double-blinded against matched placebo groups. Comparisons of active treatments vs pooled placebo were supportive secondary end points.

Results  Of 338 randomized participants (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean [SD] body weight, 104.5 [23.8] kg; mean [SD] body mass index, 37.5 [6.8]), 319 (94.4%) completed the trial, and 271 (80.2%) completed treatment. The mean weight change from baseline was –15.8% with semaglutide vs –6.4% with liraglutide (difference, –9.4 percentage points [95% CI, –12.0 to –6.8]; P < .001); weight change with pooled placebo was –1.9%. Participants had significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs 12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all P < .001). Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide. Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide.

Conclusions and Relevance  Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks.

Trial Registration  ClinicalTrials.gov Identifier: NCT04074161

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