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

Abstract

Importance: Weight loss improves cardiometabolic risk factors in people with overweight or obesity. Intensive lifestyle intervention and pharmacotherapy are the most effective noninvasive weight loss approaches.

Objective: To compare the effects of once-weekly subcutaneous semaglutide, 2.4 mg vs placebo for weight management as an adjunct to intensive behavioral therapy with initial low-calorie diet in adults with overweight or obesity.

Design, setting, and participants: Randomized, double-blind, parallel-group, 68-week, phase 3a study (STEP 3) conducted at 41 sites in the US from August 2018 to April 2020 in adults without diabetes (N = 611) and with either overweight (body mass index ≥27) plus at least 1 comorbidity or obesity (body mass index ≥30).

Interventions: Participants were randomized (2:1) to semaglutide, 2.4 mg (n = 407) or placebo (n = 204), both combined with a low-calorie diet for the first 8 weeks and intensive behavioral therapy (ie, 30 counseling visits) during 68 weeks.

Main outcomes and measures: The co-primary end points were percentage change in body weight and the loss of 5% or more of baseline weight by week 68. Confirmatory secondary end points included losses of at least 10% or 15% of baseline weight.

Results: Of 611 randomized participants (495 women [81.0%], mean age 46 years [SD, 13], body weight 105.8 kg [SD, 22.9], and body mass index 38.0 [SD, 6.7]), 567 (92.8%) completed the trial, and 505 (82.7%) were receiving treatment at trial end. At week 68, the estimated mean body weight change from baseline was -16.0% for semaglutide vs -5.7% for placebo (difference, -10.3 percentage points [95% CI, -12.0 to -8.6]; P < .001). More participants treated with semaglutide vs placebo lost at least 5% of baseline body weight (86.6% vs 47.6%, respectively; P < .001). A higher proportion of participants in the semaglutide vs placebo group achieved weight losses of at least 10% or 15% (75.3% vs 27.0% and 55.8% vs 13.2%, respectively; P < .001). Gastrointestinal adverse events were more frequent with semaglutide (82.8%) vs placebo (63.2%). Treatment was discontinued owing to these events in 3.4% of semaglutide participants vs 0% of placebo participants.

Conclusions and relevance: Among adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in significantly greater weight loss during 68 weeks. Further research is needed to assess the durability of these findings.

Trial registration: ClinicalTrials.gov Identifier: NCT03611582.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Wadden reports receiving grants from Novo Nordisk (from grant support to the University of Pennsylvania) and personal fees from Novo Nordisk for service on a scientific advisory board during the conduct of the study, as well as personal fees from WW International (formerly Weight Watchers) for service on a scientific advisory board outside the submitted work. Dr Bailey reports receiving grants, personal fees, and nonfinancial support (writing assistance) from Novo Nordisk during the conduct of the study. Dr Billings reports receiving personal fees from Novo Nordisk, Sanofi, and Eli Lilly outside the submitted work. Dr Davies is co-funded by the NIHR Leicester Biomedical Research Centre and reports receiving consulting fees from Novo Nordisk; advisory board member, speaker, and consulting fees from Sanofi-Aventis, Eli Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca, and Janssen; advisory board fees from Lexicon, Servier, and Gilead Sciences Ltd; speaker fees from Napp Pharmaceuticals; and grants from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, AstraZeneca, and Janssen outside the submitted work. Dr Frias reports receiving research support grants from Novo Nordisk during the conduct of the study; grants and personal fees from Boehringer Ingelheim, Eli Lilly, Merck, Novo Nordisk, and Sanofi; and grants from Janssen and Pfizer outside the submitted work. Dr Koroleva reports being an employee of Novo Nordisk A/S and holding shares in the company. Dr Lingvay reports receiving advisory board fees and consulting fees from AstraZeneca, consulting fees from Bayer HealthCare Pharmaceuticals, Eli Lilly and Company, Intarcia, Intercept Pharmaceuticals, Janssen Global Services, MannKind Corporation, Target Pharma, Valeritas, and Zealand Pharma; advisory board fees from Boehringer Ingelheim and Sanofi US Services; grant support, paid to UT Southwestern, from Merck; grant support, paid to her institution, from Mylan Pharmaceuticals and Pfizer; grant support, paid to UT Southwestern; and advisory board fees, consulting fees, and travel support from Novo Nordisk. Dr O'Neil reports receiving grants from Novo Nordisk during the conduct of the study; grants from Epitomee Medical, Eli Lilly, and WW International; and personal fees from Robard, Gedeon Richter, WebMD, and Novo Nordisk outside the submitted work. Dr Rubino reports receiving writing assistance from Novo Nordisk during the conduct of the study; serving as a clinical investigator for AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; and reports owning Novo Nordisk shares of stock outside the submitted work. Dr Skovgaard reports spousal employment at Novo Nordisk. Dr Wallenstein reports receiving personal fees from Novo Nordisk during the conduct of the study and outside the submitted work. Dr Garvey reports receiving grants from Novo Nordisk; serving as site principal investigator for the clinical trial, which was sponsored by his university during the conduct of the study; receiving grants from Lexicon and Pfizer outside the submitted work; and serving as an ad hoc consultant on advisory committees for Jazz Pharmaceuticals, Boehringer Ingelheim, Novo Nordisk, and Pfizer. In each instance, he received no financial compensation, nor was there a financial relationship. No other disclosures were reported.

Figures

Figure 1.. Participant Flow in the STEP 3 Trial of Semaglutide in Adults With Overweight or Obesity

aParticipants could meet more than 1 exclusion or randomization criterion. bAdverse events leading to permanent discontinuation of trial product (participants may have discontinued due to ≥1 adverse event): (1) gastrointestinal disorders: constipation, n = 2 (semaglutide); diarrhea/explosive diarrhea, n = 2 (semaglutide); eructation/belching, n = 1 (semaglutide); flatulence/excessive gas, n = 1 (semaglutide); nausea/worsening nausea, n = 7 (semaglutide); retching/dry heaves, n = 1 (semaglutide); and vomiting/worsening vomiting/recurrent vomiting, n = 6 (semaglutide). (2) General disorders and administration site conditions/hepatobiliary disorders: biliary colic/gallbladder pain, n = 1 (semaglutide); biliary dyskinesia, n = 1 (semaglutide); and injection site hematoma, n = 1 (placebo). (3) Infections and infestations: diverticulitis, n = 1 (placebo). (4) Injury, poisoning, and procedural complications: concussion, n = 1 (semaglutide). (5) Investigations: amylase increased/elevated amylase, n = 1 (semaglutide); blood creatine phosphokinase increased/elevated creatine kinase, n = 1 (semaglutide); and lipase increased/elevated lipase, n = 1 (semaglutide). (6) Metabolism and nutrition disorders: loss of appetite, n = 1 (semaglutide). (7) Musculoskeletal and connective tissue disorders: right-sided flank pain, n = 1 (placebo). (8) Nervous system disorders: headache, n = 1 (semaglutide); and worsening of migraine, n = 1 (semaglutide). (9) Psychiatric disorders: anxiety/worsening anxiety, n = 3 (semaglutide), n = 1 (placebo). (10) Skin and subcutaneous tissue disorders: hair thinning, n = 1 (semaglutide); hair loss, n = 1 (placebo); burning under skin of the right leg, n = 1 (semaglutide); and generalized pruritic rash, n = 1 (placebo). cA total of 5.6% of participants were lost to follow-up. In the semaglutide group, 12 were lost to follow-up by week 38, and in the placebo group, 5 were lost to follow-up by week 25.

Figure 2.. Body Weight–Related Efficacy End Points

A, The observed mean percentage change in body weight over time for participants in the full analysis set for the in-trial period (from randomization to last contact with the trial site, regardless of treatment discontinuation or rescue intervention). Error bars represent 95% CIs of the mean. B, The observed proportions of participants attaining at least 5% (co–primary end point), 10%, 15%, and 20% reductions in baseline body weight by week 68 in the full analysis set. The proportions shown are cumulative, such that the 88.6% of semaglutide-treated participants who lost more than 5% of baseline body weight includes the 75.3% of participants who lost more than 10%, and so on. See eFigure 4 in Supplement 1 for corresponding on-treatment data (during treatment with the trial product [any dose of trial medication administered within the previous 2 weeks]).