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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Rubino reported being a clinical investigator for Boehringer Ingelheim, AstraZeneca, and Novo Nordisk; receiving honoraria from WebMD, speaker fees, consulting fees, scientific advisory fees, and honoraria from Novo Nordisk, grants from SARL, and personal fees from Medscape, PeerView, and the Endocrine Society; and being a shareholder in Novo Nordisk. Dr Greenway reported receiving grants from Novo Nordisk, Pennington Biomedical Research Center, and NuSirt to his institution during the conduct of the study and personal fees from Pfizer, NovMeta Pharma, Melior Discoveries, Jenny Craig, Basic Research, Gedeon Richter Pharma, Jazz Pharmaceuticals, General Nutrition Corp, Dr Reddy’s Lab, and Regeneron and stock ownership in Academic Technology Ventures, Energesis, Ketogenic Health Systems, MetaSYn Therapeutics, Plensat, Slim Health Nutrition, UR Labs, and Rejuvenate Bio. In addition, Dr Greenway has a patent issued for orlistat and a patent pending for pramlintide/albuterol. Also, Dr Greenway served on the Novo Nordisk advisory board for the development of liraglutide that is now approved and was a comparator drug in the trial described in the present article. Dr Khalid reported being an employee of Novo Nordisk. Dr O’Neil reported receiving grants from Novo Nordisk during the conduct of the study and grants from WW International, Eli Lilly, and Epitomee Medical and personal fees from Pfizer, Robard Corporation, Novo Nordisk, WebMD, and Gedeon Richter outside the submitted work. Dr Rosenstock reported receiving scientific advisory board fees, honoraria, consulting fees, and grants/research support from Novo Nordisk (during the conduct of the study and outside the submitted work), Applied Therapeutics, Boehringer Ingelheim, Eli Lilly, Intarcia, Oramed, Hanmi, and Sanofi; honoraria or consulting fees from Zealand; and grants/research support from Genentech, Novartis, Pfizer, REMD Biotherapeutics, vTv Therapeutics, Metacrine, Merck, and Janssen outside the submitted work. Dr Sørrig reported being a full-time employee and shareholder of Novo Nordisk. Dr Wadden reported receiving grants from Novo Nordisk on behalf of the University of Pennsylvania and scientific advisory board fees from Novo Nordisk and WW (formerly Weight Watchers). Dr Wizert reported being a full-time employee and shareholder of Novo Nordisk. Dr Garvey reported 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, Pfizer, Eli Lilly, and Epitomee 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.

Figures

Figure 1.. Participant Disposition and Dosing During the Trial

A, Flow of participants during the Semaglutide Treatment Effect in People With Obesity Trial. B, The proportions of participants on or below the target dose at the end of the dose escalation period (week 16 for semaglutide, week 4 for liraglutide), at weeks 20 and 68, and for the last dose. Data presented are observed (ie, as-measured) proportions during the in-trial period (the time from randomization to last contact with trial site, irrespective of treatment discontinuation or rescue intervention), based on the numbers of participants remaining in the trial at each time point (except for the last dose, which is based on the number of treatment completers). On target indicates a dose of 2.4 mg for semaglutide and 3.0 mg for liraglutide; below target, a dose of >0.0 to <2.4 mg for semaglutide and >0.0 to <3.0 mg for liraglutide; missing data, no dosing information was provided at the visit; and treatment completers, participants who were receiving treatment at week 68. Data are only presented for the active treatment groups. aPooled placebo data. Data from the 2 placebo groups were pooled to increase power for statistical analyses of active treatments vs placebo, while limiting the number of participants required. bThese participants were trial completers. Participants were considered trial completers if they attended the week 75 end–of–follow-up visit, regardless of whether they completed treatment. cThese participants were trial completers who did not complete treatment. dOther reasons for premature treatment discontinuation are listed in eTable 6 in Supplement 3. eThese participants were treatment completers: they were receiving treatment at week 68, regardless of whether they completed the trial. One participant in the semaglutide group completed treatment without completing the trial. fThe numbers and proportions of participants who were below the target dose are shown in eTable 7 in Supplement 3 and are based on the total number of participants with dose data at each time point (ie, excluding those with missing data).

Figure 2.. Percentage Change in Body Weight From Baseline to Week 68 (Observed In-Trial Data; Full Analysis Set)

Data presented are observed (ie, as-measured) changes during the in-trial period (the time from randomization to last contact with trial site, irrespective of treatment discontinuation or rescue intervention) for the full analysis set. Data for the on-treatment period are presented in eFigure 5 in Supplement 3. The middle lines within each box represent the median observed changes from baseline; the symbols in the boxes represent the mean observed percentage change; the box tops and bottoms represent the interquartile range; the whiskers extend to the most extreme observed values with 1.5 times the IQR of the nearer quartile; and the symbols beyond these points represent the observed values outside that range. More negative values indicate greater reductions. Numbers shown below the graph are the number of participants with observed data at each time point. Participant numbers in the legend are for the full analysis set. Data are only presented for the active treatment groups.

Figure 3.. Change in Absolute Body Weight From Baseline to Week 68 for Individual Participants (Observed In-Trial Data; Full Analysis Set)

Data presented are observed (ie, as-measured) changes during the in-trial period (the time from randomization to last contact with trial site, irrespective of treatment discontinuation or rescue intervention) for each individual participant in the full analysis set. Solid lines are for treatment completers (ie, participants who were receiving treatment at week 68), and dashed lines are for participants who prematurely discontinued treatment. A total of 117 participants in the semaglutide, 2.4 mg, group and 117 in the liraglutide, 3.0 mg, group had a week 68 assessment and so contribute to the data. Data are only presented for the active treatment groups. The middle lines within each box represent the median data; the symbols in the boxes represent the mean data; the box tops and bottoms represent the interquartile range; and the whiskers extend to the most extreme observed values with 1.5 times the IQR of the nearer quartile. The gray line indicates baseline.