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Clinical Trial
. 2021 Apr 13;325(14):1414-1425.
doi: 10.1001/jama.2021.3224.

Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial

Domenica Rubino  1 , Niclas Abrahamsson  2 , Melanie Davies  3   4 , Dan Hesse  5 , Frank L Greenway  6 , Camilla Jensen  5 , Ildiko Lingvay  7 , Ofri Mosenzon  8 , Julio Rosenstock  9 , Miguel A Rubio  10 , Gottfried Rudofsky  11 , Sayeh Tadayon  5 , Thomas A Wadden  12 , Dror Dicker  13 ; STEP 4 Investigators
Collaborators, Affiliations
Clinical Trial

Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial

Domenica Rubino et al. JAMA. .

Abstract

Importance: The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown.

Objective: To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly.

Design, setting, and participants: Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes.

Interventions: A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups.

Main outcomes and measures: The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]).

Results: Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P < .001). Waist circumference (-9.7 cm [95% CI, -10.9 to -8.5 cm]), systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%).

Conclusions and relevance: Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks.

Trial registration: ClinicalTrials.gov Identifier: NCT03548987.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Rubino reported being a clinical investigator for Boehringer Ingelheim and AstraZeneca and receiving speaker fees, consulting fees, and honoraria from Novo Nordisk and being a shareholder in Novo Nordisk. Dr Davies reported receipt of consultant, advisory board member, and speaker fees from Novo Nordisk, Sanofi, Eli Lilly, and Boehringer Ingelheim; advisory board member and speaker fees from AstraZeneca; advisory board member fees from Gilead Sciences, Janssen, and Lexicon; speaker fees from Napp Pharmaceuticals and Takeda Pharmaceuticals International, and grants from AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Janssen, and Sanofi. Dr Hesse reported receipt of personal fees from Novo Nordisk. Dr Greenway reported receipt of grants from Pennington Biomedical Research Center and NuSirt to his institution; research funding from NovMeta Pharma and Melior Discoveries; receipt of consulting fees from Basic Research, Dr. Reddy’s Laboratories, Jazz Pharmaceuticals, General Nutrition Corporation, and Regeneron Pharmaceuticals; receipt of scientific advisory board fees from Jenny Craig and Pfizer; and stock ownership in Academic Technology Ventures, Ketogenic Health Systems, Plensat, UR Labs, and Rejuvenate Bio. In addition, Dr Greenway has a patent issued for orlistat and a patent pending for pramlintide/albuterol. Ms Jensen reported receipt of personal fees from Novo Nordisk. Dr Lingvay reported receipt of grants, personal fees, and nonfinancial support from Novo Nordisk and Sanofi; personal fees and nonfinancial support from Eli Lilly, AstraZeneca, and Boehringer Ingelheim; personal fees from Janssen, Intercept, Intarcia, TARGETPharma, Mannkind, Valeritas, Bayer, and Zealand Pharma; grants and nonfinancial support from Merck and Pfizer; and grants from Mylan. Dr Mosenzon reported receipt of grants from Novo Nordisk and AstraZeneca through Hadassah Medical Center; advisory board and speaker’s bureau fees from Novo Nordisk, AstraZeneca, Eli Lilly, Merck Sharp & Dohme, and Sanofi; speaker’s bureau fees from Boehringer Ingelheim and Janssen; and advisory board fees from BOL Pharma. Dr Rosenstock reported receipt of scientific advisory board fees, honoraria, consulting fees, and grants/research support from Novo Nordisk, Applied Therapeutics, Boehringer Ingelheim, Eli Lilly, Intarcia, Oramed, and Sanofi; honoraria or consulting fees from Zealand; and grants/research support from Genentech, Novartis, Pfizer, REMD Biotherapeutics, and vTv Therapeutics. Dr Rubio reported receipt of personal fees from Novo Nordisk. Dr Tadayon reported being a full-time employee of and shareholder in Novo Nordisk. Dr Wadden reported receipt of grants from Novo Nordisk received on behalf of the University of Pennsylvania and scientific advisory board fees from Novo Nordisk and WW (formerly Weight Watchers). Dr Dicker reported receipt of personal fees, nonfinancial support, and grants from Novo Nordisk and grants from Eli Lilly. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Flow in the Semaglutide Treatment Effect in People With Obesity (STEP) 4 Trial
aThese participants received once-weekly semaglutide (safety analysis set). bRun-in failures were defined as participants not meeting all 3 randomization criteria: attend the randomization visit, reach the semaglutide maintenance dose of 2.4 mg by week 16 (±3 days), and be receiving semaglutide, 2.4 mg, at week 20. cOther reasons are listed in eTable 9 in Supplement 1. dOther reasons are listed in eTable 10 in Supplement 1.
Figure 2.
Figure 2.. Effect of Semaglutide, 2.4 mg Once Weekly, Compared With Placebo on Efficacy Outcomes During the Entire Trial (Full Analysis Set)
Data presented in panels A, B, and C are observed data for the full analysis set from the in-trial period (the time from week 0 to the date of last contact with trial site). Error bars represent 95% confidence intervals for the mean. Participant numbers shown denote those contributing to the mean. The dashed vertical line at week 20 represents the randomization time point. Data in the shaded area on the right in panel C are estimated mean changes from week 0 to week 68 for the treatment policy estimand, analyzed using the full analysis set. (The treatment policy estimand assessed the treatment effect regardless of treatment discontinuation or rescue intervention using analysis of covariance, with randomized treatment as a factor and baseline end point value as a covariate, and a multiple imputation approach for missing data.) Data in panel D are observed data among all randomized participants with a week 68 assessment from the in-trial period (the time from week 0 to the date of last contact with trial site).
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