This article is available to subscribers. Subscribe now. Already have an account? Sign in

Original ArticleFree Preview

Once-Weekly Semaglutide in Adults with Overweight or Obesity

List of authors.
  • John P.H. Wilding, D.M.,
  • Rachel L. Batterham, M.B., B.S., Ph.D.,
  • Salvatore Calanna, Ph.D.,
  • Melanie Davies, M.D.,
  • Luc F. Van Gaal, M.D., Ph.D.,
  • Ildiko Lingvay, M.D., M.P.H., M.S.C.S.,
  • Barbara M. McGowan, M.D., Ph.D.,
  • Julio Rosenstock, M.D.,
  • Marie T.D. Tran, M.D., Ph.D.,
  • Thomas A. Wadden, Ph.D.,
  • Sean Wharton, M.D., Pharm.D.,
  • Koutaro Yokote, M.D., Ph.D.,
  • Niels Zeuthen, M.Sc.,
  • and Robert F. Kushner, M.D.
  • for the STEP 1 Study Group*

Abstract

Background

Obesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed.

Methods

Download a PDF of the Research Summary.

In this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (27 in persons with 1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions.

Results

The mean change in body weight from baseline to week 68 was ?14.9% in the semaglutide group as compared with ?2.4% with placebo, for an estimated treatment difference of ?12.4 percentage points (95% confidence interval [CI], ?13.4 to ?11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was ?15.3 kg in the semaglutide group as compared with ?2.6 kg in the placebo group (estimated treatment difference, ?12.7 kg; 95% CI, ?13.7 to ?11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]).

Conclusions

In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

Digital Object ThumbnailQUICK TAKE VIDEO SUMMARY
Weekly Semaglutide in Adults with Overweight or Obesity
?01:46

Funding and Disclosures

Supported by Novo Nordisk.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Dr. Wilding reports receiving advisory board fees, paid to his institution, from Astellas Pharma, grant support and fees for membership on a data and safety monitoring board, both paid to University of Liverpool, lecture fees, and travel support from AstraZeneca, advisory board fees, paid to his institution, and lecture fees from Boehringer Ingelheim, Napp, and Sanofi Pasteur, advisory board fees, paid to his institution, from Eli Lilly, Janssen Global Services, Rhythm, and Wilmington Healthcare, lecture fees from Mundipharma, grant support, advisory board fees, and fees for serving as an investigator, all paid to University of Liverpool, and lecture fees from Novo Nordisk, and advisory board fees from Takeda Medical Research Foundation; Dr. Batterham, receiving consulting fees from Boehringer Ingelheim, Pfizer, and ViiV Healthcare and consulting fees and lecture fees from Novo Nordisk; Dr. Calanna, being employed by Novo Nordisk; Dr. Davies, receiving grant support from AstraZeneca, lecture fees from AstraZeneca Pharma India, advisory board fees from BI-LLY Alliance, Lexicon Pharmaceuticals, and Sanofi, advisory board fees and lecture fees from Boehringer Ingelheim and Eli Lilly, lecture fees from Boehringer Ingelheim (China), Boehringer Ingelheim (Philippines), Boehringer Ingelheim Saudi Arabia Trading, Boehringer Ingelheim (Poland), Napp Pharmaceuticals, Sanofi Romania, and Sanofi (Japan), advisory board fees and lecture fees from Boehringer Ingelheim International, and grant support, lecture fees, and advisory board fees from Novo Nordisk; Dr. Van Gaal, receiving lecture fees from AstraZeneca and Boehringer Ingelheim and advisory board fees and lecture fees from Merck and Novo Nordisk; Dr. Lingvay, receiving advisory board fees and consulting fees from AstraZeneca, consulting fees from Bayer HealthCare Pharmaceuticals, Eli Lilly, Intarcia, Intercept Pharmaceuticals, Janssen Global Services, MannKind, 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 his institution, from Mylan Pharmaceuticals and Pfizer, and grant support, paid to UT Southwestern, advisory board fees, consulting fees, and travel support from Novo Nordisk; Dr. McGowan, receiving educational fees from AstraZeneca, Merck, and Orexigen Therapeutics, lecture fees from Janssen Biotech, advisory board fees from Johnson & Johnson Health Care Systems, grant support, paid to Guys and St. Thomas Hospital, consulting fees, and educational fees from Novo Nordisk, and owning stock in Reset Health Clinics; Dr. Rosenstock, receiving grant support, advisory board fees, and travel support from Applied Therapeutics, Intarcia, and Oramed, grant support and consulting fees from AstraZeneca, grant support, advisory board fees, lecture fees, and travel support from Boehringer Ingelheim, Novo Nordisk, and Sanofi US Services, grant support and advisory board fees from Eli Lilly, grant support from Genentech, GlaxoSmithKline, Janssen Biotech, Lexicon Pharmaceuticals, Novartis, Pfizer, and REMD Biotherapeutics, and advisory board fees from Zealand Pharma; Dr. Tran, being employed by and owning stock in Novo Nordisk; Dr. Wadden, receiving grant support, paid to the University of Pennsylvania, and advisory board fees from Novo Nordisk and advisory board fees from WW International; Dr. Wharton, receiving lecture fees from AstraZeneca and Bausch and Lomb and grant support, lecture fees, and advisory board fees from Novo Nordisk; Dr. Yokote, receiving lecture fees from Amgen, Janssen Pharmaceuticals, Kyowa Hakko Kirin, Novartis Pharma, and Sanofi, grant support and lecture fees from Astellas Pharma, Daiichi Sankyo, Eli Lilly Japan, Merck Sharp and Dohme, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda Pharmaceutical, advisory board fees and lecture fees from AstraZeneca, grant support, lecture fees, and advisory board fees from Kowa Company and Novo Nordisk, and lecture fees and advisory board fees from Sanofi; Mr. Zeuthen, being employed by and owning stock in Novo Nordisk; and Dr. Kushner, receiving advisory board fees from Novo Nordisk and Weight Watchers. No other potential conflict of interest relevant to this article was reported.

This article was published on February 10, 2021, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank the trial participants and the trial site staff; Lisa von Huth Smith of Novo Nordisk, Denmark, for support with data presentation of participant-reported outcomes and critical review of an earlier draft of the manuscript; and Paul Barlass of Axis, a division of Spirit Medical Communications Group, for medical writing and editorial assistance with an earlier draft of the manuscript (funded by Novo Nordisk).

Author Affiliations

From the Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool (J.P.H.W.), University College London Centre for Obesity Research, Division of Medicine, University College London (R.L.B.), the National Institute of Health Research, UCLH Biomedical Research Centre (R.L.B.), the Centre for Weight Management and Metabolic Surgery, University College London Hospital (R.L.B.), and the Department of Diabetes and Endocrinology, Guys and St. Thomas NHS Foundation Trust (B.M.M.), London, and the Diabetes Research Centre, University of Leicester (M.D.) and the NIHR Leicester Biomedical Research Centre (M.D.), Leicester all in the United Kingdom; Novo Nordisk, S?borg, Denmark (S.C., M.T.D.T., N.Z.); the Department of Endocrinology, Diabetology, and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium (L.F.V.G.); the Departments of Internal Medicine/Endocrinology and Population and Data Sciences, University of Texas Southwestern Medical Center (I.L.), and the Dallas Diabetes Research Center at Medical City (J.R.) both in Dallas; the Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia (T.A.W.); York University, McMaster University and Wharton Weight Management Clinic, Toronto (S.W.); the Department of Endocrinology, Hematology, and Gerontology, Graduate School of Medicine, Chiba University and Department of Diabetes, Metabolism, and Endocrinology, Chiba University Hospital, Chiba, Japan (K.Y.); and the Division of Endocrinology, Feinberg School of Medicine, Northwestern University, Chicago (R.F.K.).

Address reprint requests to Dr. Kushner at Northwestern University Feinberg School of Medicine, 645 N. Michigan Ave., Suite 530, Chicago, IL 60611, or at .

A complete list of investigators in the STEP 1 trial is provided in the Supplementary Appendix, available at NEJM.org.