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Publications

Journal Article Ahead of print

PubMed: 42253238 DOI: 10.1056/NEJMoa2600751

Survodutide Once Weekly for the Treatment of Adults with Obesity.

N Engl J Med

Authors: Carel W le Roux, Sean Wharton, Elena Startseva, Isabel M Kloer, Samina Ajaz Hussain, Anna Unseld, Biykem Bozkurt, Jamy D Ard, Harold E Bays, Pawel Bogdański, Elif I Ekinci, Ania M Jastreboff, Linong Ji, Wataru Ogawa, Sue D Pedersen, Kirsi H Pietiläinen, Naveed Sattar, Jochen Seufert, Kaj Stenlöf, André P van Beek, Roman Vangoitsenhoven, Martina Brueckmann, Ramy Younes, Lee M Kaplan

Affiliations

  • University College Dublin School of Medicine, Dublin.
  • Ulster University, Coleraine, United Kingdom.
  • McMaster University, Hamilton, ON, Canada.
  • University of Toronto, Toronto.
  • Boehringer Ingelheim International, Ingelheim am Rhein, Germany.
  • Boehringer Ingelheim Pharma, Biberach, Germany.
  • Winters Center for Heart Failure Research, Cardiovascular Research Institute, Baylor College of Medicine, Houston.
  • Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC.
  • Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC.
  • Monroe Biomedical Research, Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY.
  • Department of Obesity Treatment, Metabolic Disorders, and Clinical Dietetics, Poznan University of Medical Sciences, Poznan, Poland.
  • Australian Centre for Accelerating Diabetes Innovation (ACADI), University of Melbourne, Parkville, VIC, Australia.
  • Department of Medicine, Melbourne Medical School, University of Melbourne, Melbourne, VIC, Australia.
  • Centre for Research and Education in Diabetes and Obesity, Austin Health, Heidelberg, VIC, Australia.
  • Department of Endocrinology, Austin Health, Heidelberg, VIC, Australia.
  • Section of Endocrinology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT.
  • Section of Endocrinology, Department of Pediatrics, Yale School of Medicine, New Haven, CT.
  • Yale Obesity Research Center (Y-Weight), Yale School of Medicine, New Haven, CT.
  • Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing.
  • Peking University Diabetes Center, Beijing.
  • Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
  • Section of Metabolic Disease, Division of Translational Research, Kobe University Graduate School of Medicine, Kobe, Japan.
  • C-ENDO Diabetes and Endocrinology Clinic, Calgary, AB, Canada.
  • University of Calgary, Calgary, AB, Canada.
  • Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki.
  • Healthy Weight Hub, Abdominal Center, Helsinki University Hospital, Helsinki.
  • School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, United Kingdom.
  • Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
  • Center for Sleep and Wake Disorders, Institute of Medicine, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
  • Department of Internal Medicine, Carlanderska Hospital, Gothenburg, Sweden.
  • Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
  • Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
  • Department of Endocrinology, University Hospitals Leuven, Leuven, Belgium.
  • First Department of Medicine, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany.
  • Obesity and Metabolism Institute, Boston.
  • Geisel School of Medicine at Dartmouth, Hanover, NH.

Abstract

BACKGROUND

Although medications with glucagon-like peptide-1 (GLP-1) receptor agonist activity have transformed the management of obesity and shown substantial cardiometabolic benefits, unmet needs remain. Survodutide, an investigational glucagon receptor-GLP-1 receptor dual agonist, led to substantial weight reduction in a phase 2 trial involving adults with obesity without diabetes.

METHODS

In this phase 3, double-blind trial, we randomly assigned adults with a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or higher, or 27 or higher with at least one obesity-related complication (excluding diabetes), in a 1:1:1 ratio to receive once-weekly survodutide administered subcutaneously at a dose adjusted up to 3.6 mg or 6.0 mg or placebo, in addition to counseling for lifestyle modification. The two primary end points were the percent change in body weight and a reduction in body weight of at least 5% from baseline to week 76. The primary efficacy analysis was conducted according to the treatment-regimen estimand, which incorporates the effects of any early discontinuation of survodutide or placebo, the use of protocol-prohibited obesity medications, and a prolonged dose-escalation period.

RESULTS

Among 725 participants (241 in the 3.6-mg survodutide group, 242 in the 6.0-mg survodutide group, and 242 in the placebo group), the mean age was 47.1 years; 294 participants (40.6%) were men. At baseline, the mean BMI was 37.9, and the mean body weight was 108.8 kg. At week 76, the mean change in body weight from baseline according to the treatment-regimen estimand was -12.2% (95% confidence interval [CI], -13.6 to -10.8) in the 3.6-mg group, -13.0% (95% CI, -14.4 to -11.6) in the 6.0-mg group, and -5.4% (95% CI, -6.9 to -4.0) in the placebo group; 72.6%, 71.9% and 46.3% of the participants, respectively, had weight reduction of at least 5% (P<0.001 for all comparisons with placebo). The most common adverse events were gastrointestinal symptoms (typically mild to moderate), which occurred in 80.9% of the participants in the 3.6-mg group, in 89.7% of those in the 6.0-mg group, and in 47.9% of those in the placebo group. No deaths were reported.

CONCLUSIONS

Survodutide led to significantly greater reductions in body weight than placebo in adults with obesity without diabetes. (Funded by Boehringer Ingelheim; SYNCHRONIZE-1 ClinicalTrials.gov number, NCT06066515.).

MeSH

Diabetes Mellitus, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Body Weight, Obesity, Weight Loss, Glucagon, Therapeutics