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Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined

List of authors.
  • Julie R. Lundgren, M.D., Ph.D.,
  • Charlotte Janus, Ph.D.,
  • Simon B.K. Jensen, M.Sc.,
  • Christian R. Juhl, M.D.,
  • Lisa M. Olsen, M.Sc.,
  • Rasmus M. Christensen, B.Sc.Med.,
  • Maria S. Svane, M.D., Ph.D.,
  • Thomas Bandholm, Ph.D.,
  • Kirstine N. Bojsen-M?ller, M.D., Ph.D.,
  • Martin B. Blond, M.D., Ph.D.,
  • Jens-Erik B. Jensen, M.D., Ph.D.,
  • Bente M. Stallknecht, M.D., D.M.Sc.,
  • Jens J. Holst, M.D., D.M.Sc.,
  • Sten Madsbad, M.D., D.M.Sc.,
  • and Signe S. Torekov, Ph.D.

Abstract

Background

Weight regain after weight loss is a major problem in the treatment of persons with obesity.

Methods

In a randomized, head-to-head, placebo-controlled trial, we enrolled adults with obesity (body-mass index [the weight in kilograms divided by the square of the height in meters], 32 to 43) who did not have diabetes. After an 8-week low-calorie diet, participants were randomly assigned for 1 year to one of four strategies: a moderate-to-vigorousCintensity exercise program plus placebo (exercise group); treatment with liraglutide (3.0 mg per day) plus usual activity (liraglutide group); exercise program plus liraglutide therapy (combination group); or placebo plus usual activity (placebo group). End points with prespecified hypotheses were the change in body weight (primary end point) and the change in body-fat percentage (secondary end point) from randomization to the end of the treatment period in the intention-to-treat population. Prespecified metabolic health-related end points and safety were also assessed.

Results

After the 8-week low-calorie diet, 195 participants had a mean decrease in body weight of 13.1 kg. At 1 year, all the active-treatment strategies led to greater weight loss than placebo: difference in the exercise group, ?4.1 kg (95% confidence interval [CI], ?7.8 to ?0.4; P=0.03); in the liraglutide group, ?6.8 kg (95% CI, ?10.4 to ?3.1; P<0.001); and in the combination group, ?9.5 kg (95% CI, ?13.1 to ?5.9; P<0.001). The combination strategy led to greater weight loss than exercise (difference, ?5.4 kg; 95% CI, ?9.0 to ?1.7; P=0.004) but not liraglutide (?2.7 kg; 95% CI, ?6.3 to 0.8; P=0.13). The combination strategy decreased body-fat percentage by 3.9 percentage points, which was approximately twice the decrease in the exercise group (?1.7 percentage points; 95% CI, ?3.2 to ?0.2; P=0.02) and the liraglutide group (?1.9 percentage points; 95% CI, ?3.3 to ?0.5; P=0.009). Only the combination strategy was associated with improvements in the glycated hemoglobin level, insulin sensitivity, and cardiorespiratory fitness. Increased heart rate and cholelithiasis were observed more often in the liraglutide group than in the combination group.

Conclusions

A strategy combining exercise and liraglutide therapy improved healthy weight loss maintenance more than either treatment alone. (Funded by the Novo Nordisk Foundation and others; EudraCT number, 2015-005585-32; ClinicalTrials.gov number, NCT04122716.)

Funding and Disclosures

Presented in part at the 80th Annual Meeting of the American Diabetes Association (June 12C16, 2020) and the 56th Annual Meeting of the European Association for the Study of Diabetes (Sept. 21C25, 2020).

Supported by an Excellence grant (NNF16OC0019968, to Dr. Torekov) from the Novo Nordisk Foundation, by a grant (to Dr. Torekov) from the Novo Nordisk Foundation Center for Basic Metabolic Research, by a grant (NNF15CC0018486, to Dr. Torekov) from the Novo Nordisk Foundation Tripartite Immunometabolism Consortium, by Helsefonden, by a Ph.D. grant (to Dr. Lundgren) from the Faculty of Health and Medical Sciences, University of Copenhagen, and by a Ph.D. grant (to Dr. Janus) from the Danish Diabetes Academy and Department of Biomedical Sciences, University of Copenhagen.

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

Drs. Lundgren and Janus contributed equally to this article.

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

Author Affiliations

From the Department of Biomedical Sciences (J.R.L., C.J., S.B.K.J., C.R.J., L.M.O., R.M.C., M.B.B., B.M.S., J.J.H., S.S.T.), the Novo Nordisk Foundation Center for Basic Metabolic Research (J.R.L., C.J., S.B.K.J., C.R.J., L.M.O., R.M.C., J.J.H., S.S.T.), the Department of Clinical Medicine (T.B., J.-E.B.J.), University of Copenhagen, and the Departments of Endocrinology (M.S.S., K.N.B.-M., J.-E.B.J., S.M.) and Clinical Research (T.B.), Copenhagen University HospitalCAmager and Hvidovre, Copenhagen, and the Steno Diabetes Center Copenhagen, Gentofte (M.B.B.) all in Denmark.

Address reprint requests to Dr. Torekov at the Department of Biomedical Sciences, University of Copenhagen, Panum Rm. 12.4.06, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark, or at .

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