Weight loss maintenance in obesity more effective with GLP-1RA and exercise than either treatment alone

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

Literature - Lundgren JR, Janus C, Jensen SBK, et al. - N Engl J Med. 2021;384:1719-1730. doi: 10.1056/NEJMoa2028198.

Introduction and methods

Weight regain after weight loss is a major problem in the treatment of individuals with obesity. The GLP-1RA liraglutide is used in the treatment of obesity. It induces weight loss and maintains diet-induced weight loss for at least 1 year primarily due to a suppressed appetite [1-6]. Diet management or structured exercise programs can also sustain weight loss, as well as lifestyle interventions that simultaneously encourage calorie restrictions and increase physical activity [1, 7-14]. However, which strategy is most effective in the prevention of weight gain after weight loss has not been assessed thoroughly.

This study assessed the efficacy of 1-year treatment with a moderate-to-vigorous intensity exercise program, liraglutide treatment at a dose of 3 mg per day, or the combination of exercise with liraglutide compared to placebo for the maintenance of a healthy diet-induced weight loss in individuals with obesity

This investigator-initiated, randomized, head-to-head, placebo-controlled trial included individuals with obesity (32-43 kg/m²) without diabetes. Individuals followed a low-calorie diet of 800 kcal per day for 8 weeks (pre-randomization phase). Only participants (n=195) who had achieved a weight loss of ≥5% of their baseline body weight were randomized (1:1:1:1) to the 1) exercise group (placebo plus exercise), 2) liraglutide group (liraglutide plus usual activity), 3) combination group (liraglutide plus exercise), or 4) placebo group (placebo plus usual activity). Exercise was defined as a minimum of 150 minutes per week of moderate-intensity or 75 minutes per week of vigorous-intensity aerobic physical activity, or an equivalent combination of both. The primary endpoint was change in body weight from randomization to week 52. Secondary outcome was change in body-fat percentage. Also prespecified metabolic health-related end points and safety were investigated. Participants remained in the trial if the use of liraglutide or placebo was discontinued.

Main results

  • After a low-calorie diet of 8 weeks, participants had a mean 13.1 kg (95% CI: 12.4 to 13.7) reduction in body weight.
  • After 52 weeks, bodyweight was further reduced by a mean of 3.4 kg in the combination group. In contrast, body weight in the placebo group increased by a mean of 6.1 kg, which resulted in a treatment difference of -9.5 kg (95% CI: -13.1 to -5.9 kg, P<0.001).
  • The liraglutide group maintained their body weight loss (absolute weight difference -0.7 kg), with a treatment difference of -6.8 kg (95% CI: -10.4 to -3.1 kg, P<0.001) compared to the placebo group.
  • The absolute weight difference in the exercise group was 2.0 kg ,with a treatment difference as compared with placebo of -4.1 kg (95% CI: -7.8 to -0.4 kg, P=0.03).
  • 33% Of participants in the combination group lost ≥20% of their body weight compared to 22% in the liraglutide group, 18% in the exercise group, and only 2% in the placebo group.
  • The body weight loss from the pre-randomization phase to the end of the trial was 15.7% in the combination group, 13.4% in the liraglutide group, 10.9% in the exercise group, and 6.7% in the placebo group.
  • The reduction in body-fat percentage from baseline to end of the trial was greatest in the combination group with a treatment effect of -3.9 percentage points (95% CI: -5.4 to -2.5) compared to placebo, was smaller in the exercise group with a treatment effect of -2.2 percentage points (95% CI: -3.8 to -0.7) and smaller in the liraglutide group with a treatment effect of -2.0 percentage point (95% CI: -3.5 to -0.6). The body-fat percentage in the placebo group was increased by 0.4 percentage points.
  • Exercise, liraglutide treatment, or both were associated with decreased fat mass and waist circumference compared to placebo. These reductions were twice as large in the combination group compared to the exercise or liraglutide groups.
  • Participants in the groups with liraglutide treatment reported more gastrointestinal adverse events, decreased appetite and dizziness compared to the other two groups. Cholelithiasis and palpitations were more commonly reported in the group with liraglutide than in the combination group. Increased resting heart rate was association with liraglutide treatment after 1 year, not with the combination strategy.


This trial demonstrated that a combination strategy of exercise and liraglutide treatment was more effective in maintaining healthy diet-induced weight loss after 1 year than either liraglutide or exercise alone in individuals with obesity and without diabetes. The placebo group showed an increase in body weight and body-fat percentage compared to the other three treatment groups.


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Find this article online at N Eng J Med.

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