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.

Conclusion

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.

References

Show references

1. Iepsen EW, Lundgren J, Dirksen C, et al. Treatment with a GLP-1 receptor agonist diminishes the decrease in free plasma leptin during maintenance of weight loss. Int J Obes (Lond) 2015; 39: 834-41.

2. Astrup A, Rossner S, Van Gaal L, et al. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 2009; 374: 1606-16.

3. Pi-Sunyer X, Astrup A, Fujioka K, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med 2015; 373: 11-22.

4. Iepsen EW, Zhang J, Thomsen HS, et al. Patients with obesity caused by melanocortin-4 receptor mutations can be treated with a glucagon-like peptide-1 receptor agonist. Cell Metab 2018; 28(1): 23-32.e3.

5. Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet induced weight loss: the SCALE Maintenance randomized study. Int J Obes (Lond) 2013; 37: 1443-51.

6. van Can J, Sloth B, Jensen CB, et al. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, nondiabetic adults. Int J Obes (Lond) 2014; 38: 784-93.

7. Church TS, Earnest CP, Skinner JS, Blair SN. Effects of different doses of physical activity on cardiorespiratory fitness among sedentary, overweight or obese postmenopausal women with elevated blood pressure: a randomized controlled trial. JAMA 2007; 297: 2081-91.

8. Willis LH, Slentz CA, Bateman LA, et al. Effects of aerobic and/or resistance training on body mass and fat mass in overweight or obese adults. J Appl Physiol (1985) 2012; 113: 1831-7.

9. Ross R, Dagnone D, Jones PJH, et al. Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men: a randomized, controlled trial. AnnIntern Med 2000; 133: 92-103.

10. Lean ME, Leslie WS, Barnes AC, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet 2018; 391: 541-51.

11. Astbury NM, Aveyard P, Nickless A, et al. Doctor Referral of Overweight People to Low Energy total diet replacement Treatment (DROPLET): pragmatic randomized controlled trial. BMJ 2018; 362:k3760.

12. Lean MEJ, Leslie WS, Barnes AC, et al. Durability of a primary care-led weight management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomized trial. Lancet Diabetes Endocrinol 2019; 7: 344-55.

13. The Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013; 369: 145-54.

14. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393-403.

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