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Lundgren JR, Janus C, Jensen SBK, et al. Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined. N Engl J Med. 2021 May 6;384(18):1719-1730. doi: 10.1056/NEJMoa2028198. (Original study)

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-vigorous-intensity 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.).

Discipline Area Score
Internal Medicine 7 / 7
Endocrine 6 / 7
Public Health 6 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Special Interest - Obesity -- Physician 6 / 7
Comments from MORE raters

Endocrine rater

This RCT adds useful information regarding the additive effects of a GLPRA and exercise, with the combination of both being superior to each alone. Most importantly, it supports the benefit of adding an exercise program to GLP1RA treatment.

General Internal Medicine-Primary Care(US) rater

I have some experience with this in patients with Type 2 DM. The weight loss can be impressive, resulting in better glucose control. I have no experience, however, in using it as an adjunct to weight loss.

General Internal Medicine-Primary Care(US) rater

Similar to recent results about semaglutide and weight loss.

Public Health rater

These are exciting results, but the trend to increasing weight gain (see Figure 1) is worrying. Long-term results are needed.

Special Interest - Obesity -- Physician rater

This is a welcome addition to the growing list of ways/means to lose and maintain weight loss. Maintaining the weight loss is particularly difficult and frustrating for people struggling with obesity. However, this cohort is from Denmark and it is not clear whether similar results can be expected in the US, especially in the African-American, Latino, and Native American populations where obesity is more prevalent. One positive side of the study is that the drug used is already widely available for treatment of type 2 diabetes and is known to be relatively safe. Planning a similar study involving a broad spectrum of the US population will be very useful.

Special Interest - Obesity -- Physician rater

The emerging data on the weight-loss effect of semaglutide and liraglutide may change how we think about surgical or endoscopic therapies for weight loss. The amount of weight loss maintained exceeds what we`ve seen in past non-surgical weight loss therapies. Getting 5-year data when available will be the key for me.
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