A combination of moderate to vigorous intensity exercise and treatment with a glucagon-like peptide-1 (GLP-1) receptor agonist (liraglutide) following several weeks of low calorie, diet-induced weight loss is more effective for improving healthy weight loss, compared with either regimen alone, in patients with obesity. This, according to a study in the New England Journal of Medicine.

The randomized, head-to-head, placebo-controlled trial was conducted from August 2016 to November 2019 and included adults aged 18 to 65 years with obesity, which was defined as having a body mass index (BMI) of 32 to 43 kg/m2. The participants adhered to a low-calorie diet of 800 kcal/day for 8 weeks.

Patients who had weight loss of at least 5% of their baseline body weight were then randomly assigned to 1 of 4 treatment groups for 1 year: exercise plus placebo (exercise group), liraglutide plus usual activity (liraglutide group), exercise plus liraglutide (combination group), or placebo plus usual activity (placebo group). The change in body weight from randomization to week 52 was the primary endpoint, and change in the percentage of body fat was the secondary endpoint.

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Participants in the exercise and combination groups were encouraged to attend supervised group exercise sessions involving 30 minutes of vigorous-intensity, interval-based indoor cycling and 15 minutes of circuit training twice a week. They were also encouraged to perform moderate to vigorous intensity exercise on their own twice a week.

A total of 215 participants (mean age, 42±12 years; 63% women) started the low-calorie diet, of whom 195 (mean age, 43±12 years; 64% women) had a weight loss of at least 5% of their baseline body weight and were randomly assigned to treatment groups.

At week 52, 166 participants (85%), including 40 of 48 (83%) in the exercise group, 41 of 49 (84%) in the liraglutide group, 45 of 49 (92%) in the combination group, and 40 of 49 (82%) in the placebo group, were assessed for the primary endpoint.

The patients’ body weight decreased by a mean of -13.1 kg (95% CI, 12.4 to 13.7) during the 8-week low-calorie diet, for a mean reduction in body weight of 12%.

After 1 year, participants’ body weight decreased by an additional mean of −3.4 kg in the combination group but increased by a mean of 6.1 kg in the placebo group, resulting in a treatment difference of −9.5 kg (95% CI, −13.1 to −5.9; P <.001). The initial weight loss was maintained in the exercise group, with a treatment effect vs placebo of −4.1 kg (95% CI, −7.8 to −0.4; P =.03).

Liraglutide treatment was also associated with maintaining the initial weight loss, with a treatment effect vs placebo of −6.8 kg (95% CI, −10.4 to −3.1; P <.001). In the combination group, the treatment effect vs exercise was −5.4 kg (95% CI, −9.0 to −1.7; P =.004), and the treatment effect vs liraglutide was −2.7 kg (95% CI, −6.3 to 0.8; P =.13).

Patients’ body fat was further reduced in the combination group by −1.7 percentage points (95% CI, −3.2 to −0.2) vs the exercise group (P =.02) and by −1.9 percentage points (95% CI, −3.3 to −0.5) compared with the liraglutide group (P =.009).

The combination strategy was associated with improved glycated hemoglobin levels, insulin sensitivity, cardiorespiratory fitness, physical functioning, and emotional well-being. At 1 year, liraglutide treatment alone was associated with an increased resting heart rate; this finding was not observed with the combination strategy.

Adverse events were observed in 100% of liraglutide group-only participants, in 92% of the combination group, 86% in the placebo group, and 81% of the exercise group. Serious adverse events were observed in 12% of the liraglutide group, 8% of the combination group, 8% of the exercise group, and 4% of the placebo group.

Gastrointestinal adverse events, decreased appetite, and dizziness were more frequently reported in the groups that received liraglutide. Adverse events that occurred in at least 10% of all study participants included urinary tract infections and palpitations.

The study authors noted that their findings may not be generalizable to patients aged >65 years, those with a BMI of >43 kg/m2, those who have comorbid conditions such as type 2 diabetes, and in those with a low adherence to moderate to vigorous intensity exercise.

“The combined strategy reduced the body weight and body-fat percentage approximately twice as much as the single-treatment strategies did and was associated with additional health benefits, such as improvements in the glycated hemoglobin level, insulin sensitivity, cardiorespiratory fitness, physical functioning, and emotional well-being,” the author’s concluded.

Disclosure: This research was funded by the Novo Nordisk Foundation and others. Some of the study authors declared affiliations with pharmaceutical companies. Please see the original reference for a full list of disclosures.


Lundgren JR, Janus C, Jensen SBK, et al. Healthy weight loss maintenance with exercise, liraglutide, or both combined. N Engl J Med. 2021;384(18):1719-1730. doi: 10.1056/NEJMoa2028198