The combination worked better than either alone for long-term effects

Liraglutide combined with an exercise program bested either the drug or exercise alone for losing weight over the course of a year for adults with obesity who did not have diabetes, according to a randomized, head-to-head, placebo-controlled trial published in New England Journal of Medicine.

“All active-treatment groups decreased body weight and body-fat percentage after one year, as compared with the increases observed in the placebo group,” wrote Julie R. Lundgren, MD, PhD, from the department of Biomedical Sciences and the Novo Nordisk Foundation Center for Metabolic Research, in Copenhagen, Denmark, and colleagues. “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.”

Losing weight and keeping it off was the focus of Lundgren and colleagues’ study.

“Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is used in the treatment of obesity because it induces weight loss and maintains low-calorie diet–induced weight loss for at least 1 year, primarily by means of appetite inhibition,” the study authors wrote. But would combining the drug with exercise further the impact on weight loss over one year?

The study authors randomized adults with obesity (body-mass index of 32 to 43) to one of four strategies for one year:

  • The exercise group: moderate to- vigorous–intensity exercise program plus placebo.
  • Liraglutide group: Treatment with liraglutide (3.0 mg per day) plus usual activity.
  • Combination group: Exercise program plus liraglutide therapy.
  • Placebo group: Placebo plus usual activity.

All participants first underwent an eight-week low-calorie (800 kcal per day) diet. The exercise program arms consisted of either 150 minutes per week of moderate-intensity aerobic activity or 75 minutes per week of vigorous-intensity aerobics. The participants could choose one or a combination of both. They were also assigned to an exercise coach and had a six-week initial phase that included supervised exercise consisting of 30 minutes of vigorous-intensity, interval-based indoor cycling, and 15 minutes of circuit training two times a week, and then were encouraged to perform exercises such as cycling, walking, or running, two times a week on their own.

The primary endpoint of the study was weight loss at one year and the secondary endpoint was change in body mass at one year. Safety of liraglutide as well as other prespecified metabolic health-related endpoints were assessed.

All in all, 215 participants completed the low-cal diet from August 2016 through November 2019. Of these 195 lost at least 5% of their baseline body weight and these participants were randomized to one of the four arms of the trial. One hundred sixty-six completed the 52-week trial—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.

“The initial low-calorie diet resulted in a mean body-weight reduction of 12% of the baseline body weight among the participants who underwent randomization,” Lundgren and colleagues reported. “After one year, the combination of exercise and liraglutide therapy induced an additional reduction in body weight, resulting in a total weight loss of 16%.”

The results at one year were as follows:

  • All of the active-treatment strategies—combination, liraglutide alone, or exercise alone—had greater weight loss than placebo. The 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 group had better weight loss results 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 group saw a 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).
  • Improvements in glycated hemoglobin level, insulin sensitivity and cardiorespiratory fitness was only seen in the combination group.

In looking at safety, about 10% of the participants had urinary tract infections, palpitations and five participants discontinued taking liraglutide (2) or placebo (3) due to adverse events. Those who receive liraglutide reported gastrointestinal side effects, decreased appetite and dizziness more often than those who did not. “Cholelithiasis as a serious adverse event and palpitations were reported more frequently in the liraglutide group than in the combination group,” the study authors reported.

For latest news and updates

Of note, those participants who only received liraglutide had an increased resting heart rate, but this was not reported in the combination group.

Most of the participants who completed the 52-week trial were male, average age of 43, with a mean BMI of 32.6 and body fat percentage of 38.6% at randomization. Exclusion criteria included individuals with diabetes.

“The percentage of participants who completed the trial was high in all the groups (82 to 92%) and was highest in the combination group, which shows that a combination of moderate-to-vigorous–intensity exercise and liraglutide treatment is feasible,” the study authors noted. “Only the combined treatment was associated with improvements in insulin sensitivity and physical functioning as compared with placebo.”

Limitations of the study include that the results may not be generalizable to individuals older than age 65, those with higher BMIs, those who have comorbidities such as type 2 diabetes, and those who do not adhere to exercise programs, or have limitations that make exercising difficult.

  1. The combination of liraglutide and exercise led to weight loss maintenance over one year compared with either exercise or the medication alone.

  2. The combination was also associated with additional health benefits, such as improvements in the glycated hemoglobin level, insulin sensitivity, cardiorespiratory fitness, physical functioning, and emotional well-being.

Candace Hoffmann, Managing Editor, BreakingMED™

The study was funded by Novo Nordisk Foundation, the Novo Nodisk Foundation Tripartite Immunometabolism Consortium, by Helsefonden, the Faculty of Health and Medical Sciences at the University of Copenhagen, the Danish Diabetes Academy and the Department of Biomedical Sciences at the University of Copenhagen.

Lundgren had no disclosures.

Cat ID: 187

Topic ID: 76,187,730,187,795,192,518,917,925