Exercise plus liraglutide beat either alone for fat loss in one-year trial

Adults with obesity who combined a year of structured exercise with the GLP-1 drug liraglutide lost more weight and more body fat than those who did either alone, according to a randomized trial published in the New England Journal of Medicine ^[1].

How the trial was set up

The trial enrolled adults aged 18 to 65 with a body-mass index of 32 to 43 and no diabetes ^[1]. Everyone first followed an 800-calorie-per-day diet for eight weeks. The 195 participants who lost at least 5% of their starting weight were then randomly assigned to one of four strategies for a year: exercise plus placebo, liraglutide 3.0 mg per day plus usual activity, exercise plus liraglutide, or placebo plus usual activity ^[1]. All participants attended 12 individual consultations that included dietetic support ^[1].

The exercise program was built around World Health Organization activity recommendations: at least 150 minutes a week of moderate activity, or 75 minutes of vigorous activity, or a mix ^[1]. Participants were encouraged to attend supervised group sessions twice a week — 30 minutes of vigorous interval cycling plus 15 minutes of circuit training — and to exercise on their own twice a week ^[1]. Liraglutide was injected under the skin, starting at 0.6 mg a day and increasing weekly toward 3.0 mg a day ^[1].

After the low-calorie diet phase, participants had lost an average of 13.1 kg ^[1]. The trial was run at Hvidovre Hospital and the University of Copenhagen in Denmark. The Novo Nordisk Foundation was among the funders, and Novo Nordisk supplied the liraglutide and placebo pens ^[1].

What the trial found

At one year, all three active strategies led to greater weight loss than placebo. The difference was 4.1 kg for exercise alone (95% confidence interval, −7.8 to −0.4), 6.8 kg for liraglutide alone (95% CI, −10.4 to −3.1), and 9.5 kg for the combination (95% CI, −13.1 to −5.9) ^[1].

The combination beat exercise alone by 5.4 kg (95% CI, −9.0 to −1.7) ^[1]. The 2.7 kg difference versus liraglutide alone (95% CI, −6.3 to 0.8) did not reach statistical significance ^[1].

The combination reduced body-fat percentage by 3.9 percentage points — about twice the decrease in the exercise group (−1.7 percentage points; 95% CI, −3.2 to −0.2) and the liraglutide group (−1.9 percentage points; 95% CI, −3.3 to −0.5) ^[1]. Only the combination group showed improvements in glycated hemoglobin, insulin sensitivity, and cardiorespiratory fitness ^[1].

Increased heart rate and cholelithiasis, or gallstones, were seen more often in the liraglutide-only group than in the combination group ^[1]. The trial measured many other endpoints, including lean mass, waist and hip circumference, and blood pressure ^[1].

Why it matters for patients

The drug tested here is liraglutide, a once-daily GLP-1 injection. It is not semaglutide (sold as Ozempic, Wegovy, and Rybelsus) or tirzepatide (Mounjaro and Zepbound), the medicines most US patients are prescribed today. No comparable randomized trial that adds a structured exercise program to semaglutide or tirzepatide with a full year of follow-up has been reported.

That gap matters because the trial's main problem is one many patients recognize: weight regain after weight loss ^[1]. The study was designed to test what holds weight off after a low-calorie diet, not what starts it. Exercise added roughly doubled the fat loss achieved by the drug alone, but it did not significantly improve weight loss beyond the drug by itself — the weight difference between those two groups was not statistically significant ^[1].

Two limits are worth noting. The participants had obesity but not diabetes, and everyone in the trial received dietetic counseling, which is not the same as usual care ^[1]. The exercise was supervised by instructors with degrees in exercise physiology and included heart-rate monitoring ^[1], a level of support that is not typical outside a trial.

What has not been reported

No longer-term follow-up of these participants beyond the one-year treatment period is described ^[1]. The trial registration numbers are EudraCT 2015-005585-32 and ClinicalTrials.gov NCT04122716 ^[1]. Whether the same added benefit would appear with injected or oral semaglutide, or with tirzepatide, has not been disclosed.