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Liraglutide (Saxenda) in combination with exercise yielded significant long-term weight loss in adults with obesity, a head-to-head trial found.

After 8 weeks on a low-calorie diet, adults on liraglutide (3 mg/day) who also engaged in a moderate-to-vigorous–intensity exercise program saw the greatest amount of weight loss at 1 year -- 9.5 kg (21 lb) more than seen with placebo and usual activity (P<0.001), reported Signe S. Torekov, PhD, of the University of Copenhagen in Denmark, and colleagues.

The combination "was more effective in improving healthy weight loss than either treatment alone," the group wrote in the .

Both treatment strategies alone also yielded significant weight loss after 1 year when compared with the control group on placebo:

• Exercise-alone group: -4.1 kg (9 lbs)
• Liraglutide-alone group: -6.8 kg (15 lb)

Of note, those on combination liraglutide and exercise experienced 5.4 kg (12 lb) more weight loss than those on exercise alone (P=0.004).

On the other hand, the weight loss of those who exercised while on liraglutide wasn't significantly better than that seen with liraglutide alone (-2.7 kg [6 lb] difference, P=0.13).

Combination treatment specifically targeted body fat, as those on liraglutide plus exercise saw an average drop of 3.9% from baseline -- nearly double that of those only exercising (-1.7%, P=0.02). Those on liraglutide alone saw an average 1.9% drop in body fat from baseline (P=0.009).

As for cardiometabolic outcomes, only patients with liraglutide in their treatment strategy achieved a significant hemoglobin A1c reduction. Also, only those on combination treatment saw reductions in HOMA-IR and waist-to-hip ratio and increases in the Matsuda index and physical functioning.

However, those on liraglutide alone did see an increase in heart rate, as well as cholelithiasis and palpitations. As expected with a GLP-1 receptor agonist, gastrointestinal side effects such as nausea and diarrhea were more common among liraglutide users.

The trial enrolled 195 participants in Denmark ages 18 to 65 with obesity. Those with type 1 or type 2 diabetes were excluded.

All participants adhered to an 800-calorie-per-day diet for 8 weeks in order to achieve an initial weight loss of at least 5% of baseline body weight. Those who achieved this were then randomized in a 1:1:1:1 ratio for the following year: exercise plus placebo, liraglutide plus usual activity, exercise plus liraglutide, or placebo plus usual activity.

Exercise plans, planned and monitored by physiologists, consisted of a minimum target of 150 minutes per week of moderate-intensity aerobic physical activity, 75 minutes per week of vigorous-intensity aerobic physical activity, or a combination of the two.

Liraglutide was started at a dose of 0.6 mg per day and subsequently titrated to 3.0 mg daily.

Some limitations of the trial included exclusion of people over age 65, those with diabetes, and severe obesity (BMI over 43), which constrains generalizability.

The FDA approved liraglutide in December 2014 for chronic weight management in adults with a BMI of 30 and over, or with a BMI of 27 or more and at least one weight-related medical condition. This injectable GLP-1 receptor agonist was first approved under the trade name Victoza for treating type 2 diabetes at doses of 0.6, 1.2, and 1.8 mg. In August 2017, it also gained an indication for reducing the risk of major cardiovascular events such as heart attack, stroke, or death in adults with type 2 diabetes mellitus with known heart disease.

Novo Nordisk's other GLP-1 receptor agonist, semaglutide, also recently succeeded in the STEP series of weight loss trials. Currently approved as 7 mg and 14 mg oral tablets (Rybelsus) and a 0.5 mg and 1 mg injectable form (Ozempic) for type 2 diabetes, once-weekly injections of 2.4 mg of semaglutide yielded a 14.9% average weight loss after 68 weeks in a large group of adults with a BMI of 30 or higher.

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