Mechanisms for liraglutide-induced weight loss are poorly understood.OBJECTIVE:
We investigated the effects of liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese non-diabetic individuals.DESIGN:
Participants (N=49, 18-75 years, body mass index: 30-40 kgm-2) were randomized to two of three treatments: liraglutide 1.8mg, 3.0mg, or placebo in a double-blind, incomplete crossover trial. After 5 weeks, 24-h energy expenditure (EE) and substrate oxidation were measured in a respiratory chamber. Gastric emptying (acetaminophen absorption method), glycemic parameters and appetite were assessed during a 5-h meal test. Ad libitum energy intake during a subsequent lunch was also assessed.RESULTS:
Five-hour gastric emptying (AUC0-300 min) was found to be equivalent for liraglutide 1.8 versus 3.0mg (primary end point), and for both liraglutide doses versus placebo, as 90% confidence intervals for the estimated treatment ratios were contained within the prespecified interval (0.80-1.25). However, 1-h gastric emptying was 23% lower than placebo with liraglutide 3.0mg (P=0.007), and a nonsignificant 13% lower than placebo with liraglutide 1.8mg (P=0.14). Both liraglutide doses similarly reduced fasting glucose (0.5-0.6 mmol l-1 versus placebo, P<0.0001), glucose Cmax and 1-h AUC versus placebo; only liraglutide 3.0mg reduced iAUC0-300 min (by ˜26% versus placebo, P=0.02). Glucagon iAUC0-300 min decreased by ˜30%, and iAUC0-60 min for insulin and C-peptide was ˜20% lower with both liraglutide doses versus placebo. Liraglutide doses similarly increased mean postprandial satiety and fullness ratings, reduced hunger and prospective food consumption and decreased ad libitum energy intake by ˜16%. Liraglutide-associated reductions in EE were partly explained by a decrease in body weight. A relative shift toward increased fat and reduced carbohydrate oxidation was observed with liraglutide. Clinicaltrials.gov ID:NCT00978393. Funding: Novo Nordisk.CONCLUSION:
Gastric emptying AUC0-300min was equivalent for liraglutide 1.8 and 3.0 mg, and for liraglutide versus placebo, whereas reductions in 1-h gastric emptying of 23% with liraglutide 3.0mg and 13% with 1.8mg versus placebo were observed. Liraglutide 3.0mg improved postprandial glycemia to a greater extent than liraglutide 1.8 mg. Liraglutide-induced weight loss appears to be mediated by reduced appetite and energy intake rather than increased EE.