Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults

INTRODUCTION: 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 kg m(-2)) were randomized to two of three treatments: liraglutide 1.8 mg, 3.0 mg, 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 (AUC(0-300 min)) was found to be equivalent for liraglutide 1.8 versus 3.0 mg (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 3.0 mg (P = 0.007), and a nonsignificant 13% lower than placebo with liraglutide 1.8 mg (P = 0.14). Both liraglutide doses similarly reduced fasting glucose (0.5-0.6 mmol l(-1) versus placebo, P < 0.0001), glucose C-max and 1-h AUC versus placebo; only liraglutide 3.0 mg reduced iAUC(0-300 min) (by similar to 26% versus placebo, P = 0.02). Glucagon iAUC(0-300 min) decreased by similar to 30%, and iAUC(0-60 min) for insulin and C-peptide was similar to 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 B16%. 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 AUC(0-300min) 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 3.0 mg and 13% with 1.8 mg versus placebo were observed. Liraglutide 3.0 mg 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.