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

Abstract

IntroductionMechanisms for liraglutide-induced weight loss are poorly understood.ObjectiveWe investigated the effects of liraglutide on gastric emptying, glycemic parameters, appetite, and energy metabolism in obese non-diabetic individuals.DesignParticipants (N=49, 18-75 years, BMI: 30-40 kgm-2) were randomized to 2 of 3 treatments: liraglutide 1.8 mg, 3.0 mg, or placebo in a double-blind, incomplete crossover trial. After 5 weeks, 24-hour energy expenditure and substrate oxidation were measured in a respiratory chamber. Gastric emptying (acetaminophen absorption method), glycemic parameters, and appetite were assessed during a 5-hour meal test. Ad libitum energy intake during a subsequent lunch was also assessed.ResultsFive-hour gastric emptying (AUC0-300min) was found to be equivalent for liraglutide 1.8 versus 3.0 mg (primary endpoint), and for both liraglutide doses versus placebo, as 90% CIs for the estimated treatment ratios were contained within the pre-specified interval (0.80-1.25). However, 1-hour gastric emptying was 23% lower than placebo with liraglutide 3.0 mg (P=0.007), and a non-significant 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 Cmax and 1-hour AUC versus placebo; only liraglutide 3.0 mg reduced iAUC0-300min (by ~26% versus placebo, P=0.02). Glucagon iAUC0-300min 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 energy expenditure 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.ConclusionGastric emptying AUC0-300min was equivalent for liraglutide 1.8 and 3.0 mg, and for liraglutide versus placebo, whereas reductions in 1-hour 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 energy expenditure.International Journal of Obesity accepted article preview online, 3 September 2013. doi:10.1038/ijo.2013.162