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

Abstract

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 Cmax and 1-h AUC versus placebo; only liraglutide 3.0 mg reduced iAUC(0-300 min) (by ∼26% versus placebo, P=0.02). Glucagon iAUC(0-300 min) decreased by ∼30%, and iAUC(0-60 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 AUC(0-300 min) 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.

Figure 1

Trial design FBG, fasting blood glucose.

Figure 2

Effect of liraglutide and placebo on gastric emptying. Data are presented as mean±s.e.

Figure 3

Effect of liraglutide and placebo on postprandial glucose, glucagon, insulin, and C-peptide concentrations. Data are presented as mean±s.e.

Figure 4

Appetite ratings (assessed by visual analog scale, VAS) following the breakfast meal, and energy intake during ad libitum lunch meal, served 5 h after breakfast. Data for energy intake are estimated means, appetite ratings are presented as mean±s.e. and treatment differences are calculated using the parametric linear mixed-effect model on the original outcome values. The model included effects of subject, period and treatment group and the subject effect was included as a random effect. ETD, estimated treatment difference; OAS, overall appetite score. OAS=(satiety + fullness + (100−hunger) + (100−prospective food consumption))/4.

Figure 5

Total 24-h energy expenditure. Data are estimated means. Treatment differences were calculated using the parametric linear mixed-effect model including effects of period and treatment group. Subject was included as a random effect. ETD, estimated treatment difference.