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

• Published in: International Journal of Obesity Vol. 38; no. 6; pp. 784 - 793
• Main Authors: van Can, J, Sloth, B, Jensen, C B, Flint, A, Blaak, E E, Saris, W H M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2014; Nature Publishing Group
• Subjects: 631/443/319; 692/699/2743/393; 692/700/2817; Absorption; Adolescent; Adult; Aged; Appetite; Appetite - drug effects; Biological and medical sciences; Blood Glucose - drug effects; Body Mass Index; Body weight; Body Weight - drug effects; Cross-Over Studies; Diabetes; Diabetes. Impaired glucose tolerance; Double-Blind Method; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Energy; Energy Intake - drug effects; Energy Metabolism - drug effects; Epidemiology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Gastric Emptying - drug effects; Gastrointestinal system; Glucagon; Glucagon-Like Peptide 1 - analogs & derivatives; Glucagon-Like Peptide 1 - therapeutic use; Glucose; Glycated Hemoglobin A - drug effects; Health Promotion and Disease Prevention; Humans; Hunger; Hypoglycemic Agents - therapeutic use; Insulin; Internal Medicine; Investigations; Liraglutide; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Middle Aged; Motility; Nutrition; Obesity; Obesity - complications; Obesity - drug therapy; Oral administration; Original; original-article; Oxidation; Patient outcomes; Peptides; Physiological aspects; Physiological research; Public Health; Satiation; Toxicology; Treatment Outcome; Weight control; Weight Loss - drug effects; Netherlands; energy intake; substrate oxidation; weight management; energy expenditure; postprandial glucose; Endocrinopathy; Energy metabolism; Body weight; Glucose; Hypoglycemic agent; Daily; Gastrointestinal hormone; Energy; Energetic cost; Adult; Oxidation; Nutritional status; Human; Appetite; Stomach; Obesity; Digestive system; Postprandial; Diabetes mellitus; Nutrition disorder; Weight loss; Gastric emptying; Corporal biometry; Glucagon like peptide 1; Substrate; Analog; Glycemia; Liraglutide
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2013.162

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 ∼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.