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: Basingstoke Nature Publishing Group 01.06.2014
• Subjects: Adolescent; Adult; Aged; Appetite; Appetite - drug effects; Biological and medical sciences; Blood Glucose - drug effects; Body Mass Index; 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; 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; Humans; Hypoglycemic Agents - therapeutic use; Investigations; Liraglutide; Male; Medical sciences; Metabolic diseases; Metabolism; Middle Aged; Motility; Nutrition; Obesity; Obesity - complications; Obesity - drug therapy; Oral administration; Original; Oxidation; Patient outcomes; Peptides; Physiological aspects; Physiological research; Satiation; Toxicology; Treatment Outcome; Weight control; Weight Loss - drug effects; Netherlands; Endocrinopathy; Energy metabolism; Body weight; substrate oxidation; Glucose; energy expenditure; Hypoglycemic agent; Daily; Gastrointestinal hormone; Energy; Energetic cost; Adult; Oxidation; Nutritional status; Human; Appetite; energy intake; Stomach; Obesity; Digestive system; Postprandial; Diabetes mellitus; Nutrition disorder; Weight loss; weight management; Gastric emptying; Corporal biometry; Glucagon like peptide 1; postprandial glucose; Substrate; Analog; Glycemia; Liraglutide
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/ijo.2013.162

Mechanisms for liraglutide-induced weight loss are poorly understood. We investigated the effects of liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese non-diabetic individuals. 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. 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. Novo Nordisk. 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.