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

ABSTRACT: 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.

SUBMITTER: van Can J

PROVIDER: S-EPMC4052428 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

van Can J J Sloth B B Jensen C B CB Flint A A Blaak E E EE Saris W H M WH

International journal of obesity (2005) 20130903 6

<h4>Introduction</h4>Mechanisms for liraglutide-induced weight loss are poorly understood.<h4>Objective</h4>We investigated the effects of liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese non-diabetic individuals.<h4>Design</h4>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 expe ...[more]

PMID: 23999198

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Project description:ObjectiveHaving demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years.DesignA randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers.SubjectsA total of 564 adults (n=90-98 per group; body mass index 30-40 kg m(-2)) enrolled, 398 entered the extension and 268 completed the 2-year trial. Participants received diet (500 kcal deficit per day) and exercise counseling during 2-week run-in, before being randomly assigned (with a telephone or web-based system) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg, n=90-95), placebo (n=98) or open-label orlistat (120 mg × 3, n=95). After 1 year, liraglutide/placebo recipients switched to liraglutide 2.4 mg, then 3.0 mg (based on 20-week and 1-year results, respectively). The trial ran from January 2007-April 2009 and is registered with Clinicaltrials.gov, number NCT00480909.ResultsFrom randomization to year 1, liraglutide 3.0 mg recipients lost 5.8 kg (95% confidence interval 3.7-8.0) more weight than those on placebo and 3.8 kg (1.6-6.0) more than those on orlistat (P0.0001; intention-to-treat, last-observation-carried-forward). At year 2, participants on liraglutide 2.4/3.0 mg for the full 2 years (pooled group, n=184) lost 3.0 kg (1.3-4.7) more weight than those on orlistat (n=95; P<0.001). Completers on liraglutide 2.4/3.0 mg (n=92) maintained a 2-year weight loss of 7.8 kg from screening. With liraglutide 3.0 mg, 20-week body fat decreased by 15.4% and lean tissue by 2.0%. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting. With liraglutide 2.4/3.0 mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52 and 59%, with improvements in blood pressure and lipids.ConclusionLiraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors.

Project description:Objective:This study aimed to explore whether treatment with the glucagon-like peptide-1 (GLP-1) analog liraglutide reduces intimal hyperplasia after coronary stent implantation via regulation of glycemic variability, the NLRP3 inflammasome, and IL-10 in diabetic swine. Methods:Fifteen pigs were divided into a diabetes mellitus (DM) group (n = 6), a DM + liraglutide treatment group (L group) (n = 6) and a sham group (n = 3). A total of 24 everolimus-eluting stents were implanted in the left anterior descending and right coronary arteries at 3 weeks. A novel continuous glucose monitoring system (GMS) was used for 2 weeks. The means and standard deviations (SDs) were measured and calculated by the GMS. At 22 weeks, the lumen area (LA), neointimal thickness (NIT), neointimal area (NIA), and percent area stenosis (%AS) were analyzed by optical coherence tomography. Plasma tumor necrosis factor-?, interleukin-6, and interleukin-10 were assayed by ELISA. The intima protein expression levels of NLRP3, interleukin-1?, interleukin-18 and interleukin-10 were examined using Western blot analysis. Histology was used to evaluate the healing response. In an in vitro study, THP-1 cells were divided into control, high glucose (HG), HG + liraglutide, and HG + liraglutide + Exe(9-39) (a GLP-1 receptor inhibitor) groups. Results:The L group had a lower SD, NIT, NIA, and %AS; a larger LA; reduced inflammation and injury scores; lower expression levels of tumor necrosis factor-?, interleukin-6, NLRP3, interleukin-1?, and interleukin-18; and higher expression of interleukin-10 compared with those of the DM group (p < 0.05). In the in vitro study, similar results were obtained in the HG + liraglutide group, and Exe(9-39) abolished the effect of liraglutide (p < 0.05). Conclusions:Liraglutide treatment reduces intimal hyperplasia after stent implantation via regulation of glycemic variability, the NLRP3 inflammasome, and IL-10 in diabetic pigs in a GLP-1 receptor-dependent manner. Reducing the inflammation induced by glycemic variability may be one of the cardioprotective mechanisms of liraglutide.

Project description:IntroductionOnce-weekly semaglutide 1 mg is a novel glucagon-like peptide-1 receptor agonist (GLP-1 RA) for the treatment of type 2 diabetes that has demonstrated significantly greater reductions in glycated haemoglobin (HbA1c) and body weight than the GLP-1 RA once-daily liraglutide 1.2 mg in the SUSTAIN 10 trial. The present analysis aimed to evaluate the long-term cost-effectiveness of once-weekly semaglutide 1 mg versus once-daily liraglutide 1.2 mg from a UK healthcare payer perspective.MethodsLong-term outcomes were projected using the IQVIA CORE Diabetes Model (version 9.0), with baseline characteristics and treatment effects sourced from SUSTAIN 10. Patients were assumed to initiate treatment with GLP-1 RAs and continue treatment until HbA1c exceeded 7.5%, at which point GLP-1 RAs were discontinued and basal insulin was initiated. Pharmacy costs and costs of complications were measured in 2018 pounds sterling (GBP), with future costs and outcomes discounted at 3.5% per annum. Utilities were taken from published sources.ResultsIn the base-case analysis, once-weekly semaglutide 1 mg was associated with an increase in discounted life expectancy of 0.21 years and discounted quality-adjusted life expectancy of 0.30 quality-adjusted life-years, compared with once-daily liraglutide 1.2 mg. Clinical benefits were achieved at reduced costs, with lifetime cost savings of GBP 140 per patient with semaglutide versus liraglutide, owing to a reduction in diabetes-related complications, in particular cardiovascular disease (mean cost saving of GBP 279 per patient). Therefore, once-weekly semaglutide 1 mg was dominant compared with once-daily liraglutide 1.2 mg. The results of the sensitivity analyses were similar, demonstrating the robustness of the base-case analysis.ConclusionsOnce-weekly semaglutide 1 mg is a cost-effective treatment option versus once-daily liraglutide 1.2 mg, based on the SUSTAIN 10 trial, from a UK healthcare payer perspective.

Dataset Information

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

Publications

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

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