Search

Aims: To investigate the hypothesis that weight loss with the glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) liraglutide alone would lead to a greater reduction in the proportion of fat to lean tissue mass when compared to caloric restriction (CR) alone, as well as when compared to treatment with sitagliptin, a dipeptidyl peptidase‐4 (DPP‐4) inhibitor, that also enhances GLP‐1 activity ‐ to determine the independent effects of each treatment. Methods: A total of 88 adults with obesity and prediabetes were randomized to 14 weeks of intervention with CR (−390 kcal/d), liraglutide (1.8 mg/d), or the dipeptidyl peptidase‐4 inhibitor sitagliptin (100 mg/d) as a weight‐neutral comparator. Changes between groups in appetite and hunger ratings measured via visual analogue scales, dietary intakes, body weight, body composition via dual energy x‐ray absorptiometry, and resting energy expenditure via indirect calorimetry were assessed using the Kruskal‐Wallis test or Pearson's chi‐squared test. Results: Weight loss ≥5% of baseline body weight occurred in 44% of participants in the CR group, 22% of the liraglutide group and 5% of the sitagliptin group (p = 0.02). The ratio of fat to lean mass decreased by 6.5% in the CR group, 2.2% in the liraglutide group, and 0% in the sitagliptin group (p = 0.02). Visceral fat reduced by 9.5% in the CR group, 4.8% in the liraglutide group, and 0% in the sitagliptin group (p = 0.04). A spontaneous reduction in dietary simple carbohydrates in the CR group was associated with improved homeostatic model assessment of insulin resistance score (HOMA‐IR). Conclusions: Although both liraglutide and CR are valuable strategies for cardiometabolic risk reduction, CR was associated with greater weight loss and more favourable improvements in body composition than treatment with liraglutide alone. Differences in the response to each of these interventions enables patients to be stratified to the most optimal intervention for their personal risk factors. [ABSTRACT FROM AUTHOR]

Aim: To test the hypothesis that glucagon‐like peptide‐1 receptor (GLP‐1R) agonists have beneficial effects on vascular endothelial function, fibrinolysis and inflammation through weight loss‐independent mechanisms. Materials and Methods: Individuals with obesity and prediabetes were randomized to 14 weeks of the GLP‐1R agonist liraglutide, hypocaloric diet or the dipeptidyl peptidase‐4 inhibitor sitagliptin in a 2:1:1 ratio. Treatment with drug was double blind and placebo‐controlled. Measurements were made at baseline, after 2 weeks prior to significant weight loss and after 14 weeks. The primary outcomes were measures of endothelial function: flow‐mediated vasodilation (FMD), plasminogen activator inhibitor‐1 (PAI‐1) and urine albumin‐to‐creatinine ratio (UACR). Results: Eighty‐eight individuals were studied (liraglutide N = 44, diet N = 22, sitagliptin N = 22). Liraglutide and diet reduced weight, insulin resistance and PAI‐1, while sitagliptin did not. There was no significant effect of any treatment on endothelial vasodilator function measured by FMD. Post hoc subgroup analyses in individuals with baseline FMD below the median, indicative of greater endothelial dysfunction, showed an improvement in FMD by all three treatments. GLP‐1R antagonism with exendin (9‐39) increased fasting blood glucose but did not change FMD or PAI‐1. There was no effect of treatment on UACR. Finally, liraglutide, but not sitagliptin or diet, reduced the chemokine monocyte chemoattractant protein‐1 (MCP‐1). Conclusion: Liraglutide and diet reduce weight, insulin resistance and PAI‐1. Liraglutide, sitagliptin and diet do not change FMD in obese individuals with prediabetes with normal endothelial function. Liraglutide alone lowers the pro‐inflammatory and pro‐atherosclerotic chemokine MCP‐1, indicating that this beneficial effect is independent of weight loss. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors increase endogenous glucagon‐like peptide‐1 (GLP‐1). We hypothesized that genetic variation in the gene encoding the GLP‐1 receptor (GLP1R) could affect the metabolic response to DPP‐4 inhibition. To evaluate the relationship between the GLP1R rs6923761 variant (G‐to‐A nucleic acid substitution) and metabolic responses, we performed mixed meal studies in individuals with type 2 diabetes mellitus and hypertension after 7‐day treatment with placebo and the DPP‐4 inhibitor sitagliptin. This analysis is a substudy of NCT02130687. The genotype frequency was 13:12:7 GG:GA:AA among individuals of European ancestry. Postprandial glucose excursion was significantly decreased in individuals carrying the rs6923761 variant (GA or AA) as compared with GG individuals during both placebo (P = 0.001) and sitagliptin treatment (P = 0.045), while intact GLP‐1 levels were similar among the genotype groups. In contrast, sitagliptin lowered postprandial glucose to a greater degree in GG as compared with GA/AA individuals (P = 0.035). The relationship between GLP1R rs6923761 genotype and therapies that modulate GLP‐1 signalling merits study in large populations. [ABSTRACT FROM AUTHOR]