LBSUN306 Effects Of Glp-1 Receptor Agonism, Dpp4 Inhibition, And Hypocaloric Diet On Metabolic Parameters In Obese Pre-diabetic Individuals: A Randomized-controlled Trial

BACKGROUND: GLP-1 receptor (GLP1R) agonists reduce glucose, weight and cardiovascular risk. Understanding the weight loss-dependent mechanisms of these benefits will inform treatment and drug development. This study compared metabolic responses among GLP1R agonist (liraglutide), DPP4 inhibitor (sitagliptin), and hypocaloric diet treatments. METHODS: We randomized 88 obese, pre-diabetic individuals in a 2: 1: 1 ratio to liraglutide, sitagliptin, or diet for 14 weeks. Treatment was double-blinded and placebo-controlled for drug. Individuals completed a mixed meal at baseline, 2 and 14 weeks. The GLP1R antagonist exendin (9-39) and vehicle were infused in a randomized crossover design at 2 and 14 weeks. Within-subject change was assessed using paired t-test. Between-treatment effects were analyzed using generalized least squares linear regression. RESULTS: Baseline characteristics were similar (mean age 50, 32% men, 13% black). Liraglutide and diet caused weight loss at 14 weeks (L: -2.7kg 95%CI [-3.8, -1.7], P<0. 001; D: -5. 0 [-7. 0, -2.9], P<0. 001), while sitagliptin did not (-0.7 [-1.7, 0.2], P=0.13). Liraglutide decreased fasting glucose (FG) at 2 (-10.8mg/dL [-14. 0, -7.7], P<0. 001) and 14 weeks (-10.2 [-13.3, -7.2], P<0. 001), while sitagliptin did not. Diet decreased FG at 14 weeks (-3. 0 [-5.9, -0.1], P=0. 04). Liraglutide decreased post-prandial glucose (PPG) compared to sitagliptin (-6.6 [-11.4, -1.7], P<0. 01) and diet (-8.5 [-13.3, -3.6], P<0. 01) at 2 weeks, and compared to sitagliptin (-7.1 [-11.9, -2.2], P<0. 01) at 14 weeks. Exendin increased FG and PPG in all treatments. Liraglutide and diet decreased fasting insulin and HOMA-IR at 2 (HOMA-IR: L: -1.3 [-2.2, -0.3], P=0. 01; D: -1.9 [-3.2, -0.6], P<0. 01) and 14 weeks (L: -1.2 [-2. 0, -0.3], P=0. 01, D: -2.3 [-3.9, -0.6], P=0. 01), while sitagliptin did not. No treatment significantly changed post-prandial insulin. Exendin increased post-prandial insulin in all treatments. Sitagliptin significantly increased fasting and post-prandial GLP-1 at 2 (fasting: 5.2pg/mL [2.9, 7.6], P<0. 001) and 14 weeks (4. 0 [2.7, 5.3], P<0. 001), while diet did not. We could not quantify fasting endogenous GLP-1 in the liraglutide group due to cross-reactivity of the assay with liraglutide. Liraglutide increased peak post-prandial GLP-1 (baseline-subtracted 14 weeks: 17.6 [13.5, 21.6], P<0. 001). Exendin increased GLP-1 in all treatment groups, with greatest increase after sitagliptin (26. 0 [22.6, 29.5], P<0. 001), followed by liraglutide (10.9 [8.3, 13.4], P<0. 001), then diet (4.8 [0.2, 9.4], P=0. 04). CONCLUSIONS: Liraglutide lowered glucose and increased peak post-prandial GLP-1 in obese pre-diabetic individuals without raising insulin. GLP1R antagonism increased glucose and insulin in all, and increased post-prandial GLP-1 levels to a greater extent in sitagliptin-treated than in liraglutide-treated individuals. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.