LBSUN306 Effects Of Glp-1 Receptor Agonism, Dpp4 Inhibition, And Hypocaloric Diet On Metabolic Parameters In Obese Pre-diabetic Individuals: A Randomized-controlled Trial
Authors: Mashayekhi Mona , Nian Hui , Howard Sara E , Perkins Bradley , Devin Jessica K , Yu Chang , Silver Heidi , Luther James M , Brown Nancy J 
Published: November 2022

Abstract

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&lt;0. 001; D: -5. 0 [-7. 0, -2.9], P&lt;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&lt;0. 001) and 14 weeks (-10.2 [-13.3, -7.2], P&lt;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&lt;0. 01) and diet (-8.5 [-13.3, -3.6], P&lt;0. 01) at 2 weeks, and compared to sitagliptin (-7.1 [-11.9, -2.2], P&lt;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&lt;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&lt;0. 001) and 14 weeks (4. 0 [2.7, 5.3], P&lt;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&lt;0. 001). Exendin increased GLP-1 in all treatment groups, with greatest increase after sitagliptin (26. 0 [22.6, 29.5], P&lt;0. 001), followed by liraglutide (10.9 [8.3, 13.4], P&lt;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.