770-P: The Glucose-Lowering Effect of the Bile Acid Sequestrant Sevelamer Is Not Mediated by Glucagon-Like Peptide-1

Abstract

Bile acid sequestrants are cholesterol-lowering drugs, which also improve glycemic control in patients with type 2 diabetes (T2D). The mechanism behind the glucose-lowering effect of bile acid sequestrants is unknown but has been proposed to involve glucagon-like peptide 1 (GLP-1) secretion. Using the GLP-1 receptor antagonist exendin(9-39), we investigated the GLP-1-mediated contribution to the glucose-lowering effect of the bile acid sequestrant sevelamer in patients with T2D. In a randomized, double-blind, placebo-controlled, crossover study, patients (9 men/6 women) with T2D (median [interquartile range] age 68 [63-71] years, BMI 30.1 [26.6-33.0] kg/m2, HbA1c 48 [45-61] mmol/mol (6.5 [6.3-7.7]%), on metformin mono-therapy) underwent two 14-day treatment periods with either sevelamer or placebo in a randomized order. After each treatment period, patients participated in two experimental days, each involving a four-hour liquid meal test with concomitant infusion of exendin(9-39) or saline. Compared to placebo, sevelamer lowered both fasting plasma glucose concentrations ((mean ± SEM) 8.7 ± 0.3 vs. 10.2 ± 0.5 mmol/L, P <0.001) and postprandial plasma glucose excursions (baseline-subtracted area under the curve (bsAUC): 456.5 ± 40.3 vs. 620 ± 63.6 mmol/L × min, P <0.001). In both treatment periods, exendin(9-39) increased the glucose bsAUC compared to saline (P <0.001) with no absolute or relative difference between the two treatment periods (∆bsAUC: 365 ± 34.4 mmol/L × min [170 ± 27.6%] (sevelamer) vs. 428 ± 58.2 mmol/L × min [165 ± 40.2%] (placebo treatment), P = 0.17). In conclusion, using the GLP-1 receptor antagonist exendin(9-39), we were not able to detect a GLP-1-mediated glucose-lowering effect of sevelamer; leaving the mechanism behind the glucose-lowering effect of sevelamer unresolved. Disclosure H. H. Nerild: Employee; Spouse/Partner; Novo Nordisk. A. Brønden: None. D. P. Sonne: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S.