Elucidating the glucose-lowering effect of the bile acid sequestrant sevelamer

Henriette H Nerild, Andreas Brønden, Abdullah E Haddouchi, Anne-Marie Ellegaard, Bolette Hartmann, Jens F Rehfeld, Jens J Holst, David P Sonne, Tina Vilsbøll, Filip K Knop*

*Corresponding author for this work

Abstract

AIM: Bile acid sequestrants are cholesterol-lowering drugs, which also improve glycaemic control in people with type 2 diabetes. The mechanism behind the glucose-lowering effect is unknown but has been proposed to be mediated by increased glucagon-like peptide-1 (GLP-1) secretion. Here, we investigated the glucose-lowering effects of sevelamer including any contribution from GLP-1 in people with type 2 diabetes.

MATERIALS AND METHODS: In a randomized, double-blind, placebo-controlled, crossover study, 15 people with type 2 diabetes on metformin monotherapy underwent two 17-day treatment periods with the bile acid sequestrant sevelamer and placebo, respectively, in a randomized order and with an interposed wash-out period of minimum 6 weeks. On days 15 and 17 of each treatment period, participants underwent experimental days with 4-h liquid meal tests and application of concomitant infusion of exendin(9-39)NH2 or saline.

RESULTS: Compared with placebo, sevelamer improved insulin sensitivity (assessed by homeostatic model assessment of insulin resistance) and beta-cell sensitivity to glucose and lowered fasting and postprandial plasma glucose concentrations. In both treatment periods, exendin(9-39)NH2 increased postprandial glucose excursions compared with saline but without absolute or relative difference between the two treatment periods. In contrast, exendin(9-39)NH2 abolished the sevelamer-induced improvement in beta-cell glucose sensitivity.

CONCLUSIONS: The bile acid sequestrant sevelamer improved insulin sensitivity and beta-cell sensitivity to glucose, but using the GLP-1 receptor antagonist exendin(9-39)NH2 we were not able to detect a GLP-1-mediated glucose-lowering effect of sevelamer in individuals with type 2 diabetes. Nevertheless, the sevelamer-induced improvement of beta-cell sensitivity to glucose was shown to be GLP-1-dependent.

Original languageEnglish
JournalDiabetes, Obesity and Metabolism
Volume26
Issue number4
Pages (from-to)1252-1263
Number of pages12
ISSN1462-8902
DOIs
Publication statusPublished - Apr 2024

Keywords

  • bile acid sequestrant
  • clinical trial
  • drug mechanism
  • GLP-1
  • randomized trial
  • sevelamer
  • type 2 diabetes

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