Effects of colesevelam on glucose absorption and hepatic/peripheral insulin sensitivity in patients with type 2 diabetes mellitus

Abstract

Aim: Colesevelam lowers glucose and low-density lipoprotein cholesterol levels in patients with type 2 diabetes mellitus. This study examined the mechanisms by which colesevelam might affect glucose control.

Methods: In this 12-week, randomized, double-blind, placebo-controlled study, subjects with type 2 diabetes and haemoglobin A(1c) (HbA(1c)) ≥7.5% on either stable diet and exercise or sulphonylurea therapy were randomized to colesevelam 3.75 g/day (n = 16) or placebo (n = 14). Hepatic/peripheral insulin sensitivity was evaluated at baseline and at week 12 by infusion of (3) H-labelled glucose followed by a 2-step hyperinsulinemic-euglycemic clamp. Two 75-g oral glucose tolerance tests (OGTTs) were conducted at baseline, one with and one without co-administration of colesevelam. A final OGTT was conducted at week 12. HbA(1c) and fasting plasma glucose (FPG) levels were evaluated pre- and post-treatment.

Results: Treatment with colesevelam, compared to placebo, had no significant effects on basal endogenous glucose output, response to insulin or on maximal steady-state glucose disposal rate. At baseline, co-administration of colesevelam with oral glucose reduced total area under the glucose curve (AUC(g)) but not incremental AUC(g). At week 12, neither total AUC(g) nor incremental AUC(g) were changed from pre-treatment values in either group. Post-load insulin levels increased with colesevelam at 30 and 120 min, but these changes in total area under the insulin curve (AUC(i)) and incremental AUC(i) did not differ between groups. Both HbA(1c) and FPG improved with colesevelam, but treatment differences were not significant.

Conclusions: Colesevelam does not affect hepatic or peripheral insulin sensitivity and does not directly affect glucose absorption.

Figure 1

Study design. All subjects received colesevelam 3.75 g co-administered with the glucose load on day 1.

Figure 2

Subject disposition.

Figure 3

(a) Serum insulin concentrations during the insulin clamp studies. (b) Free fatty acid concentrations during the insulin clamp studies.

Figure 4

(a) Rates of endogenous glucose output in the basal state and during the low-rate (60 mU/m²/min) and high-rate (120 mU/m²/min) insulin infusions. Results are shown for the placebo and colesevelam groups at baseline and after 12 weeks of randomized treatment. Vertical lines indicate standard errors. (b) Rates of glucose disposal during the low-rate (60 mU/m²/min) and high-rate insulin infusion (120 mU/m²/min). Results are shown for the placebo and colesevelam groups at baseline and after 12 weeks of randomized treatment. Vertical lines indicate standard errors.

Figure 5

Plasma glucose concentrations following the oral glucose tolerance test. Results are shown for the placebo and colesevelam groups at baseline and after 12 weeks of randomized treatment.