Improving glycemic and cholesterol control through an integrated approach incorporating colesevelam - a clinical perspective

Ronald B Goldberg, Ronald B Goldberg

Abstract

Bile sequestrants have been used for almost 50 years to lower low density lipoprotein cholesterol (LDL-C). The advent of colesevelam in 2000 provided a more tolerable add-on LDL-C-lowering agent with an excellent safety record and with likely benefit for coronary heart disease events. Colesevelam lowers LDL-C approximately 15%, and has an additive effect when combined with statin or non-statin lipid-modifying agents. It also tends to increase triglyceride levels. The discovery that bile sequestrants also lower glucose levels led to definitive large-scale clinical trials testing the effect of colesevelam as a dual antihyperglycemic agent with LDL-C-lowering properties in type 2 diabetic subjects on metformin-, sulfonylurea- or insulin-based therapy with inadequate glycemic control. Colesevelam was found to lower hemoglobin A1c (HbA1c) by approximately 0.5% compared to placebo over the 16- to 26-week period, and had similar effects on the lipid profile in these diabetic subjects, as had previously been demonstrated in non-diabetic individuals. Colesevelam was well tolerated, with constipation being the most common adverse effect, and did not cause weight gain or excessive hypoglycemia. Colesevelam thus combines antihyperglycemic action with LDL-C-lowering properties, and should be useful in the management of type 2 diabetes.

Keywords: LDL-cholesterol; colesevelam; hyperglycemia; treatment.

Figures

Figure 1
Figure 1
The enterohepatic circulation of bile acids. Abbreviations: FXR, farnesoid X receptor; CYP7A1, cholesterol 7α-hydroxylase.
Figure 2
Figure 2
Comparison of the structures of cholestyramine and colesevelam.
Figure 3
Figure 3
Percentage change in total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride (TG) levels from baseline (week 0) to the end of treatment (week 6) in patients who received placebo or colesevelam hydrochloride therapy. Reproduced with permission from Davidson MH, Dillon MA, Gordon B, et al Colesevelam hydrochloride (Cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal. side effects. Arch Intern Med. 1999;159:1893–1900. Copyright © 1999 American Medical Association. All rights reserved.
Figure 4
Figure 4
Effect of addition of colesevelam to atorvastatin 10 mg. LDL-C and Total-C values are expressed as mean; HDL-C and TG values are expressed as median; *p Atherosclerosis. 2001;158:407–416. Copyright © 2001 Elsevier.
Figure 5
Figure 5
Summary of effect of add-on colesevelam 3.75 g/day to metformin-, sulfonylurea-, and insulin-based treatment on the placebo-controlled HbA1c reduction at study end from baseline, in subjects with type 2 diabetes (intention to treat population, last observation carried forward).,,
Figure 6
Figure 6
Least squares mean (SEM) change from baseline in glycated hemoglobin A1c (HbA1c) A), fasting plasma glucose (FPG) B), and fructosamine C) levels in subjects (intent-to-treat population without last observation carried forward imputation) receiving colesevelam hydrochloride, 3.75 g/d, or placebo for 16 weeks. Goldberg RB, Fonseca VA, Truitt KE, Jones MR. Efficacy and safety of colesevelam in patients with type 2 diabetes mellitus and inadequate glycemic control receiving insulin-based therapy. Arch Intern Med. 2008;168(14):1531–1540. Copyright © 2008 American Medical Association. All rights reserved. Abbreviations: FPG, fasting plasma glucose; COL, colesevelam; PL, placebo.

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