Colesevelam hydrochloride: A novel agent in patients with type 2 diabetes.

Hyperglycemia and hyperlipidemia are both risk factors for the development of various complications in patients with type 2 diabetes mellitus. Colesevelam hydrochloride is a novel agent that can improve both hypercholesterolemia and hyperglycemia in such patients. It is an orally administered bile acid sequestrant with high capacity for binding bile acids. This drug can offer potential new diabetes treatment along with other drugs.

INTRODUCTION

Hyperglycemia is a risk factor for microvascular complications in patients with type 2 diabetes.[1] Apart from hyperglycemia, dyslipidemia also contributes to the risk of developing complications in patients with type 2 diabetes.[2] Even the National Cholesterol Education Program (NCEP) Adult Treatment Panel III has recommended achieving low-density lipoprotein cholesterol (LDL-C) goals of < 100 mg / dl for patients with diabetes as they are at high risk of developing cardiovascular events.[3] Thus, new treatment regimens that can improve both glycemic control and lipid management in type 2 diabetes patients will be clinically beneficial. In this regard, colesevelam hydrochloride, the LDL-C lowering medication, which is also indicated for glycemic control seems promising.[4]

Colesevelam hydrochloride was previously approved as an adjunct to diet and exercise, to reduce elevated LDL-C in patients with primary hyperlipidemia.[5] On January 18, 2008, this agent was also approved as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes.[4]

MECHANISM OF ACTION

Colesevelam is a bile acid sequestrant (BAS) with a high capacity for binding bile acids in the intestine,[5] thereby impeding their re-absorption and enterohepatic circulation. This leads to the upregulation of the hepatic enzyme, cholesterol 7-alpha-hydroxylase, causing an increase in the conversion of cholesterol to bile acids and the activity of the hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase (rate limiting step of cholesterol synthesis). The number of hepatic LDL receptors is also increased, thus increasing the clearance of LDL-C from the blood, resulting in decreased serum LDL-C levels.

The exact mechanism by which colesevelam improves glycemic control is unknown. The various explanations suggested are — colesevelam acts in the gastrointestinal tract, thereby reducing the amount of glucose absorbed or by binding with the bile acids it disrupts the enterohepatic pathway of bile metabolism, which has indirect effects on glucose metabolism.[24]

PHARMACOKINETICS

Colesevelam is a hydrophilic, water insoluble polymer that is not hydrolyzed by digestive enzymes. It is neither absorbed nor metabolized systematically. It is excreted by the intestines only.[6] There is little evidence for clinically significant interactions involving colesevelam.[7] Pharmacokinetic studies with colesevelam have not shown clinically significant effects on the bioavailability of digoxin, fenofibrate, lovastatin, metoprolol, quinidine, valproic acid, warfarin or statins.[8]

ADVERSE EFFECTS

Reported adverse events from the various clinical trials include flatulence, dyspepsia, and diarrhea.[9] Colesevelam should not be used for the treatment of type I diabetes or for the treatment of diabetic ketoacidosis. Colesevelam is contraindicated in individuals with bowel obstruction, those with serum triglyceride (TG) concentrations of > 500 mg / dL or with a history of hypertriglyceridemia-induced pancreatitis. Caution should be exercised when treating patients with TG levels > 300 mg / dL.

Colesevelam may decrease the absorption of fat-soluble vitamins A, D, E, and K. Patients on vitamin supplements should take their vitamins at least four hours prior to colesevelam. Caution should be exercised when treating patients with a susceptibility to vitamin K or fat soluble vitamin deficiencies.[5]

CLINICAL EVIDENCES

The efficacy of colesevelam for the improvement of glycemic control was assessed in three double-blind, placebo-controlled trials in which this agent was combined with metformin, sulfonylureas, or insulin.[21011] In the first trial, the patients already receiving treatment with metformin alone (n = 159), or metformin in combination with other oral agents (n = 157), were randomized to receive either colesevelam 3.8 g / d or placebo as an add-on therapy, for 26 weeks. The addition of colesevelam to metformin alone was associated with a - 0.4% least-squares mean change (LSMC) in the glycated hemoglobin (HbA1c) level from the baseline, versus no change with the addition of placebo (treatment difference, - 0.5%; P = .002). The addition of colesevelam to metformin in combination with other oral antidiabetic agents was also associated with a - 0.4% LSMC in HbA1c versus a 0.3% LSMC with the addition of placebo (treatment difference, - 0.6%; P < 0.001).[10]

In another trial, patients reporting inadequate glycemic control with sulfonylurea alone (n = 156) or sulfonylurea plus other oral antidiabetic agents were randomized to receive either colesevelam 3.75 g / d or placebo as an add-on therapy, for 26 weeks. The addition of colesevelam to sulfonylurea alone was associated with a - 0.3% LSMC in the HbA 1clevel; the addition of colesevelam to sulfonylurea plus other oral antidiabetic agents was associated with a - 0.4% LSMC in HbA1c.[2]

In another 16-week study, involving 287 type 2 diabetes patients being treated with insulin monotherapy or in combination with an oral anti-diabetes agent, addition of colesevelam 3.75g / dl decreased LDL-C by 12.8%, increased triglycerides by 21.5%, lowered HbA1c by 0.5%, and fasting glucose levels by 14.6mg / dl.[11]

INDICATIONS AND USAGES

Colesevelam is indicated as an adjunct to diet and exercise, to reduce elevated LDL-C in patients with primary hyperlipidemia, as a monotherapy or in combination with an HMG-CoA reductase inhibitor. Another indication is to improve glycemic control in adults with type 2 diabetes mellitus.[12]

CONCLUSION

Colesevelam offers physicians a new treatment option that addresses two cardiovascular risk factors, high LDL-cholesterol and blood glucose in patients with type 2 diabetes. The inclusion of colesevelam may represent a novel therapeutic add-on strategy for improving multiple metabolic parameters in these patients.