Pharmacology Update

Colesevelam Hydrochloride Tablets (Welcholä): Use in Type 2 Diabetes Mellitus

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliot is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.

Colesevelam is a bile-sequestering agent approved in 2000 for the treatment of hypercholesterolemia. It has recently been shown to be effective as add-on therapy for Type 2 diabetics. Earlier this year the FDA approved colesevelam for reducing glycemia in this patient population. Colesevelam is marketed by Daiichi Sankyo, Inc., as Welcholä.

Indications

Colesevelam is indicated as adjunct to diet and exercise to improve glycemic control in adults with Type 2 diabetes mellitus. It is also indicated as monotherapy or in combination with a statin to reduce elevated LDL-cholesterol in patients with primary hyperlipidemia (Fredrickson Type IIa).1

Dosage

Colesevelam is available as 625 mg tablets. The recommended dose is 6 tablets once daily or 3 tablets twice daily. Tablets should be taken with a meal and liquid.1

Potential Advantages

Colesevelam, when added to a sulfonylurea, metformin, or insulin-based therapy, results in a significant reduction in HbA1c.1-3 It has the added benefit of lowering LDL-cholesterol.

Potential Disadvantages

Treatment with colesevelam represents a high pill burden as 6 tablets are taken daily. Common adverse events include constipation, dyspepsia, hypoglycemia, nausea, and elevation of triglyceride levels.1 Drugs that may interact with colesevelam such as glyburide, levothyroxine, and oral contraceptives should be taken at least 4 hours prior to colesevelam.1

Comments

The efficacy of colesevelam in Type 2 diabetes was demonstrated in 3 randomized, placebo-controlled trials. Two 26-week studies were performed in patients on oral drugs only, metformin-based (n = 300) or sulfonylurea-based (n = 436).1,3 The third was a 16-week study in insulin-based patients (n = 280).1,2 Patients had mean baseline HbA1c ranging from 8.1% to 8.3%. Overall, the addition of colesevelam (3.75 g/day) resulted in modest but statistically significant placebo-corrected mean reduction in HbA1c of 0.5% (P < 0.001 in all three studies). There was a mean reduction in LDL-C that ranged from 12% to 15% across the 3 studies. A modest reduction of fasting plasma glucose (-14 to -15 mg/dL) was also observed. Elevation of triglycerides was observed and reached statistical significance in patients on sulfonylurea-based therapy (+20%) and insulin-based therapy (+23%).1 Adverse events associated with colesevelam (vs placebo) are gastrointestinal tract-related including constipation (11% vs 7%) and dyspepsia (8.3% vs 3.5%). The mechanism of action of colesevelam is not known. Lipid and glucose homeostasis appeared to be linked in part through the bile acid pathway.4 Certain bile acids are endogenous ligands of the farnesoid X receptor and have been implicated in glucose metabolism.5

Clinical Implications

Colesevelam offers another drug as add-on therapy to improve glycemic as well as lipid control in Type 2 diabetics, thus addressing 2 of the risk factors in this population. However the reductions in HbA1c were modest. In contrast, sitagliptin, when added to metformin or pioglitazone, produced a mean reduction of 0.7%.6,7 Colesevelam is listed in the American College of Endocrinology's Road Maps to Achieve Glycemic Control in Type 2 Diabetes Mellitus as one of the drugs for add-on therapy in patients not adequately controlled on monotherapy.8

References

1. Welchol Product Information. Tokyo: Daiichi Sankyo, Inc.; January 2008. Available at: www.welchol.com/pdf/Welchol_PI.pdf. Accessed Nov. 18, 2008.

2. Goldberg RB, et al. Efficacy and safety of colesevelam in patients with type 2 diabetes mellitus and inadequate glycemic control receiving insulin-based therapy. Arch Intern Med 2008;168:1531-1540.

3. Fonseca VA, et al. Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately controlled type 2 diabetes on sulfonyl-urea-based therapy. Diabetes Care 2008;31:1479-1484.

4. Goldfine AB. Modulating LDL cholesterol and glucose in patients with type 2 diabetes mellitus: Targeting the bile acid pathway. Curr Opin Cardiol 2008;23:502-511.

5. Stayrook KR, et al. Regulation of carbohydrate metabolism by the farnesoid X receptor. Endocrinology 2005; 146:984-991.

6. Charbonnel B, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006;29:2638-2643.

7. Rosenstock J, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: A 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 2006;28:1556-1568.

8. American Association of Clinical Endocrinologists. Available at: www.aace.com/pub/roadmap/. Accessed Oct. 10, 2008.