Colesevelam: Bile acid-binding agent approved to improve glycemic control in adult patients with type 2 diabetes

Colesevelam (Welchol) was approved on January 18, 2008, as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes.

Colesevelam is a nonabsorbed, polymeric, lipid- and glucose-lowering agent that binds bile acids in the intestine. The mechanism by which colesevelam improves glycemic control in patients with type 2 diabetes is unknown. Colesevelam was previously approved as an adjunct to diet and exercise to reduce elevated low-density lipoprotein (LDL) cholesterol in patients with primary hyperlipidemia as monotherapy or in combination with a hydroxymethyl-glutaryl-coenzyme A reductase inhibitor; 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 mellitus.

Efficacy. The efficacy of colesevelam for the improvement of glycemic control was assessed in 3 double-blind, placebo-controlled trials in which this agent was combined with either metformin, sulfonylureas, or insulin. In the first trial, patients already receiving treatment with metformin alone (n=159) or metformin in combination with other oral agents (n=157) were randomized to also receive either colesevelam 3.8 g/d or placebo for 26 weeks. At Week 26, the addition of colesevelam to metformin alone was associated with a –0.4% least-squares mean change in hemoglobin (Hb) A1c level from 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% least-squares mean change in HbA1c from baseline versus a 0.3% least-squares mean change from baseline with the addition of placebo (treatment difference, –0.6%; P<.001). In the second trial, patients already receiving treatment with a sulfonylurea alone (n=156) or a sulfonylurea in combination with other oral antidiabetic agents (n=304) were randomized to also receive either colesevelam 3.8 g/d or placebo for 26 weeks. At Week 26, the addition of colesevelam to a sulfonylurea alone was associated with a –0.3% least-squares mean change in HbA1c level from baseline versus a 0.5% least-squares mean change from baseline with the addition of placebo (treatment difference, –0.8%; P<.001); the addition of colesevelam to a sulfonylurea in combination with other oral antidiabetic agents was associated with a –0.4% least-squares mean change in HbA1c from baseline versus no change from baseline with the addition of placebo (treatment difference, –0.4%; P<.001). In the third study, patients already receiving treatment with insulin alone (n=116) or insulin in combination with other oral agents (n=171) were randomized to also receive either colesevelam 3.8 g/d or placebo for 26 weeks. At Week 26, the addition of colesevelam to insulin alone was associated with a –0.4% least-squares mean change in HbA1c level from baseline versus a 0.2% least-squares mean change from baseline with the addition of placebo (treatment difference, –0.6%; P<.001); the addition of colesevelam to insulin in combination with other oral antidiabetic agents was associated with a –0.4% least-squares mean change in HbA1c from baseline versus no change from baseline with the addition of placebo (treatment difference, –0.4%; P<.001).

Safety. Colesevelam's effect on cardiovascular morbidity and mortality has not yet been determined. This agent has been associated with increased serum triglyceride concentrations; severe hypertriglyceridemia can cause acute pancreatitis. Caution should therefore be exercised in the treatment of patients with triglyceride levels >300 mg/dL; this agent is contraindicated in patients with triglyceride levels >500 mg/dL. Lipid parameters should be assessed before initiation of colesevelam treatment and periodically thereafter. Bile acid sequestrants can decrease the absorption of vitamins A, D, E, and K. Because colesevelam can cause constipation, this agent is not recommended for patients with gastroparesis or other gastrointestinal (GI) motility disorders; colesevelam is also not recommended for patients who have had major GI tract surgery and who may be at risk for bowel obstruction. This agent reduces the GI absorption of some drugs. The most common adverse events associated with colesevelam treatment include constipation, nasopharyngitis, dyspepsia, hypoglycemia, nausea, and hypertension.