Bile Acid Sequestrant

Colesevelam (Welchol)

Colesevelam (Welchol), a specifically-engineered, non-absorbed polymer that binds bile acids in the intestine thereby impeding their resorption, is approved as an adjunct to diet and exercise to improve glycemic control adults with type 2 diabetes (T2D). It had been previously approved for treatment of primary hyperlipidemia as monotherapy or in combination with a hydroxymethyl-glutaryl-coenzyme A (HMG-A) reductase inhibitor (“statin”).

Mechanism of Action

The mechanism(s) by which colesevelam and several of the older bile acid sequestrants (BASs) improve glycemic control has not been elucidated, although several have been proposed. These include BAS-induced alterations in luminal bile acid composition, increases in incretins such as cholecystokinin, effects on hepatocyte nuclear factor 4 alpha 4, and “deactivation” of farsenoid X receptors by BAS, possibly resulting in an increase in pancreatic insulin secretion or an increase in pancreatic beta cell sensitivity to glucose.

Clinical Efficacy

The effect of colesevelam on glycemic control was first noted in a post hoc analysis of the results of safety data from a lipid-lowering trial in patients with dyslipidemia and T2D during which colesevelam also reduced fasting plasma glucose ( FPG) levels by 12%. A subsequent small randomized, placebo-controlled pilot study in 65 patients with T2D inadequately controlled (mean baseline glycosylated hemoglobin (A1C): 7.9% colesevelam, 8.1% placebo) on previous antidiabetic therapy demonstrated that colesevelam, added to stable oral antidiabetic drug (OAD) therapy, significantly reduced A1C by -0.5% compared with placebo, and by -1.0% in patients with a baseline A1C of ≥8.0%, as well as reducing FPG by 14 mg/dL. In addition, low-density lipoprotein cholesterol (LDL-C) was significantly reduced by -11.7% (P = 0.007) from baseline in the colesevelam group.

Subsequently, three larger phase 3 clinical trials were conducted in patients with T2D who had not achieved A1C goals with insulin-containing therapy or OADs. One 16-week, double-blind, placebo-controlled trial evaluated the antihyperglycemic effects of colesevelam in 287 patients uncontrolled (A1C 7.5% to 9.5%, inclusive) on insulin alone or in combination with an OAD. Following a 2-week single-blind placebo run-in, subjects were randomized to either colesevelam 3.75 g/day or placebo (mean baseline A1C: 8.3% in both colesevelam and placebo groups). Daily mean insulin use was similar in both groups at baseline. Patients were maintained on existing oral agents and insulin doses were to remain within ±10% of the baseline dose. At week 16, the mean change from baseline in A1C was -0.41% for colesevelam and +0.09% for placebo (treatment effect -0.50%; P <0.0001) (Figure 16-1-A). As expected, colesevelam-treated patients also experienced a reduction in mean LDL-C (12.8%, P = 0.05).

A second, 28-week, randomized, placebo-controlled study was conducted in 316 patients with inadequately controlled T2D (mean baseline A1C: 8.2% and 8.1%, colesevelam and placebo groups, respectively) who were receiving a stable dose of MET or MET plus additional OADs for 3 months. After a 2-week, single-blind placebo run-in period, patients were randomized to 26 weeks’ treatment with colesevelam 3.75 g/day or placebo added to their previous MET-based regimen. As shown in Figure 16-1-B, at week 26, colesevelam therapy resulted in significant mean placebo-corrected A1C reduction of -0.54% (P <0.001), with a significant treatment difference as early as week 6 (-0.46%; P <0.001). Mean LDL-C levels also decreased from baseline by 15.9% (P = 0.01).

The third phase 3 trial also was a randomized, 28-week study conducted in 461 patients who were inadequately controlled (mean baseline A1C: 8.2% and 8.3%, colesevelam and placebo groups, respectively) while receiving a stable dose of an SFU alone or in combination with other OADs for 3 months. After the 2-week, placebo run-in period, patients were treated either with colesevelam (mean dose 3.75 g/day) or placebo added to their previous SFU-based regimen. After 26 weeks of treatment with colesevelam, there was a significant mean placebo-corrected A1C reduction of -0.54% (P <0.0001), and a significant treatment difference of -0.44% was seen as early as week 6 (P <0.001) (Figure 16-1-C). In addition, patients treated with colesevelam also had significantly greater reductions in FPG and fructosamine levels, and as expected, there were significant decreases in LDL-C (16.7%, P = 0.01) and apo B and increases in apo A-I and triglycerides.

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Adverse Events

In double-blind, placebo-controlled trials in patients with T2D, colesevelam was well-tolerated with no serious drug-related adverse events (AEs). A total of 6.7% of colesevelam-treated patients and 3.2% of placebo-treated patients were discontinued from the diabetes trials due to AEs. This difference was due largely to gastrointestinal (GI) adverse reactions, such as abdominal pain and constipation. The incidence of constipation was 8.7% with colesevelam and 2.0% with placebo. Dyspepsia was reported in 3.9% of colesevelam-treated patients compared with 1.4% of those who received placebo, while 3.0% of colesevelam-treated patients reported nausea and 1.4% of placebo patients reported nausea. Hypoglycemia occurred in 3% of patients receiving colesevelam and in 2.3% of those who received placebo. Although, like the older BASs, colesevelam may increase triglycerides, the increases were significant only in two of the phase 3 trials.

Prescribing Colesevelam

The recommended dose of colesevelam to improve glycemic control in patients with T2D is 3,750 mg/day administered as 6 tablets (625 mg) once daily or 3 tablets twice daily taken with a meal or liquid. A sugar-free, oral-suspension formulation is also available and may be more convenient to take (vs multiple tablets) for many patients. One packet containing 3,750 mg of colesevelam mixed with water can be taken once daily. Colesevelam is contraindicated in patients with a history of bowel obstruction, serum triglyceride concentrations >500 mg/dL, and a history of hypertriglyceridemia-induced pancreatitis. Colesevelam should not be used for glycemic control in patients with type 1 diabetes as monotherapy or for treating diabetic ketoacidosis (DKA). It had not been extensively studied in combination with a dipeptidyl peptidase-4 inhibitor (DPP-4) inhibitor or in combination with a thiazolidinediones (TZD).

This article was last updated: October 26, 2022