reveals adverse reactions that have been reported in at least 2% of patients, and more commonly than placebo, during clinical trials. In such trials, colesevelam has been employed in patients with estimated glomerular filtration rate as low as 30 mL/minute/1.73 m2
without difficulty with regards to safety or efficacy. While BAS are contraindicated in patients with complete biliary obstruction, in which bile is not secreted into the intestine, there are otherwise no special considerations in patients with hepatic impairment. Pooled analyses of clinical studies has revealed a small, but statistically significant, increase in the level of liver transaminase as well as alkaline phosphatase, which have, however, remained within the normal reference range.101
As the medication on a weight basis is approximately four times more potent than cholestyramine, less resin bulk in the intestine results in a reduction of bothersome gastrointestinal side effects of constipation, flatulence, and bloating in comparison with firstgeneration agents.1
While no study has directly compared colesevelam with the older BAS, in the Lipid Research Clinics Coronary Primary Prevention Trial, 39% of patients taking cholestyramine reported moderate-to-severe constipation in the first year of study,1
a figure far exceeding that reported in clinical trials with colesevelam. During postmarketing surveillance, bowel obstruction with cholestyramine, while extremely rare, has been reported.103
This may be related to the relative impotence of this first-generation BAS and the resulting bulk of cholestyramine resin (8–24 g) needed to achieve a hypocholesterolemic effect. Use of colesevelam of course is contraindicated in patients with a history of bowel obstruction. Pooled analyses from studies with a relatively small number of patients have revealed a small, but statistically significant, decrease in the blood levels of fat soluble vitamins, which have, however, remained within the normal reference range.101
This is probably related to less than optimal solubilization of vitamins A, D, E, and K through interference with micelle formation in the absence of intestinal free bile acids. It is currently recommended that individuals taking supplements of the above vitamins take them at least 4 hours before or after taking colesevelam.106
The potential for other drug interactions has been discussed earlier. The oral suspension formulation of colesevelam described previously does contain 48 mg of phenylalanine per 3.75 g packet of colesevelam and should be avoided in patients with known phenylketonuria. While clinical experience is quite limited, colesevelam is the only lipid-lowering agent given a pregnancy category “B” rating by the FDA, with first-generation BAS cholestyramine and colestid granules, fibrates, nicotinic acid, and ezetimibe rated “C” and statins rated “X.” The reader is referred to the colesevelam (WelChol®
, Parsippany, NJ) manufacturer’s package insert106
for a comprehensive review of product use recommendations.
Adverse effects of colesevelam hydrochloride
As colesevelam is not appreciably absorbed (see previous section “The colesevelam molecule”), discussion of systemic toxicology related directly to the molecule itself or metabolites is not germane. While originally perceived as merely biological detergents aiding in the solubilization and absorption of dietary fats, over the past decade it has been demonstrated that bile acids, through their known agonist activity at the nuclear FXR transcription factor, act as hormones involved in multiple different physiological systems as previously described in this manuscript. While the pharmacodynamic activity of BAS is ultimately dependent upon their ability to bind and remove bile acids from the intestinal tract, these “nonsystemic” pharmacologic preparations, by decreasing the availability of bile acids at their receptors, have the potential to have both multiple beneficial, as well as deleterious, systemic effects. Examples of the former would include the lowering of LDL-C, increase in HDL-C, and decrease in FBS, postprandial sugar, and HbA1c
. An example of the latter might be the triglyceride elevation associated with their use in certain patients. Indeed, the use of colesevelam is contraindicated in patients with serum triglycerides in excess of 500 mg/dL and should be used only with caution in patients with serum triglycerides between 300–500 mg/dL.106
While additional pernicious effects are always possible, it is gratifying to know that after nearly 90 years of clinical use of this therapeutic class, there has never been a “black box” label warning issued, or any evidence of increased malignancy or other serious “off-target” systemic effects related to the use of BAS.