A 50-week extension study on the safety and efficacy of colesevelam in adults with primary hypercholesterolemia.
BACKGROUND
Colesevelam is a bile acid sequestrant that differs structurally from traditional bile acid sequestrants, allowing it to bind bile acids with greater affinity. Studies have shown that colesevelam significantly reduces low-density lipoprotein cholesterol (LDL-C) levels and, in some cases, significantly increases high-density lipoprotein cholesterol (HDL-C) levels in adults with primary hypercholesterolemia.


OBJECTIVE
To investigate the safety and efficacy of colesevelam in adults with primary hypercholesterolemia.


METHODS
This multicenter, open-label, titration-based extension study enrolled subjects who completed one of three multicenter, randomized, double-blind, placebo-controlled phase II studies with colesevelam. This study consisted of a 4-week washout/dietary stabilization period, a 50-week open-label treatment period, and a 2-week follow-up period.


METHODS
Ten clinical centers within the US.


METHODS
Males and females 18 years of age or older who had completed a previous short-term (4- or 6-week) phase II clinical study with colesevelam.


METHODS
At week 0 (following a 4-week washout of all lipid-lowering medication), subjects initiated treatment with colesevelam at a dosage of 1.5 g/day. Colesevelam was uptitrated to a maximum dosage of 3.75 g/day as necessary to achieve a 15-30% reduction from baseline in LDL-C level. At week 12, an HMG-CoA reductase inhibitor (statin) or niacin (nicotinic acid) could be added if colesevelam 3.75 g/day was not sufficient to result in a 15-30% reduction from baseline in LDL-C level.


METHODS
The primary efficacy measure was the change in LDL-C level from baseline to week 50 across all treatment regimens. Secondary efficacy parameters included the change and percent change in total cholesterol, HDL-C, and triglyceride levels from baseline to week 50. There were three cohorts analyzed: (i) colesevelam monotherapy (included all subjects who received colesevelam monotherapy, regardless of dose); (ii) all treatment regimens (included all subjects who received colesevelam monotherapy or colesevelam plus low-dose statin or niacin therapy); and (iii) combination therapy (included only subjects who received colesevelam plus low-dose statin therapy). Two additional cohorts were also evaluated: (iv) maximum-dose colesevelam monotherapy (included only subjects who received colesevelam 3.75 g/day monotherapy); and (v) all maximum-dose colesevelam treatment regimens (included all subjects who received colesevelam 3.75 g/day, either as monotherapy or in combination with low-dose statin or niacin therapy).


RESULTS
In total, 272 subjects were screened, 260 enrolled, and 186 completed the study. In total, 255 subjects were included in the intent-to-treat population. The maximum dosage of colesevelam (3.75 g/day) was taken by 50% of subjects (n = 94/188) at week 50; only 38 subjects received low-dose statin or niacin by study end. At week 50, LDL-C levels were significantly (p < 0.001) reduced from baseline across all treatment regimens (by 29.6 mg/dL [from 185.8 to 156.2 mg/dL; 15.0%]). Colesevelam also significantly reduced total cholesterol levels and significantly increased HDL-C and triglyceride levels across all treatment regimens (p < 0.001 for all). Drug-related adverse events were reported by 36.2% of subjects across all treatment regimens (and by 47.4% of subjects who received colesevelam plus low-dose statin or niacin therapy).


CONCLUSIONS
In this study, colesevelam was found to be safe and effective for the management of LDL-C levels in adults with primary hypercholesterolemia.
Davidson
Michael H
MH
The University of Chicago Pritzker School of Medicine, Chicago, IL, USA. michaeldavidson@radiantresearch.com
Donovan
Joanne M
JM
Misir
Soamnauth
S
Jones
Michael R
MR
D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000499:Allylamine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D000069472:Colesevelam Hydrochloride; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged
D000924:Anticholesteremic Agents; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D000499:Allylamine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000069472:Colesevelam Hydrochloride