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PubMed2000

Drug interactions with colesevelam hydrochloride, a novel, potent lipid-lowering agent.

Colesevelam hydrochloride (colesevelam) is a novel, potent, bile acid-binding agent that has been shown to lower LDL cholesterol a mean of 19% at a dose of 3.8 g/d. We studied the pharmacokinetics of colesevelam coadministered with six drugs: digoxin and warfarin, agents with narrow therapeutic indices; sustained-release verapamil and metoprolol; quinidine, an antiarrhythmic with a narrow therapeutic index; and valproic acid, an antiseizure medication. Six individual studies were single-dose, crossover, with or without a 4.5-g dose of colesevelam. Plasma levels were determined using validated analytical methods. Values for the ratio of ln[AUC(0-t)] with and without colesevelam were 107% for quinidine, 102% for valproic acid, 89% for digoxin, 102% for warfarin, 82% for verapamil, and 112% for metoprolol. Values for the ratio of ln[Cmax] with and without colesevelam were 107% for quinidine, 92% for valproic acid, 96% for digoxin, 99% for warfarin, 69% for verapamil, and 112% for metoprolol. The 90% confidence intervals for these ratios and for values of ln[AUC(0-inf)] that could be determined were within the 80-125% range, with the exception of verapamil. In this study, verapamil had great interindividual variability, with a 28-fold range in Cmax and an 11-fold range in AUC(0-t). In summary, pharmacokinetic studies with colesevelam did not show clinically significant effects on absorption of six other coadministered drugs.

Allylamine↗
PubMed2002

Absorption of colesevelam hydrochloride in healthy volunteers.

OBJECTIVE: To assess whether colesevelam hydrochloride is absorbed in healthy volunteers. METHODS: A single-center, open-label, radiolabeled study was performed with 16 healthy volunteers. Subjects were administered non-radiolabeled colesevelam hydrochloride 1.9 g twice daily for 4 weeks, followed by a single dose of [14C]-colesevelam 2.4 g (480 pCi). These subjects continued to receive non-radioactive colesevelam 1.9 g twice daily for 4 days after administration of the radiolabeled dose. Blood, urine, and feces were collected immediately prior to administration of [14C]-colesevelam and at specified intervals after administration. The whole-blood equivalent concentration of colesevelam was calculated using data collected throughout the 96 hours following radiolabeled drug administration. The proportion of [14C]-colesevelam excreted through urine or feces was calculated based on the amount of radioactivity recovered up to 216 hours after the radiolabeled dose. RESULTS: The mean cumulative total recovery of [14C]-colesevelam in urine and feces was 0.05% and 74%, respectively. Excluding 2 subjects for whom cumulative recovery was <25%, the mean cumulative fecal recovery was 82%. The mean maximum whole-blood equivalent concentration of colesevelam was 0.165+/-0.10 microg equiv/g 72 hours after administration of [14C]-colesevelam, which was estimated to be 0.04% of the administered dose. All blood samples contained <4 times the number of background counts (dpm). CONCLUSIONS: The cumulative recovery data in urine and feces are consistent with the conclusion that colesevelam is not absorbed and is excreted entirely through the gastrointestinal system.

Allylamine↗
PubMed2002

Colesevelam hydrochloride.

The pharmacology, pharmacodynamics, clinical efficacy, drug interactions, adverse effects, and dosage and administration of colesevelam hydrochloride are reviewed. Colesevelam hydrochloride is a nonabsorbed lipid-lowering agent approved for use alone or in combination with hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors for the reduction of low-density-lipoprotein (LDL) cholesterol in patients with primary hypercholesterolemia. Colesevelam forms nonabsorbable complexes with bile acids in the gastrointestinal (GI) tract, resulting in changes in plasma lipid levels, including total, LDL, and high-density-lipoprotein cholesterol and triglycerides. Colesevelam has been reported to be four to six times as potent as traditional bile acid sequestrants (BASs), perhaps because of its greater binding affinity for glycocholic acid. Unlike cholestyramine and colestipol, colesevelam appears to reduce LDL cholesterol in a dose-dependent manner. In clinical trials, colesevelam demonstrated efficacy either alone or in combination with HMG-CoA reductase inhibitors in the treatment of primary hypercholesterolemia. Combination therapy appeared to be more effective than monotherapy. Although infection, headache, and GI adverse effects have been reported for colesevelam, the rates do not differ significantly from those occurring with placebo. The constipation that typically hinders compliance with traditional BASs is minimal. In one study, the rate of compliance with colesevelam was 93%. There is little evidence of clinically significant interactions involving colesevelam. The maintenance dosage is three 625-mg tablets twice daily or six tablets once daily, taken with meals. Colesevelam provides an effective alternative to cholestyramine and colestipol while offering the potential for fewer adverse effects and better compliance. Studies are needed to directly compare colesevelam with traditional BASs.

Allylamine↗
PubMed2001

Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively.

Colesevelam hydrochloride is a novel, potent, non-absorbed lipid-lowering agent previously shown to reduce low density lipoprotein (LDL) cholesterol. To examine the efficacy and safety of coadministration of colesevelam and atorvastatin, administration of these agents alone or in combination was examined in a double-blind study of 94 hypercholesterolemic men and women (baseline LDL cholesterol > or =160 mg/dl). After 4 weeks on the American Heart Association Step I diet, patients were randomized among five groups: placebo; colesevelam 3.8 g/day; atorvastatin 10 mg/day; coadminstered colesevelam 3.8 g/day plus atorvastatin 10 mg/day; or atorvastatin 80 mg/day. Fasting lipids were measured at screening, baseline and 2 and 4 weeks of treatment. LDL cholesterol decreased by 12-53% in all active treatment groups (P<0.01). LDL cholesterol reductions with combination therapy (48%) were statistically superior to colesevelam (12%) or low-dose atorvastatin (38%) alone (P<0.01), but similar to those achieved with atorvastatin 80 mg/day (53%). Total cholesterol decreased 6-39% in all active treatment groups (P<0.05). High density lipoprotein cholesterol increased significantly for all groups including placebo (P<0.05). Triglycerides decreased in patients taking atorvastatin alone (P<0.05), but were unaffected by colesevelam alone or in combination. The frequency of side effects did not differ among groups. At recommended starting doses of each agent, coadministration of colesevelam and atorvastatin was well tolerated, efficacious and produced additive LDL cholesterol reductions comparable to those observed with the maximum atorvastatin dose.

Adult↗
PubMedDate not supplied

Dietary administration of colesevelam hydrochloride does not affect fertility or reproductive performance in rats.

Colesevelam hydrochloride (HCl) (WelChol; Sankyo Pharma) is a novel, highly potent, bile acid-binding polymer used for the treatment of hypercholesterolemia. The primary aim of this study was to determine the effects of dietarily administered colesevelam HCl on fertility and reproductive performance parameters. To assess these effects, sexually mature Sprague-Dawley rats were randomized to one of five treatment groups: feed alone, feed plus control article (SigmaCell), or feed plus colesevelam HCl 200, 1000, or 2000 mg/kg/day. Male and female rats were administered the appropriate group agent for 28 and 15 days, respectively, and were subsequently paired together for cohabitation and mating. Females continued to receive the test agent in their dietary formulation through presumed gestation day (GD) 7. Presumed pregnant females underwent cesarean section on GD 20. Food consumption rate, body weight, gross necropsy, and standard preclinical tests for reproduction and fertility were performed for each test animal. No statistically significant differences were found between control and drug-treated groups for any tested endpoints of reproduction. All animals placed in cohabitation successfully mated. Uterine and litter end points were unaffected by dosages of colesevelam HCl as high as 2000 mg/kg/day. There were no significant differences between treatment group litter averages in the number of corpora lutea, implantation sites, litter size, live fetuses, body weights, early/late resorptions, and the number of dams with viable fetuses. In addition, no external alterations of fetal morphology were attributable to treatment with colesevelam HCl when administered up to the embryo implantation stage. In male animals, no significant differences were found between the colesevelam HCl and control study groups in the average caudal epididymal sperm count or sperm concentration, total number of motile and nonmotile sperm, and the total percentage of motile sperm. Based on these data, colesevelam HCl does not have any significant adverse reproductive or fertility effects in rats, even when administered at doses approximately 30 times greater than the approved clinical dose.

Administration, Oral↗
PubMed2000

Colesevelam hydrochloride: a non-absorbed, polymeric cholesterol-lowering agent.

Colesevelam hydrochloride (formerly known as Cholestagel((R)) and re-named WelCholtrade mark, GelTex Pharmaceuticals, Inc. and Sankyo Parke-Davis) is a new, polymeric, high potency, water-absorbing hydrogel. It has been shown to be a safe and effective cholesterol-lowering agent with a non-systemic mechanism of action, good tolerability and minimal side effects. To date, the lipid-lowering activity of colesevelam has been evaluated in approximately 1400 subjects. Colesevelam reduces low density lipoprotein (LDL)-cholesterol levels, in a dose-dependent manner, by as much as 20% (median) in patients with hypercholesterolaemia. Dosing regimen evaluations indicate that colesevelam is effective at both once per day and twice daily dosing and that concurrent administration of colesevelam with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), specifically lovastatin, does not alter the absorption of the statin. Combination therapy with HMG-CoA reductase inhibitors, including lovastatin, simvastatin and atorvastatin, produces an additional reduction (8 - 16%) in LDL-cholesterol levels above that seen with the statin alone. The overall incidence of adverse effects with colesevelam alone and in combination with statins is comparable with that seen with placebo. Colesevelam lacks the constipating effect seen with typical bile acid sequestrants, a trait that would be expected to improve compliance with lipid-lowering therapy. Colesevelam, recently approved by the US FDA, represents a valuable non-absorbed alternative in the armamentarium against hypercholesterolaemia, both for monotherapy and combination therapy, as an adjunct to diet and exercise.

Allylamine↗
PubMed2005

Colesevelam hydrochloride does not cause maternal or fetal toxicity in rats and rabbits.

WelChol (colesevelam hydrochloride), a bile acid sequestrant for the treatment of hypercholesterolemia, was evaluated for adverse effects on reproduction and fetal development using standard preclinical tests. During gestation, Sprague-Dawley rats used in the developmental toxicity study received feed, feed/control article or feed plus 300, 1,000 or 3,000 mg/kg/day colesevelam whereas rats in the pre- and postnatal toxicity study received vehicle or 100, 300 or 1,000 mg/kg/day colesevelam via gavage. New Zealand white rabbits received control or 100, 500 or 1,000 mg/kg/day colesevelam via gavage. No deaths, premature deliveries or gross pathologic lesions were observed up to gestation day (GD) 20 for rats and GD 28 for rabbits. No significant differences in the number of pregnant animals, average litter size, percentage of viable fetuses, fetal body weights, number of corpora lutea, fetal viability, or gross malformations were observed versus controls. Pre- and postnatal effects were assessed in pregnant rats receiving 100, 300 or 1,000 mg/kg/day colesevelam from GD 6 to postpartum day 22. Gestation, parturition and lactation in F(0) generation dams were similar between treatment and control groups. Colesevelam did not affect physical or neurological development or induce gross pathological changes in F(1) generation rats. Colesevelam does not produce developmental toxicity in rats or rabbits, nor does it exhibit pre- or postnatal toxicity in rats at the tested doses.

Allylamine↗
PubMed2001

Low-dose combination therapy with colesevelam hydrochloride and lovastatin effectively decreases low-density lipoprotein cholesterol in patients with primary hypercholesterolemia.

BACKGROUND: Colesevelam hydrochloride is a novel, lipid-lowering agent that binds bile acids with high affinity. A multicenter, randomized, double-blind, placebo-controlled, parallel-design study was conducted to assess the efficacy and tolerability of combination low-dose colesevelam and lovastatin treatment in patients with primary hypercholesterolemia. HYPOTHESIS: Combination therapy with low doses of colesevelam and lovastatin decreases low density (LDL) cholesterol with minimal adverse events. METHODS: Following a 4- to 6-week dietary lead in, 135 patients were randomized into five groups for a 4-week treatment period: placebo, colesevelam 2.3 g at dinner, lovastatin 10 mg at dinner, the combination of colesevelam and lovastatin given at dinner (dosed together), and combination treatment with colesevelam given at dinner and lovastatin administered at bedtime (dosed apart). RESULTS: Combination colesevelam and lovastatin treatment decreased LDL cholesterol by 34% (60 mg/dl, p < 0.0001) and 32% (53 mg/dl, p < 0.0001) when colesevelam and lovastatin were dosed together or dosed apart, respectively. Both combination therapies were superior to either agent alone (p < 0.05). Decreases in LDL cholesterol exceeded the combined decreases observed for colesevelam alone (13 mg/dl, 7%) and lovastatin alone (39 mg/dl, 22%). Both combination treatments reduced total cholesterol by 21% (p < 0.0001) and apolipoprotein B by 24% (p < 0.0001). Neither combination treatment significantly altered high-density lipoprotein cholesterol or triglycerides. Adverse side effects were not significantly different among randomized groups. CONCLUSIONS: Combination colesevelam and lovastatin was efficacious and well tolerated, resulting in additive decreases in LDL cholesterol levels whether or not both agents were administered simultaneously.

Allylamine↗
PubMedDate not supplied

Colesevelam hydrochloride: a novel bile acid-binding resin.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of colesevelam hydrochloride, a bile acid-binding resin. METHODS: MEDLINE searches (1966-June 2000) and manufacturer prescribing literature were employed to find articles on colesevelam. Additional studies and abstracts were identified from the bibliographies of reviewed literature. STUDY SELECTION AND DATA EXTRACTION: All articles identified from data sources were evaluated, and all information deemed relevant was included in this review. Priority was given to randomized, double-blind, placebo-controlled studies. FINDINGS: Colesevelam HCl is a nonabsorbed hydrogel with bile acid sequestrant properties. Monotherapy using colesevelam in once-daily or two divided daily doses of 1.5-4.5 g has produced significant reductions in total cholesterol and low-density lipoprotein (LDL) cholesterol. Mean LDL cholesterol decreases to 20% have been noted when the patient is on 3.75-4.5 g/d. Increases in high-density lipoprotein (HDL) cholesterol have been observed (up to 9%), whereas triglycerides (TG) have increased significantly to 25% in some studies. In unpublished studies, combined use of colesevelam plus hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor have produced greater reductions in LDL cholesterol than either the statin or colesevelam administered alone. The efficacy of colesevelam monotherapy is slightly less than or similar to cholestyramine or colestipol in decreasing LDL cholesterol, although colesevelam is more potent on a gram-to-gram basis. Adverse effects have been minimal with colesevelam in published studies; this suggests an advantage over cholestyramine or colestipol therapy. Colesevelam appears to be more cost-effective than the packet dosage form of the brand formulation of the older bile acid resins. Care in selection of an appropriate agent should be exercised when considering the issues of adverse effects and palatability. CONCLUSIONS: Colesevelam alone or combined with an HMG-CoA reductase inhibitor is effective in the reduction of total and LDL cholesterol. Since colesevelam is formulated as a tablet, problems with palatability such as with the powder formulation of the bile acid-binding resins are likely to be eliminated.

Adult↗
PubMed1999

Colesevelam hydrochloride (cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects.

OBJECTIVES: To compare colesevelam hydrochloride (Cholestagel), a nonabsorbed hydrogel with bile acid-sequestering properties, with placebo for its lipid-lowering efficacy, its effects on laboratory and clinical safety parameters, and the incidence of adverse events. METHODS: Following diet and placebo lead-in periods, placebo or colesevelam was administered at 4 dosages (1.5, 2.25, 3.0, or 3.75 g/d) for 6 weeks with morning and evening meals to men and women with hypercholesterolemia (low-density lipoprotein cholesterol level >4.14 mmol/L [>160 mg/dL]). Patients returned to the clinic every 2 weeks throughout the treatment period for lipid parameter measurements and adverse event assessments. Samples were collected for serum chemistry profiles, hematologic studies, coagulation studies, and vitamin level assessment at baseline and after 6 weeks of treatment. RESULTS: Among the 149 patients randomized, 137 completed the study. Low-density lipoprotein cholesterol concentrations decreased in a dosage-dependent manner by 0.11 mmol/L (4.2 mg/dL) (1.8%) in the 1.5-g/d colesevelam treatment group and up to 1.01 mmol/L (39 mg/dL) (19.1%) in the 3.75-g/d colesevelam treatment group. Low-density lipoprotein cholesterol concentrations at the end of treatment were significantly reduced from baseline levels in the 3.0- and 3.75-g/d colesevelam treatment groups (P = .01 and P<.001, respectively). Total cholesterol levels demonstrated a similar response to colesevelam treatment, with an 8. 1% decrease from baseline in the 3.75-g/d treatment group (P<.001). High-density lipoprotein cholesterol levels rose significantly in the 3.0- and 3.75-g/d colesevelam treatment groups, by 11.2% (P=.006) and 8.1% (P=.02), respectively. Median triglyceride levels did not change from baseline, nor were there any significant differences between treatment groups. The incidence of adverse events was similar among all groups. CONCLUSIONS: Colesevelam therapy is effective for lowering low-density lipoprotein cholesterol concentrations in persons with moderate hypercholesterolemia. It lacks the constipating effect of other bile acid sequestrants, demonstrating the potential for increased compliance.

Adult↗
PubMed2001

Effectiveness of colesevelam hydrochloride in decreasing LDL cholesterol in patients with primary hypercholesterolemia: a 24-week randomized controlled trial.

OBJECTIVE: To evaluate the efficacy, tolerability, and safety of colesevelam hydrochloride, a new nonsystemic lipid-lowering agent. PATIENTS AND METHODS: In this double-blind, placebo-controlled trial performed in 1998, 494 patients with primary hypercholesterolemia (low-density lipoprotein [LDL] cholesterol level > or = 130 mg/dL and < or = 220 mg/dL) were randomized to receive placebo or colesevelam (2.3 g/d, 3.0 g/d, 3.8 g/d, or 4.5 g/d) for 24 weeks. Fasting serum lipid profiles were measured to assess efficacy. Adverse events were monitored, and discontinuation rates and compliance rates were analyzed. The primary outcome measure was the mean absolute change of LDL cholesterol from baseline to the end of the 24-week treatment period. RESULTS: Colesevelam lowered mean LDL cholesterol levels 9% to 18% in a dose-dependent manner (P<.001), with a median LDL cholesterol reduction of 20% at 4.5 g/d. The reduction in LDL cholesterol levels was maximal after 2 weeks and sustained throughout the study. Mean total cholesterol levels decreased 4% to 10% (P<.001), while median high-density lipoprotein cholesterol levels increased 3% to 4% (P<.001). Median triglyceride levels increased by 5% to 10% in placebo and colesevelam treatment groups relative to baseline (P<.05), but none of these differences were significantly different from placebo. Mean apolipoprotein B levels decreased 6% to 12% in an apparent dose-dependent manner (P<.001). No significant differences occurred in adverse events or discontinuation rates between groups, and compliance rates were between 88% and 92% for all groups. CONCLUSIONS: Colesevelam was efficacious, decreasing mean LDL cholesterol levels by up to 18%, and well tolerated without serious adverse events.

Adult↗
PubMed2006

Effects of colesevelam hydrochloride (WelChol) on biomarkers of inflammation in patients with mild hypercholesterolemia.

Inflammation is pivotal in atherogenesis. High-sensitivity C-reactive protein (hs-CRP), the prototypic marker of inflammation, has been shown to predict cardiovascular events. Colesevelam hydrochloride (HCl) (WelChol, Sankyo Pharma Incorporated, Parsippany, New Jersey), a specifically engineered bile acid sequestrant, has been shown to be effective in lowering low-density lipoprotein (LDL) cholesterol levels in monotherapy and in combination with statins or fenofibrate. Previously, we have shown that statins lower hs-CRP levels; however, a paucity of data is available examining the effect of colesevelam HCl on hs-CRP levels. The aim of this study was to examine the effect of colesevelam HCl therapy (3.75 g/day for 6 weeks) on hs-CRP in patients with mild hypercholesterolemia in a randomized, double-blind, placebo-controlled study. Twenty-five subjects on colesevelam HCl and 23 subjects on placebo completed the study. The median baseline hs-CRP levels for the treatment and placebo groups are 3.4 and 3.1 mg/L, respectively. Colesevelam HCl therapy resulted in a significant reduction in LDL cholesterol levels (p < 0.001). No significant changes were found in total triglyceride or high-density lipoprotein cholesterol levels between the 2 groups. Furthermore, colesevelam HCl therapy resulted in a significant reduction in hs-CRP levels compared with baseline and placebo (15.9% and 18.7% median reduction, respectively, p < 0.025). No correlation was found between LDL cholesterol lowering and hs-CRP lowering (r = 0.3). In conclusion, our results show that colesevelam HCl monotherapy significantly lowered hs-CRP levels in a double-blind, placebo-controlled study.

Adult↗
PubMed2006

Lipoprotein effects of combined ezetimibe and colesevelam hydrochloride versus ezetimibe alone in hypercholesterolemic subjects: a pilot study.

Two drug classes act in the intestine to lower cholesterol. Ezetimibe inhibits cholesterol absorption, whereas bile acid-binding resins enhance cholesterol excretion via enhanced conversion to bile acids. Combining these 2 classes may be beneficial, but cholestyramine binds ezetimibe, and the combined effect of colesevelam hydrochloride and ezetimibe was little studied. The aim of the study was to determine if adding colesevelam HCl to ezetimibe provides additional lowering of low-density lipoprotein- and apolipoprotein B-containing lipoproteins or alters ezetimibe levels. Twenty subjects with low-density lipoprotein cholesterol (LDL-C) levels of 130 mg/dL or higher were enrolled and taught a National Cholesterol Education Program Step I diet. At a second baseline visit, lipoproteins were measured and subjects were randomly allocated to (1) ezetimibe 10 mg daily with placebo colesevelam HCl twice daily (E) or (2) ezetimibe 10 mg daily with 1.875 g colesevelam HCl twice daily (E + C). Lipoproteins were measured 6 and 12 weeks after initiating treatment. Baseline characteristics (mean +/- SD) were statistically indistinguishable in E vs E + C: LDL-C (mg/dL), 167 +/- 26 and 158 +/- 27; triglyceride, 134 +/- 75 and 140 +/- 67; and BMI, 29.4 +/- 4.9 and 27.8 +/- 6.6 kg/m(2), respectively. Percent changes after 12 weeks in E vs E + C were as follows: LDL-C, -24 +/- 12 vs -30 +/- 11 (P = .102); triglyceride, -19 +/- 34 vs 36 +/- 85 (P = .054; at 6 weeks, P = .009); total cholesterol, -19 +/- 9 vs -15 +/- 8 (P = .50); non-high-density lipoprotein cholesterol, -25 +/- 10 vs -21 +/- 11 (P = .70); apolipoprotein B, -31 +/- 14 vs -22 +/- 14 (P = .41). Plasma ezetimibe levels at 12 weeks were 21% lower in E + C vs E, a nonsignificant difference (P = .54). In conclusion, in the short term, colesevelam HCl may not consistently add cholesterol-lowering benefit to ezetimibe. This observation requires confirmation.

Adult↗
PubMed2006

Effects of colesevelam hydrochloride on low-density lipoprotein cholesterol and high-sensitivity C-reactive protein when added to statins in patients with hypercholesterolemia.

Elevated high-sensitivity C-reactive protein (hs-CRP) levels are associated with an increased risk of atherosclerotic coronary heart disease (CHD). The addition of the bile acid sequestrants, such as colesevelam hydrochloride (HCl), to statins further reduces low-density lipoprotein (LDL) cholesterol levels. However, the effects of approved cholesterol-lowering bile acid sequestrants on hs-CRP have not previously been reported. Three randomized, double-blind, placebo-controlled, parallel, 6-week clinical trials of similar design investigated the efficacy of adding colesevelam HCl to stable simvastatin, atorvastatin, or pravastatin treatment in 204 patients with primary hypercholesterolemia. The primary end point was the mean percent change in the LDL cholesterol levels. Secondary end points included the effects on other lipid parameters and hs-CRP levels. A pooled analysis showed that adding colesevelam HCl to statin therapy significantly lowered LDL cholesterol levels (21 mg/dl or 16% mean reduction from baseline, p = 0.0013, and 11 mg/dl or 9% mean reduction compared with placebo, p = 0.0003). Four times as many patients receiving colesevelam HCl plus a statin achieved a LDL cholesterol target of <100 mg/dl compared with patients receiving a statin plus placebo (39% vs 10%, respectively, p <0.0001). The incidence of mild gastrointestinal adverse effects was slightly higher in the colesevelam HCl plus statin group than in the placebo plus statin group. Finally, the differences in the change in hs-CRP levels with colesevelam HCl plus statin therapy were significant compared with the changes with placebo plus statin (median change -23%, p = 0.0069). In conclusion, this is the first report suggesting that an approved cholesterol-lowering bile acid sequestrant, specifically colesevelam HCl, decreases hs-CRP levels when added to statin therapy.

Allylamine↗
PubMed2006

Colesevelam hydrochloride in the management of dyslipidemia.

Dyslipidemia is a highly heterogeneous group of disorders strongly influenced by both genetic and environmental factors. Dyslipidemia significantly increases risk for atherosclerotic disease and all of its various clinical manifestations. Identifying patients with dyslipidemia and initiating therapies aimed at normalizing the lipid profile has been demonstrated to significantly reduce the risk for myocardial infarction, stroke and cardiovascular mortality in both the primary and secondary prevention settings. Guidelines in Europe, Canada and the USA emphasize the need to reduce the burden of atherogenic lipoproteins in serum and to raise levels of high-density lipoproteins in patients at risk for cardiovascular events. Statins have emerged as front-line therapy for managing dyslipidemia, especially in patients with elevated serum levels of low-density lipoprotein cholesterol. As guidelines emphasize the need to reduce serum low-density lipoprotein cholesterol to lower levels, goal attainment can be challenging. The use of combination therapy increases the likelihood of therapeutic success for many patients. Furthermore, a significant percentage of patients with dyslipidemia either cannot achieve goals on statin monotherapy, choose not to take a statin or do not tolerate these drugs due to adverse side effects, such as myalgias, weakness or hepatotoxicity. This article summarizes the pharmacology, clinical efficacy and safety of colesevelam hydrochloride, a bile acid-binding resin. Bile acid-binding resins are orally administered anion-exchange resins that are not absorbed systemically. These agents bind bile acids and reduce their reabsorption at the level of the terminal ileum and prevent their enterohepatic recirculation. Colesevelam has a favorable side effect and toxicity profile and significantly impacts serum levels of lipoproteins when used as monotherapy or when used in combination with either statins or ezetimibe.

Allylamine↗
PubMed2005

Safety and efficacy of colesevelam hydrochloride in combination with fenofibrate for the treatment of mixed hyperlipidemia.

OBJECTIVE: The aim of this study was to evaluate the amount of low-density lipoprotein cholesterol (LDL-C) reduction achieved by adding the specifically engineered bile acid sequestrant (SE-BAS) colesevelam HCl to a stable dose of fenofibrate in patients with mixed hyperlipidemia. RESEARCH DESIGN AND METHODS: Patients with mixed hyperlipidemia (n = 129) were enrolled in a randomized, double-blind, placebo-controlled, parallel-group study investigating the efficacy of fenofibrate plus colesevelam HCl versus fenofibrate monotherapy. After a 4- to 8-week washout period, subjects received fenofibrate 160 mg/day for 8 weeks and were then randomized to receive colesevelam HCl 3.75 g/day or placebo, in addition to fenofibrate 160 mg/day, for 6 weeks. MAIN OUTCOMES MEASURES: The primary efficacy endpoint was mean percent change in LDL-C during randomized treatment. Secondary endpoints included absolute and percent changes in mean levels of LDL-C, triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, total cholesterol (TC), and apolipoproteins (apo) A-I and B during randomized treatment and from washout to end of randomized treatment. RESULTS: Of the 129 patients randomized to treatment, 119 completed the study. After 6 weeks of treatment, fenofibrate plus colesevelam HCl produced a mean percent change in LDL-C of -10.4% versus +2.3% with fenofibrate monotherapy (p < 0.0001). Fenofibrate plus colesevelam HCl was significantly more effective than fenofibrate alone at reducing levels of non-HDL-C, TC, and apo B (p < or = 0.0002). Colesevelam HCl did not significantly affect the TG-lowering effects of fenofibrate. Both treatment regimens were safe and well tolerated. CONCLUSIONS: Compared with fenofibrate monotherapy in patients with mixed hyperlipidemia, fenofibrate/colesevelam HCl combination therapy significantly reduced mean LDL-C, non-HDL-C, TC, and apo B levels without significantly affecting the TG-lowering or HDL-C-raising effects of fenofibrate. Fenofibrate/colesevelam HCl combination therapy is a safe, useful alternative for the treatment of mixed hyperlipidemia.

Allylamine↗