Effects of Colesevelam Hydrochloride on Low-Density Lipoprotein Cholesterol and High-Sensitivity C-Reactive Protein When Added to Statins in Patients With Hypercholesterolemia
2006; Elsevier BV; Volume: 97; Issue: 8 Linguagem: Inglês
10.1016/j.amjcard.2005.11.039
ISSN1879-1913
AutoresHarold Bays, Michael H. Davidson, Michael R. Jones, Stacey L. Abby,
Tópico(s)Drug Transport and Resistance Mechanisms
ResumoElevated 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. 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 2.0 mg/dl; an alanine or aspartate transaminase concentration >2.5 times the upper limit of normal; a fasting plasma glucose concentration ≥300 mg/dl; a creatine kinase concentration >3 times the upper limit of normal; or received treatment with lipid-lowering drugs (other than the entry criteria statin) within 10 weeks before visit 1. Patients were also excluded if they had serious or significant medical conditions that the investigators considered could potentially compromise study participant safety. The primary efficacy parameter in all 3 studies was the mean percent change in LDL cholesterol levels from baseline to end point. Secondary efficacy parameters included the absolute change and the percent change in high-density lipoprotein (HDL) cholesterol, total cholesterol, apolipoprotein (apo) A-I, apo-B, and triglyceride levels, and the absolute change in hs-CRP level. Each study was powered to evaluate changes in LDL cholesterol. However, the studies were not powered to detect changes in additional secondary variables; thus, a pooled analysis was conducted to evaluate the changes in these variables. Additionally, a post hoc analysis was conducted to determine the median percent change in hs-CRP. Safety was assessed by evaluating the incidence of treatment-emergent adverse events, changes in laboratory safety parameters, vital signs, and physical examination findings. Efficacy and tolerability were assessed during weeks 4 and 6 of the treatment period. Lipid profiles and inflammatory markers were assayed at a central laboratory (Medical Research Laboratories International, Highland Heights, Kentucky). The total cholesterol and triglyceride levels were measured by enzyme assays. HDL cholesterol levels were measured by cholesterol oxidase assay of the supernatant from the precipitate of non-HDL lipoproteins with heparin and manganese chloride. LDL cholesterol levels were calculated by the Friedewald formula if the triglyceride level was <400 mg/dl. If the triglyceride concentration was ≥400 mg/dl, LDL cholesterol levels were determined directly by the betaquant method. Apo-B and apo-A-I levels were quantified by immunonephelometry. hs-CRP levels were quantified using a hs-CRP assay, also by immunonephelometry (Dade Behring, Deerfield, Illinois). Sample sizes were determined using the following assumptions: a statistical significance level of 5%, a power of 80%, a dropout rate of 10%, a pooled SD of 12%, and a difference of 10% between the percent change in LDL cholesterol levels in the colesevelam HCl group and placebo group. Safety analyses were performed on the population of all randomized subjects, which included all patients who took ≥1 dose of randomized study medication. Lipid parameters and hs-CRP data were reported for the intent-to-treat population, defined as all randomized subjects who took ≥1 dose of randomized study medication and had a baseline lipid measurement and ≥1 post-baseline lipid assessment taken within 72 hours of the last dose of randomized study medication. Baseline measurements were taken at week 0 (after completion of the 4-week statin run-in phase), and the end point measurements were the last observed measurements taken within 72 hours of the last dose of randomized study medication. An analysis of covariance model was used for all efficacy end points, with treatment and center as factors and centralized baseline as a covariate. Least-square means, corresponding to 2-tailed 95% confidence intervals, and p values were calculated for treatment differences (colesevelam HCl vs placebo). The median values are reported for parameters not normally distributed. p Values were obtained from the Cochran-Mantel-Haenszel test in nonparametric analysis of covariance, and 95% confidence intervals were estimated using the Hodges-Lehmann estimator and Tukey method for mean values and the Hodges-Lehmann estimator and Moses method for median values. The flow of patients through the trials is depicted in Figure 2. A total of 204 patients were randomized in the 3 trials. In conducting the pooled analyses, it was discovered that 1 patient in the placebo group of the atorvastatin study had been dispensed medication from another study. Thus, that patient's data were excluded from the population of all randomized patients. This did not affect the numbers of patients included in the efficacy analyses (intent-to-treat population). Pooled subject demographics were similar among the 3 groups (Table 2).Table 2Pooled baseline demographics at screening of all patients randomized to treatment who received at least one dose of study medicationDemographic CharacteristicStatin+ Placebo (n = 69)+ Colesevelam HCl (n = 134)Age (yrs) (mean ± SD)58.0 ± 10.257.3 ± 11.3Men32 (46%)59 (44%)Women37 (54%)75 (56%)White45 (65%)87 (65%)Black7 (10%)12 (9%)Asian0 (0%)3 (2%)Hispanic17 (25%)32 (24%)Coronary heart disease or peripheral vascular disease4 (6%)14 (10%)Type 2 diabetes mellitus⁎Mean baseline fasting glucose level was 104.1 ± 25.2 and 105.2 ± 34.1 mg/dl in placebo and colesevelam HCl groups, respectively; mean end-of-study glucose level was 104.4 ± 29.2 and 103.0 ± 27.7 mg/dl in placebo and colesevelam HCl group, respectively.10 (14%)18 (13%)Mean body mass index (kg/m2)28.8 ± 4.328.5 ± 4.6No significant differences were reported between pooled treatment groups. Mean baseline fasting glucose level was 104.1 ± 25.2 and 105.2 ± 34.1 mg/dl in placebo and colesevelam HCl groups, respectively; mean end-of-study glucose level was 104.4 ± 29.2 and 103.0 ± 27.7 mg/dl in placebo and colesevelam HCl group, respectively. Open table in a new tab No significant differences were reported between pooled treatment groups. A pooled analysis of all 3 trials showed that the groups receiving colesevelam HCl plus statin therapy had significantly greater mean reductions in LDL cholesterol levels compared with baseline values and compared with the end-of-study placebo plus statin groups (Table 3). Four times as many patients administered colesevelam HCl achieved a LDL cholesterol target level of <100 mg/dl1National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.Circulation. 2002; 106: 3143-3421PubMed Google Scholar compared with patients administered placebo (39% vs 10%, respectively, p <0.0001). Colesevelam HCl plus statins also significantly lowered total cholesterol levels from baseline values and more than the placebo plus statin values, although the reduction in apo-B levels with colesevelam HCl plus statins compared with that with placebo plus statins was not significant. Triglyceride and apo-A-I levels increased significantly in the colesevelam HCl plus statin group compared with baseline and compared with the placebo plus statin group. However, the increase in HDL cholesterol levels with colesevelam HCl was not significant in the pooled data.Table 3Pooled analysis of absolute and percent change in lipid parameters from baseline to end point in patients receiving statins (atorvastatin, simvastatin, or pravastatin) alone or in combination with colesevelam hydrochloride (HCl)BaselineEnd PointLS Absolute Change from Baseline (95% CI)Absolute Treatment Difference (95% CI)LS % Change from Baseline (95% CI)% Treatment Difference (95% CI)Mean LDL-C (mg/dl)Statin + placebo (n = 67)129.9120.2−10.2 (−15.5 to −4.9)−6.5 (−10.5 to −2.5)Statin + colesevelam HCl (n = 127)132.6111.3−21.0 (−24.9 to −17.2)−10.8 (−17.4 to −4.3)⁎p <0.01;−15.7 (−18.6 to −12.9)−9.2 (−14.1 to −4.3)†p ≤0.001;Mean HDL-C (mg/dl)Statin + placebo (n = 67)51.851.5−0.3 (−1.7 to 1.1)−0.4 (−3.0 to 2.2)Statin + colesevelam HCl (n = 127)51.651.5−0.1 (−1.2 to 0.9)+0.2 (−1.4 to 1.8)0.0 (−1.9 to 2.0)+0.5 (−2.6 to 3.5)Mean total cholesterol (mg/dl)Statin + placebo (n = 67)211.9203.8−8.6 (−14.4 to −2.7)−3.4 (−6.1 to −0.7)Statin + colesevelam HCl (n = 127)214.1197.6−16.3 (−20.5 to −12.0)−7.7 (−14.9 to −0.5)‡p <0.05.−7.2 (−9.2 to −5.3)−3.9 (−7.2 to −0.5)‡p <0.05.Median triglycerides (mg/dl)Statin + placebo (n = 67)154.0139.0+4.3 (−5.5 to 12.5)+4.1 (−1.8 to 9.9)Statin + colesevelam HCl (n = 127)137.0159.0+20.9 (12.8 to 29.8)+15.5 (3.0 to 30.0)‡p <0.05.+16.3 (10.5 to 23.4)+11.0 (2.2 to 19.8)‡p <0.05.Mean apo-A-I (mg/dl)Statin + placebo (n = 67)160.5159.4−1.0 (−4.8 to 2.8)−0.2 (−2.6 to 2.2)Statin + colesevelam HCl (n = 127)158.9166.1+7.2 (4.5 to 10.0)+8.2 (3.6 to 12.9)†p ≤0.001;+4.8 (3.1 to 6.6)+5.1 (2.1 to 8.0)†p ≤0.001;Mean apo-B (mg/dl)Statin + placebo (n = 67)127.5119.7−8.5 (−13.0 to −4.0)−5.8 (−9.2 to −2.3)Statin + colesevelam HCl (n = 127)131.1119.3−11.4 (−14.8 to −8.1)−2.9 (−8.4 to 2.5)−8.3 (−10.9 to −5.8)−2.5 (−6.7 to 1.6)Treatment difference = colesevelam HCl − placebo.CI = confidence interval; HDL-C = HDL cholesterol; LDL-C = LDL cholesterol; LS = least square. p <0.01;† p ≤0.001;‡ p <0.05. Open table in a new tab Treatment difference = colesevelam HCl − placebo. CI = confidence interval; HDL-C = HDL cholesterol; LDL-C = LDL cholesterol; LS = least square. The lipid results of the patient trials are given in Table 4.Table 4Percent change in lipid parameters from baseline to end point in patients receiving statins (atorvastatin, simvastatin, or pravastatin) alone or in combination with colesevelam hydrochloride (HCl)Mean Baseline (mg/dl)Mean End Point (mg/dl)LS Mean Percent Change from Baseline (95% CI)Percent Treatment Difference (95% CI)LDL-CSimvastatin + placebo (n = 25)126.1123.3−1.1 (−8.4 to 6.2)Simvastatin + colesevelam HCl (n = 44)132.1107.6−18.6 (−24.1 to −13.1)⁎p <0.05 compared with baseline;−17.5 (−26.7 to −8.3)†p <0.001 compared with statin + placebo;Atorvastatin + placebo (n = 23)131.7112.9−13.5 (−20.0 to −7.0)⁎p <0.05 compared with baseline;Atorvastatin + colesevelam HCl (n = 38)133.2109.9−17.2 (−22.3 to −12.1)⁎p <0.05 compared with baseline;−3.7 (−12.0 to 4.5)Pravastatin + placebo (n = 19)132.6125.0−4.7 (−12.4 to 2.9)Pravastatin + colesevelam HCl (n = 45)132.7116.0−11.9 (−17.4 to −6.3)⁎p <0.05 compared with baseline;−7.1 (−14.9 to 0.6)HDL-CSimvastatin + placebo (n = 25)57.057.01.0 (−3.6 to 5.6)Simvastatin + colesevelam HCl (n = 44)52.253.22.0 (−1.4 to 5.5)1.0 (−4.8 to 6.8)Atorvastatin + placebo (n = 23)49.148.7−1.0 (−5.4 to 3.4)Atorvastatin + colesevelam HCl (n = 38)51.351.61.0 (−2.4 to 4.3)2.0 (−3.6 to 7.5)Pravastatin + placebo (n = 19)48.347.5−1.1 (−5.8 to 3.6)Pravastatin + colesevelam HCl (n = 45)51.449.9−2.5 (−5.9 to 1.0)−1.3 (−6.1 to 3.4)Total cholesterolSimvastatin + placebo (n = 25)211.4208.9−0.7 (−5.7 to 4.3)Simvastatin + colesevelam HCl (n = 44)214.7196.7−8.2 (−12.0 to −4.4)⁎p <0.05 compared with baseline;−7.5 (−13.8 to −1.2)‡p <0.05 compared with statin + placebo.Atorvastatin + placebo (n = 23)214.0198.3−6.6 (−11.3 to −1.9)⁎p <0.05 compared with baseline;Atorvastatin + colesevelam HCl (n = 38)213.4194.7−8.4 (−12.1 to −4.8)⁎p <0.05 compared with baseline;−1.8 (−7.7 to 4.2)Pravastatin + placebo (n = 19)210.1203.8−3.0 (−7.5 to 1.5)Pravastatin + colesevelam HCl (n = 45)214.1201.0−5.3 (−8.3 to −2.4)⁎p <0.05 compared with baseline;−2.3 (−7.6 to 3.0)Triglycerides (median)Simvastatin + placebo (n = 25)146.0128.02.1 (−7.3 to 11.3)Simvastatin + colesevelam HCl (n = 44)140.8174.017.8 (8.1 to 28.5)⁎p <0.05 compared with baseline;15.0 (1.3 to 28.7)‡p <0.05 compared with statin + placebo.Atorvastatin + placebo (n = 23)163.5161.09.4 (−6.2 to 25.3)Atorvastatin + colesevelam HCl (n = 38)125.5151.515.5 (5.5 to 28.3)⁎p <0.05 compared with baseline;8.8 (−6.7 to 23.1)Pravastatin + placebo (n = 19)155.5139.04.7 (−6.6 to 13.5)Pravastatin + colesevelam HCl (n = 45)145.5152.016.4 (3.8 to 29.4)⁎p <0.05 compared with baseline;9.4 (−6.4 to 30.9)Apo A-ISimvastatin + placebo (n = 25)169.9167.0−1.3 (−5.8 to 3.2)Simvastatin + colesevelam HCl (n = 44)162.2171.35.7 (2.3 to 9.0)⁎p <0.05 compared with baseline;6.9 (1.3 to 12.6)‡p <0.05 compared with statin + placebo.Atorvastatin + placebo (n = 23)158.6160.01.7 (−2.3 to 5.6)Atorvastatin + colesevelam HCl (n = 38)156.2163.74.9 (1.9 to 8.0)⁎p <0.05 compared with baseline;3.3 (−1.7 to 8.2)Pravastatin + placebo (n = 19)150.5148.8−1.3 (−5.8 to 3.1)Pravastatin + colesevelam HCl (n = 45)157.9163.14.1 (1.2 to 6.9)⁎p <0.05 compared with baseline;5.4 (0.1 to 10.7)‡p <0.05 compared with statin + placebo.Apo BSimvastatin + placebo (n = 25)124.4118.3−4.4 (−10.7 to 1.8)Simvastatin + colesevelam HCl (n = 44)131.1116.4−10.7 (−15.3 to −6.0)⁎p <0.05 compared with baseline;−6.2 (−14.0 to 1.6)Atorvastatin + placebo (n = 23)129.5117.2−8.9 (−15.0 to −2.7)⁎p <0.05 compared with baseline;Atorvastatin + colesevelam HCl (n = 38)130.3116.9−9.6 (−14.4 to −4.9)⁎p <0.05 compared with baseline;−0.8 (−8.5 to 7.0)Pravastatin + placebo (n = 19)129.1124.7−3.4 (−8.7 to 1.8)Pravastatin + colesevelam HCl (n = 45)131.8124.3−4.8 (−8.2 to −1.4)⁎p <0.05 compared with baseline;−1.4 (−7.6 to 4.9)Abbreviations as in Table 3. p <0.05 compared with baseline;† p <0.001 compared with statin + placebo;‡ p <0.05 compared with statin + placebo. Open table in a new tab Abbreviations as in Table 3. The pooled analysis of all 3 trials showed that the change in hs-CRP levels with colesevelam HCl added to statins was significant compared with the change in hs-CRP when placebo was added to statin therapy (Table 5). Although not powered to detect changes in additional secondary variables, the results from these patient trials showed that combining colesevelam HCl with either simvastatin (p = 0.0154) or pravastatin (p = 0.0279) was associated with significantly greater median percent reductions in hs-CRP levels (data not shown). The absolute median hs-CRP levels at baseline and end point for the patient trials are shown in Figure 3.Table 5Pooled analysis of median percent change in high-sensitivity C-reactive protein (hs-CRP) levels from baseline to end point in patients receiving statins (atorvastatin, simvastatin, or pravastatin) alone or in combination with colesevelam hydrochloride (HCl)TreatmentBaseline (mg/L)End Point (mg/L)LS Median Percent Change from Baseline at End Point (95% CI)Statin + placebo (n = 64)1.62.0+17.2 (2.8 to 35.0)Statin + colesevelam HCl (n = 123)1.61.3−6.2 (−15.8 to 5.9)Treatment difference (%)−23.3 (−40.0 to −6.3)⁎p <0.01.Treatment difference = colesevelam HCl − placebo.Abbreviations as in Table 3. p <0.01. Open table in a new tab Treatment difference = colesevelam HCl − placebo. Abbreviations as in Table 3. No serious drug-related adverse events were reported by any study patient. One patient in the colesevelam HCl group and 1 in the placebo group of the pravastatin study experienced a serious adverse event (cholecystitis and transient ischemic attack, respectively) during treatment, but these events were not considered by the investigators to be related to the study drugs. No deaths occurred during any of the studies. The incidence of drug-related treatment-emergent adverse event rates was higher in patients receiving colesevelam HCl in combination with simvastatin, atorvastatin, or pravastatin (26%, 20%, and 13%, respectively) than in those receiving statins plus placebo (0% to 13%), but most adverse events were mild. The adverse events reported in ≥5% of patients in any 1 treatment group are listed in Table 6. The incidence of mild gastrointestinal adverse effects was numerically higher in the colesevelam HCl plus statin group than in the placebo plus statin group. Fewer than 5% of patients in any of the statin-plus-placebo or statin-plus-colesevelam HCl treatment groups withdrew from the studies as a result of adverse events.Table 6Summary of treatment-emergent adverse events by system organ class and preferred term for individual trials (≥5% in one or two treatment groups) for all randomized patientsAdverse EventSimvastatinAtorvastatinPravastatin+ Placebo (n = 25)+ Colesevelam HCl (n = 47)+ Placebo (n = 24)+ Colesevelam HCl (n = 40)+ Placebo (n = 20)+ Colesevelam HCl (n = 47)Gastrointestinal disorders3 (12.0)12 (25.5)1 (4.2)8 (20.0)2 (10.0)7 (14.9)Constipation0 (0.0)4 (8.5)0 (0.0)5 (12.5)——Dyspepsia1 (4.0)4 (8.5)0 (0.0)2 (5.0)——Abdominal pain lower————1 (5.0)0 (0.0)Abdominal tenderness————1 (5.0)1 (2.1)Diarrhea NOS————1 (5.0)1 (2.1)Nausea————1 (5.0)2 (4.3)Musculoskeletal and connective tissue disorders4 (16.0)3 (6.4)7 (29.2)1 (2.5)1 (5.0)5 (10.6)Myalgia2 (8.0)1 (2.1)2 (8.3)0 (0.0)——Arthralgia——4 (16.7)0 (0.0)1 (5.0)2 (4.3)Joint crepitation——2 (8.3)0 (0.0)——Infections and infestations——2 (8.3)6 (15.0)1 (5.0)6 (12.8)Urinary tract infection NOS——0 (0.0)2 (5.0)——Tooth abscess————1 (5.0)0 (0.0)Hepatobiliary disorders————1 (5.0)0 (0.0)Cholecystitis NOS————1 (5.0)0 (0.0)Data are presented as numbers (percentages).Dash indicates that, in that trial, adverse event occurred in <5% of patients in both the colesevelam HCl and placebo groups.NOS = not otherwise specified. Open table in a new tab Data are presented as numbers (percentages). Dash indicates that, in that trial, adverse event occurred in <5% of patients in both the colesevelam HCl and placebo groups. NOS = not otherwise specified. The BASs, cholestyramine and colestipol, have been shown to reduce the risk of CHD events when administered either as monotherapy2The Lipid Research ClinicsThe Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease.JAMA. 1984; 251: 351-364Crossref PubMed Scopus (3379) Google Scholar, 3The Lipid Research ClinicsThe Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering.JAMA. 1984; 251: 365-374Crossref PubMed Scopus (2071) Google Scholar, 4Brensike J.F. Levy R.I. Kelsey S.F. Passamani E.R. Richardson J.M. Loh I.K. Stone N.J. Aldrich R.F. Battaglini J.W. Moriarty D.J. et al.Effects of therapy with cholestyramine on progression of coronary arteriosclerosis results of the NHLBI Type II Coronary Intervention Study.Circulation. 1984; 69: 313-324Crossref PubMed Scopus (521) Google Scholar, 5Levy R.I. Brensike J.F. Epstein S.E. Kelsey S.F. Passamani E.R. Richardson J.M. Loh I.K. Stone N.J. Aldrich R.F. Battaglini J.W. et al.The influence of changes in lipid values induced by cholestyramine and diet on progression of coronary artery disease results of NHLBI Type II Coronary Intervention Study.Circulation. 1984; 69: 325-337Crossref PubMed Scopus (286) Google Scholar, 6Watts G.F. Lewis B. Brunt J.N. Lewis E.S. Coltart D.J. Smith L.D. Mann J.I. Swan A.V. Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas' Atherosclerosis Regression Study (STARS).Lancet. 1992; 339: 563-569Abstract PubMed Scopus (720) Google Scholar or as a part of combination therapy.7Blankenhorn D.H. Nessim S.A. Johnson R.L. Sanmarco M.E. Azen S.P. Cashin-Hemphill L. Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts.JAMA. 1987; 257: 3233-3240Crossref PubMed Scopus (1308) Google Scholar, 8Brown G. Albers J.J. Fisher L.D. Schaefer S.M. Lin J.T. Kaplan C. Zhao X.Q. Bisson B.D. Fitzpatrick V.F. Dodge H.T. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B.N Engl J Med. 1990; 323: 1289-1298Crossref PubMed Scopus (1867) Google Scholar, 9Kane J.P. Malloy M.J. Ports T.A. Phillips N.R. Diehl J.C. Havel R.J. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens.JAMA. 1990; 264: 3007-3012Crossref PubMed Scopus (702) Google Scholar, 10Whitney E.J. Krasuski R.A. Personius B.E. Michalek J.E. Maranian A.M. Kolasa M.W. Monick E. Brown B.G. Gotto Jr, A.M. A randomized trial of a strategy for increasing high-density lipoprotein cholesterol levels effects on progression of coronary heart disease and clinical events.Ann Intern Med. 2005; 142: 95-104Crossref PubMed Scopus (212) Google Scholar These BASs also effectively reduce LDL cholesterol levels,2The Lipid Research ClinicsThe Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease.JAMA. 1984; 251: 351-364Crossref PubMed Scopus (3379) Google Scholar, 3The Lipid Research ClinicsThe Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering.JAMA. 1984; 251: 365-374Crossref PubMed Scopus (2071) Google Scholar, 4Brensike J.F. Levy R.I. Kelsey S.F. Passamani E.R. Richardson J.M. Loh I.K. Stone N.J. Aldrich R.F. Battaglini J.W. Moriarty D.J. et al.Effects of therapy with cholestyramine on progression of coronary arteriosclerosis results of the NHLBI Type II Coronary Intervention Study.Circulation. 1984; 69: 313-324Crossref PubMed Scopus (521) Google Scholar, 5Levy R.I. Brensike J.F. Epstein S.E. Kelsey S.F. Passamani E.R. Richardson J.M. Loh I.K. Stone N.J. Aldrich R.F. Battaglini J.W. et al.The influence of changes in lipid values induced by cholestyramine and diet on progression of coronary artery disease results of NHLBI Type II Coronary Intervention Study.Circulation. 1984; 69: 325-337Crossref PubMed Scopus (286) Google Scholar but are often poorly tolerated and have significant drug interactions.11Bays H. Dujovne C. Colesevelam HCl a non-systemic lipid-altering drug.Expert Opin Pharmacother. 2003; 4: 779-790PubMed Google Scholar Colesevelam HCl is a specifically engineered BAS that has also shown efficacy in reducing LDL cholesterol levels and is generally well tolerated, with fewer drug interactions than seen with conventional BASs.11Bays H. Dujovne C. Colesevelam HCl a non-systemic lipid-altering drug.Expert Opin Pharmacother. 2003; 4: 779-790PubMed Google Scholar These studies were conducted to determine the effects of colesevelam HCl plus stable statin therapy with regard to the mean percent change in the levels of LDL cholesterol, other lipid parameters, and hs-CRP. All 3 presented studies were similar in design and end points assessed. A limitation to these studies was that an unexpected, unusually large, favorable statin-plus-placebo effect on lipid variables was observed in 2 of the studies, which helped account for the lack of statistical significance observed for some of the lipid parameters in the colesevelam HCl plus statins group when compared with the placebo plus statin group. These finding were at odds with previous trials of colesevelam HCl and statin combination therapy in which the combination significantly reduced LDL cholesterol levels more than statins alone,11Bays H. Dujovne C. Colesevelam HCl a non-systemic lipid-altering drug.Expert Opin Pharmacother. 2003; 4: 779-790PubMed Google Scholar, 12Davidson M.H. Toth P. Weiss S. McKenney J. Hunninghake D. Isaacsohn J. Donovan J.M. Burke S.K. Low-dose combination therapy with colesevelam hydrochloride and lovastatin effectively decreases low-density lipoprotein cholesterol in patients with primary hypercholesterolemia.Clin Cardiol. 2001; 24: 467-474Crossref PubMed Scopus (92) Google Scholar, 13Hunninghake D. Insull Jr, W. Toth P. Davidson D. Donovan J.M. Burke S.K. Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively.Atherosclerosis. 2001; 158: 407-416Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 14Knapp H.H. Schrott H. Ma P. Knopp R. Chin B. Gaziano J.M. Donovan J.M. Burke S.K. Davidson M.H. Efficacy and safety of co
Referência(s)