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Colesevelam Hydrochloride (Cholestagel) a New, Potent Bile Acid Sequestrant Associated with a Low Incidence of Gastrointestinal Side Effects

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Colesevelam Hydrochloride (Cholestagel) a New, Potent Bile Acid Sequestrant Associated with a Low Incidence of Gastrointestinal Side Effects ORIGINAL INVESTIGATION Colesevelam Hydrochloride (Cholestagel) A New, Potent Bile Acid Sequestrant Associated With a Low Incidence of Gastrointestinal Side Effects Michael H. Davidson, MD; Maureen A. Dillon; Bruce Gordon, MD; Peter Jones, MD; Julie Samuels, MD; Stuart Weiss, MD; Jonathon Isaacsohn, MD; Phillip Toth, MD; Steven K. Burke, MD Objectives: To compare colesevelam hydrochloride mg/dL) (19.1%) in the 3.75-g/d colesevelam treatment (Cholestagel), a nonabsorbed hydrogel with bile acid– group. Low-density lipoprotein cholesterol concentra- sequestering properties, with placebo for its lipid- tions at the end of treatment were significantly reduced lowering efficacy, its effects on laboratory and clinical from baseline levels in the 3.0- and 3.75-g/d colesevelam safety parameters, and the incidence of adverse events. treatment groups (P = .01 and P,.001, respectively). To- tal cholesterol levels demonstrated a similar response to Methods: Following diet and placebo lead-in periods, colesevelam treatment, with an 8.1% decrease from base- placebo or colesevelam was administered at 4 dosages (1.5, line in the 3.75-g/d treatment group (P<.001). High- 2.25, 3.0, or 3.75 g/d) for 6 weeks with morning and density lipoprotein cholesterol levels rose significantly evening meals to men and women with hypercholester- in the 3.0- and 3.75-g/d colesevelam treatment groups, olemia (low-density lipoprotein cholesterol level .4.14 by 11.2% (P = .006) and 8.1% (P = .02), respectively. mmol/L [.160 mg/dL]). Patients returned to the clinic Median triglyceride levels did not change from baseline, every 2 weeks throughout the treatment period for lipid nor were there any significant differences between parameter measurements and adverse event assess- treatment groups. The incidence of adverse events was ments. Samples were collected for serum chemistry pro- similar among all groups. files, hematologic studies, coagulation studies, and vita- min level assessment at baseline and after 6 weeks of Conclusions: Colesevelam therapy is effective for low- treatment. ering low-density lipoprotein cholesterol concentra- tions in persons with moderate hypercholesterolemia. It Results: Among the 149 patients randomized, 137 com- lacks the constipating effect of other bile acid seques- pleted the study. Low-density lipoprotein cholesterol con- trants, demonstrating the potential for increased com- centrations decreased in a dosage-dependent manner pliance. 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 Arch Intern Med. 1999;159:1893-1900 LEVATED SERUM concentra- Bile acid sequestrants interrupt the From the Chicago Center for tions of cholesterol, particu- enterohepatic circulation of bile acids by Clinical Research, Chicago, Ill larly low-density lipoprotein binding with them in the intestine to form (Dr Davidson); GelTex (LDL) cholesterol, constitute an insoluble complex that is excreted in Pharmaceuticals Inc, Waltham, a risk factor for the develop- the feces.10 The depletion of the bile acid Mass (Ms Dillon and ment of coronary heart disease (CHD).1-3 pool alters hepatic cholesterol homeosta- Dr Burke); the Rogosin E A direct correlation exists between hyper- sis, producing an increase in surface- Institute, New York, NY cholesterolemia and cardiovascular disease active LDL receptors and decreased se- (Dr Gordon); the Baylor Lipid 4,5 11 Clinic, Houston, Tex mortality and morbidity. Clinical trials rum cholesterol levels. The safety and (Dr Jones); National Clinical have demonstrated that aggressive reduction lipid-lowering efficacy of cholestyramine Research, Richmond, Va of lipid levels reduces this risk in patients resin and colestipol hydrochloride, 2 of the (Dr Samuels); the San Diego with and without CHD.1,6,7 In fact, each 1% most commonly prescribed bile acid se- Endocrine and Medical Clinic, reduction of LDL cholesterol lowers the risk questrants, which have been in use for over San Diego, Calif (Dr Weiss); of CHD by 2%.1,8 Diet and lifestyle interven- 20 years, have been demonstrated repeat- the Metabolic and tionsaregenerallythefirststepstakentoward edly. Bile acid sequestrants alone reduce Atherosclerosis Research reducing lipid levels but often have small and LDL cholesterol concentrations by 10% to Center, Cincinnati, Ohio inconsistent effects. Therefore, pharmaco- 30%.1,12 Combination therapy of bile acid (Dr Isaacsohn); and the Midwest Institute for Clinical logical measures are necessary for those sequestrants with niacin or lovastatin pro- Research Inc, Indianapolis, Ind patients who continue to have elevated lipid duces even larger LDL cholesterol reduc- 9 6,13 (Dr Toth). levels following diet and lifestyle changes. tions of up to 60%. ARCH INTERN MED/ VOL 159, SEP 13, 1999 1893 ©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 PATIENTS AND METHODS determine patient eligibility for the trial, (2) diet/washout (6 weeks for patients currently receiving lipid-lowering PATIENTS medication and 4 weeks for others) to normalize the effect of diet on lipid profiles and to allow for the washout of other Men and women aged 18 years or older who had elevated lipid-lowering drugs, (3) placebo run-in (4 weeks) to as- LDL cholesterol levels were screened for participation in sess compliance prior to randomization, and (4) drug treat- the study at 1 of 6 clinical research centers. Individuals were ment (6 weeks) to compare the safety and efficacy of ineligible if they had tendinous xanthomas, thyroid dis- colesevelam therapy with placebo. ease, clinically significant liver or renal disease, vasculitis, At the time of screening (week −8), all lipid-lowering human immunodeficiency virus infection, poorly con- medications were discontinued, and patients were in- trolled diabetes, poorly controlled hypertension (systolic structed to follow a National Cholesterol Education Pro- blood pressure .160 mm Hg or diastolic blood pressure gram (NCEP) Step 1 diet (total fat intake #30% of total .105 mm Hg), unstable cardiac disease, recent myocar- energy, saturated fat intake #10% of energy, and choles- dial infarction or cardiac bypass surgery (within 2 months terol intake ,300 mg/d) for 4 weeks. Participants were pro- of screening), any evidence of active malignant neoplasm, vided with copies of the educational booklets, Step by Step: any clinically significant unstable medical condition, or any Eating to Lower Your High Blood Cholesterol15 and The 2D serum chemistry or hematologic abnormalities at screen- Food Portion Visual.16 Nutrient intake was estimated using ing. Patients were also excluded from participation if they the University of Minnesota Nutrition Coordination Cen- had a history of dysphagia, swallowing disorder, or motil- ter’s Nutrition Data System, version 2.8 (Minneapolis, Minn, ity disorder of the intestines. Individuals who used probu- 1996). Twenty-four–hour dietary recalls were centrally ad- col in the prior year, used fibrates in the month before ministered by telephone by the Nutrient Analysis Center screening, or had a recent history of ethanol or drug use at the Chicago Center for Clinical Research on 2 noncon- were also ineligible. Pregnant women and nursing moth- secutive days within the last 2 weeks of both the diet lead-in ers were excluded from participation, and women of child- period and the treatment period. bearing potential were required to undergo a urine preg- After the NCEP Step 1 diet stabilization period, pa- nancy test and to be adequately protected against pregnancy. tients returned to the clinic (week −4) for measurement of Patients could not take lipid-lowering medications con- fasting lipid profiles. Placebo was administered (single- currently. Patients were asked to avoid intentional changes blind) to be taken as 5 capsules twice per day with meals in diet during the study, such as fasting or binge eating; if for 4 weeks. Patients returned to the clinic after 2 weeks of they were taking fiber supplements (ie, cellulose, methyl- the placebo run-in period (week −2) and again at the end of cellulose, psyllium, polycarbophil, or bran), patients were the placebo run-in period (week 0) for lipid profile mea- also asked to maintain constant intake levels throughout surements, treatment compliance review, and safety assess- the study. ment. Criteria for entrance into the double-blind treatment This study was conducted in accordance with the US period required at least 80% compliance with placebo in the Code of Federal Regulations for clinical studies (21 CFR) final 2 weeks of the placebo run-in period and mean (weeks and the Declaration of Helsinki. Before the study started, −4 and −2) LDL cholesterol (4.14 mmol/L [160 mg/dL]) the investigators at each site forwarded copies of the pro- and TG (3.39 mmol/L [300 mg/dL]) levels. Furthermore, tocol and consent form of the study to an appropriately con- the difference between the 2 lipid measurements at weeks stituted institutional review board that reviewed and ap- −4 and −2 had to be 12% or more. If the difference was proved the informed consent and the protocol. Signed greater than 12%, a third measurement was obtained and informed consent was obtained from each patient prior to the mean of the 3 measurements was used to determine entering the study. eligibility. At week 0, the study drug was dispensed to patients STUDY DESIGN meeting all lipid and nonlipid criteria in a double-blind fashion according to a computer-generated randomiza- This was a
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