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Colesevelam

A Review of its Use in Hypercholesterolemia

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Summary

Abstract

Colesevelam hydrochloride (Cholestagel®, WelChol®) is an orally administered, non-absorbable, polymeric, bile-acid-binding agent with a higher affinity for glycocholic acid in vitro and greater capacity for binding bile acids in vivo than other bile-acid-binding agents.

In randomized controlled trials in patients with primary hypercholesterolemia, colesevelam monotherapy reduced mean serum low-density lipoprotein-cholesterol (LDL-C) levels by 9–19%. In combination with an HMG-CoA reductase inhibitor (statin) or fenofibrate, colesevelam induced additive reductions in LDL-C 10–16% greater than those achieved by monotherapy with a statin (in patients with primary hypercholesterolemia) or fenofibrate (in patients with mixed hyperlipidemia). Colesevelam was generally well tolerated, with a relatively low incidence of gastrointestinal adverse events and a high compliance rate. Thus, colesevelam provides a useful addition to primary therapy with statins in the treatment of primary hypercholesterolemia, or fenofibrate in the treatment of mixed hyperlipidemia.

Pharmacologic Properties

Colesevelam, like other bile-acid-binding agents, retains bile acids within the intestinal tract, preventing enterohepatic circulation, depleting hepatic bile acids, and increasing the hepatic conversion of cholesterol to bile acids.

Colesevelam is a hydrophilic, insoluble polymer that has negligible absorption and systemic distribution. It has a higher affinity in vitro for glycocholic acid than other bile-acid-binding agents, such as cholestyramine or colestipol, and a greater in vivo capacity for bile-acid excretion. In healthy volunteers with mild to moderate hypercholesterolemia, administration of colesevelam 2.3 or 3.8 g/day for 28 days increased the excretion of bile acids ≈3-fold and reduced LDL-C levels by 10% or 13%.

While other bile-acid-binding agents slow the absorption of some concomitantly administered drugs, no clinically important pharmacokinetic interactions occur between colesevelam and digoxin, fenofibrate, lovastatin, metoprolol, quinidine, valproic acid, sustained-release verapamil, or warfarin.

Therapeutic Efficacy

In patients with primary hypercholesterolemia, monotherapy with colesevelam 2.3–4.5 g/day reduced serum LDL-C levels (9–19%) in a dose-related manner during a 6- or 24-week period of treatment. Colesevelam administered in combination with atorvastatin, lovastatin, pravastatin, or simvastatin resulted in additive reductions in mean serum LDL-C levels 10–16% greater than those induced by statin monotherapy.

In patients with mixed hyperlipidemia, colesevelam 3.75 g/day for 6 weeks reduced mean serum LDL-C levels by an additional 10% when added to ongoing fenofibrate 160 mg/day therapy.

In general, colesevelam monotherapy or combination therapy was also associated with favorable changes in other serum lipid levels, reducing total cholesterol levels and inducing small but significant increases in highdensity lipoprotein-cholesterol levels. Serum triglyceride levels increased with respect to baseline levels in several trials, but these changes did not differ significantly from those with placebo, except for a decline in one trial when used in combination with simvastatin in previously untreated patients, and an increase in another when added to existing stable simvastatin therapy.

Tolerability

Overall, the adverse event profile of colesevelam as monotherapy, or in combination with statins or fenofibrate, was favorable compared with that of placebo, or monotherapy with other lipid-modifying agents, although the incidences of gastrointestinal adverse events (constipation and dyspepsia) were numerically higher in colesevelam monotherapy than placebo recipients, and the incidences of constipation and myalgia were numerically higher in recipients of colesevelam plus statin combination therapy than monotherapy. However, overall colesevelam treatment compliance was high, with only 8% of colesevelam recipients in a 24-week trial withdrawing because of treatment-related adverse events.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Yusuf S, Reddy S, Ôunpuu S, et al. Global burden of cardiovascular diseases. Part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation 2001 Nov; 104 (22): 2746–53.

    Article  PubMed  CAS  Google Scholar 

  2. Graham I, Atar D, Borch-Johnson K, et al. European guidelines on cardiovascular disease prevention in clinical practice: executive summary. Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Eur Heart J 2007 Aug 28; 28: 2375–414.

    Article  PubMed  Google Scholar 

  3. American Heart Association. Heart disease and stroke statistics: 2006 update (at-aglance version) [online]. Available from URL: http://www.americanheart.org/downloadable/heart/1140534985281Statsupdate06book.pdf [Accessed 2007 Aug 25].

  4. Tolonen H, Keil U, Ferrario M, et al. Prevalence, awareness and treatment of hypercholesterolaemia in 32 populations: results from the WHO MONICA project. Int J Epidemiol 2005; 34 (1): 181–92.

    Article  PubMed  Google Scholar 

  5. European Medicines Agency. Summary of product characteristics (Cholestagel) [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/cholestagel/H-512-PI-en.pdf [Accessed 2006 Jul 30].

  6. Daiichi Sankyo Inc. WelChol® tablets (colesevelam hydrochloride) prescribing information [online]. Available from URL: http://www.welchol.com/pdfs/fullPI.pdf [Accessed 2006 Oct 25]

  7. Zema MJ. Colesevelam HCl and ezetimibe combination therapy provides effective lipid-lowering in difficult-to-treat patients with hypercholesterolemia. Am J Ther 2005 Jul–Aug; 12 (4): 306–10.

    Article  PubMed  Google Scholar 

  8. Bays HE, Rhyne J, Abby S, et al. Lipid lowering effects of colesevelam HCl in combination with ezetimibe. Curr Med Res Opin 2006 Oct; 22 (11): 2191–200.

    Article  PubMed  CAS  Google Scholar 

  9. Rivers SM, Kane MP, Busch RS, et al. Colesevelam hydrochloride-ezetimibe combination lipid-lowering therapy in patients with diabetes or metabolic syndrome and a history of statin intolerance. Endocr Pract 2007 Jan–Feb; 13 (1): 11–6.

    PubMed  Google Scholar 

  10. Knopp RH, Tsunehara C, Retzlaff BM, et al. Lipoprotein effects of combined ezetimibe and colesevelam hydrochloride versus ezetimibe alone in hypercholesterolemic subjects: a pilot study. Metabolism 2006 Dec; 55 (12): 1697–703.

    Article  PubMed  CAS  Google Scholar 

  11. Zieve FJ, Kalin MF, Schwartz SL, et al. Results of the Glucose-lowering effect of WelChol Study (GLOWS): a randomized, double-blind, placebo-controlled pilot study evaluating the effect of colesevelam hydrochloride on glycemic control in subjects with type 2 diabetes. Clin Ther 2007 Jan; 29 (1): 74–83.

    Article  PubMed  CAS  Google Scholar 

  12. Daiichi Sankyo, Inc. announces filing of supplemental new drug application for Welchol in the treatment of type 2 diabetes mellitus [media release]. Daiichi Sankyo, Inc., 2007 Jan 2.

  13. Heller DP, Burke SK, Davidson DM, et al. Absorption of colesevelam hydrochloride in healthy volunteers. Ann Pharmacother 2002 Mar; 36: 398–403.

    Google Scholar 

  14. Melian EB, Plosker GL. Colesevelam. Am J Cardiovasc Drug 2001; 1 (2): 141–6.

    Article  CAS  Google Scholar 

  15. Rosenbaum DP, Petersen JS, Ducharme S, et al. Absorption, distribution and excretion of GT31-104, a novel bile acid sequestrant, in rats and dogs after acute and subchronic administration. J Pharm Sci 1997 May; 86 (5): 591–5.

    Article  PubMed  CAS  Google Scholar 

  16. Donovan JM, Von Bergmann K, Setchell KDR, et al. Effects of colesevelam HCl on sterol and bile acid excretion in patients with type IIa hypercholesterolemia. Dig Dis Sci 2005 Jul; 50 (7): 1232–8.

    Article  PubMed  CAS  Google Scholar 

  17. Braunlin W, Zhorov E, Smisek D, et al. In vitro comparison of bile acid binding to colesevelam and other bile acid sequestrants. Polymer Reprints 2000; 41 (1): 708–9.

    CAS  Google Scholar 

  18. Center for Drug Evaluation and Research. Application number: 21–141 and 21–176 pharmacological review(s) [online]. Available from URL: http://www.access-data.fda.gov/scripts/cder/drugsatfda/index.cfm [Accessed 2006 Aug 28].

  19. Davidson MH, Dillon MA, Gordon B, et al. Colesevelam hydrochloride (cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects. Arch Intern Med 1999 Sep 13; 159 (16): 1893–900.

    Article  PubMed  CAS  Google Scholar 

  20. Insull Jr W, Toth P, Mullican W, et al. Effectiveness of colesevelam hydrochloride in decreasing LDL cholesterol in patients with primary hypercholesterolemia: a 24-week randomized controlled trial. Mayo Clin Proc 2001; 76 (10): 971–82.

    Article  PubMed  CAS  Google Scholar 

  21. Davidson MH, Toth P, Weiss S, et al. Low-dose combination therapy with colesevelam hydrochloride and lovastatin effectively decreases low-density lipoprotein cholesterol in patients with primary hypercholesterolemia. Clin Cardiol 2001 Jun; 24: 467–74.

    Google Scholar 

  22. Bays HE, Davidson M, Jones MR, et al. Effects of colesevelam hydrochloride on low-density lipoprotein cholesterol and high-sensitivity C-reactive protein when added to statins in patients with hypercholesterolemia. Am J Cardiol 2006 Apr 15; 97 (8): 1198–205.

    Article  PubMed  CAS  Google Scholar 

  23. Hunninghake D, Insull W, Toth P, et al. Coadministration of colesevelam hydrochloride with atorvastatin lowers LDL cholesterol additively. Atherosclerosis 2001 Oct; 158: 407–16.

    Google Scholar 

  24. Knapp HH, Schrott H, Ma P, et al. Efficacy and safety of combination simvastatin and colesevelam in patients with primary hypercholesterolemia. Am J Med 2001; 110 (5): 352–60.

    Article  PubMed  CAS  Google Scholar 

  25. McKenney J, Jones M, Abby S. Safety and efficacy of colesevelam hydrochloride in combination with fenofibrate for the treatment of mixed hyperlipidemia. Curr Med Res Opin 2005 Sep; 21 (9): 1403–12.

    Article  PubMed  CAS  Google Scholar 

  26. Donovan JM, Stypinski D, Stiles MR, et al. Drug interactions with colesevelam hydrochloride, a novel, potent lipid-lowering agent. Cardiovasc Drugs Ther 2000 Dec; 14 (6): 681–90.

    Article  PubMed  CAS  Google Scholar 

  27. Donovan JM, Kisicki JC, Stiles MR, et al. Effect of colesevelam on lovastatin pharmacokinetics. Ann Pharmacother 2002 Mar; 36: 392–7.

    Google Scholar 

  28. Jones MR, Baker BA, Mathew P. Effect of colesevelam HCl on single-dose fenofibrate pharmacokinetics. Clin Pharmacokinet 2004; 43 (13): 943–50.

    Article  PubMed  CAS  Google Scholar 

  29. Sankyo Pharma. Colesevelam hydrochloride clinical executive summary. Rockville (MD): Sankyo Pharma, 2000. (Data on file).

  30. European Medicines Agency. Scientific discussion (Cholestagel) [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/cholestagel/586403en6.pdf [Accessed 2006 Jul 30].

  31. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterollowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005 Oct 8; 366 (9493): 1267–78.

    Article  PubMed  CAS  Google Scholar 

  32. Executive summary of the 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). JAMA 2001 May 16; 285 (19): 2486–97.

  33. Armani A, Toth PP. Colesevelam hydrochloride in the management of dyslipidemia. Expert Rev Cardiovasc Ther 2006 May; 4 (3): 283–91.

    Article  PubMed  CAS  Google Scholar 

  34. Pearson TA, Laurora I, Chu H, et al. The lipid treatment assessment project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000 Feb 28; 160 (4): 459–67.

    Article  PubMed  CAS  Google Scholar 

  35. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004 Jul 13; 110 (2): 227–39.

    Article  PubMed  Google Scholar 

  36. Cheng AY, Leiter LA. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Curr Opin Cardiol 2006 Jul; 21 (4): 400–4.

    PubMed  Google Scholar 

  37. Davidson MH. Combination therapy for dyslipidemia: safety and regulatory considerations. Am J Cardiol 2002; 90 (10 Suppl. 2): 50K–60K.

    Article  PubMed  CAS  Google Scholar 

  38. Knopp RH, Gitter H, Truitt T, et al. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J 2003; 24 (8): 729–41.

    Article  PubMed  CAS  Google Scholar 

  39. 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) [online]. Available from URL: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf [Accessed 2006 Sep 20].

  40. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984 Jan 20; 251 (3): 351–64.

  41. Andrade SE, Walker AM, Gottlieb LK, et al. Discontinuation of antihyperlipidemic drugs: do rates reported in clinical trials reflect rates in primary care settings? N Engl J Med 1995 Apr 27; 332 (17): 1125–31.

    Article  PubMed  CAS  Google Scholar 

  42. Jones P, Kafonek S, Laurora I, et al. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998 Mar 1; 81 (5): 582–7.

    Article  PubMed  CAS  Google Scholar 

  43. Jacobson TA. Statin safety: lessons from new drug applications for marketed statins. Am J Cardiol 2006 Apr 17; 97 (8A): 44C–51C.

    Article  PubMed  CAS  Google Scholar 

  44. Tardif JC, Heinonen T, Orloff D, et al. Vascular biomarkers and surrogates in cardiovascular disease. Circulation 2006; 113 (25): 2936–42.

    Article  PubMed  Google Scholar 

  45. The 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 (3): 365–74.

  46. Dorr AE, Gundersen K, Schneider Jr JC, et al. Colestipol hydrochloride in hypercholesterolemic patients—effect on serum cholesterol and mortality. J Chronic Dis 1978 Jan; 31 (1): 5–14.

    Article  PubMed  CAS  Google Scholar 

  47. The lipid research clinics coronary primary prevention trial results. I: reduction in incidence of coronary heart disease. JAMA 1984; 251 (3): 351–64.

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Authors and Affiliations

  1. Wolters Kluwer Health ∣ Adis, 41 Centorian Drive, Private Bag 65901 Mairangi Bay, North Shore, 0754, Auckland, New Zealand

    Dean M. Robinson & Gillian M. Keating

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  1. Dean M. Robinson
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  2. Gillian M. Keating
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Corresponding author

Correspondence to Dean M. Robinson.

Additional information

Various sections of the manuscript reviewed by:

H.E. Bays, Louisville Metabolic and Atherosclerosis Research Center Incorporated, Louisville, Kentucky, USA; E. Bruckert, Service d’Endocrinologie-Metabolisme, Centre de Detection et de Prevention de l’Atherosclerose, Groupe Hospitalier Pitie, Paris, France; D. Gavish, Department of Medicine A, Wolfson Medical Center, Holon, Israel; P.H. Jones, Baylor Lipid Clinic, Section of Atherosclerosis, Baylor College of Medicine, Houston, Texas, USA; L. Ose, Lipid Clinic, Medical Department, Rikshospitalet, Oslo, Norway; J. Schaefer, Department of Internal Medicine and Cardiology, Philipps University of Marburg, Marburg, Germany; H.G Schrott, Department of Preventive Medicine, University of Iowa College of Medicine, Iowa City, Iowa, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘colesevelam,’ identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Wolters Kluwer Health | Adis). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search term was ‘colesevelam.’ Searches were last updated 6 Nov 2007.

Selection: Studies in patients with hypercholesterolemia who received colesevelam. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: colesevelam, hyperlipidemia, hypercholesterolemia, pharmacodynamics, pharmacokinetics, tolerability, therapeutic use.

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Robinson, D.M., Keating, G.M. Colesevelam. Am J Cardiovasc Drugs 7, 453–465 (2007). https://doi.org/10.2165/00129784-200707060-00009

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