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Toxicity of antilipidemic agents: Facts and fictions

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Abstract

Dyslipidemias, particularly elevated low-density lipoprotein and low high-density lipoprotein cholesterol, are associated with increased cardiovascular morbidity and mortality and frequently require the use of lipid-lowering drugs to reduce risk. These drugs include statins, fibrates, niacin, and intestinal-acting drugs such as bile acid resins and ezetimibe, which can be used as monotherapy or in combination. Short- and long-term safety concerns often influence the selection of a lipid-altering medication. A balance of efficacy with a favorable safety and tolerability profile is necessary for optimal therapeutic benefits. Recent evidence suggests that there may be differences in the adverse event potential among the available lipid-altering drugs, even within the same class. Awareness of clinically relevant adverse events with monotherapy may assist in the safe selection of individualized lipid-lowering therapy regimens, as well as the potential for drug-drug interactions that may pose a unique challenge in selecting combination drug regimens.

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References

  1. Scandinavian Simvastatin Survival Group: Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994, 344:1383–1389.

    Article  Google Scholar 

  2. Shepherd J, Cobbe SM, Ford I, et al.: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study. N Engl J Med 1995, 333:1301–1307.

    Article  PubMed  CAS  Google Scholar 

  3. Downs JR, Clearfield M, Weis S, et al.: Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TEXCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998, 279:1615–1622.

    Article  PubMed  CAS  Google Scholar 

  4. Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002, 360:7–22.

    Article  Google Scholar 

  5. Simes J, Furberg CD, Braunwald E, et al.: Effects of pravastatin on mortality in patients with and without coronary heart disease across a broad range of cholesterol levels. The Prospective Pravastatin Pooling Project. Eur Heart J 2002, 23:207–215.

    Article  PubMed  CAS  Google Scholar 

  6. Sever PS, Dahlof B, Poulter NR, et al., for the ASCOT Investigators: Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA); a multicentre randomised controlled trial. Lancet 2003, 361:1149–1158.

    Article  PubMed  CAS  Google Scholar 

  7. Staffa JA, Chang J, Green L: Cerivastatin and reports of fatal rhabdomyolysis [letter]. N Engl J Med 2002, 346:539–540.

    Article  PubMed  Google Scholar 

  8. Furberg CD, Pitt B: Withdrawal of cerivastatin from the world market. Curr Control Trial Cardiovasc Med 2001, 2:205–207.

    Article  Google Scholar 

  9. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults: 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, 285:2486–2497.

    Article  Google Scholar 

  10. Fruchart JC, Brewer HB, Leitersdorf E: Consensus for the use of fibrates in the treatment of dyslipoproteinemia and coronary heart disease. Am J Cardiol 1998, 81:912–917.

    Article  PubMed  CAS  Google Scholar 

  11. Sacks FM, and Expert Group on HDL Cholesterol: The role of high-density lipoprotein (HDL) cholesterol in the prevention and treatment of coronary heart disease: expert group recommendations. Am J Cardiol 2002, 90:139–143.

    Article  PubMed  CAS  Google Scholar 

  12. Tavintharan S, Kashyap ML: The benefits of niacin in atherosclerosis. Curr Atheroscler Rep 2001, 3:74–82.

    PubMed  CAS  Google Scholar 

  13. Xydakis AM, Ballantyne CM: Combination therapy for combined dyslipidemia. Am J Cardiol 2002, 90:21K-29K.

    Article  PubMed  CAS  Google Scholar 

  14. Servuys PW, de Feyter P, Macaya C, et al., for the Lescol Intervention Prevention Study investigators: Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention. JAMA 2002, 256:3215–3222.

    Article  Google Scholar 

  15. Maron DJ, Fazio S, Linton MF: Current perspectives on statins. Circulation 2000, 101:207–213.

    PubMed  CAS  Google Scholar 

  16. Bottorff M, Hansten P: Long-term safety of hepatic hydroxymethylglutaryl coenzyme A reductase inhibitors. The role for metabolism, monograph for physicians. Arch Intern Med 2000, 160:2273–2280.

    Article  PubMed  CAS  Google Scholar 

  17. Bolego C, Baetta R, Bellosta S, et al.: Safety considerations for statins. Curr Opin Lipidol 2002, 13:637–644.

    Article  PubMed  CAS  Google Scholar 

  18. Farmer JA, Torre-Amione G: Comparative tolerability of the HMG-CoA reductase inhibitors. Drug Safety 2000, 23:197–213.

    Article  PubMed  CAS  Google Scholar 

  19. Corsini A, Bellosta S, Baetta R, et al.: New insights into pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther 1999, 84:413–428.

    Article  PubMed  CAS  Google Scholar 

  20. Muscari A, Puddu GM, Puddu P: Lipid-lowering drugs: are adverse effects predictable and reversible?. Cardiology 2002, 97:115–121.

    Article  PubMed  CAS  Google Scholar 

  21. Chong PH, Yim BT: Rosuvastatin for the treatment of patients with hypercholesterolemia. Ann Pharmacother 2002, 36:93–101.

    Article  PubMed  CAS  Google Scholar 

  22. Pasternak RC, Smith SC, Bairey-Merz CN, et al., for the Writing Committee Members: ACC/AHA/NHLBI. Clinical advisory on the use and safety of statins. J Am Coll Cardiol 2002, 40:567–572.

    Article  PubMed  Google Scholar 

  23. Maitland-Van Der Zee AH, Klungel OH, Stricker BH, et al.: Genetic polymorphisms: importance for response to HMG-CoA reductase inhibitors. Atherosclerosis 2002, 163:213–222.

    Article  PubMed  CAS  Google Scholar 

  24. Black DM: A general assessment of the safety of HMG-CoA reductase inhibitors (statins). Curr Atheroscler Rep 2002, 4:34–41.

    PubMed  Google Scholar 

  25. Tolman KG: The liver and lovastatin. Am J Cardiol 2002, 89:1374–1380.

    Article  PubMed  CAS  Google Scholar 

  26. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002, 288:2998–3007.

    Article  Google Scholar 

  27. Ballantyne CM, Corsini A, Davidson MH, et al.: Risk for myopathy with statin therapy in high-risk patients. Arch Intern Med 2003, 163:553–564.

    Article  PubMed  CAS  Google Scholar 

  28. Thompson PD, Clarkson P, Karas RH: Statin-associated myopathy. JAMA 2003, 289:1681–1690.

    Article  PubMed  CAS  Google Scholar 

  29. Smith CC, Bernstein LI, Davis RB, et al.: Screening for statin-related toxicity. The yield of transaminase and creatine kinase measurements in a primary care setting. Arch Intern Med 2003, 163:688–692.

    Article  PubMed  CAS  Google Scholar 

  30. Coleman ML, Olson MF: Rho-GTPase signaling pathways in the morphological changes associated with apoptosis. Cell Death Differ 2002, 9:493–504.

    Article  PubMed  CAS  Google Scholar 

  31. Guijarro C, Bianco-Colio LM, Ortego M, et al.: 3-hydroxy-3-methylglutaryl-coenzyme A reductase and isoprenylation inhibitors induce apoptosis in vascular smooth muscle cells in culture. Circ Res 1998, 83:490–500.

    PubMed  CAS  Google Scholar 

  32. Laaksonen R, Ojala JP, Tikkanen MJ, et al.: Decreases in serum ubiquinone do not result in reduced muscle levels in muscle tissue during short-term simvastatin treatment in humans. Clin Pharmacol Ther 1995, 57:62–66.

    Article  PubMed  CAS  Google Scholar 

  33. De Pinieux G, Chariot P, Ammi-Said M, et al.: Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reductase inhibitors on serum ubiquinone and blood lactate/pyruvate ratio. Br J Clin Pharmacol 1996, 42:333–337.

    Article  PubMed  CAS  Google Scholar 

  34. Phillips PS, Haas RH, Bannykh S, et al.: Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med 2002, 137:581–585.

    PubMed  Google Scholar 

  35. Robins SJ: PPARalpha ligands and clinical trials, cardiovascular risk reduction with fibrates. J Cardiovasc Risk 2001, 8:195–201.

    Article  PubMed  CAS  Google Scholar 

  36. Rubins HB, Robins SJ, Collins D, et al., for the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group: Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med 1999, 341:410–418.

    Article  PubMed  CAS  Google Scholar 

  37. BIP Study Group: Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary heart disease: The Bezafibrate Infarction Prevention (BIP) Study. Circulation 2000, 102:21–27.

    Google Scholar 

  38. Guay DR: Update on fenofibrate. Cardiovasc Drug Rev 2002, 4:281–302.

    Google Scholar 

  39. Najib J: Fenofibrate in the treatment of dyslipidemia: a review of the data as they relate to the new suprabioavailable tablet formulation. Clin Ther 2002, 24:2022–2050.

    Article  PubMed  CAS  Google Scholar 

  40. Diabetes Atherosclerosis Intervention Study Investigators: Effect of fenofibrate on progression of coronary artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomized study. Lancet 2001, 357:905–910.

    Article  Google Scholar 

  41. Maiguma T, Fujisaki K, Itoh Y, et al.: Cell-specific toxicity of fibrates in human embryonal rhabdomyosarcoma cells. Arch Pharmacol 2003, 367:289–296.

    Article  CAS  Google Scholar 

  42. Piepho RW: The pharmacokinetics and pharmacodynamics of agent proven to raise high-density lipoprotein cholesterol. Am J Cardiol 2001, 86:35L-40L.

    Article  Google Scholar 

  43. Yim BT, Chong PH: Niacin-ER and lovastatin treatment of hypercholesterolemia and mixed dyslipidemia. Ann Pharmacother 2003, 37:106–115.

    Article  PubMed  CAS  Google Scholar 

  44. Capuzzi DM, Guyton JR, Morgan JM, et al.: Efficacy and safety of an extended-release niacin (Niaspan): a long-term study. Am J Cardiol 1998, 82:74U-81U.

    Article  PubMed  CAS  Google Scholar 

  45. Grundy SM, Vega GL, McGovern ME, et al.: Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial. Arch Intern Med 2002, 162:1568–1576.

    Article  PubMed  CAS  Google Scholar 

  46. Shek A, Ferrill MJ: Statin-fibrate combination therapy. Ann Pharmacother 2001, 35:908–917.

    Article  PubMed  CAS  Google Scholar 

  47. Pauciullo P, Borgnino C, Paoletti R, et al.: Efficacy and safety of fluvastatin and bezafibrate in patients with mixed hyperlipidaemia (FACT study). Atherosclerosis 2000, 150:429–436.

    Article  PubMed  CAS  Google Scholar 

  48. Taher TH, Dzavik V, Reteff EM, et al.: Tolerability of statin-fibrate and statin-niacin combination therapy in dyslipidemic patients at high risk for cardiovascular events. Am J Cardiol 2002, 89:390–394.

    Article  PubMed  CAS  Google Scholar 

  49. Farnier M, Bortolini M, Salko T, et al.: Frequency of creatine kinase elevation during treatment with fluvastatin in combination with fibrates (bezafibrate, fenofibrate, or gemfibrozil). Am J Cardiol 2003, 91:238–240.

    Article  PubMed  CAS  Google Scholar 

  50. Prueksaritanont T, Subramanian R, Fang X, et al.: Glucuronidation of statins in animals and humans: a novel mechanism of statin lactonization. Drug Metab Dispos 2002, 30:505–512.

    Article  PubMed  CAS  Google Scholar 

  51. Prueksaritanont T, Zhao JJ, Ma B, et al.: Mechanistic studies on metabolic interactions between gemfibrozil and statins. J Pharmacol Exp Ther 2002, 301:1042–1051.

    Article  PubMed  CAS  Google Scholar 

  52. Prueksaritanont T, Tang C, Qiu Y, et al.: Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos 2002, 30:1280–1287.

    Article  PubMed  CAS  Google Scholar 

  53. Brown BG, Zhao XQ, Chait A, et al.: Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001, 345:1583–1592.

    Article  PubMed  CAS  Google Scholar 

  54. Kashyap MK, McGovern ME, Berra K, et al.: Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia. Am J Cardiol 2002, 89:672–678.

    Article  PubMed  CAS  Google Scholar 

  55. McGovern ME, Cefali EA, Balandis S, et al.: Safety of combination therapy with once-daily niacin extended-release/lovastatin in over 4,000 patients participating in the impact of medical subspecialty on patient compliance to treatment (IMPACT) study [abstract]. J Am Coll Cardiol 2003, 41(suppl):245A.

    Google Scholar 

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  1. Center for Cardiovascular Disease Prevention, Baylor College of Medicine, 6565 Fannin, Suite B160A, Mailstop A601, 77030, Houston, TX, USA

    Antonios M. Xydakis MD & Peter H. Jones MD

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  1. Antonios M. Xydakis MD
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  2. Peter H. Jones MD
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Xydakis, A.M., Jones, P.H. Toxicity of antilipidemic agents: Facts and fictions. Curr Atheroscler Rep 5, 403–410 (2003). https://doi.org/10.1007/s11883-003-0012-3

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