, Volume 61, Issue 2, pp 197–206 | Cite as

Safety Profiles for the HMG-CoA Reductase Inhibitors

Treatment and Trust
Review Article


Hypercholesterolaemia is a chronic condition that often requires life-long treatment, making the safety of lipid-lowering drugs a critical issue. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (‘statins’) are commonly used as the pharmacotherapeutic treatment of choice for patients with hypercholesterolaemia. These agents have consistently demonstrated a positive safety and tolerability profile, and are recommended by the US National Cholesterol Education Program guidelines and by the European Joint Task Force for Prevention of Coronary Heart Disease to be used after, or in addition to, a first-line approach with diet. Several large-scale clinical trials have shown HMG-CoA reductase inhibitors to be efficacious and well tolerated, and to be associated with a low rate of treatment withdrawal due to adverse events. These studies included mortality and morbidity end-points, and comprised both primary-and secondary-prevention trials. Hepatic, renal and muscular systems are rarely affected during HMG-CoA reductase inhibitor therapy and the few drug interactions that can occur with concomitantly administered drugs are well documented. There is no conclusive evidence linking HMG-CoA reductase inhibitors to the development of cancer in humans. In long term studies with various HMG-CoA reductase inhibitors, there was no increase in cancer rates compared with placebo. Thus, it can be concluded that HMG-CoA reductase inhibitors are well tolerated, effective treatments for hypercholesterolaemia.


Simvastatin Atorvastatin Pravastatin Lovastatin Fluvastatin 
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  1. 1.
    National Cholesterol Education Program (NCEP). Summary of the second report of the NCEP expert panel on the detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II). JAMA 1993; 269(23): 3015–23CrossRefGoogle Scholar
  2. 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 Group. N Engl J Med 1995; 333(20): 1301–7PubMedCrossRefGoogle Scholar
  3. 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(20): 1615–22Google Scholar
  4. 4.
    Scandinavian Simvastatin Survival Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–9Google Scholar
  5. 5.
    Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels: the Cholesterol and Recurrent Events Trial (CARE) investigators. N Engl J Med 1996; 335(14): 1001–9PubMedCrossRefGoogle Scholar
  6. 6.
    LIPID Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels: the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med 1998; 339(19): 1349–57CrossRefGoogle Scholar
  7. 7.
    Sirtori CR. Pharmacology and mechanism of action of the new HMG-CoA reductase inhibitors. Pharmacol Res 1990; 22: 555–63PubMedCrossRefGoogle Scholar
  8. 8.
    Wood D, De Backer G, Faergeman O, et al. Prevention of coronary heart disease in clinical practice: recommendations of the Second Joint Task Force of European and other Societies on Coronary Prevention. Atherosclerosis 1998; 140(2): 199–270PubMedCrossRefGoogle Scholar
  9. 9.
    Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia. Arch Intern Med 1991; 151(1): 43–9Google Scholar
  10. 10.
    Bradford RH, Shear CL, Chremos AN, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results: two-year efficacy and safety follow-up. Am J Cardiol 1994; 74: 667–73PubMedCrossRefGoogle Scholar
  11. 11.
    Herd JA, Ballantyne CM, Farmer JA, et al. Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol 1997; 80: 278–86PubMedCrossRefGoogle Scholar
  12. 12.
    Pitt B, Waters D, Brown WV, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease: Atorvastatin versus Revascularization Treatment (AVERT) Investigators. N Engl J Med 1999; 341(2): 70–6PubMedCrossRefGoogle Scholar
  13. 13.
    Garnett WR. Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am J Health Syst Pharm 1995; 52(15): 1639–45PubMedGoogle Scholar
  14. 14.
    Bocan TM, Ferguson E, McNally W, et al. Hepatic and non-hepatic sterol synthesis and tissue distribution following administration of a liver selective HMG-CoA reductase inhibitor, CI-981: comparison with selected HMG-CoA reductase inhibitors. Biochim Biophys Acta 1992; 1123(2): 133–44PubMedCrossRefGoogle Scholar
  15. 15.
    Yee HS, Fong NT. Atorvastatin in the treatment of primary hypercholesterolemia and mixed dyslipidemias. Ann Pharmacother 1998; 32(10): 1030–43PubMedCrossRefGoogle Scholar
  16. 16.
    Arky R, medical consultant. Physician’s Desk Reference. 53rd ed. Montvale (NJ): Medical Economics Company Inc., 1999Google Scholar
  17. 17.
    Pierce LR, Wysowski DK, Gross TP. Myopathy and rhabdo-myolysis associated with lovastatin-gemfibrozil combination therapy. JAMA 1990; 264(1): 71–5PubMedCrossRefGoogle Scholar
  18. 18.
    Reaven P, Witztum JL. Lovastatin, nicotinic acid, and rhabdomyolysis [letter]. Ann Intern Med 1988; 109(7): 597–8PubMedGoogle Scholar
  19. 19.
    Norman DJ, Illingworth DR, Munson J, et al. Myolysis and acute renal failure in a heart-transplant recipient receiving lovastatin. N Engl J Med 1988; 318(1): 46–7PubMedCrossRefGoogle Scholar
  20. 20.
    Ayanian JZ, Fuchs CS, Stone RM. Lovastatin and rhabdomyolysis. Ann Intern Med 1988; 109(8): 682–3PubMedGoogle Scholar
  21. 21.
    Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole. N Engl J Med 1995; 333(10): 664–5PubMedCrossRefGoogle Scholar
  22. 22.
    Ahmed SM, Clasen ME, Donnelly JE. Management of dyslipidemia in adults. Am Fam Physician 1998; 57(9): 2192–2204, 2207–8PubMedGoogle Scholar
  23. 23.
    Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther 1998; 64: 477–83PubMedCrossRefGoogle Scholar
  24. 24.
    Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primaryprevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med 1987; 317(20): 1237–45PubMedCrossRefGoogle Scholar
  25. 25.
    Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT). The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA 1984; 251(3): 351–64Google Scholar
  26. 26.
    Kaplan JR, Muldoon MF, Manuck SB, et al. Assessing the observed relationship between low cholesterol and violence-related mortality: implications for suicide risk. Ann N Y Acad Sci 1997; 836(29): 57–80PubMedCrossRefGoogle Scholar
  27. 27.
    Santiago JM, Dalen JE. Cholesterol and violent behavior. Arch Intern Med 1994; 154: 1317–21PubMedCrossRefGoogle Scholar
  28. 28.
    Wysowski DK, Gross TP. Deaths due to accidents and violence in two recent trials of cholesterol-lowering drugs. Arch Intern Med 1990; 150: 2169–72PubMedCrossRefGoogle Scholar
  29. 29.
    Hibbeln JR, Umhau JC, George DT, et al. Plasma total cholesterol concentrations do not predict cerebrospinal fluid neurotransmitter metabolites: implications for the biophysical role of high unsaturated fatty acids. Am J Clin Nutr 2000; 71 Suppl. 1: 331–8Google Scholar
  30. 30.
    Iso H, Jacobs DR, Wentworth D, et al. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intervention Trial (MRFIT). N Engl J Med 1989; 320: 904–10PubMedCrossRefGoogle Scholar
  31. 31.
    Yano K, Popper JS, Kagan A, et al. Epidemiology of stroke among Japanese men in Hawaii during 24 years of follow-up: the Honolulu Heart Program. Health Rep 1994; 6(1): 28–38PubMedGoogle Scholar
  32. 32.
    Iribarren C, Jacobs DR, Sadler M, et al. Low total serum cholesterol and intracerebral hemorrhagic stroke: is the association confined to elderly men? The Kaiser Permanente Medical Care Program. Stroke 1996; 21(11): 1993–8CrossRefGoogle Scholar
  33. 33.
    Okumura K, Iseki K, Wakugami K, et al. Low serum cholesterol as a risk factor for hemorrhagic stroke in men: a community-based mass screening in Okinawa, Japan. Jpn Circ J 1999; 63(1): 53–8PubMedCrossRefGoogle Scholar
  34. 34.
    Rubins HD, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol: Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) Study Group. N Engl J Med 1999; 341(6): 410–8PubMedCrossRefGoogle Scholar
  35. 35.
    Newman TB, Hulley SB. Carcinogenicity of lipid-lowering drugs. JAMA 1996; 275(1): 55–60PubMedCrossRefGoogle Scholar
  36. 36.
    Faggiotto A, Paoletti R. State-of-the-art lecture. Statins and blockers of the renin-angiotensin system: vascular protection beyond their primary mode of action. Hypertension 1999; 34 (4 Pt 2): 987–96PubMedCrossRefGoogle Scholar
  37. 37.
    Newman A, Clutterbuck RD, Powles RL, et al. A comparison of the effect of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors simvastatin, lovastatin, and pravastatin on leukaemic and normal bone marrow progenitors. Leuk Lymphoma 1997; 24(5-6): 533–7PubMedCrossRefGoogle Scholar
  38. 38.
    Macaulay RJ, Wang W, Dimitroulakos J, et al. Lovastatin-induced apoptosis of human medulloblastoma cell lines in vitro. J Neurooncol 1999; 42(1): 1–11PubMedCrossRefGoogle Scholar
  39. 39.
    Dimitroulakos J, Nohynek D, Backway KL, et al. Increased sensitivity of acute myeloid leukemias to lovastatin-induced apoptosis: a potential therapeutic approach. Blood 1999; 93(4): 1308–18PubMedGoogle Scholar
  40. 40.
    Lovastatin Study Groups I through IV. Lovastatin 5-year safety and efficacy study. Arch Intern Med 1993; 153(9): 1079–87CrossRefGoogle Scholar
  41. 41.
    Pedersen TR, Wilhelmsen L, Faergeman O. Extended follow-up of patients in the Scandinavian Simvastatin Survival Study (4S) shows increased survival benefit of simvastatin therapy [abstract]. Circulation 1998; 98 Suppl.: 451Google Scholar
  42. 42.
    Jacobson TA, Amorosa LF. Combination therapy with fluvastatin and niacin in hypercholesterolemia: a preliminary report on safety. Am J Cardiol 1994; 73(14): 25D–9DPubMedCrossRefGoogle Scholar
  43. 43.
    Nawrocki JW, Weiss SR, Davidson MH, et al. Reduction of LDL cholesterol by 25% to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor. Arterioscler Thromb Vasc Biol 1995; 15(5): 678–82PubMedCrossRefGoogle Scholar
  44. 44.
    Black DM, Bakker-Arkema RG, Nawrocki JW. An overview of the clinical safety profile of atorvastatin (Lipitor), a new HMG-CoA reductase inhibitor. Arch Intern Med 1998; 158(6): 577–84PubMedCrossRefGoogle Scholar
  45. 45.
    Davidson M, McKenney J, Stein E, et al. Comparison of one-year efficacy and safety of atorvastatin versus lovastatin in primary hypercholesterolemia: Atorvastatin Study Group I. Am J Cardiol 1997; 79(11): 1475–81PubMedCrossRefGoogle Scholar
  46. 46.
    Bertolini S, Bon GB, Campbell LM, et al. Efficacy and safety of atorvastatin compared to pravastatin in patients with hypercholesterolemia. Atherosclerosis 1997; 130(1–2): 191–7PubMedCrossRefGoogle Scholar
  47. 47.
    Kuhlmann J, Muck W, Bischoff H. Cerivastatin (BAY w 6228): a novel HMG-CoA reductase inhibitor. Cardio Drug Rev 1998; 16: 415–20Google Scholar
  48. 48.
    McClellan KJ, Wiseman LR, McTavish D. Cerivastatin. Drugs 1998; 55(3): 415–20PubMedCrossRefGoogle Scholar
  49. 49.
    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; 81(5): 582–7PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  1. 1.Chicago Center for Clinical ResearchChicagoUSA

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