Is cholesterol lowering with statins the gold standard for treating patients with cardiovascular risk and disease?

To the Editor: In his excellent editorial on statins, Dr. Sinatra (1) touched on the issue of carcinogenicity related to these medications. He noted the association between lipid-lowering drugs and carcinogenicity in rodents, and he mentioned the increased rate of breast cancer reported in the Cholesterol and Recurrent Events Trial (CARE) of postmenopausal U.S. women using statins. (2,3) Although the results of the Scandinavian Simvastatin Survival Study (4S), (4) with its 7-year follow-up, are reassuring in terms of statin cancer risk, (1) the results of other recent studies are more disturbing. The Prospective Study of Pravastatin in the Elderly at Risk study, (5) conducted in Scotland, noted an increased rate of solid tumors in elderly patients treated with pravastatin, and a study performed in Japan found an increased rate of lymphomas in patients using statins. (6) The latter finding is particularly unsettling, because statins are known to inhibit tumor necrosis factor-[alpha], (7) and targeted tumor necrosis factor-[alpha] inhibitors have been associated with the development of lymphoma. (8) Dr. Sinatra (1) estimated that as many as 36 million Americans could eventually be prescribed statin therapy according to current guidelines. Until the carcinogenicity of statins can be defined better, the use of these widely prescribed--probably overprescribed--medications should be limited, and other methods of cardiovascular disease reduction such as diet, exercise, and [omega]-3 fatty acid supplementation should be pursued vigorously.

Raphael B. Stricker, MD

Department of Medicine

California Pacific Medical Center 

San Francisco, CA

Billi Goldberg, MPA 

International DNCB Study Group

San Francisco, CA

References

(1.) Sinatra ST. Is cholesterol lowering with statins the gold standard for treating patients with cardiovascular risk and disease? South Med J 2003;96:220-222 (editorial).

(2.) Sacks FM, Pfeffer MA, Moye L, et al. Rationale and design of a secondary prevention trial of lowering normal plasma cholesterol levels after acute myocardial infarction: The Cholesterol and Recurrent Events Trial (CARE). Am J Cardiol 1991;68:1436-1446.

(3.) Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335:1001-1009.

(4.) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389.

(5.) Shepherd J, Blauw GJ, Murphy MB, et al; PROSPER study group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): A randomised controlled trial--PROspective Study of Pravastatin in the Elderly at Risk. Lancet 2002;360:1623-1630.

(6.) Murashige N, Hiroshi I, Matsuo K, et al. Increased incidence of lymphoid malignancies in patients receiving statins (HMG-CoA reductase inhibitors): A case-control study involving 1102 patients. Blood 2002;100:467a.

(7.) Solheim S, Seljeflot I, Arnesen H, et al. Reduced levels of TNF [alpha] in hypercholesterolemic individuals after treatment with pravastatin for 8 weeks. Atherosclerosis 2001; 157:411-415.

(8.) Brown SL, Greene MH, Gershon SK, et al. Tumor necrosis factor antagonist therapy and lymphoma development: Twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 2002;46:3151-3158.

In Reply: I concur with Stricker and Goldberg, who reemphasize the need for caution when it comes to prescribing statin therapy. Because 10- to 20year follow-up data are lacking for 3 -hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, the possibility of carcinogenicity-related risk must be a concern when prescribing these agents for extended periods of time. Careful consideration of treatment indications includes stratification of cardiac risk to determine when intervention with this powerful class of pharmacotherapeutic agents is indicated.

Although it is imperative to avoid overusing statin therapy for cholesterol lowering, the risk-to-benefit ratio is tipped in favor of this drug intervention for patients at high cardiac risk. This population includes patients with a documented history of coronary artery disease, unstable angina, and acute coronary syndrome, as well as patients in whom high calcium burdens are identified (>1,000 score on the basis of electron beam computed tomography). In these special populations, measures to improve plaque stabilization and promote plaque reversal must be initiated.

Research has consistently suggested that statin drugs do modify inflammatory mediators for high-risk populations for whom double-blind, placebo-controlled trials correlate statin therapy with major reductions in death, myocardial infarction, and stroke. (1) In patients with cardiac vulnerability, statin use can certainly be justified, and underuse in such high-risk cardiovascular patients should be avoided.

Statin drugs inhibit the synthesis of 3 -hydroxy-3-methylghitaryl-coenzyme A reductase liver enzyme and in turn block manyother biochemical pathways, one of which is the endogenous formation of coenzyme [Q.sub.10] (Co[Q.sub.10]). Diminished CO[Q.sub.10] levels have been associated with both cancer and impaired cardiac function in an animal model and in humans. (2-4)

At the third conference of the international Coenzyme [Q.sub.10] Association, held in November 2002 in London, England, the results of a pilot study were presented. The study involved six patients who were undergoing statin therapy for hyperlipidemia. Abnormalities of diastolic dysfunction occurred with a frequency of 67% after 6 months of statin therapy. (5) Although it may take 10 to 20 years for diastolic dysfunction to manifest as impaired systolic function, long-term statin use could be undesirable in some patients, particularly those whose baseline [CoQ.sub.10] levels are suboptimal.

Carcinogenicity and cardiomyopathy could prove to be serious long-term effects of statin therapy. Although high-risk cardiovascular patients stand to benefit the most from statin therapy, overuse of this treatment modality to lower cholesterol in otherwise healthy individuals is not smart medical practice.

Stephen T. Sinatra, MD, FACC 

New England Heart Center

Manchester, CT

References

1. Ellis CJ, Scott R. Cardiovascular disease and lipid management in New Zealand: Progress at last! N Z Med J 2002;115:197-199.

(2.) Satoh K, Yamato A, Nakai T, et al. Effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on mitochondrial respiration in ischaemic dog hearts. Br J Pharmacol 1995;116:1894-1898.

(3.) Folkers K, Osterborg A, Nylander M, et al. Activities of vitamin [Q.sub.10] in animal models and a serious deficiency in patients with cancer. Biochem Biophys Res Commun 1997; 234:296-299.

(4.) Langsjoen PH, Langsjoen AM. The clinical use of statins and the association of depletion of the essential cofactor coenzyme [Q.sub.10]: A review of the pertinent human and animal data. Biofactors (in press).

(5.) Silver MA, Langsjoen PH, Szabo S, et al. Statin cardiomyopathy? A potential role for coenzyme [Q.sub.10] therapy for stain-induced changes in diastolic LV performance. Biofactors (in press).