Is Cholesterol Lowering the Gold Standard?
To the Editor: In his excellent editorial on statins, Dr. Sinatra 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 post-menopausal U.S. women using statins. Although the results of the Scandinavian Simvastatin Survival Study (4S), with its 7-year follow-up, are reassuring in terms of statin cancer risk, the results of other recent studies are more disturbing. The Prospective Study of Pravastatin in the Elderly at Risk study, 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. The latter finding is particularly unsettling, because statins are known to inhibit tumor necrosis factor-




, and targeted tumor necrosis factor-



inhibitors have been associated with the development of lymphoma. Dr. Sinatra 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



-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

In Reply: I concur with Stricker and Goldberg, who reemphasize the need for caution when it comes to prescribing statin therapy. Because 10- to 20-year 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 dis-ease, 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. 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-methylglutaryl-coenzyme A reductase liver enzyme and in turn block manyother biochemical pathways, one of which is the endogenous formation of coenzyme Q₁₀ (CoQ10). Diminished CoQ₁₀ levels have been associated with both cancer and impaired cardiac function in an animal model and in humans.

At the third conference of the International Coenzyme Q₁₀ 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. 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 CoQ₁₀ 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