Low cholesterol, statins, and cancer risk: Déjà vu all over again

There has been an epidemiologic association of low total cholesterol levels with increased risk of cancer noted for several decades.¹ When lovastatin was introduced in 1987, with a mechanism that inhibited cellular production of cholesterol and reduced total and low-density lipoprotein cholesterol (LDL-C) levels to a greater degree than any previous therapy, some raised the question whether statins might increase cancer risk. With the subsequent completion of randomized placebo-controlled statin trials, the cardiovascular disease benefits became very evident, and there was reassurance that cancer risk was not increased. Because of the larger general use of statins in the past 10 years, there have been observational data in statin users that the risk for some cancers may be lower compared to nonusers.^2-4 A plausible explanation for a "protective" effect for statins is related to the in vitro demonstrated "pleotropic" effect they have on cell proliferation.⁵ More recently, however, meta-analyses of statin trials have not confirmed a protective effect, but rather show no effect on cancer incidence with statin exposure up to 5 years.^6-7 The

cohort study by Setoguchi et al

Cardiology Review

in this issue of confirms, in an older population, that statin use does not confer either

an

increase

or a

decrease in the risk of colorectal, lung, or breast cancer.

However, these data still do not answer the question of whether low cholesterol levels are associated with increased cancer risk. It appears that statin use doesn't increase cancer risk, yet a recent meta-analysis of statin trials has suggested that the on-treatment LDL-C level is significantly inversely associated with cancer incidence.⁸ At a time when most clinicians are convinced that "lower LDL-C is better" with regard to cardiovascular outcomes, and are using statins at higher doses to achieve those low LDL-C levels, how are we to reconcile this apparent contradiction? There may be some comfort in the subgroup analysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) and the Treating to New Targets (TNT) trials, which showed no detrimental effect on cancer incidence in their lowest LDL-C populations (<40 mg/dL and <64 mg/dL, respectively) who received 80 mg atorvastatin.^9-10

The earlier observational studies that suggested low serum cholesterol levels were associated with increased cancer risk could have been confounded by the fact that undetected pre-existing diseases, such as cancer, can reduce cholesterol levels. Those studies that excluded individuals with cancer that developed early in the observational period, however, found that the risk was not altered.¹¹

The authors of this most recent meta-analysis are cautious to state that their data do not demonstrate causality between the low ontreatment LDL-C levels or statin use and cancer risk. It is important to remember that the statin trials, including PROVE IT and TNT, were powered to detect cardiovascular outcomes, which occur at a high rate and in a relatively short time in the recruited populations. Cancer incidence is lower and may take longer than 5 years to manifest, making it difficult to ascertain the long-term safety of statins or the relationship of low cholesterol to cancer incidence.

At the present time, the data support the fact that statin use does not increase cancer risk within 5 years of treatment, and there are too little, if any, data to say whether statins can reduce cancer incidence. Statins should be used for cardiovascular disease prevention in high-risk individuals where the clear benefit outweighs any risk. Whether very low LDL-C levels, either statin-induced or not, are related to cancer risk needs further assessment in large cohort studies, such as the one in this issue, and in intensive statin treatment trials soon to be completed.