In the last 2 decades, the benefit of lowering low-density lipoprotein (LDL) cholesterol has been shown beyond reasonable doubt (1- 2). Both death and disability from the progress of coronary artery disease can be delayed, and there is recent evidence showing that disabling stroke also can be avoided (3). Few issues in modern medicine have been so thoroughly studied or so consistently shown to be beneficial.

All things have a price, however, and the concern that cholesterol-lowering agents or cholesterol lowering itself might in some way be harmful persists (4). Given the large number of individuals in Western societies who carry LDL levels high enough to accelerate atherosclerosis, such concerns are certainly rational. Although it would be ideal to manage most individuals with elevated LDL levels with lifestyle interventions such as dietary change, regular exercise, weight loss, and smoking cessation, the reality is that these changes are difficult to institute and difficult to maintain. Moreover, dietary change is unlikely to produce the degree of LDL lowering that is required to be maximally effective in preventing atherosclerotic events. Drugs, particularly statins, are easier for most patients and provide a beneficial effect even without significant lifestyle change.

In this issue of the Journal, Alsheikh-Ali et al. (5) present an analysis of controlled trials of statins published through November 2005. The study examined the relationship of changes in LDL levels and statin dosage with elevated liver enzymes, rhabdomyolysis, and new diagnoses of cancer. Changes in LDL levels, as reflected in absolute LDL reductions, percent LDL reduction, or achieved LDL levels all were unrelated to elevated liver enzyme levels or to rhabdomyolysis. Higher doses of statins, on the other hand, were associated with elevated liver enzymes but not rhabdomyolysis, although cases of the latter were too infrequent to permit definite conclusions.

With new cancer cases, a different picture emerged. There was a trend toward more new cases with increasing drug dosage and a more significant relationship between achieved LDL levels and new cancer cases. No relationship seemed to exist between either the absolute or the percent change in LDL level. Of course, only those trials reporting incident cancer cases could be used, and the investigators carefully list this as well as other limitations of this analysis. Nevertheless, this finding highlights an issue that has been repeatedly raised, that is, does the process of lowering LDL, particularly to very low levels, introduce hazards of its own in either causing or accelerating the progress of cancer.

In truth, currently available data cannot provide a definitive answer to this question. In the data that contributed to this analysis there is no single form of cancer that predominates, so that the effect of low achieved LDL would have to have been one that stimulated neoplasia in a variety of tissues. Although not impossible, such a universal trigger mechanism would have to involve some change in cell biology or immunity not yet described or related to cholesterol metabolism. In addition, because these trials generally lasted 5 years or less, such an effect of low LDL would have to be unusually rapid, particularly in producing new cancer cases.

Other explanations for this trend might include a chance observation, or simply that in some individuals surviving coronary death allows expression of heretofore occult cancer. Indeed, among different individual trials, contradictory findings exist. For example, in the Treating to New Targets Study (included in this analysis), the lowest quintile of achieved LDL levels also had the lowest number of cancer deaths (6).

It is possible to address this issue further even without more trials. The investigators point out that their analysis is dependent on those studies that have published the number and types of incident cancers. Several have not. Data sets exist, however, from a large number of LDL-lowering trials, including trials of statins, other drugs, diet, and even ileal bypass surgery. If these data sets could be made available for further analyses, we would be in a better position to decide whether there might be a real problem with very low LDL cholesterol levels that should be addressed. Such an analysis could be supported, at relatively low cost, by a neutral source, such as the National Institutes of Health. Funds for such analyses could be awarded on the basis of a peer-reviewed competition with the understanding that the trial data sets would be made available for further study. This would be dependent on the willingness of those in control of these data sets to provide them. They would, of course, require financial and logistical support to do so.

As the investigators note, the findings in this study, although very provocative, can only be regarded as hypothesis generating. They are in no way definitive. They do not dictate changes in current policies or recommendations.

In the long debate over cholesterol lowering that has occurred over the past 3 decades, it has sometimes been stated that we should withhold such interventions if there is any reason to suspect that they might be harmful. The remarkably consistent clinical trials of the last 2 decades, however, have complicated such rationalizations. Withholding cholesterol-lowering therapy is itself very harmful. These current findings provide insufficient evidence that there is any problem with LDL lowering that outweighs its significant benefits on vascular disease.

Lowering LDL represents an intervention of long duration, and we must continue to be vigilant in ensuring that its benefit clearly outweighs its risk. On the other hand, we must not allow that vigilance to deny the benefits of LDL lowering to those who need it.