Few drugs are more widely known and prescribed than the statins, which are designed to lower elevated blood cholesterol. These drugs are indisputably effective in reducing low-density lipoprotein, or LDL – the so-called "bad" cholesterol – which has been linked to an increased risk of heart attack, ischemic stroke, and peripheral artery disease. So prevalent has the use of these drugs become that, in 2005, 144.5 million statin prescriptions were written in the US alone, representing sales in excess of $16 billion. Just one such drug, Lipitor (atorvastatin), made by Pfizer, not only represents 44% of all US statin prescriptions; it is also the bestselling drug in the world.

Since the first statin, Mevacor, was introduced in 1987, data on the safety and effectiveness of these drugs have accumulated. There are presently 17,000 articles on statins in the peer-reviewed literature. Statins can have some well-documented adverse effects, notably muscle pain, weakness, and fatigue, elevation of liver enzymes, and, occasionally, headache and nausea. For the people most likely to benefit from statins, however, the potential side effects need to be weighed against the cardiovascular protection that these drugs are known to provide.

The medical consensus is that statins are generally safe and effective. They almost certainly will lower LDL, and relatively few people will be affected by adverse effects such as muscle damage (which may be prevented by taking Coenzmye Q10 supplements). On balance, the benefits seem to outweigh the risks. Yet, until recently, the risk-vs.-benefit equation has not factored in the question of cancer. Does the use of statins to lower LDL increase, decrease, or leave unaffected one's risk of particular cancers or cancer in general? The evidence here is maddeningly contradictory. On the one hand, a number of studies from good research centers have concluded (a) that there is no evidence of any association between statins and an increased risk of cancer; and (b) that, in fact, statins may actually reduce the risk of certain types of cancer. On the other hand, there have been several studies – from equally reputable institutions – suggesting exactly the opposite, i.e., that statin use may indeed be associated with an increased risk of cancer. Settling this uncertainty is obviously an important public health issue given the vast numbers of people taking these drugs.

So, what is the current state of the evidence concerning statins and cancer risk? First of all, to clarify, there are many different statins. Here are the most popular brands:
Simvastatin = Zocor
Lovastatin = Mevacor
Fluvastatin = Lescol
Pravastatin = Pravachol
Atorvastatin = Lipitor
Rosuvastatin = Crestor

The first three are classified as hydrophobic drugs, the second three as hydrophilic. As we shall see, these distinctions are important in relation to cancer risk.

The following selected examples illustrate the current contradictory evidence on this subject:
• A 2004 study in the Lancet reported on participants in the Scandinavian Simvastatin Survival Study (4S). This trial investigated cause-specific mortality as well as cancer incidence five years after formal closure of the trial. No difference in cancer incidence or mortality was found between the group of patients taking statins and the group taking placebo (Strandberg 2004).

• A group of Spanish researchers from the University of Barcelona reported that their case-controlled study of 2,362 patients had uncovered evidence of an important protective effect of statins against lymphoma (Fortuny 2007).

• An analysis of data from the large-scale Women's Health Initiative showed that while hydrophilic statins such as Pravachol, Lipitor, and Crestor did not confer any reduction in breast cancer risk, the hydrophobic statins such as Zocor, Mevacor, and Lescol were associated with an 18% reduction in the relative risk of breast cancer.

• Boston University epidemiologists reviewed the relationship between statin use and the risk of ten different major cancers. Again, the results were inconclusive. "The present data do not support either positive or negative associations between statin use and the occurrence of 10 cancer types," the authors wrote (Coogan 2007).

• The same team of epidemiologists analyzed data on statin use for 1,809 colon cancer patients and matched controls. Writing in the Journal of the National Cancer Institute, the epidemiologists concluded that there did not appear to be any association between statin use and the risk of colon cancer (Coogan, Smith 2007).

All of this would argue that statins do not increase the risk of cancer and may, in select instances, decrease that risk. However, the picture is not consistently bright, and some cardiologists are warning that aggressive statin use might indeed be associated with increased incidence of cancer.

Statins, LDL, and Cancer
A July 2007 paper in the American Journal of Cardiology has introduced an important new perspective on the issue of statins and cancer (Alsheikh-Ali 2007). The study, carried out by Dr. Richard Karas and colleagues at Tufts University School of Medicine, Boston, was designed to examine whether there was any relationship between a patient's blood level of LDL and that patient's risk of cancer. The study also looked at two other statin-related adverse effects: elevated liver enzymes and a rare, but potentially serious, muscular side effect known as rhabdomyolysis. Perhaps not surprisingly, the Tufts researchers found that the dosage of statins had a direct influence on the likelihood and severity of adverse effects, with higher dosages being associated with an increased incidence of such effects.

However, Karas and his team also discovered that the lower the blood level of LDL achieved through the use of statins, the greater the risk of cancer. The researchers observed "a significant and linear relationship" between LDL levels and the risk of developing a new cancer, an effect that was especially marked at LDL levels below 100 milligrams per deciliter (mg/dL). The study concludes: "...the risk of cancer is significantly associated with lower achieved LDL levels. These findings suggest that ...the cardiovascular benefits of low achieved levels of LDL-C may in part be offset by an increased risk of cancer." These are frightening words and about the last thing that cardiologists and their patients want to hear, since current recommendations specify that the optimal target level of LDL for cardiovascular benefit should be less than 100mg/dL.

Reducing LDL or "bad" cholesterol is a cornerstone of cardiologists' efforts to control the epidemic of heart disease, America's (and the world's) number-one killer disease. Moreover, there has been a recent push to drive optimum LDL levels even lower than are currently recommended. In April 2004, some leading cardiologists called for a target reduction of LDL to 65 mg/dL, to be achieved by taking up to 80 mg per day of Lipitor. Although this recommendation grew out of a study that tested this thesis only in patients with severe cardiovascular disease who were already hospitalized because of a ruptured plaque in their coronary arteries, many doctors were quick to extrapolate these findings to patients in general. "This is really a big deal," Dr. David Waters, a professor of medicine at the University of California in San Francisco, said of these findings. "We have in our hands the power to reduce the risk of heart disease by a lot. It's very exciting." (New York Times, March 8, 2004).

The Barking Dog
Professor Karas, in an interview with the online medical news service Heartwire, took pains to point out that his research categorically did not indicate that statins cause cancer. The study has established only that there is a correlation between lowered levels of LDL and cancer; no causal link has been demonstrated.

To explain the difference between correlation and causation, Karas coined the analogy of the barking dog. "I have a dog, and every time an airplane goes over my house, my dog goes out into the backyard and barks at the plane. That airplane has never landed in my yard. Now we could say there is a very strong association between my dog barking and planes not landing in my yard, but there certainly is no cause and effect."

In other words, it is the low level of blood LDL that is the concern here, not the use of statins themselves. "What we're always doing in terms of trying to take care of patients is balance benefit and risk," Karas said. "This analysis was really focused on trying to enhance our understanding of the risk side of that equation. It has produced a provocative and interesting result that raises a lot of new questions... but it's a complicated message, and the conclusion people will jump to if they are not being careful is that statins cause cancer. We don't know that, and our data don't show that."

It can be hard to make sense of statements such as this. Confusing correlation with causation is an easy mistake, and one that even physicians commonly make. Let me again emphasize that the Karas study does not show that statins cause cancer. What it does seem to suggest is that low levels of LDL are associated with increased cancer risk.

Yet the primary reason that one takes statins is precisely to lower one's LDL. So while statins may not be carcinogenic in themselves, their use to push LDL levels below 100 mg/dL – at least according to this one study – seems to be associated with increased cancer risk. If true, this is a "damned if you do, damned if you don't" proposition. If we assume that levels of LDL below 100mg/dL offer better protection against heart disease, then the more you decrease your risk of heart disease, the more you increase your risk of cancer! And what will happen, long-term, if cardiologists adopt the proposal of some of their peers that optimum LDL be lowered to 65mg/dL or less? Will that lead to a concomitant rise in cancer incidence?

As cardiovascular disease specialist Dr. Thomas Pearson of the Department of Rochester School of Medicine, New York pointed out, it has been known since at least the 1970s – before statins were even invented or LDL became a household term – that cancer risk was heightened in patients with the lowest cholesterol levels. Indeed, conventional medical wisdom at that time said that when a patient's cholesterol levels were seen to fall significantly over a short period of time, a cancer diagnosis often followed.

While not arguing against the use of statins per se, the Karas study does call into question the assumption that disease can be effectively managed by manipulating one particular biomarker: a biochemical or physiological metric whose relationship to the entire disease process is far from clear. It also points to the necessity of following the effect of drugs long-term, not just for the specific disease that they are designed to treat or prevent, but for their impact on health in general, including cancer incidence and mortality.

How Low Should We Go?
In an editorial accompanying the publication of the Karas study, Dr. John LaRosa of the State University of New York, Brooklyn, expressed the opinion that the study had focused attention on an issue that urgently needed to be addressed; namely, does the process of lowering LDL, particularly to very low levels, introduce hazards of its own in either causing or accelerating the process of cancer?

In the management of cardiovascular disease risk, statins have undoubtedly been extremely effective for countless patients and, in the opinion of most cardiovascular specialists, have saved many lives. But the issue of whether it is always beneficial to push LDL levels below 100 mg/dL, much less to 65 mg/dL, remains unclear. If the Karas study stands up to future scrutiny, it may be necessary to rethink current recommendations for drastically lowering LDL in many individuals. Lower may not always be better.

Resource Note
An insightful overview of the risks and benefits of statins is available at the University of California, San Diego, Statin Study Group website: http://medicine.ucsd.edu/SES/index.htm.
(March 2008: Bad link above. Try https://www.statineffects.com/info/)

This UCSD site is edited by Beatrice Golomb, MD, PhD, who maintains a database on statins and has published many papers concerning these drugs. You can read comments on one of Dr. Golomb's most recent papers, documenting the generally dismissive response of physicians to patients' complaints concerning side effects of statins at: http://cancerdecisions.com/093007.html.

Ralph W. Moss, PhD
www.cancerdecisions.com

References
Alsheikh-Ali AA, Maddukuri PV, Han H, et al. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol. 2007;50:409-418.

Cauley JA, McTiernan A, Rodabough RJ, et al. Statin use and breast cancer: prospective results from the Women's Health Initiative. J Natl Cancer Inst. 2006;98:700-707.

Coogan PF, Rosenberg L, Strom BL. Statin use and the risk of 10 cancers. Epidemiology. 2007;18:213-219.

Coogan PF, Smith J, Rosenberg L. Statin use and risk of colon cancer. J Natl Cancer Inst. 2007;99:32-40.

Fortuny J, de Sanjosé S, Becker N, et al. Statin use and risk of lymphoid neoplasms: results from the European Case-Control Study EPILYMPH. Cancer Epidemiol Biomarkers Prev. 2006;15:921-925.

Heart Protection Study Collaborative Group. The effects of cholesterol lowering with simvastatin on cause-specific mortality and on cancer incidence in 20,536 high-risk people: a randomised placebo-controlled trial. BMC Med. 2005;3:6.

Peppercorn J, Blood E, Winer E, et al. Association between pharmaceutical involvement and outcomes in breast cancer clinical trials. Cancer. 2007;109(7):1239-1246.

Strandberg TE, Pyorala K, Cook TJ, et al. Mortality and incidence of cancer during 10-year follow-up of the Scandinavian Simvastatin Survival Study (4S). Lancet. 2004;364:771-777.