THE BARKING DOG

Prof. 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 for laypeople 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, NY 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 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.

NOTE

An insightful overview of the risks and benefits of statins is available at the University of California, San Diego, Statin Study Group Web site:
http://medicine.ucsd.edu/SES/index.htm

This UCSD site is edited by Beatrice Golomb, MD, PhD, who maintains a database on statins and has published many papers concerning these drugs. One of Dr. Golomb’s most recent papers, documenting the generally dismissive response of physicians to patients’ complaints concerning side effects of statins, was mentioned in a previous issue of this newsletter which you can read by clicking or going to:
http://cancerdecisions.com/093007.html

--Ralph W. Moss, Ph.D.

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(5):409-18.

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(10):700-7

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(1):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):1239-46.

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(9436):771-7.