Boston, MA - There is an inverse and significant association between on-treatment LDL-cholesterol levels and cancer in statin-treated patients, an association that remained even after adjustment for age and other variables, a new analysis has shown [1]. However, there was a similar relationship between LDL-cholesterol levels and incident cancer among control patients not treated with statins, report investigators, and statin therapy, despite significantly reducing LDL-cholesterol levels, was not associated with an increased risk of cancer.

"We found that there is indeed an association, that the lower the LDL cholesterol, the higher the risk of cancer," senior investigator Dr Richard Karas (Tufts University School of Medicine, Boston, MA) told heartwire. "Despite the LDL-lowering capacity of statins, however, the data are quite reassuring that statins don't increase the risk of cancer."

The analysis, published online today as an expedited paper in the Journal of the American College of Cardiology (JACC), was prompted by a 2007 study published in JACC by Dr Alawi Alsheikh-Ali (Tufts University School of Medicine), of which Karas was also senior author. The study, reported by heartwire at that time, was initially designed to determine whether there was a correlation between the extent to which statins lowered LDL-cholesterol levels and liver and muscle toxicity, but it raised some alarm, as it showed lower LDL-cholesterol levels were associated with an increased risk of cancer in various statin studies.

"This raised the obvious question and concern that interventions that lower LDL cholesterol might offset the lowered risk of heart disease by increasing the risk of cancer," said Karas. "There is a bit of a conundrum, because previous studies have looked at whether the use of statins increased the risk of cancer, and the answer to that was no. So we had a bit of quandary: how could it be that low LDL is associated with a higher risk of cancer, but statins, which lower LDL cholesterol, don't seem to cause cancer?"

With these questions in mind, Alsheikh-Ali and Karas, as lead and senior investigators, respectively, reviewed data from 15 randomized controlled trials of statins that included >1000 person-years of follow-up to determine whether statin-mediated reductions in LDL cholesterol were associated with a cancer risk. Overall, they reviewed data on 51 797 patients treated with statins and 45 043 patients treated with a placebo, and patients were followed for, on average, 4.5 years. During that time, there were 5752 new cases of cancer reported.

Assessing on-treatment LDL-cholesterol levels and incident cancer in the statin arms, they observed a significant inverse relationship between on-treatment LDL levels and cancer risk, with 2.2 incident cancers per 1000 patient-years for every 10-mg/dL decrease in LDL cholesterol. The relationship was significant after adjustment for various baseline variables, including age, gender, smoking status, diabetes mellitus, hypertension, and body-mass index. Similarly, they also observed an inverse relationship between on-treatment LDL-cholesterol levels and cancer risk among individuals treated with placebo, with 1.2 incident cancer per 1000 patient-years for every 10-mg/dL decrease in LDL cholesterol.

After analyzing whether statin use was associated with cancer risk compared with placebo, Karas said it was not. Among placebo-treated patients, there was an average of 12.6 new cancer cases for 1000 person-years of follow-up. With 2.2 cancers for every 10-mg/dL decrease in LDL cholesterol, and statin interventions lowering LDL cholesterol a mean of 40 mg/dL, there would be approximately eight more cancer cases per 1000 person-years of follow-up in the statin arms. This was not the case, however, as the cancer rate among those treated with a statin was 12.7 per 1000 person-years of follow-up, nearly identical to the placebo arm.

Although Karas said the data are reassuring that statins do not increase the risk of cancer, he said the study is a wake-up call for heart-disease researchers to track and monitor the development of cancer so there is a better understanding of the overall risk and benefit of these interventions. In addition, there is a need for more basic science research to understand the biology behind the association between low LDL-cholesterol levels and cancer risk.

"We don't know why it's true, and we can only speculate about the reason," Karas told heartwire. One possible mechanism might be related to the counterbalancing role of the inflammatory system and atherosclerosis. Individuals who develop atherosclerosis, he said, have overactive immune systems, whereas those without atherosclerosis have a low activation of the immune system. "People with low levels of LDL also have a low risk of atherosclerosis, but it's not known if they have low levels of inflammatory reactions. That's important, because the immune system is part of the surveillance system for ridding the body of cancer. Your own immune system is trying to find cells that are mutating into cancer cells and get rid of them."

Two editorials accompany the publication of the analysis by Alsheikh-Ali and colleagues, one by Dr Daniel Steinberg [2] and one by Drs Ori Ben-Yehuda and Anthony DeMaria [3], all of whom are from the University of California, San Diego (UCSD).

Commenting on the findings, Steinberg, an advocate of pushing LDL-cholesterol levels to as low 50 mg/dL to prevent cardiovascular disease, agrees with the investigators about the safety of statin therapy, noting that statins had "nothing to do with" the cancer risk observed with the low levels of LDL cholesterol. Untreated subjects, he points out, had the same "low-LDL/higher-cancer-risk" relationship as those treated with statins, and the epidemiologic correlation should not be interpreted as a causal connection.

To account for the association between low LDL cholesterol and cancer risk, Steinberg believes this is the "unsuspected-sickness phenomenon," with cholesterol levels lowered by subclinical disease. He notes that cancers can significantly lower cholesterol levels almost a decade before they surface clinically. "The randomly recruited cohorts in the large statin trials undoubtedly included some subjects who had low LDL levels at the time they entered the study because they already had cancer," writes Steinberg. "Low LDL is the result, not the cause, of cancer."

Karas is not convinced of such an interpretation, noting that the studies excluding the first five years of follow-up, when cancer is likely to show up in individuals with latent disease, still show an excess of cancer among those with low LDL-cholesterol levels. Moreover, most randomized, controlled, clinical trials include only healthy patients, with cancer patients not likely to be enrolled.

In a review paper published just a few weeks ago [4], Steinberg, along with Drs Christopher Glass and Joseph Witztum (both also from UCSD), said clinicians are doing "too little, too late" and pushed for more aggressive use of lipid-lowering therapies and earlier intervention in the development of atherosclerosis. In his editorial, he reiterates his case, writing that low LDL-cholesterol levels do not carry any intrinsic danger of cancer or other serious consequences.

Ben-Yehuda and DeMaria, the editors of JACC, write that the 2007 Alsheikh-Ali paper that first uncovered the cancer risk stimulated intense scrutiny and discussion. They are not entirely convinced the issue is resolved, either. The Effects of Simvastatin and Ezetimibe on Clinical Outcomes in Patients with Aortic Stenosis (SEAS) trial, a study presented last month during a press conference and slated for presentation at the European Society of Cardiology 2008 Congress in Munich, Germany in September, also had significantly higher rates of cancer in the active arm compared with the placebo-treated patients.

While an analysis of two other studies—IMPROVE-IT and SHARP—showed no excess of cancers, Ben-Yehuda and DeMaria write that the link between low LDL-cholesterol levels and cancer has not yet been resolved, even if it appears that statins do not increase the risk of cancer. Like Karas, they note the reporting of cancer rates is incomplete in many studies, and further research is needed. They are reassured by the Tufts University analysis, but new data from SEAS highlight the need for more study.