from Heartwire — a professional news service of WebMD

July 25, 2007 — Results from a new analysis, initially designed to determine whether there was a correlation between the extent to which statins lowered low-density lipoprotein (LDL)-cholesterol levels and liver and muscle toxicity, suggests that the cardiovascular benefits of achieved levels of LDL cholesterol might be offset by an increased risk of cancer. In an analysis of patients enrolled in large, randomized statin trials, investigators observed a "significant and linear relationship" between achieved LDL levels and the risk of new cancer cases.

"The statin trials have clearly shown that statin therapy, overall, reduces cardiovascular risk," said senior investigator Dr Richard Karas (Tufts-New England Medical Center, Boston, MA). "These findings don't change that. They're based on the same studies. But a component of that, perhaps one of the costs of that, is a relationship between the LDL lowering and cancer risk."

Speaking with heartwire, Karas said there is concern about how the new findings will be reported and interpreted, especially if the message causes some patients to stop taking statins. "What we're always doing in terms of trying to take care of patients is balance benefit and risk," he 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."

In an editorial accompanying the published study, which appears in the July 31, 2007 issue of the Journal of the American College of Cardiology, Dr John LaRosa (State University of New York Downstate Medical Center, Brooklyn) observes that the benefits of all drugs come with a price. While these new data do not provide definitive answers to the question of cancer risk associated with lowering cholesterol levels, he said the finding highlights an issue that has been repeatedly raised: 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?

LaRosa, who is the chair of the steering committee of the Pfizer-sponsored Treating to New Targets (TNT) study, said the findings should be viewed only as hypothesis generating. While clinicians should continue to be vigilant in ensuring the benefits of statins outweigh the risks, this vigilance should not deny the benefits of LDL lowering to those who need it, he said, a sentiment echoed by the study authors. "The bottom line is that at the current time clinical practice should not change," said Karas.

Initially Only Looked at Muscle and Liver Toxicity

Speaking with heartwire, Karas said the cancer association was a surprise and initially wasn't even on his group's radar. The Boston researchers conducted their analysis examining the relationship of the degree of LDL-cholesterol lowering to liver toxicity and rhabdomyolysis in 23 randomized, controlled trials assessing statin therapy, including, among others, the Scandinavian Simvastatin Survival Study (4S), West of Scotland Coronary Prevention Study (WOSCOPS), Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) study, the Heart Protection Study (HPS), and the more recent trials of intensive vs moderate lipid-lowering therapy such as Pravastatin or Atorvastatin Evaluation and Infection Therapy ( PROVE-IT), TNT, and Incremental Decrease in End Points Through Aggressive Lipid Lowering ( IDEAL).

Investigators also studied the effect of drug dosage on liver and muscle toxicity. In the first analysis, no matter how investigators looked at the extent of LDL reduction, as a relative or absolute reduction or achieved LDL-cholesterol levels, they observed no relationship between how much the cholesterol was lowered and the risk of liver or muscle toxicity. In the second analysis, however, when they looked at muscle toxicity on the basis of the dose of the drugs, they found that the higher the dose of statins used in the study, the higher the risk of toxicity to the liver.

"Overall, statins are very safe, but the safety implication here is that it does matter how you lower LDL-cholesterol levels," said Karas. "In other words, the high-dose statins are associated with a higher risk of side effects. This does then have implications for how we practice medicine, the question being, and it's just a question, as to whether or not we might be better off using multiple medications, all at modest doses, to try to get the cholesterol targets that we want to get to, to minimize side effects and maximize the benefit."

Cancer Findings

Considering these findings worthy of publication, the group submitted the manuscript to the Journal of the American College of Cardiology, but, as noted in an editorial comment by journal editors Dr Anthony DeMaria and Ori Ben-Yehuda, the researchers were asked to include cancer in the analysis because "this was the other major side effect often feared from statin therapy." Of the 23 statin therapy trials, 13 studies included the number of patients with newly diagnosed cancer. Overall, there was no significant relationship between percent and absolute reductions in LDL-cholesterol levels. There was, however, a highly significant inverse relationship between achieved LDL-cholesterol levels and rates of newly diagnosed cancer (R ² = 0.43, p = 0.009). The researchers found one additional incident of cancer per 1000 patients with low LDL levels when compared with patients with higher LDL levels. The new cancers were not of any specific type or location.

To heart wire , Karas said the findings are paradoxical in light of recent meta-analyses concluding there is no significant increase in the risk of cancer with statin therapy. Karas stressed, however, that the new findings are observational, hypothesis generating, and in no way definitive. "This is an association at this point," he said. "It might have nothing to do with cause and effect. The best analogy is to say that 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. "Even if the risk of cancer is increased with statin use, Karas said clinicians would have to balance the magnitude of that risk with the benefits of statin therapy."

Dr Thomas Pearson (University of Rochester School of Medicine, NY), who was not affiliated with the study, told heart wire that the results should be interpreted carefully.

"In many ways it is déjà vu all over again," said Pearson. "In the 1970s, there were several papers describing higher risks from cancer in those with the lowest cholesterol levels. This is from the prestatin era. Old-time clinicians will tell you that monitoring cholesterol levels is useful, such that when they start to fall, you should look for a cancer. Indeed, the MRFIT study looked at this and showed the shorter the interval between the cancer diagnosis and the blood test, the lower the cholesterol."

For this reason, said Pearson, one should assume the very low cholesterol levels in patients with cancer on statins are due to a cancer-low cholesterol link rather than a statin-cancer association.

In his editorial, LaRosa points out that no single form of cancer predominates, "so the effect of low achieved LDL would have to have been one that stimulates neoplasia in a variety of tissues." In addition, the effect of low LDL-cholesterol levels would have to be unusually rapid, given that most statin trials lasted five years or less, in producing new cancers.

Most important, LaRosa said it is possible to further address the cancer risk without further trials. Karas and colleagues had access to just 13 studies reporting the number and type of incident cancers. Other data sets have not been published, but an analysis of other LDL-lowering trials, including statin studies, other drug studies, diet, or even ileal-bypass surgery trials, supported by a neutral source such as the National Institutes of Health, could determine whether there is a significant problem with low LDL-cholesterol levels that needs to be addressed, said LaRosa.

Study Generated Scrutiny and Discussion

In their editorial comment, DeMaria and Ben-Yehuda write that in the five years they have been editors at Journal of the American College of Cardiology, no other manuscript stimulated such intense scrutiny and discussion.

"Given the growing public angst regarding the safety of prescription medications, all were concerned that the paper contained great potential for harm and good," they write. "In the end, we agreed to publish the article with as much caution and perspective as possible."

The editorialists point out the manuscript has limitations, as noted by Karas and colleagues, including the retrospective use of summary data, use of data from clinical trials rather than real-world experience, and the lack of standardization of adverse events in the individual trials. Given the limitations, and the potential that physicians, patients, and the media might misinterpret the results, several associate editors argued that the paper not be published.

"However, in the final analysis, the consensus was that these findings could not be ignored, that they did indeed warrant further investigation, and that they should be aired in public," write DeMaria and Ben-Yehuda.

Karas reports that he has received research grants from AstraZeneca and Kos Pharmaceuticals; has served on the speakers' bureaus and/or received honoraria from Kos, AstraZeneca, Merck, and Pfizer; and has served as a consultant to Kos. LaRosa reports honoraria for speaking or consulting from Pfizer, Bristol-Myers Squibb, and Merck.

J Am Coll Cardiol. 2007;50:409-422.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

Clinical Context

Study Highlights

• Researchers sought relevant articles on MEDLINE published prior to November 2005. Only trials of statins with at least 1000 person-years of follow-up were evaluated.
• The main study outcome was the relationship between reduction in LDL cholesterol levels and rates of elevated liver enzymes and rhabdomyolysis. The authors also examined the dose of statins in promoting these adverse events and the effect of LDL cholesterol level reduction on the rate of cancer.
• Researchers examined 23 statin treatment groups with 75,317 patients and 309,506 total person-years of follow-up. Almost all of these trials provided data on liver enzymes and rhabdomyolysis.
• There was no significant relationship between percentage of LDL cholesterol level lowering and rates of elevated liver enzymes or rhabdomyolysis. Similarly, absolute LDL cholesterol level reduction and achieved LDL cholesterol levels did not correlate with these adverse events.
• Conversely, higher dose of statins were associated with increased rates of elevated liver enzymes. For each 10% reduction in LDL cholesterol levels, the rate of elevated liver enzymes per 100,000 person-years was 2.5 times higher with high-dose vs low-dose statins.
• There were insufficient data to determine the relationship between the dose of statins and the rates of rhabdomyolysis.
• 13 trials reported data on cancer outcomes. The percent of LDL cholesterol level lowering and absolute LDL cholesterol level lowering had no effect on the rate of incident cancer. However, there was an inverse relationship between achieved LDL cholesterol levels and the rates of cancer. There was a small but statistically significant increase in the risk for cancer among users of high-dose vs low-dose statins.

Pearls for Practice

• A previous study of pravastatin among older adults at high risk for cardiovascular disease demonstrated a benefit of pravastatin vs placebo in the combined outcome of coronary heart disease death and nonfatal myocardial infarction. However, treatment with pravastatin had no significant effect on stroke risk and was associated with a higher risk for incident cancer.
• The current analysis of previous research suggests that although higher statin doses can promote higher rates of elevated liver enzymes, there is no significant relationship between elevated liver enzymes or rhabdomyolysis and the degree of LDL cholesterol level reduction. However, lower achieved LDL cholesterol level was associated with an increased risk for cancer.

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