Relationship Between Low LDL and Cancer

This from an email to me yesterday from Indox Consulting. More contradictions in medical research:

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 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."

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 (R2 = 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 heartwire, 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 heartwire 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.