Statin Use in Patients With Very Low LDL Cholesterol Levels Safe, Beneficial

Michael O'Riordan

August 03, 2007

August 3, 2007 (Stanford, CA) - Statins used in patients with extremely low LDL cholesterol levels are safe and may lead to improved survival, according to the results of a new study [1]. This survival benefit, say investigators, was observed across multiple subgroups, including patients with LDL cholesterol levels <40 mg/dL and those without documented coronary artery disease.

"We're seeing more and more people coming back to clinic with cholesterol levels well below the goal we had intended," lead investigator Dr Nicholas Leeper (Stanford University School of Medicine, CA) told heartwire . "If you start a patient after his acute coronary syndrome on a statin, and he comes back a few months later and his LDL is 50 mg/dL, or even 40 mg/dL, we were realizing that we didn't know what to do with these patients, whether it was safe to continue, whether we had to back off or stop treatment. We also didn't know what happens to patients who come in with very low LDL levels, for whatever reason, if they are to be started with a statin."

The results of the study, published online in the July 30, 2007 issue of Circulation, showed that not only are the drugs safe, with no risk of cancer at two years, but they also might improve survival in patients with very low LDL cholesterol levels, said Leeper.

You Can't be Too Rich, Too Thin, or Have Too Low an LDL Cholesterol Level

Although there has been a recent shift in clinical care toward more aggressive lipid management, including treatment in patients with acute coronary syndrome and those with stable atherosclerotic vascular disease, there have been concerns raised about the safety of treating patients with very low LDL cholesterol levels. Some reports, for example, have shown an association between very low cholesterol levels and adverse outcomes, such as noncardiac mortality and malignancy, said Leeper. One report, published last month, and reported by heartwire at the time, showed a highly significant inverse relationship between achieved LDL-cholesterol levels and rates of newly diagnosed cancer, a surprising finding that researchers said needed further study.

Treating with high-dose statin therapy, said Leeper, often results in patients getting well below the LDL goal of 70 mg/dL, but the long-term safety of statin use in these patients is still unclear. For this reason, the Stanford investigators sought to investigate the safety and clinical outcomes associated with statin therapy in patients with very low LDL levels, such as less than 60 mg/dL.

"When I first started practicing, we had LDL goals of 130, and then it was 100, and now in the wake of TNT and PROVE-IT, we're starting to be more aggressive," said Leeper. "For most patients that we see in cardiology, that goal is now 70 mg/dL or less. We're using a lot of high-potency statins and they can profoundly reduce cholesterol levels; it's very reasonable to see patients come back with these very low LDL levels, but we need to know if they're safe."

In total, more than 6000 consecutive patients were identified from a tertiary-care medical center or affiliated community clinic. Statin therapy was defined as a prescription during the 150 days after the low LDL value--less than 60 mg/dL--was obtained. Of the 6000 patients, 4295 had a prescription for any medication during the observation period, with statins prescribed to 60% of patients with LDL cholesterol levels <60 mg/dL. Patients were, on average, 65 years old, and approximately half had diabetes mellitus or ischemic heart disease.

During a median follow-up of two years, there were 510 deaths. After controlling for the propensity to receive a statin, statin therapy was associated with a significant 35% reduction in the risk of death. The lower mortality was observed across various subgroups, including a 42% reduction in total mortality among those treated with a statin at baseline, a 49% reduction among those with LDL cholesterol levels <40 mg/dL, and a 42% reduction among those without ischemic heart disease.

Based on the findings, Leeper said the investigators began to joke that "you can't be too rich, too thin, or have too low a cholesterol level."

No Cancer Signal

In terms of potential side effects, statin therapy was not associated with an increase in any adverse events. No cases of rhabdomyolysis were reported, nor was there a risk of developing liver enzyme elevations. Importantly, there was no increase in the risk of malignancy or renal insufficiency.

"We wanted to look at various different side effects because statins appear to be a wonder drug from many perspectives, but of course we're always reticent to go so aggressive until we have long-term outcomes," said Leeper. "There have been some trials suggesting possible hazards for certain cancers, renal dysfunction, rhabdomyolysis, but in this analysis, in two years of follow-up, we didn't find any risk associated with low LDL levels."

Like other analyses, the study did not address the possible mechanisms of benefit, although it is clear that the benefit of statins extends beyond their ability to lower LDL cholesterol levels. Continued plaque stabilization and the prevention of atheroma development are possible, said Leeper, as are other benefits that have not yet been outlined.

The investigators reported no conflicts of interest.

  1. Leeper NJ, Ardehali R, deGoma EM, Heidenreich PA. Statin use in patients with extremely low low-density lipoprotein levels is associated with improved survival. Circulation 2007; 116:613-618.

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