Lowering LDL cholesterol to very low levels is safe, analysis shows

October 13, 2005

Boston, MA - With the collective wisdom and the clinical-trial evidence in support of the lower-is-better hypothesis, a new analysis has shown that very low LDL-cholesterol levels are also safe. A recent analysis of one of the cholesterol trials has shown that treating patients to LDL-cholesterol levels <80 mg/dL was not associated with adverse safety effects and in fact might be associated with a lower clinical event rate.

"There had been some nagging concerns about a possible relationship between very low levels of cholesterol and adverse outcomes, with some people suggesting that we exercise caution," lead investigator Dr Stephen Wiviott (Brigham and Women's Hospital, Boston, MA) told heart wire . "It's a minority opinion, but nonetheless, it is something that needed to be addressed. While this is a small group of patients, the data from this study, one of the largest studies published in patients with these levels of cholesterol, suggest that it doesn't appear that the side effects of cholesterol-lowering medications are associated with very low levels of cholesterol achieved."

The results of the study, an analysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy—Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22), are published in the October 18, 2005 issue of the Journal of the American College of Cardiology.

Some worried about the risks of LDL going too low

Speaking with heart wire , Wiviott said some of the earliest statin studies were initially criticized for increases in traumatic deaths and suicides. He pointed out, however, that most of the safety concerns regarding very low cholesterol levels were derived from epidemiologic studies, where very low cholesterol levels in patients not taking statins were associated with an increased risk of death, bleeding, and cancer. In patients taking statins, there were also previous concerns that pharmacologically lowering LDL-cholesterol levels beyond currently recommended treatment targets might result in increases in muscle and liver toxicity.

In PROVE-IT, a study published in 2004 and reported by heart wire at that time, intensive lipid lowering with atorvastatin (Lipitor, Pfizer) 80 mg daily provided greater protection from death and cardiovascular events compared with pravastatin (Pravachol, Bristol-Myers Squibb) 40 mg daily in patients recently hospitalized with acute coronary syndromes. The purpose of this analysis was to examine the safety and clinical efficacy of patients achieving very low levels of cholesterol. As a result, Wiviott and colleagues limited the analysis to the intensive-treatment arm and divided the subjects into subgroups by achieved lipid levels at four months: >80 mg/dL to 100 mg/dL, >60 mg/dL to 80 mg/dL, >40 mg/dL to 60 mg/dL, and <40 mg/dL.

Overall, muscle side effects were infrequent and there were no episodes of rhabdomyolysis reported. In addition, there did not appear to be any relationship between achieved LDL-cholesterol levels and the development of muscle side effects. Regarding liver-related side effects, there was also no relationship between achieved LDL-cholesterol levels and the frequency of either liver-enzyme elevations or discontinuation of high-dose statin therapy for abnormal liver-enzyme levels.

When investigators looked at the primary efficacy end point of the trial, they observed a trend toward lower cardiovascular events in patients who achieved very low LDL-cholesterol levels, with the lowest rates in the subgroups of <40 mg/dL and >40 mg/dL to 60 mg/dL. Wiviott noted that while these findings are "hypothesis generating," the data are in line with the evidence of previous statin trials—that is, lower event rates with each successive lowering of LDL-cholesterol targets.

"To me, looking at the accumulated evidence from PROVE-IT, as well as studies like A to Z [Aggrastat to Zocor] and TNT [Treating to New Targets], the appropriate thing to do in high-risk patients is treat them early with high doses of statins," said Wiviott. "What this tells us is that when you see that patient in your clinic and you're checking cholesterol and it's very low, it is not a signal for concern. You don't need to back off treatment simply because you've gotten the cholesterol beyond the guideline-recommended targets."

Wiviott noted that many clinicians tend to become concerned about laboratory abnormalities, whether too high or too low, when treating patients. These data suggest that very low levels of LDL cholesterol are not cause for concern. "The message from the statin trials over the past 10 years is that lower is better," he said. "From this trial, what I think we can say is that lower also appears to be safe."

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