Statins Do Not Eliminate Risk of Low HDL-Cholesterol Levels

November 18, 2009

November 17, 2009 (Orlando, Florida) Low levels of HDL cholesterol, even among statin-treated patients, are associated with a significantly increased risk of cardiovascular disease, particularly the risk of MI, a new study has shown. To reduce the residual risk of disease among these well-treated patients, researchers say clinicians should also focus on HDL-cholesterol levels, despite the failure of recent HDL-cholesterol–raising drugs and the lack of hard outcomes data.

"In common clinical practice, my sense is that among healthcare providers, once they aggressively lower LDL-cholesterol levels, the thinking is that they have done all they can do to remove their patient's cardiovascular disease risk," senior investigator Dr Richard Karas (Tufts Medical Center, Boston, MA) told heartwire . "The thinking is that because the LDL-cholesterol levels are so well treated, we won't have to worry about HDL cholesterol."

Presenting the results of a new meta-analysis here at the American Heart Association (AHA) 2009 Scientific Sessions, Karas stressed that the findings are not meant to minimize the use of statin medications for lowering LDL cholesterol, a cornerstone for reducing cardiovascular disease morbidity and mortality. Instead, he said, the results show that statins do not mitigate the risks associated with low HDL-cholesterol levels.

HDL Cholesterol an Elusive Target

Low levels of HDL cholesterol are known to be associated with increased cardiovascular disease risk, and many high-profile studies in the past have focused on raising HDL cholesterol. One cholesteryl ester transfer protein inhibitor, however, Pfizer's torcetrapib, bombed when it was shown the drug increased the risk of death and cardiovascular events. Other agents, including Merck's anacetrapib, are still in development and don't appear to have the same early off-target toxicity as torcetrapib, a drug that increased blood pressure.

To heartwire , Karas said that although statins reduce the risk of cardiovascular disease, event rates in statin-treated patients remain unacceptably high. It is unclear, he said, whether the cardiovascular disease risk associated with low levels of HDL cholesterol is altered by statin therapy.

ARBITER 6-HALTS Study Shows Benefit of Raising HDL Cholesterol

HDL cholesterol again played a role at the AHA annual meeting when Dr Allen Taylor (Medstar Research Institute, Washington, DC) and colleagues presented data from the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: HDL and LDL Treatment Strategies in Atherosclerosis (ARBITER 6-HALTS) study.

As reported by heartwire , extended-release niacin (Niaspan, Abbott), when combined with statin therapy, significantly reduced carotid intima-media thickness in patients with low LDL-cholesterol levels, whereas the addition of ezetimibe (Zetia, Merck/Schering-Plough) to a statin, a combination designed to further lower LDL-cholesterol levels, did not.

Two major HDL-cholesterol-raising and outcome studies are under way. The National Institutes of Health is sponsoring the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study, a five-year trial of 3300 patients with atherogenic dyslipidemia treated with simvastatin alone or simvastatin plus extended-release niacin. Another trial, the Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), is also under way and will assess whether a new combination tablet, containing extended-release niacin and a specific blocker of prostaglandin D2 to prevent flushing, prevents cardiovascular events in patients with existing vascular disease.

In the meta-analysis, Karas and colleagues obtained data from 20 randomized controlled clinical trials, including more than 137 000 subjects, to determine whether statin therapy altered the risk associated with low HDL-cholesterol levels. Among the studies, the median baseline and on-treatment HDL-cholesterol levels were 45 mg/dL and 48 g/dL, respectively; these levels were similar among statin-treated patients and controls.

After adjustment for LDL-cholesterol levels and age, a 10-mg/dL increase in HDL-cholesterol levels prevented 7.6 MIs per 1000 patient-years in statin-treated patients; this benefit was nearly identical in healthy controls. Similarly, every 10-mg/dL increase in HDL cholesterol prevented 9.7 cardiovascular-disease events per 1000 patient-years in statin-treated patients and 9.9 cardiovascular events in the control arms.

"The study did produce the finding that the lower the HDL-cholesterol level, the higher the cardiovascular-disease risk, particularly the risk of myocardial infarction," said Karas. "In other words, what this study shows us is that statins don't alter the risks associated with low HDL-cholesterol levels."

To highlight the magnitude of benefit of raising HDL-cholesterol levels, Karas noted there was an approximate 26% reduction in the risk of MI and a 25% reduction in the risk of cardiovascular-disease events in the statin-treated patients for every 40-mg/dL decrease in LDL cholesterol. This translates into four MIs prevented per 1000 patient-years.

The study, he said, reinforces the importance of raising HDL-cholesterol levels, despite the bust of previous drugs and the recent failure of Merck's niacin/laropiprant combination, a drug formerly known as Cordaptive, to gain US Food and Drug Administration approval.

"The failure of torcetrapib was wrongly interpreted as a failure of HDL-cholesterol raising rather than the off-target toxicity produced by that particular drug," said Karas. "So although people had begun to pay attention to HDL cholesterol in recent years, I think the focus has now shifted back to LDL cholesterol. This study shows us, though, that treating LDL-cholesterol levels is simply not enough."