Low HDL, in Statin-Treated Patients, Associated with Increased CVD Risk

The inverse relationship between HDL-cholesterol levels and cardiovascular outcomes remained significant even after adjustment for on-treatment LDL-cholesterol levels, age, hypertension, diabetes, and tobacco use, report investigators.

Senior investigator Dr Richard Karas (Tufts Medical Center, Boston, MA), states that, "Even when you have adequately treated patients with a statin, the risk associated with low levels of HDL cholesterol remains and the magnitude of that risk is quite large."

In the meta-analysis, Karas and colleagues obtained data from 20 randomized controlled clinical trials, including landmark statin studies such as the 4S trial, the Heart Protection Study, the ALLHAT and ASCOT lipid-lowering arms, and JUPITER, among others, 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 mg/dL, respectively, and these levels were similar among statin-treated patients and controls.

After adjustment for LDL-cholesterol levels and age, a 10-mg/dL decrease in HDL-cholesterol levels was associated with 7.1 more MIs per 1000 patient-years in statin-treated patients and 8.3 MIs per 1000 patient-years among healthy controls. The inverse association between HDL-cholesterol levels and MI did not differ statistically between the statin-treated and control patients, and similar results were observed with other cardiovascular disease outcomes.

Estimated number of additional events for every 10-mg/dL decrease in HDL cholesterol:

Karas said the study suggests that unaddressed HDL-cholesterol levels contribute to the residual risk observed in patients who are treated with traditional lipid-lowering therapies. "There is a sense among physicians that if you lower the LDL cholesterol with a statin, then other factors, like HDL cholesterol, don't matter…. That's not true."

Karas said he is aggressive in treating patients with low HDL-cholesterol levels, starting them with niacin, a drug that some clinicians, as well as patients, contend is difficult to use because of side effects, most notably flushing. Karas tells his patients that flushing will occur, probably a half dozen times or so, but that it will stop. He pointed out that national registry data show that most individuals who have an MI also have low levels of HDL cholesterol, but "only about 10% to 15% of patients leave the hospital on any drug to increase HDL cholesterol."

Discussing the study, Dr. James de Lemos (University of Texas Southwestern, Dallas), who was not affiliated with the analysis, said it is plausible that low levels of HDL cholesterol explain some of the residual risk in patients who are aggressively treated with statins. However, he said that he is waiting for the results of the National Institutes of Health-sponsored Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study before he begins to routinely treat these low HDL-cholesterol levels.

De Lemos said he is not sure that starting niacin in acute coronary syndrome (ACS) patients, despite low HDL-cholesterol levels, is a good idea. "There are lots of issues with the drug," he said, "particularly flushing, with not all patients being able to tolerate it, so I worry about starting a drug that causes side effects in the ACS setting because they might stop other medications, such as aspirin and statins, as well." If he is going to start niacin, de Lemos said he prefers to start the drug in the office setting where he has an established relationship with a patient and can educate them about the drug's potential side effects.

The AIM-HIGH trial is a five-year study of 3300 patients with atherogenic dyslipidemia treated with simvastatin alone or simvastatin plus extended-release niacin, and results are expected in September 2012. Another trial, the Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), run by the University of Oxford, 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. Results of HPS2-THRIVE are expected in 2013.

Despite these two trials with niacin, Karas said that clinicians are also in need of better HDL-raising therapies. The field received a boost last month when the Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) investigators showed that anacetrapib (Merck, Whitehouse Station, NJ) significantly decreased LDL-cholesterol levels by 36% and increased HDL-cholesterol levels by a whopping 138% when compared with placebo. Anacetrapib, a new cholesteryl ester transfer protein (CETP) inhibitor, had these positive effects on LDL- and HDL-cholesterol levels without the off-target adverse safety profile that plagued Pfizer's torcetrapib.