For patients with existing atherosclerotic disease treated with intensive cholesterol-lowering therapy, serum high-density lipoprotein-cholesterol (HDL-c) levels are not predictive of risk of future vascular events, but they were predictive of risk for patients who were not on cholesterol-lowering therapy or on low to moderate doses.

The prospective SMART (Second Manifestation of ARTerial disease) cohort study was published Aug. 21 in the Journal of the American College of Cardiology, and followed 6,111 patients with existing atherosclerotic disease for a mean of 5.4 years. In patients who were not on any cholesterol-lowering therapy, every 0.1 mmol/L of higher serum HDL-c, the risk of a recurrent vascular event was five percent lower (HR=0.95). In patients who were taking typical doses of statins or other cholesterol-lowering agents, every increase of 0.1 mmol/L in serum HDL-c reduced the risk of a recurrent vascular event by six percent (HR=0.94). But in patients taking high doses of cholesterol-lowering agents, different levels of HDL-c were not associated with any difference in the risk for another vascular event.

“The intensity of lipid-lowering therapy modified the relationship between HDL-c and vascular events,” said lead author Anton van de Woestijne, MD, University Medical Center Utrecht, Utrecht, Netherlands. “The inverse association between HDL-c and vascular events gradually changed with increasing intensity of lipid-lowering medication. For patients on intensive lipid-lowering therapy, the overall risk of vascular events is lower compared to patients using no or usual dose lipid-lowering, but there was no relation between HDL-c and vascular risk in that group.”

The new results support earlier trials, including JUPITER and TNT, that suggested a less robust relationship between increasing HDL-c and decreasing vascular risk as the intensity of cholesterol-lowering therapy rises.

“We are in a state of clinical equipoise with clinical trials of HDL-raising therapies that do not reduce cardiovascular risk when the LDL-c is lowered to an average of 70 mmol/L,” said Jacques Genest, MD, McGill University Health Center/Royal Victoria Hospital in Montreal, Canada in an editorial comment. “Current guidelines for the prevention and treatment of cardiovascular disease should continue to focus on LDL-c as the major therapeutic target. There is little support from clinical trials to attempt to raise HDL-c pharmacologically. We might have to re-think the link of causality between HDL-c and cardiovascular disease. We need to develop better biomarkers of HDL function and test them in clinical trials.”

Keywords: Cholesterol, Biomarkers, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Canada, Cardiovascular Diseases, Risk Factors, Lipoproteins, HDL