HDL-raising: A good hypothesis gone bad

"The Framingham data are not quite so right. In these large clinical trials, the inverse relationship between HDL and cardiovascular events was seen only at very low HDL levels – below 30 mg/dL – and not across the broad spectrum," according to the cardiologist.

The most persuasive challenge to the concept that raising HDL will translate into reduced risk of CHD comes from a recent genetic analysis, Dr. Vogel continued. This ambitious project, sponsored by the National Institutes of Health, the Wellcome Trust, the European Union, the British Heart Foundation, and the German government, tracked the prevalence of 14 genetic variants associated with increased HDL in 20 studies totaling more than 100,000 subjects, including nearly 21,000 with a myocardial infarction. The presence of these HDL-raising genes was not associated with reduced risk of MI (Lancet 2012;380:572-80).

What can physicians committed to evidence-based medicine do at this point to prevent cardiovascular events in their patients with low HDL?

Prescribe a statin, regardless of their LDL level, Dr. Vogel said. A consistent finding in the landmark statin trials was that patients with low baseline HDL levels were at higher risk of coronary events, and therefore statin therapy had its biggest benefit. That benefit wasn’t due to the drugs’ small effect on HDL, but rather to their LDL-lowering.

In addition, considerably weaker evidence suggests fibrates may have a limited role in reducing cardiovascular risk in two selected populations. One is in patients with mild to moderate chronic kidney disease, for whom a recent meta-analysis of 10 clinical trials including nearly 17,000 participants showed fibrate therapy reduced the risk of major cardiovascular events by 30% and the risk of cardiovascular mortality by 40% (J. Am. Coll. Cardiol. 2012;60:2061-71). Dr. Vogel rates this evidence worthy of a level IIb recommendation, meaning "you might consider a fibrate in folks with mild to moderate chronic impairment of renal function."

Another group of patients in which fibrate therapy might reasonably be considered are those with a triglyceride level in excess of 200 mg/dL and an HDL level below 35 mg/dL. In subgroup analyses of virtually all of the major fibrate clinical trials, a benefit was shown in that subgroup. Dr. Vogel gives fibrate therapy in such patients a IIb recommendation as well.

As for lifestyle modification as a means of boosting HDL, moderate alcohol consumption, physical exercise, smoking cessation, and weight loss have all been shown to increase HDL. All of these are healthful behaviors, but there is very little hard data to show whether the cardiovascular benefits come from the increase in HDL or some other mechanism.

"If you want to do something in terms of lifestyle modification, tell your patients to run from bar to bar," he quipped.

Dr. Vogel reported having no financial conflicts.

b.jancin@elsevier.com