Niacin in Patients with Low HDL Receiving Statins

Published - Written by Lisa Rosenbaum

A 65 year-old man with known coronary disease comes to your office seeking advice. He had his first MI at age 56, had PCI at the time, and has been medically managed since. His LDL is below 70 on 40 mg of simvastatin, but his HDL has always been stubbornly low, hovering in the low 30s despite changes in exercise and improvements in diet. In light of data suggesting the cardio-protective effect of higher HDL levels, he began extended-release niacin two years ago. His HDL is up, he’s been free of cardiac events, and has tolerated the niacin jut fine. But he saw on the news that niacin might not be as beneficial as we once thought, and may even cause strokes. What should you recommend?

In this week’s NEJM, the authors of the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) trial share their results. The question:  do higher HDL levels indeed prove protective, independent of low LDL, among high-risk patients on a statin? The short answer is no.

In this study over three thousand patients with known cardiovascular disease, low HDL, and high triglycerides were randomized to placebo or extended release niacin. Of note, given that niacin is known to cause flushing, the placebo arm also received a very low dose of niacin to preserve blinding. All patients were treated with a statin, or statin plus ezetimibe, to achieve a target LDL of between 40 and 80. The primary endpoint was a composite of death from coronary disease, nonfatal MI, ischemic stroke, hospitalization for ACS, or revascularization, (either coronary or cerebral). The trial was powered to detect a 25% reduction in events. Did it aim too high?

It wasn’t that niacin failed to increase HDL. Indeed, those in the niacin arm achieved a 25% increase in HDL, and a 29% reduction in triglycerides. But, at a mean follow up of 36 months, niacin failed to reduce cardiovascular events. The primary endpoint occurred less frequently than expected, at around 16% in both groups. Importantly, the LDL averaged below 70 in both arms at three-year follow up. When an interim analysis revealed niacin’s lack of efficacy, as well as the concerning finding that those in the niacin arm had a higher rate of ischemic stroke, the data monitoring board recommended the trial be stopped early.

Where does this leave us, then, for patients with known CAD, low LDL on statin treatment, but persistent dyslipidemia? The jury is still out. Before retiring niacin completely, some questions are worth asking. First, is it possible that even the small dose of niacin in the placebo arm proved sufficiently beneficial to mitigate significant difference between the groups? And what about generalizability? High-risk patients, such as those recently hospitalized for ACS were excluded, and there were few women and minorities enrolled. Finally, how to interpret the higher rate of stroke in the niacin arm? Given that no similar association has been previously observed, could the finding stem simply from statistical chance?

Given these potential pitfalls, the good news is that four large trials are underway that promise to shed further light on the HDL hypothesis. Until then, what to tell patients such as the one above?  As is the case for much of medicine, there’s just no right answer.