Aiming high is usually a good strategy for achieving a goal… except when it backfires. That’s what happened with a large clinical trial dubbed AIM-HIGH. It was suddenly stopped more than a year ahead of schedule, casting a cloud over the use of niacin, a safe, effective medication with a proven track record for raising levels of protective high-density lipoprotein (HDL).
AIM-HIGH was designed to gauge whether adding a prescription form of niacin (Niaspan) to a cholesterol-lowering statin makes sense for people with low HDL. This combination had been tested in earlier trials, all of which showed a benefit. The big difference in AIM-HIGH was the very low target for low-density lipoprotein (LDL, the so-called bad cholesterol): between 40 and 80 milligrams per deciliter (mg/dL).
The trial included 3,414 volunteers, all at high risk for a future heart attack or stroke — more than half had survived a heart attack, three-quarters had high blood pressure, and nearly all had coronary artery disease. All of the volunteers took simvastatin (Zocor) and, if needed, a second cholesterol-lowering medication called ezetimibe (Vytorin) to drive LDL below 80 mg/dL. Half took niacin, the other half a placebo.
After almost three years, HDL levels in the niacin group were 22% higher than HDL levels in the control group. That should have been helpful, but it didn’t translate into improved prevention. When the trial’s safety panel analyzed preliminary results, niacin didn’t offer any additional benefit. A small and highly unexpected difference in the rate of ischemic (clot-caused) stroke — 1.6% in the niacin group versus 0.7% in the statin-only group — contributed to the panel’s decision to halt AIM-HIGH early.
What’s going on?
Niacin, also known as vitamin B3 and nicotinic acid, is one of the oldest cholesterol-altering drugs. It has been used to lower total cholesterol and to increase HDL since the early 1960s. One of the first large heart disease trials, the Coronary Drug Project, showed in 1975 that niacin reduced the chance of having a second heart attack by 27% during the five-year trial and reduced the chance of dying over 15 years by 11%. The more recent ARBITER 6-HALTS trial was stopped early in 2009 when its safety panel concluded that niacin plus a statin was superior to ezetimibe plus a statin, causing a greater reduction in cholesterol-filled plaque in the carotid artery. In between these bookends, other trials have shown benefits for niacin.
What could account for niacin’s failure to deliver a cardiovascular benefit even though it substantially boosted HDL?
One possibility is the participants’ rock-bottom LDLs. Getting LDL below 70 mg/dL can halt or even reverse artery-clogging atherosclerosis. With LDL down in that neighborhood, HDL’s ability to protect arteries may be superfluous.
What about the stroke problem in AIM-HIGH? That hasn’t been seen in previous clinical trials, and some have even shown that niacin use decreases the risk of ischemic stroke.
An international trial called HPS2-THRIVE is doing the same thing as AIM-HIGH — comparing niacin versus a placebo in 20,000 men and women with vascular disease, all of whom are taking a statin to reach an LDL level below 77 mg/dL. Begun in 2006, its results are expected in 2013. They should tell us if AIM-HIGH’s results were a blip on the radar or something worth paying attention to.
Until then, AIM-HIGH suggests that if your HDL is low, taking niacin may offer little in the way of extra protection if your LDL is under 80 mg/dL. If your LDL is high, though, niacin may be good for your heart and arteries. And if you can’t take a statin, niacin is still a good alternative for lowering LDL.