Is niacin ineffective? Or did AIM-HIGH miss its target?
ABSTRACTThe AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) found, in an interim analysis, no cardiovascular benefit from taking extended-release niacin (Niaspan). In fact, there was a trend toward a greater risk of ischemic stroke, which did not reach statistical significance. But questions remain about this complex trial, which included intensive statin therapy in the active-treatment group and the control group.
KEY POINTS
- The study was stopped early because of the concerns raised by the interim analysis.
- The AIM-HIGH results can be interpreted in several ways: perhaps niacin is no good as a preventive agent; perhaps raising levels of high-density lipoprotein cholesterol (HDL-C) is flawed as a preventive strategy; perhaps AIM-HIGH had methodologic flaws; or perhaps statins are so good that, once you prescribe one, anything else you do will not make much of a difference.
- It seems reasonable to continue niacin treatment in patients who need its multiple lipid-modifying effects. It is uncertain if clinicians will be less likely to prescribe niacin therapy until we have clear evidence of clinical benefit. As for HDL-C, it remains to be determined whether any therapy targeting quantitative or qualitative changes will be beneficial.
The recent publication of the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes)1 has thrown the use of niacin as a lipid-modifying therapy into question. The trial was stopped early because an interim analysis found that the patients who took extended-release niacin had no clinical benefit. In addition, it found a trend toward more ischemic strokes, though this finding was later found not to be statistically significant.
Complicating the interpretation, while both the treatment group and the control group in the study received statin therapy, the researchers attempted to keep low-density lipoprotein cholesterol (LDL-C) levels equal, meaning that patients in the control group received more intensive statin therapy than those in the treatment group. And the placebo that the control patients received was actually a low dose of niacin, to induce flushing and thus to blind study participants and their physicians to which drug they were taking.
In the article that follows, I will explore the background, design, findings, and implications of this key trial and try to untangle the many questions about how to interpret it.
LOWERING LDL-C REDUCES RISK, BUT DOES NOT ELIMINATE IT
Large randomized controlled trials have consistently shown that lowering the level of LDL-C reduces cardiovascular event rates by 25% to 45% both in people who are known to have coronary artery disease and in those who are not.2–4 As a result, guidelines for preventing cardiovascular disease have increasingly emphasized maintaining low LDL-C levels. This has led to a proliferation in the use of inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) in patients at high cardiovascular risk.
However, these agents only reduce the risk—they do not eliminate it. Needed are additional therapies to complement existing LDL-C-lowering approaches to lower the cardiovascular risk even further.
Raising HDL-C: The next frontier
One such strategy for further lowering cardiovascular risk that has received considerable interest is to promote the biological activity of the “good” cholesterol.
Studies have consistently shown that the higher the plasma level of high-density lipoprotein cholesterol (HDL-C), the lower the risk of cardiovascular events, suggesting that raising HDL-C may be beneficial.5 Studies in animals with atherosclerosis show that raising HDL-C via genetic modification of the animal or direct infusion of the molecule has a favorable impact on both the size and the structure of experimental plaque.6,7
Accordingly, much activity has focused on developing new therapies that raise HDL-C more effectively than current ones.
Why niacin should protect the heart
For more than 50 years, niacin has been used to manage dyslipidemia.
In addition to raising HDL-C levels more effectively than any other agent available today, niacin also lowers the levels of LDL-C, triglycerides, and lipoprotein (a).8 Before statins were available, the Coronary Drug Project found that niacin reduced the rate of nonfatal myocardial infarction and the 15-year mortality rate.9 In addition, niacin has been shown to slow the progression of carotid intimal-medial thickness and coronary atherosclerosis, and even to reverse these processes in some trials.10–12
However, a number of issues remain about using niacin to prevent cardiovascular events. Nearly all patients who take it experience flushing, which limits its tolerability and, thus, our ability to titrate doses to levels needed for adequate lipid changes. While a number of modifications of niacin administration have been developed (eg, extended-release formulations and products that inhibit flushing), no large study has tested the clinical efficacy of these strategies. Furthermore, until AIM-HIGH, no large-scale trial had directly evaluated the impact of niacin therapy on a background of statin therapy.
AIM-HIGH STUDY DESIGN
The intent of the AIM-HIGH trial was to determine whether extended-release niacin (Niaspan) would reduce the risk of cardiovascular events when added to therapy with a statin—in this case, simvastatin (Zocor) supplemented with ezetimibe (Zetia).1
The trial was funded by the National Heart, Lung, and Blood Institute (NHLBI) and by Abbott Laboratories, which also supplied the extended-release niacin and the ezetimibe. Merck donated the simvastatin.
Patient characteristics
The patients were all at least 45 years of age with established, stable coronary heart disease, cerebrovascular or carotid arterial disease, or peripheral arterial disease. They also had to have low levels of HDL-C (< 40 mg/dL in men, < 50 mg/dL in women), elevated triglycerides (150–400 mg/dL), and LDL-C levels lower than 180 mg/dL if they were not taking a statin at entry.
The mean age of the patients was 64 years, 85% were men, and 92% were white. They had a high prevalence of cardiovascular risk factors: 34% had diabetes, 71% had hypertension, and 81% had metabolic syndrome. Nearly all (94%) of the patients were taking a statin at entry; 76% had been taking one for more than 1 year, and 40% had been taking one for more than 5 years.1
Simvastatin, ezetimibe, and either niacin or placebo
All lipid-modifying agents except statins and ezetimibe were stopped for least 4 weeks after enrollment.
All patients then entered a 4- to 8-week open-label period, during which they took simvastatin 40 mg daily and extended-release niacin starting at 500 mg and increased weekly up to 2,000 mg daily. Patients who could tolerate at least 1,500 mg daily were randomly assigned to treatment with either niacin 1,500 to 2,000 mg or matching placebo. Both groups continued to receive simvastatin. The placebo contained a small dose of immediate-release niacin (50 mg) in each tablet to induce flushing and to maintain blinding of treatment.
Given that niacin also lowers LDL-C, an algorithm was used to try to keep LDL-C levels roughly the same in both treatment groups. This involved adjusting the simvastatin dose and permitting the use of ezetimibe 10 mg to keep the LDL-C level between 40 and 80 mg/dL. Accordingly, participating physicians were told their patients’ LDL-C levels but were blinded to their HDL-C and triglyceride levels throughout the study.
Every 6 months, patients had a follow-up visit in the clinic, and midway through each 6-month interval they received a phone call from the investigators.1
