Niacin's effect on cardiovascular risk: Have we finally learned our lesson?

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Randomized controlled trials have unequivocally shown that lowering levels of low-density lipoprotein cholesterol (LDL-C) with statins reduces the rate of cardiovascular events.1–3 Yet many patients still have heart attacks even though they are on statins, so the search continues for other agents to lower cardiovascular risk.4

Niacin has been used for its lipid-modifying effects for more than 50 years. In addition to being the most potent agent for raising the level of high-density lipoprotein cholesterol (HDL-C), niacin decreases the atherogenic lipids triglyceride, LDL-C, and lipoprotein (a)5 and can be very effective in treating mixed dyslipidemias such as hypertriglyceridemia and low HDL-C. This is particularly important for the challenging patients seen in preventive cardiology clinics.

In 1986, before statins were available, the Coronary Drug Project6 showed that immediate-release forms of niacin lowered the rates of nonfatal myocardial infarction and long-term mortality. Later, imaging studies demonstrated that niacin slows progression of carotid intima-medial thickness and coronary atherosclerosis.7–9 Furthermore, meta-analyses of these studies suggest cardiovascular benefit for patients at high vascular risk.10

However, niacin is difficult to use in clinical practice. The near-ubiquitous experience of flushing has limited our ability to give doses high enough to modify plasma lipid levels and rates of clinical events.

To try to mitigate this side effect, investigators developed extended-release formulations and agents such as laropiprant, a chemical antagonist of the interaction between niacin and epidermal prostanoid receptors implicated as the mechanism behind flushing. Although these innovations do not eliminate flushing, they reduce it, and thus have prompted hopes of using niacin more widely in statin-treated patients. However, whether widespread use of niacin on a background of statin therapy would have an impact on cardiovascular events remained to be established.


More-tolerable formulations of niacin prompted interest in its potential to lower the residual cardiovascular risk observed in statin-treated patients. Two large clinical trials attempted to determine its impact on cardiovascular events in the contemporary era.

The AIM-HIGH study

In the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) study,11 3,414 patients at high vascular risk with low HDL-C were treated with niacin or placebo. The trial was stopped early because of no evidence of clinical benefit with niacin and because of concern about an increased risk of stroke, a finding ultimately not observed on a complete review of the data.

I reviewed the limitations of this study earlier in this journal.12 The study was small, use of low-dose niacin was allowed in the placebo group, and physicians could treat high LDL-C as they saw fit during the study, so that more patients in the placebo group received high-dose statin therapy and ezetimibe. All of this likely limited the study’s ability to measure the clinical impact of niacin. As a result, this study was not a pure evaluation of the benefits of niacin vs placebo in addition to standard medical therapy. Hope remained that a much larger study with greater statistical power and a simpler design would provide a definitive answer.

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