Nicotinic Acid Current Status in Lipid Management and Cardiovascular Disease Prevention

Nicotinic acid is back in the spotlight of controversy, and it therefore appears appropriate to consider its benefits and possible problems. Jackevicius et al have just published their concerns that per capita use of nicotinic acid in the United States far exceeds that in Canada, almost 6-fold by their calculation, with Niaspan as the main prescription product in both the countries. Apparently, their economic comparison and implied excess use in the United States were stimulated by 2 recent studies considered to cause uncertainty regarding nicotinic acid, the Atherothrombosis Intervention in Metabolic Syndrome with low HDL/ High Triglycerides: Impact on Global Health Outcomes (AIMHIGH) trial and the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2THRIVE) study. The AIM-HIGH trial reported that in patients with atherosclerotic cardiovascular (CV) disease already treated for a low-density lipoprotein cholesterol (LDL-C) level of 71 mg/dL (1.84 mmol/L), no incremental benefit occurred with the addition of nicotinic acid to statin therapy over 36 months, although significant improvements resulted in high-density lipoprotein cholesterol (HDL-C) and triglycerides. In HPS2THRIVE, nicotinic acid, combined with the antiflushing agent laropiprant, did not decrease CV risk further in the presence of statin therapy, and there was a question of increased risk of nonfatal but serious side effects. In the case of HPS2-THRIVE, the starting overall LDL-C was 1.64 mmol/L (63 mg/dL). Both of these studies involved patients on a statin with proven CV disease and essentially at the target for the high-CV risk patient of LDL-C <70 mg/dL. Showing significant benefit in this situation appears problematic, and possibly, the deck was stacked against nicotinic acid for showing more benefit due to the guideline LDL-C levels being already achieved on a statin. Nevertheless, such results must be put in context, analyzed, and debated. A National Lipid Association statement supports continued use of nicotinic acid as a statin adjunct, especially in patients with low HDL-C and high triglycerides, and points out that in the case of laropiprant in HPS2-THRIVE, the laropiprant may be a problematic factor. It is also appropriate to review that nicotinic acid has supportive evidence-based medicine, despite the current concerns. As can be summarized, there is ample evidence from multiple varied-approach studies of the benefit of a targeted reduction in LDL-C for CV disease prevention. Nicotinic acid can contribute to this LDL-C reduction in many situations. The Coronary Drug Project (CDP) was conducted between 1966 and 1975 and assessed the long-term efficacy and safety of 5 medications in men aged 30 to 64 years, with electrocardiogram-documented previous myocardial infarction (MI). At the end of the trial, nicotinic acid showed a modest benefit in decreasing definite nonfatal recurrent MI, but total mortality was not decreased. Nicotinic acid was discontinued at the end of the CDP. However, with a mean follow-up of 15 years, almost 9 years after the end of the CDP trial (the patients were not taking nicotinic acid during these 9 years after the CDP), the mortality in the nicotinic acid group was 11% lower than in the placebo group (52.0% vs 58.2%; P 1⁄4 .0004). In the Cholesterol Lowering Atherosclerosis Study using colestipol plus nicotinic acid, it was demonstrated by quantitative coronary angiography that coronary artery plaque regression is achievable with statistical significance. In a meta-analysis involving 11 clinical trials of nicotinic acid, including 9959 patients with nicotinic acid either used alone or combined with other lipid-lowering therapy, Lavigne and Karas calculated the odds ratio (OR) for CV disease events. Nicotinic acid use was associated with a significant decrease in combined end points of any CV disease event (OR: 0.66; 95% confidence interval [CI]: 0.49-0.89; P 1⁄4 .007) and major coronary heart disease (CHD) events (OR: 0.75; 95% CI: 0.59-0.96; P 1⁄4 .02). Nicotinic acid did not significantly alter the incidence of stroke, and the difference in HDL-C between treatment arms did not have a significant association with the extent of nicotinic acid effect on outcomes. In a combined analysis of 4 major studies that evaluated the effect of nicotinic acid on glucose levels, on coronary artery stenosis progression utilizing quantitative coronary angiography, and on various clinical events in a combined total of 407 patients, Phan et al found that nicotinic acid over 3 years was associated with increased blood glucose levels and an increased risk of an impaired fasting glucose but not actual diabetes mellitus.