Niacin─ A Powerfully Effective HDL Booster

•  Niacin’s effects on serum cholesterol were published first by Rudolph Altschull in 1955.¹ Niacin (nicotinic acid) has been used clinically to lower cholesterol for more than five decades.

• Emerging evidence from clinical and basic research studies indicates that novel direct anti-atherosclerotic properties might mediate nicotinic acid-induced cardiovascular protection. Niacin should be considered as a very potent therapeutic approach to reduce atherosclerosis.²

• Placebo-controlled studies show that niacin increases HDL-C, decreases LDL-C and TG levels, as well as lipoprotein(a) (Lp(a)) levels, in a dose-responsive pattern. Elevated Lp(a) is associated with increased risk, and niacin is the only commercially available lipid lowering medication that decreases Lp(a) concentrations.³

• Niacin (in a daily dose of grams as opposed to milligrams for supplement) has been shown to have potent anti-atherosclerotic effects in human and animal models. Evidence from clinical studies performed in the 1950s has shown that niacin treatment remarkably improves the plasma lipid profile as shown in Figure 087. ^{4, 5} Large clinical studies showed that niacin improves clinical cardiovascular outcomes.^{2, 4, 5}

 

• After the discovery of the nicotinic acid receptor GPR109A on adipocytes and immune cells, novel direct immunomodulatory properties of nicotinic acid have been identified. Importantly, the regulation of the release of inflammatory mediators from adipose tissue was observed, independent of lipid level amelioration. Less is known about the possible direct anti-inflammatory activities of nicotinic acid in other cells (such as hepatocytes, endothelial and vascular cells) previously indicated as key players in atherogenesis. ²

• The effects of niacin on HDL are similar to those of statins but produce greater and more consistent changes. Niacin-mediated changes in HDL are also associated with increases in apoA-1 production and ABCA1 expression in the liver.³

• Niacin also has favorable effects on lipoprotein subclasses.⁶ Niacin increases the concentration of HDL-C up to 25% and that of the large α-1 HDL particles up to two-fold while decreasing the concentration of the small preβ-1 particles.

• Regression of atherosclerosis has been shown to be more strongly correlated with increase in α-1 HDL particle level (157%) in the HDL-Atherosclerosis Treatment Study (HATS) trial. ⁷

Statin-Niacin Combination Therapy

• Niacin can be combined safely with statins with greater benefits. Combination therapy using atorvastatin 40 mg/d and prescription niacin (Niaspan) 2 g/d has shown improvements in all lipoproteins including decrease in LDL-C by 56%, non-HDL-C by 55%, TC/HDL ratio by 50%, lipoprotein(a) by 14% and increase in HDL-2 by 93%.⁴

Surprising results from AIM HIGH

The goal of AIM HIGH (Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: Impact on Global Health outcomes) trial was to compare treatment with extended-release niacin, on CVD outcome versus placebo among statin-treated patients with established vascular disease and optimally treated LDL-C and with low HDL-C and elevated triglycerides.

• Overall, 3,414 patients were randomized. The mean age was 64 years, 81% had metabolic syndrome, 71% had hypertension, and 34% had diabetes. Also, 92% had CAD and more than 50% of participants had prior heart attacks.

• The patients studied had stable, non-acute, pre-existing CVD and well-controlled LDL-C. Patients on statin therapy at study entry (94%) had mean LDL-C baselines of 71 mg/dL, median triglyceride baselines of 161 mg/dL, mean HDL-C baselines of 5 mg/dL and mean non-HDL-C of 107mg/dL.

• The trial’s relevance to patients outside the studied populations is unclear. It would be premature to extrapolate these results beyond the studied population at this time.

• In AIM-HIGH, the extended-release niacin produced the predicted effects on all lipids measured, increasing HDL levels by 20% and reducing triglycerides by around 25%. Surprisingly, high-dose niacin raised HDL, but it did not affect cardiovascular events.

• On detailed analysis, a higher proportion of the control group received Simvastatin 80mg /d and Ezetimibe 10mg/d narrowing the differences between extended release niacin and control group to 4mg/dl for HDL and 5md/dl for LDL. The difference was less than half that was estimated. Furthermore, this was an event driven trial with an anticipated 800 primary events. But only 550 primary events occured at the time the study was terminated. Put simply, in no way did this trial have the power to detect a 12.5% reduction in events according to Philip Barter (The Heart Research Institute, Sydney, Australia) who was the discussant of the study at the AHA scientific sessions when this late breaking clinical trial was presented.

• HPS-2-THRIVE is another large international trial of high-dose, extended-release niacin, which is still ongoing, with results expected in 2013. Although the dose of niacin used in this trial is comparable to that employed in AIM-HIGH, the preparation and patient population are different.

• In the mean time, it is premature to withdraw patients from niacin therapy at this time, although one could be more selective in starting niacin in those who already have very low LDL cholesterol levels (less than 40-70 mg/dl).

• It is entirely possible that potential benefits might be seen in high-risk patients such as ACS (acute coronary syndrome) or those with elevated lipoprotein(a) or very low HDL cholesterol (<30 mg/dl). Perhaps subgroup analysis in such cohorts will shed some lights.

Sources 

1. Altschul R, Hoffer A, Stephen JD. Influence of nicotinic acid on serum cholesterol in man. Arch Biochem. Feb 1955;54(2):558-559.

2. Montecucco F, Quercioli A, Dallegri F, Viviani GL, Mach F. New evidence for nicotinic acid treatment to reduce atherosclerosis. Expert Rev Cardiovasc Ther. Oct 2010;8(10):1457-1467.

3. Asztalos BF. HDL particles, coronary artery disease and niacin. J Clin. lipidology. 2010;4:405-410.

4. McKenney JM, Jones PH, Bays HE, et al. Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study). Atherosclerosis. Jun 2007;192(2):432-437.

5.Kashyap ML, McGovern ME, Berra K, et al. Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia. Am J Cardiol. 2002;89(6):672-678.

6. Kuvin JT, Dave DM, Sliney KA, et al. Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease. Am J Cardiol. Sep 15 2006;98(6):743-745.

7. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345(22):1583-1592.