Niacin and Vascular Diseases

Abstract & Commentary

By Michael H. Crawford, MD

Sources: Lee JMS, et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function. J Am Coll Cardiol. 2009; 54: 1787-1794. Taylor AJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. .N Engl J Med. 2009;361:2113-2122.

Two recent studies have demonstrated the bene-ficial effects of nicotinic acid (niacin) on carotid artery atherosclerosis. Lee et al, from the United Kingdom, performed a double-blind, randomized, controlled study of 2 gm daily of sustained release niacin added to statin therapy in 71 patients with a low HDL-cholesterol (< 40 mg/dL) and either: 1) diabetes and coronary artery disease; or 2) peripheral arterial disease. The primary endpoint was carotid wall area by MRI after one year of therapy. Statin therapy was determined by the primary physician, and no LDL-cholesterol (C) level was required for study inclusion.

Results: The average baseline LDL-C was 85 mg/dL, and the HDL-C was about 38 mg/dL. Niacin increased HDL-C by 23% to 48 mg/dL and lowered LDL-C by 19% to 69 mg/dL at one year. MRI carotid wall area was reduced by 1.1 mm2 on niacin, compared to an increase of 1.2 mm2 on placebo (p = 0.03). Lee et al concluded that in patients with vascular disease on statins with LDL-C < 100 mg/dL, niacin reduces atherosclerosis within one year.

Taylor et al, from the United States, performed a prospective, randomized, parallel group, open-label study of the addition of either extended-release niacin (2 gm/day) or ezetimibe (10 mg/day) to baseline statin therapy in 363 patients with coronary artery disease, or its equivalent, and reported the results in the 208 patients who had completed 14 months of follow-up when the study was stopped due to a lack of efficacy in one group. The primary endpoint was change in carotid intima-media thickness (CIMT) at 14 months. Entry criteria included an LDL cholesterol < 100 mg/dL and HDL-C < 50 mg/dL for men and < 55 for women.

Results: In the niacin treated group, HDL-C increased by 18% from 43 to 50 mg/dL and decreased 5% in the ezetimibe group (p < .001). LDL-C decreased 18% in the ezetimibe group and 10% in the niacin group (p < .01). CIMT decreased significantly in the niacin group, but was unchanged in the ezetimibe group (p = .003). The incidence of major cardiovascular events was also lower in the niacin group vs. ezetimibe (1 vs. 5%, p = .04). Taylor et al concluded that niacin is superior to ezetimibe in combination with a statin for reducing CIMT in patients with CAD or its equivalent.


In these two studies, known vascular disease patients on statins with reasonable LDL-C levels (< 100 mg/dL) but relatively low HDL-C (< 40 or < 50-55) were treated by the addition of high-dose niacin (2 gm/day). Both showed reductions in atherosclerosis, as measured by CIMT or carotid MRI. In both studies, measures of atherosclerosis increased in the control groups. The increase observed with placebo is not surprising, but an increase with ezetimibe was, and caused the Taylor et al study to be terminated early. In the placebo-controlled study, the mechanism is unclear since niacin reduced LDL-C and triglycerides and increased HDL-C. In the ezetimibe control study, both lowered LDL-C, although the effect was greater with ezetimibe; only niacin reduced triglycerides and increased HDL-C. It would appear that raising HDL-C and lowering triglycerides trumps further lowering of LDL-C when it is already < 100 mg/dL. However, a study of torcetrapib, which raised HDL-C 72%, showed an increase in mortality; thus, it may not be as simple as raising HDL-C. Some drugs may have other effects which mitigate the effects of otherwise favorable changes in lipid levels.

The major limitation to the more widespread use of niacin is adverse events, even with the slow release preparations used in these studies. In the placebo-controlled study, flushing occurred in 36% of the subjects; 15% withdrew from the study, largely for adverse effects. In the ezetimibe-controlled study, 37% withdrew from the niacin arm mainly because of adverse events such as flushing, pruritus, and GI upset. No one was withdrawn because of liver or muscle function test abnormalities. Thus, the statin-niacin combination seems safe. Newer agents that combine a flushing blocking drug with niacin may prove to be better tolerated.

Although these studies use a surrogate endpoint rather than clinical events, the results are encouraging that relatively low HDL-C levels, even when LDL-C is < 100 mg/dL, identify individuals in whom the addition of high-dose niacin may improve outcome.