Extended-Release Niacin or Ezetimibe and Carotid Intima–Media Thickness

The clinical use of niacin extends over 50 years. The use of niacin, characterized by the National Cholesterol Education Program as the most potent therapy for favorably altering all lipoprotein abnormalities of the atherogenic dyslipidemic profile, increases the HDL cholesterol level through a diverse mechanism of action including the induction of apolipoprotein A-I production.

Ezetimibe was licensed by the Food and Drug Administration in 2002 exclusively on the basis of its ability to reduce the LDL cholesterol level while having an acceptable short-term side effect profile.

We enrolled patients who had coronary heart disease or a coronary heart disease risk equivalent, who were receiving long-term statin therapy, and in whom an LDL cholesterol level under 100 mg per deciliter and an HDL cholesterol level under 50 mg per deciliter for men or 55 mg per deciliter for women had been achieved. From November 16, 2006, through June 4, 2009, 363 patients were enrolled in the trial. The patients were randomly assigned to receive extended-release niacin (target dose, 2000 mg per day) or ezetimibe (10 mg per day). The primary end point was the between-group difference in the change from baseline in the mean common carotid intima–media thickness after 14 months. The trial was terminated early, on the basis of efficacy, according to a prespecified analysis conducted after 208 patients had completed the trial.

The mean HDL cholesterol level in the niacin group increased by 18.4% over the 14-month study period, to 50 mg per deciliter and the mean LDL cholesterol level in the ezetimibe group decreased by 19.2%, to 66 mg per deciliter (1.7 mmol per liter). Niacin therapy significantly reduced LDL cholesterol and triglyceride levels; ezetimibe reduced the HDL cholesterol and triglyceride levels. As compared with ezetimibe, niacin had greater efficacy regarding the change in mean carotid intima–media thickness over 14 months leading to significant reduction of both mean and maximal carotid intima–media thickness for all comparisons. Paradoxically, greater reductions in the LDL cholesterol level in association with ezetimibe were significantly associated with an increase in the carotid intima–media thickness. The incidence of major cardiovascular events was lower in the niacin group than in the ezetimibe group.

Our study demonstrated that niacin showed superior efficacy to ezetimibe regarding the change in the mean carotid intima–media thickness. The change from baseline to 14 months in the mean carotid intima–media thickness was significantly different between the niacin group and the ezetimibe group. Furthermore, Niacin therapy caused a significant reduction in the mean and maximal carotid intima–media thicknesses at both 8 and 14 months. By comparison, no significant net changes in the carotid intima–media thickness were seen with ezetimibe. This comparative-effectiveness trial shows that the use of extended-release niacin causes a significant regression of carotid intima–media thickness when combined with a statin and that niacin is superior to ezetimibe.

If viewed properly, this hypothesis-generating finding is not an indictment of the overall importance of reducing LDL cholesterol for the purpose of preventing cardiovascular events, as illustrated by therapies based on statins or nonstatins (e.g., bile acid sequestrants).Rather, this adverse relationship may be attributable to the net effect of ezetimibe, a drug with diverse actions, not all of which are measured through its effects on intestinal cholesterol absorption and LDL cholesterol level. Taken together with a preexisting concern regarding the clinical effectiveness of ezetimibe, our findings challenge the usefulness of LDL cholesterol reduction as a guaranteed surrogate of clinical efficacy, particularly reduction achieved through the use of novel clinical compounds. For ezetimibe, our results indicate a disconnect between reductions in the LDL cholesterol level and increases in the carotid intima–media thickness in patients with dyslipidemia who are receiving statin therapy. Thus, we believe that prudent clinical practice currently favors the avoidance of ezetimibe, with consideration of further restriction on its use in lieu of clinically validated regimens, until its net effect on clinical outcomes can be fully ascertained.

summarised from the original article in the New England Journal of Medicine, Volume 361:2113-2122, November 26, 2009, Number 22.