Abstract
ObjectiveNiacin potently lowers triglycerides, mildly decreases LDL-cholesterol, and largely increases HDL-cholesterol. Despite evidence for an atheroprotective effect of niacin from previous small clinical studies, the large outcome trials, AIM-HIGH and HPS2-THRIVE did not reveal additional beneficial effects of niacin (alone or in combination with laropiprant) on top of statin treatment. We aimed to address this apparent discrepancy by investigating the effects of niacin without and with simvastatin on atherosclerosis development and determine the underlying mechanisms, in APOE*3Leiden.CETP mice, a model for familial dysbetalipoproteinemia (FD).Approach and ResultsMice were fed a western-type diet containing cholesterol without or with niacin (120 mg/kg/day), simvastatin (36 mg/kg/day) or their combination for 18 weeks. Similarly as in FD patients, niacin reduced total cholesterol by -39% and triglycerides by −50%, (both P<0.001). Simvastatin and the combination reduced total cholesterol (−30%; −55%, P<0.001) where the combination revealed a greater reduction compared to simvastatin (−36%, P<0.001). Niacin decreased total cholesterol and triglycerides primarily by increasing VLDL clearance. Niacin increased HDL-cholesterol (+28%, P<0.01) and mildly increased reverse cholesterol transport. All treatments reduced monocyte adhesion to the endothelium (−46%; −47%, P<0.01; −53%, P<0.001), atherosclerotic lesion area (−78%; −49%, P<0.01; −87%, P<0.001) and severity. Compared to simvastatin, the combination increased plaque stability index [(SMC+collagen)/macrophages] (3-fold, P<0.01). Niacin and the combination reduced T cells in the aortic root (−71%, P<0.01; −81%, P<0.001). Lesion area was strongly predicted by nonHDL-cholesterol (R2 = 0.69, P<0.001) and to a much lesser extent by HDL-cholesterol (R2 = 0.20, P<0.001).ConclusionNiacin decreases atherosclerosis development mainly by reducing nonHDL-cholesterol with modest HDL-cholesterol-raising and additional anti-inflammatory effects. The additive effect of niacin on top of simvastatin is mostly dependent on its nonHDL-cholesterol-lowering capacities. These data suggest that clinical beneficial effects of niacin are largely dependent on its ability to lower LDL-cholesterol on top of concomitant lipid-lowering therapy.
Highlights
The beneficial effects of niacin, known as nicotinic acid or vitamin B3, on plasma lipids and lipoproteins were first described in the 1950s [1]
The additive effect of niacin on top of simvastatin is mostly dependent on its nonHDL-cholesterol-lowering capacities
total cholesterol (TC) and TG levels were reduced by niacin (239%, P,0.001; 250%, P,0.001), simvastatin (230%, P,0.001; 219%, NS) and the combination (255%, P,0.001; 252%, P,0.001)
Summary
The beneficial effects of niacin, known as nicotinic acid or vitamin B3, on plasma lipids and lipoproteins were first described in the 1950s [1]. In patients with atherosclerotic disease or those at risk for atherosclerotic disease due to dyslipidemia, the primary goal of lipid-modifying therapy is the lowering of LDL-C [9] To this end, statins are currently the standard treatment for cardiovascular disease (CVD) resulting in a 25–45% risk reduction for cardiovascular events [10]. Considering the current treatment options, the question remains whether to further reduce LDL-C or to increase HDL-C in addition to LDL-C-lowering [12]. Due to both its nonHDL-C-lowering and HDL-C-raising properties, niacin was considered an attractive candidate for further cardiovascular risk reduction in addition to statin therapy
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