Niacin in Cardiovascular Disease: Recent Preclinical and Clinical Developments

Abstract

Abstract-Niacin has been used for more than 50 years in the treatment of cardiovascular disease, although its use has largely been superseded by better-tolerated lipid-modulating interventions. There has been a renewed interest in the HDL-cholesterol raising properties of niacin, with the appreciation that substantial cardiovascular risk remains despite effective treatment of LDL-cholesterol. This coincides with increasing evidence that the complex functional properties of HDL are not well reflected by measurement of HDL-cholesterol alone. In addition to favorable actions on lipoproteins, it is becoming apparent that niacin may also possess lipoprotein independent or pleiotropic effects including the inhibition of inflammatory pathways mediated by its receptor GPR109A, which is expressed by adipocytes and some leukocytes. In this article we consider emerging and prior clinical trial data relating to niacin. We review recent data in respect of mechanisms of action on lipoproteins, which remain complex and incompletely understood. We discuss the recent reports of anti-inflammatory effects of niacin in adipocytes and through bone marrow derived cells and vascular endothelium. These novel observations come at an interesting time, with current imaging and outcome studies leaving outstanding questions on niacin efficacy in statin-treated patients. (Arterioscler Thromb Vasc Biol. 2012;32:582-588.)

Expression of the Niacin Receptor GPR109A in Retina: More than Meets the Eye?

“…The same anti-inflammatory effect was described also in adipocytes [20]. Additional studies involving mouse and human endothelial cells demonstrated the potentiation of responses that were both antioxidant and anti-inflammatory in nature in association with GPR109A activation [11,21,22]. Investigations into the role of the receptor under normal physiologic conditions and the consequences of its activation by endogenous ligands (e.g., β-hydroxybutyrate, butyrate), which happen to be intermediates of normal metabolism, led to the discovery of a role for the receptor also in nutrient sensing and energy regulation, and in tumor suppression [17,23,24].…”

Nicotinic acid inhibits hepatic APOA gene expression: studies in humans and in transgenic mice

“…It affects the metabolism of numerous tissues, including endothelial cells, macrophages, adipose tissue, and liver, and in theory is suitable for the management of lipid abnormalities in type 2 diabetes mellitus and metabolic syndrome ( 35 ). With respect to its use as an antiatherogenic drug, NA is characterized by anti-infl ammatory effects that are mediated by binding to its receptor GPR109A, which is expressed in adipocytes and some leukocytes ( 36 ). In a recent report, it has been also shown that NA induces the expression of heme oxigenase-1 by activating Nrf2 and the p38-MAPK signaling cascade ( 37 ).…”

Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production

“…Most of the oral administration of HDL-raising agents, such as niacin, cholesteryl ester transfer protein (CETP) inhibitors, and fibrates, has yielded convincing results in increasing HDL-C levels, but the effects on reducing cardiovascular risk and enhancing RCT need to be further investigated (9)(10)(11). Turning on endogenous production of ApoA-I to facilitate new HDL particle formation is becoming one of the most attractive approaches, which is strongly supported by results from human ApoA-I transgenic mice and virus-mediated overexpression of ApoA-I in a mouse model of experimental atherosclerosis (11,12).…”