Niacin: a re-emerging pharmaceutical for the treatment of dyslipidaemia

Abstract

Dyslipidaemias, particularly those characterized by the 'atherogenic profile' of high low-density lipoprotein-cholesterol and triglycerides and low high-density lipoprotein-cholesterol, are the major modifiable risk factor for atherosclerosis. The search for drugs to favourably alter such lipid profiles, reducing the associated morbidity and mortality, remains a major research focus. Niacin (nicotinic acid) is the most effective agent available for increasing high-density lipoprotein-cholesterol, but its use is associated with side effects that negatively affect patient compliance: these appear to arise largely as a result of production of prostaglandin D(2) and its subsequent activation of the DP(1) receptor. Desire to reduce the side effects (and improve pharmacokinetic parameters) has led to the development of a number of agonists that have differing effects, both in terms of clinical potency and the severity of adverse effects. The recent discovery of the niacin G-protein-coupled receptor HM74A (GPR109A) has clarified the distinction between the mechanism whereby niacin exerts its therapeutic effects and the mechanisms responsible for the generation of side effects. This has allowed the development of new drugs that show great potential for the treatment of dyslipidaemia. However, recent advances in understanding of the contribution of prostaglandin metabolism to vascular wall health suggest that some of the beneficial effects of niacin may well result from activation of the same pathways responsible for the adverse reactions. The purpose of this review is to emphasize that the search for agonists that show higher tolerability must take into account all aspects of signalling through this receptor.

Figure 1

Actions of niacin modulate a multitude of processes that are protective against the development of atherosclerosis. The direct effects of niacin mediated through HM74A signalling inhibit adipocyte lipolysis and thus have a beneficial effect on blood lipids. Activation of nuclear receptor and prostanoid signalling pathways alters gene expression profiles in a number of cell types, eliciting profound anti-inflammatory effects. LDL, low-density lipoprotein; PGD₂, prostaglandin D₂; PPAR, peroxisome proliferator-activated receptor; ROS, reactive oxygen species.