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 D2 and its subsequent activation of the DP1 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.

Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

“…Niacin may improve endothelial function through direct effects on the vasculature [149]. Compared with placebo, 12 weeks of no-flush niacin (1.5g/day) significantly improved brachial artery FMD in healthy men with low high-density lipoprotein (HDL)-cholesterol (<1.04mmol/l) [150].…”

Atherogenic Dyslipidemia and Combination Pharmacotherapy in Diabetes: Recent Clinical Trials

“…Niacin has been shown to decrease plasma triglycerides and LDL-cholesterol by up to 35% and 15%, respectively, and increase HDL-cholesterol by up to 30% in a dose dependent manner [30]. Many of niacin's effects are thought to derive from its action on adipose tissue [73]. However, the cellular mechanism for niacin's lipidlowering effects were not fully elucidated until the identification of a G protein-coupled receptor GPR109A (HM74A) in 2003, which is highly expressed in adipose tissue, acts as a high-affinity receptor for nicotinic acid, and mediates antilipolytic effects [72,[74][75][76][77].…”

New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people?

“…Several clinical trials have demonstrated that niacin administration, either alone or combined with other lipid lowering agents, significantly reduces total mortality and coronary events, retards progression, and induces regression of coronary atherosclerosis. Following administration, niacin rapidly inhibits adipocyte lipolysis apparently through the inhibition of hepatic diacylglycerol acyltransferase 2: it leads to the inhibition of triglyceride synthesis and to the decrease of apolipoprotein B-containing lipoproteins; this is accompanied by a similarly rapid drop in plasma levels of free fatty acids [56] . The net effect is a reduced catabolism of HDL and a decreased accumulation of cholesterol esters in LDL particles.…”

“…The net effect is a reduced catabolism of HDL and a decreased accumulation of cholesterol esters in LDL particles. It has also been suggested that niacin may directly inhibit the uptake and catabolism of apolipoprotein AI-containing HDL particles, thus acting to further increase plasma levels of HDL [56] . The main problem with the use of niacin is connected to its side effects: administration of pharmacological doses of niacin is accompanied by unwanted effects, primarily a cutaneous reaction called flushing, which occurs in up to 90% of patients.…”

“…The main problem with the use of niacin is connected to its side effects: administration of pharmacological doses of niacin is accompanied by unwanted effects, primarily a cutaneous reaction called flushing, which occurs in up to 90% of patients. Niacin-induced flushing is mediated primarily by the production of prostaglandins D2 and E2 by dermal/epidermal immune cells, leading to vasodilation of blood vessels and resulting in the symptoms of redness, warmth, tingling and itching [56] . Several gastrointestinal adverse effects, such as nausea, vomiting, dyspepsia and abdominal pain, can also occur.…”