Aims:To summarise the metabolic responses to niacin that can lead to flushing and to critically evaluate flushing mitigation research.Methods and results:This comprehensive review of the mechanism of action of niacin-induced flushing critically evaluates research regarding flushing mitigating formulations and agents. Niacin induces flushing through dermal Langerhans cells where the activation of G protein-coupled receptor 109A (GPR109A) increases arachidonic acid and prostaglandins, such as prostaglandin D2 (PGD2) and prostaglandin E2 (PGE2), subsequently activating prostaglandin D2 receptor (DP1), prostaglandin E2 receptor (EP2) and prostaglandin E receptor 4 (EP4) in capillaries and causing cutaneous vasodilatation. Controlling niacin absorption rates, inhibiting prostaglandin production, or blocking DP1, EP2 and EP4 receptors can inhibit flushing. Niacin extended-release (NER) formulations have reduced flushing incidence, duration and severity relative to crystalline immediate-release niacin with similar lipid efficacy. Non-steroidal anti-inflammatory drugs (NSAIDs), notably aspirin given 30 min before NER at bedtime, further reduce flushing. An antagonist to the DP1 receptor (laropiprant) combined with an ER niacin formulation can reduce flushing; however, significant residual flushing occurs with clinically-relevant dosages.Conclusions:Niacin is an attractive option for treating dyslipidemic patients, and tolerance to niacin-induced flushing develops rapidly. Healthcare professionals should particularly address flushing during niacin dose titration.

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New data indicate that niacin alters lipoprotein metabolism in novel ways, and mediates other beneficial nonlipid changes that may be atheroprotective. This information forms the rationale for the use of niacin in combination with agents possessing complementary mechanisms of action (e.g. statins) for cardiovascular risk reduction beyond that observed with monotherapy. Further research into the specific mechanisms of niacin may identify additional targets for future drug development.

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