A "hot" topic in dyslipidemia management--"how to beat a flush": optimizing niacin tolerability to promote long-term treatment adherence and coronary disease prevention

Abstract

Niacin is the most effective lipid-modifying agent for raising high-density lipoprotein cholesterol levels, but it also causes cutaneous vasodilation with flushing. To determine the frequency of flushing in clinical trials, as well as to delineate counseling and treatment approaches to prevent or manage flushing, a MEDLINE search was conducted of English-language literature from January 1, 1985, through April 7, 2009. This search used the title keywords niacin or nicotinic acid crossed with the Medical Subject Headings adverse effects and human. Niacin flushing is a receptor-mediated, mainly prostaglandin D(2)-driven phenomenon, the frequency, onset, and duration of which are largely determined by the distinct pharmacological and metabolic profiles of different niacin formulations. Subjective assessments include ratings of redness, warmth, itching, and tingling. In clinical trials, most (>60%) niacin users experienced mild or moderate flushing, which tended to decrease in frequency and severity with continued niacin treatment, even with advancing doses. Approximately 5% to 20% of patients discontinued treatment because of flushing. Flushing may be minimized by taking niacin with meals (or at bedtime with a low-fat snack), avoiding exacerbating factors (alcohol or hot beverages), and taking 325 mg of aspirin 30 minutes before niacin dosing. The current review advocates an initially slow niacin dose escalation from 0.5 to 1.0 g/d during 8 weeks and then from 1.0 to 2.0 g in a single titration step (if tolerated). Through effective counseling, treatment prophylaxis with aspirin, and careful dose escalation, adherence to niacin treatment can be improved significantly. Wider implementation of these measures should enable higher proportions of patients to reach sufficient niacin doses over time to prevent cardiovascular events.

FIGURE 1.

Niacin metabolism. Niacin is metabolized via 2 pathways. In the first low-affinity, high-capacity pathway (pathway 1, left), niacin is conjugated with glycine to form nicotinuric acid (NUA). The second high-affinity, low-capacity pathway (pathway 2, right) involves a number of oxidation-reduction reactions that produce nicotinamide (NAM) and ultimately pyrimidine metabolites. 6HN = 6-hydroxy-nicotinamide; COOH = carboxylic acid; MNA = N-methylnicotinamide; N = nitrogen; NAD = nicotinamide adenine dinucleotide; NNO = nicotinamide-N-oxide; 2PY = N-methyl-2-pyridone-5-carboxamide; 4PY = N-methyl-4-pyridone-5-carboxamide. From Am J Cardiol, with permission from Elsevier.

FIGURE 2.

Decrease in the proportion of patients receiving extended-release niacin/simvastatin who experienced flushing and decrease in flushing intensity with increased duration of treatment in the Study to Compare the Lipid Effects of Niacin Extended-Release and Simvastatin to Atorvastatin in Subjects With Hyperlipidemia or Mixed Dyslipidemia (SUPREME). Bars depict maximum intensity of flushing experienced in each 4-wk period. No increase in flushing intensity was observed during weeks 5 to 8, when the daily dose of extended-release niacin/simvastatin was increased from 1 g/40 mg to 2 g/40 mg. From J Clin Lipidol, with permission from Elsevier.

FIGURE 3.

Severity of flushing events with and without aspirin (top and middle) and flushing incidence (bottom) in a study evaluating the effects of 1 wk of prophylaxis with 325 mg of aspirin, followed by ongoing treatment as an adjunct for flushing associated with extended-release niacin, 0.5 to 2.0 g, during treatment weeks 1 through 4. Top and Middle, Flushing events were graded on a 10-point scale ranging from mild (1-3) to very severe (10). Top, Mean maximum flushing severity scores are presented over time among patients who received aspirin treatment at any time (arms 1, 2, 4, and 5) vs patients who did not receive aspirin treatment (arms 3 and 6). Middle, The number of moderate or greater flushing events recorded per patient per week are presented over time among patients receiving aspirin treatment at any time (arms 1, 2, 4, and 5) vs patients who did not receive aspirin treatment (arms 3 and 6). *P<.05; **P<.001 vs extended-release niacin with aspirin. From Am J Cardiovasc Drugs, with permission from Wolters Kluwer Health.