No randomized trials directly address the question of frequency of liver enzyme monitoring with niacin use. Niacin use is associated with early and late hepatotoxicity (strength of recommendation [SOR]: B, based on incidence data from randomized controlled trials and systematic reviews of cohort studies). Long-acting forms of niacin (Slo-Niacin) are more frequently associated with hepatotoxicity than the immediate-release (Niacor, Nicolar) or extended-release (Niaspan) forms (SOR: B, based on 1 randomized controlled trial and systematic reviews of cohort studies).
The combination of statins and niacin at usual doses does not increase the risk of hepatotoxicity (SOR: A, based on randomized controlled trials). Screening has been recommended at baseline, 6 to 8 weeks after reaching a daily dose of 1500 mg, 6 to 8 weeks after reaching the maximum daily dose, then annually (SOR: C, based on expert opinion).
Three forms of niacin exist: immediate-release (IR), sustained-release/long-acting (SR/LA), and extended-release (ER), which is currently available only as Niaspan.1 Published incidence of niacin-induced hepatotoxicity varies according to the definition of hepatotoxicity, with a 0% to 46% rate of elevated hepatic enzymes. Hepatotoxicity includes mild liver enzyme elevations, steatosis, hepatitis, abnormal liver biopsies, or fulminant hepatic failure.2,3 Between 1982 and 1992, 11 case reports have linked IR nicotinic acid to a wide range of hepatotoxicities. For patients taking LA/SR niacin doses ≥3 g/d or switching from the IR to the LA product, 21 case reports have linked LA/SR niacin with adverse outcomes.3,4 In several of the LA/SR cases, patients were rechal-lenged with IR formulations with no recurrent hepatocellular damage.3,4 In these case reports, onset of hepatotoxicity ranged from 2 days to 18 months. In a retrospective cohort of 969 veterans taking LA/SR niacin, those who developed hepatotoxicity had onset between 1 and 28 months of initiating treatment.2 Studies evaluating the risk of hepatotoxicity with niacin alone and in combination with statins are summarized in the Table .
Because LA/SR niacin has an active metabolite (nicotinamide), hepatotoxicity is more likely to occur with the LA/SR formulation than with IR niacin.3 In a small prospective comparative study of IR and LA/SR niacin (n=46), 0/23 patients taking IR niacin exhibited hepatic toxicity, compared with 12/23 (52%) of patients taking the LA/SR formulation.5 In this study, patients receiving 1 g/d of LA/SR niacin had increases in transaminases similar to those of patients on 3 g/d of IR niacin. It is therefore recommended that if a patient cannot tolerate IR niacin and is switched to the LA/SR form, the dosage be reduced by 50% to 70%.5 At doses >2 g/d of LA/SR niacin, mean transaminases approached 3 times the upper limit of normal (ULN), supporting recommendations not to exceed this dose for LA/SR niacin.5
Several LA/SR products exist, and their differing pharmacologic and clinical properties necessitate monitoring as though starting anew when changing from one LA/SR formulation to another.1 Because of the unfavorable risk-benefit ratio of LA/SR formulations compared with other niacin formulations, production and marketing of many LA/SR niacin brands has ceased. The ER formulation (Niaspan), only available by prescription, has a balanced metabolism resulting in less hepatotoxicity (<1%).1,6 Expert opinion mandates continued annual monitoring of liver function tests (LFT) for all patients, including those on a stable ER niacin dose, no new risk factors for hepatotoxicity, and a series of normal LFTs.7
Studies of niacin toxicity
|Author, evidence||Pts/duration of Rx||Lipid therapy||Hepatotoxicity|
|Gray,2 retrospective cohort||896 pts/1–3 mos||LA/SR (Slo-Niacin) avg 1500 mg/d||2.2% probable, 4.7% possible or probable|
|Capuzzi,6 open-label, prospective||517 pts/≤96 wks||ER (Niaspan) 1000–3000 mg/d||<1% w/transaminases >3 times ULN|
|McKenney,5 randomized, double-blind, placebo-controlled||46 pts/30 wks||LA/SR niacin or IR niacin: titrated from 500 mg/d to 3000 mg/d||52% SR pts with transaminases (78% SR pts withdrew); 0% IR pts with transaminases|
|Grundy,9 randomized, double-blind, placebo-controlled||97 pts/16 wks||ER (Niaspan) 1000–1500 mg/d||0% with transaminases >3 times ULN|
|Zhao,10 randomized, double-blind, placebo-controlled||80 pts/38 mos||LA/SR niacin (Slo-Niacin) 250 mg twice daily titrated to 1000 mg twice daily or switched to IR (Niacor) titrated to 3000–4000 mg/d + simvastatin 10 mg/d titrated to maintain LDL-C||3% w/transaminases >3 times ULN (transient— resolved with temporary halt or decrease in med)|
|Parra,3 randomized, double-blind||74 pts/9 wks||IR niacin titrated to max of 3000 mg/d + fluvastatin 20 mg/d||0% with transaminases >3 times ULN|
|Davignon,11 randomized, placebo-controlled||168 pts/96 wks||LA/SR niacin (Nicobid) 1000 mg twice daily vs Nicobid 1000 mg twice daily + pravastatin 40 mg nightly||3% > 3 times baseline transaminases (Nicobid alone) vs 1.2% >3 times baseline transaminases (Nicobid + pravastatin)|
|LA/SR, long-acting/sustained release; IR, immediate release; ER, extended release; ULN, upper limit of normal; LDL-C; low-density lipoprotein cholesterol.|