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)

Brown, Marcy L.

Mertens, Marsha K.

Rizkallah, Gloria S.

University of Missouri: MOspace

F R O M T H E F A M I L Y P R A C T I C E I N Q U I R I E S N E T W O R KClinical  InquiriesMARCH 2005 / VOL 54, NO 3 · The Journal of Family Practice 265C O N T I N U E DC O N T I N U E DShould liver enzymes be checked in a patienttaking niacin?■ EVIDENCE-BASED ANSWERNo randomized trials directly address the questionof frequency of liver enzyme monitoring withniacin use. Niacin use is associated with early andlate hepatotoxicity (strength of recommendation[SOR]: B, based on incidence data from random-ized controlled trials and systematic reviews ofcohort 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 controlledtrial and systematic reviews of cohort studies). The combination of statins and niacin at usualdoses does not increase the risk of hepatotoxicity(SOR: A, based on randomized controlled trials).Screening has been recommended at baseline, 6 to8 weeks after reaching a daily dose of 1500 mg, 6to 8 weeks after reaching the maximum daily dose,then annually (SOR: C, based on expert opinion).■ EVIDENCE SUMMARYThree forms of niacin exist: immediate-release(IR), sustained-release/long-acting (SR/LA), andextended-release (ER), which is currently avail-able only as Niaspan.1 Published incidence ofniacin-induced hepatotoxicity varies according tothe definition of hepatotoxicity, with a 0% to 46%rate of elevated hepatic enzymes. Hepatotoxicityincludes mild liver enzyme elevations, steatosis,hepatitis, abnormal liver biopsies, or fulminanthepatic failure.2,3 Between 1982 and 1992, 11case reports have linked IR nicotinic acid to awide range of hepatotoxicities. For patients tak-ing LA/SR niacin doses >3 g/d or switching fromthe IR to the LA product, 21 case reports havelinked LA/SR niacin with adverse outcomes.3,4 Inseveral of the LA/SR cases, patients were rechal-lenged with IR formulations with no recurrenthepatocellular damage.3,4 In these case reports,onset of hepatotoxicity ranged from 2 days to 18months. In a retrospective cohort of 969 veteranstaking LA/SR niacin, those who developed hepa-totoxicity had onset between 1 and 28 months ofinitiating treatment.2 Studies evaluating the riskof hepatotoxicity with niacin alone and in combi-nation with statins are summarized in the Table.What are Clinical Inquiries?Clinical Inquiries answer recent questions from the practices offamily physicians. Practicing family physicians choose the mostrelevant questions submitted through a web-based voting systemoperated by the Family Physicians Inquiries Network (FPIN; onlineat www.fpin.org).FPIN is national, not-for-profit consortium of family medicinedepartments, community residency programs, academic healthsciences libraries, primary care practice-based research networks, and other specialists. Once questions are selected,FPIN editors then organize teams of clinicians and librarians toanswer them based on systematic review of the world literature.Answers are developed through an explicit, systematic method:• FPIN librarians and editors identify questions recentlyanswered in best evidence sources (e.g. Cochrane Reviews,Clinical Evidence, the US Preventive Services Task Force,Evidence Based Guidelines, a published systematic review).• FPIN librarians then conduct systematic and standardized literature searches of best evidence sources, Medline, and otherdatabases in collaboration with an FPIN clinician or clinicians. If abest evidence source has been identified, the search begins fromthe date of the search conducted for that source. Otherwise, thesearches are comprehensive.• FPIN clinician authors then choose the highest quality originalresearch sources, and critically appraise the research and integrate the findings in the Evidence Based Answer andEvidence Summary section of Clinical Inquiries. Authoritativesources are also quoted in the “Recommendations from Others”section of the Clinical Inquiry.• Each Clinical Inquiry is reviewed by 4 or more peers or editors before publication in JFP.• FPIN medical librarians are accountable for the thoroughnessof the literature search, for recording the databases searched,search hedges used and the search terms. The details of eachsearch is available to any interested reader (contact managingeditor@fpin.org).• Finally, a practicing family physician or other clinician writesan accompanying commentary to provide a clinical perspective.C L I N I C A L  I N Q U I R I E S266 MARCH 2005 / VOL 54, NO 3 · The Journal of Family Practiceform, the dosage be reduced by 50% to 70%.5 Atdoses >2 g/d of LA/SR niacin, mean transaminas-es approached 3 times the upper limit of normal(ULN), supporting recommendations not to exceedthis dose for LA/SR niacin.5Several LA/SR products exist, and their differ-ing pharmacologic and clinical properties necessi-tate monitoring as though starting anew whenchanging from one LA/SR formulation to another.1Because of the unfavorable risk-benefit ratio ofLA/SR formulations compared with other niacinformulations, production and marketing of manyBecause LA/SR niacin has an active metabolite(nicotinamide), hepatotoxicity is more likely tooccur with the LA/SR formulation than with IRniacin.3 In a small prospective comparative studyof IR and LA/SR niacin (n=46), 0/23 patients tak-ing IR niacin exhibited hepatic toxicity, comparedwith 12/23 (52%) of patients taking the LA/SRformulation.5 In this study, patients receiving 1 g/dof LA/SR niacin had increases in transaminasessimilar to those of patients on 3 g/d of IR niacin. Itis therefore recommended that if a patient cannottolerate IR niacin and is switched to the LA/SRStudies of niacin toxicityPts/duration Author, evidence of Rx Lipid therapy HepatotoxicityGray,2 retrospective 896 pts/ LA/SR (Slo-Niacin) 2.2% probable,cohort 1–3 mos avg 1500 mg/d 4.7% possible or probableCapuzzi,6 open-label, 517 pts/ ER (Niaspan) <1% w/ transaminasesprospective ≤96 wks 1000–3000 mg/d >3 times ULNMcKenney,5 randomized, 46 pts/ LA/SR niacin or IR niacin: 52% SR pts with  double-blind, 30 wks titrated from 500 mg/d to transaminases (78% SR pts placebo-controlled 3000 mg/d withdrew); 0% IR pts with  transaminasesGrundy,9 randomized, 97 pts/ ER (Niaspan) 0% with transaminases double-blind, 16 wks 1000–1500 mg/d >3 times ULNplacebo-controlledZhao,10 randomized, 80 pts/ LA/SR niacin (Slo-Niacin) 3% w/transaminases double-blind, 38 mos 250 mg twice daily titrated >3 times ULN (transient— placebo-controlled to 1000 mg twice daily or resolved with temporary halt switched to IR (Niacor) or decrease in med)titrated to 3000–4000 mg/d + simvastatin 10 mg/d titrated to maintain LDL-CParra,3 randomized, 74 pts/ IR niacin titrated to max of 3000 0% with transaminases double-blind 9 wks mg/d + fluvastatin 20 mg/d >3 times ULNDavignon,11 randomized, 168 pts/ LA/SR niacin (Nicobid) 3% > 3 times baseline placebo-controlled 96 wks 1000 mg twice daily vs transaminases (Nicobid Nicobid 1000 mg twice alone) vs 1.2% >3 timesdaily + pravastatin 40 mg baseline transaminasesnightly (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.TA B L E  ➞➞C L I N I C A L  I N Q U I R I E SMARCH 2005 / VOL 54, NO 3 · The Journal of Family Practice 267C O N T I N U E DLA/SR niacin brands has ceased. The ER formu-lation (Niaspan), only available by prescription,has a balanced metabolism resulting in less hepatotoxicity (<1%).1,6 Expert opinion mandatescontinued annual monitoring of liver functiontests (LFT) for all patients, including those on astable ER niacin dose, no new risk factors forhepatotoxicity, and a series of normal LFTs.7■ RECOMMENDATIONS FROM OTHERSElevated hepatic enzymes <3 times the ULN mayoccur but usually resolve with continued therapy orreduced doses. Enzymes >3 times the ULN requirediscontinuation of therapy.8 The American Societyof Health-System Pharmacists (ASHP) recom-mends screening at baseline, every 2 to 3 monthsfor the first year and every 6 to 12 months there-after.8 The ASHP also recommends that patients bestarted on IR niacin products, with consideration ofER products only when IR products are not tolerat-ed or alternative products are ineffective. ASHPmakes no mention of LA/SR products in their rec-ommendations.8 They recommend more frequentmonitoring for high-risk patients—risks includedoses >2 g/d for LA/SR and >3 g/d for IR; LA/SRformulations; switching between formulations; tak-ing concomitant drugs that interact (ie, sulfony-lureas); excessive alcohol use (undefined); and pre-existing liver disease (based on a bivariate analysisof factors associated with increased risk of hepatictoxicity from a single retrospective cohort study)5—and for patients who demonstrate signs/symptomsof toxicity (nausea, vomiting, malaise, loss ofappetite, right upper quadrant pain, jaundice, anddark urine).8 The National Cholesterol EducationProgram Expert Panel update in 2004 recommend-ed obtaining ALT/AST initially, 6 to 8 weeks afterreaching a daily dose of 1500 mg, 6 to 8 weeks afterreaching the maximum daily dose, then annually ormore frequently if indicated.7Gloria S. Rizkallah, PharmD, BCPS, St. LouisCollege of Pharmacy and Mercy Family Medicine; Marsha K. Mertens, MD, Mercy Family Medicine, St. Louis, Mo; Marcy L. Brown, MLS, Forbes RegionalHospital, Monroeville, Pa■ CLINICAL COMMENTARYRisk of toxicity with long-acting niacinis significant enough to avoid useOur clinical experience is that once ourpatients are on stable doses of most medicinesand have had a series of normal lab tests, weare unlikely to find toxicities from continuedroutine testing. That appears to be the casewith niacin and liver toxicity, but long-termdata are lacking for asymptomatic late reac-tions to usual niacin doses. The risk of toxicitywith “long-acting” forms of niacin is significantenough that I see no reason to use them at all.If one wants to save money, use IR niacin. Ifcost is not an issue or regular niacin is not tolerated, I use the ER Niaspan. Both of theseforms have very low rates of liver toxicity.Louis Sanner, MD, University of Wisconsin MedicalSchool, Madison Family Practice ResidencyREFERENCES1. McKenney J.  New perspectives on the use of niacin in thetreatment of lipid disorders. Arch Intern Med 2004;164:697–705.2. Gray DR, Morgan T, Chretien SD, Kashyap ML. Efficacyand safety of controlled-release niacin in dyslipoproteine-mic veterans. Ann Intern Med 1994; 121:252–258.3. Parra JL, Reddy KR. Hepatotoxicity of hypolipidemicdrugs. Clin Liver Dis 2003; 7:415–433.4. Ferenchick G, Rovner D. Hepatitis and hematemesis com-plicating nicotinic acid use. Am J Med Sci 1989;298:191–193.5. McKenney JM, Proctor JD, Harris S, Chinchili VM. A com-parison of the efficacy and toxic effects of sustained- vs.immediate-release niacin in hypercholesterolemicpatients. JAMA 1994; 271:672–700.6. Capuzzi DM, Guyton JR, Morgan JM, et al. Efficacy andsafety of an extended-release niacin (Niaspan): A long-term study. Am J Cardiol 1998; 82:74U–86U.7. Expert Panel on the Detection, Evaluation, andTreatment of High Blood Cholesterol in Adults.Executive Summary of the Third Report of the NationalCholesterol Education Program (NCEP) Expert Panel onthe Detection, Evaluation, and Treatment of High BloodCholesterol in Adults (Adult Treatment Panel III). JAMA2001; 285:2486–2497.8. ASHP Therapeutic Position Statement on the safe use ofniacin in the management of dyslipidemias. AmericanSociety of Health System Pharmacists. Am J Health-SystPharm 1997; 54:2815–2819.9. Grundy SM, Vega GL, McGovern ME, et al. Efficacy, safe-ty, and tolerability of once-daily niacin for the treatmentof dyslipidemia associated with type 2 diabetes: results ofthe assessment of diabetes control and evaluation of theefficacy of Niaspan trial. Arch Intern Med 2002;162:1568–1576.C L I N I C A L  I N Q U I R I E SC O N T I N U E D268 MARCH 2005 / VOL 54, NO 3 · The Journal of Family PracticeOne of the largest and most recent of thesestudies reports adjusted odds for development ofcoronary artery disease of 1.45 (95% confidenceinterval [CI], 1.25–1.68) for subjects in the topthird of hs-CRP levels compared with those in thebottom third.9 Odds ratios (OR) for other predic-tors of coronary artery disease are higher than this, in particular total cholesterol(OR=2.35; 95% CI, 2.03–2.74), cigarette smok-ing (OR=1.87; 95% CI, 1.62–2.22), and elevatedsystolic blood pressure (OR=1.50; 95% CI,1.30–1.73). This shows that hs-CRP does notcontribute as much as these factors to the estab-lished risk profile for coronary heart disease.These same authors go on to provide a systematic review of 22 prospective studies of hs-CRP involving 7068 patients, which showedthat an elevated hs-CRP was associated withhigher odds of developing coronary artery disease(OR=1.58; 95% CI, 1.48–1.68). They also exam-ined the largest 4 studies in their review (whichincluded 4107 cases) and found a slightly lowerOR of 1.49 (95% CI, 1.37–1.62). This meta-analy-sis included only studies published since 2000because earlier studies, which had yielded higherodds for hs-CRP, suggested a pattern consistentwith publication bias. Two very recent studies evaluating statin ther-apy for CVD suggest that CRP may be monitoredas an independent factor for predicting CVD out-comes for patients undergoing aggressive lipidtherapy.10,11 These randomized, masked trials sug-gest that CRP is directly predictive of recurrentevents among patients with known CVD. Its use-fulness may be greatest when trying to decidewhether to pursue aggressive (high-dose) statintherapy for these patients.It is not clear whether hs-CRP is a direct,causative marker for atherosclerosis or whetherit is simply a proxy marker elevated in conjunc-tion with other known risk factors. This issue,combined with the fact that its elevation does not contribute as significantly as other risk factors,makes hs-CRP an inappropriate screening testfor cardiovascular disease in the healthy adult 10. Zhao XQ, Morse JS, Dowdy AA, et al. Safety and tolera-bility of simvastatin plus niacin in patients with coronaryartery disease and low high-density lipoprotein choles-terol (The HDL Atherosclerosis Treatment Study). Am J Cardiol 2004; 93:307–312.11. Davignon J, Roederer G, Montigny M, et al. Comparativeefficacy and safety of pravastatin, nicotinic acid and thetwo combined in patients with hypercholesterolemia. Am J Cardiol 1994; 73:339–345.How useful is high-sensitivityCRP as a risk factor for coronary artery disease?■ EVIDENCE-BASED ANSWERLittle evidence supports the use of the high-sen-sitivity C-reactive protein assay (hs-CRP) as ascreening test for cardiovascular disease (CVD)in the healthy adult population. There is signifi-cant debate about its use in populations at mod-erate risk for cardiovascular disease, with someevidence suggesting its use if the results of thetest will alter treatment recommendations1(strength of recommendation [SOR]: C, based onextrapolation of consistent level 2 studies).Research to date is inadequate to determine therole of hs-CRP in risk-stratification of patientswhen considered in light of other standard riskfactors (Table).■ EVIDENCE SUMMARYC-reactive protein is a nonspecific serum markerof inflammatory response. While it is elevated ina variety of conditions, a link has been suggestedbetween CRP and pathogenesis of clinical cardio-vascular disease.1Several retrospective studies have reportedrisk ratios for developing cardiovascular disease,ranging from 2.3 to 4.4 when comparing subjectswith the highest levels of hs-CRP with those whohave the lowest levels.2–9 Though systematic biasin retrospective study design limits the interpreta-tion of these findings, the findings are of somebenefit to answering this question when large,prospective, randomized studies are not available. 

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