Simvastatin is a commonly used cholesterol lowering agent (statin) that is associated with mild, asymptomatic and self-limited serum aminotransferase elevations during therapy, and rarely with clinically apparent acute liver injury.
Simvastatin (sim" va stat' in) is an orally available inhibitor of hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the major rate-limiting enzyme in cholesterol synthesis. Like other members of its class (the “statins”), simvastatin lowers total serum cholesterol and particularly low density lipoprotein (LDL) cholesterol concentrations, thereby reducing the risk of atherosclerosis and its complications – myocardial infarction and stroke. Simvastatin was approved for use in the United States in 1991 and is still widely used with more than 40 million prescriptions being filled yearly. Current indications for simvastatin are hypercholesterolemia and reduction in risk for death from coronary, cerebrovascular and peripheral artery disease in patients with these diseases. Simvastatin is available generic forms and under the commercial name of Zocor in tablets of 5, 10, 20, 40 and 80 mg. the recommended dose is 5 to 80 mg daily based upon tolerability and lipid levels. Simvastatin is also available as a fixed combination with ezetimibe under the brand name Vytorin. Common side effects include muscle cramps, joint aches, headache and weakness.
Up to 5% of patients taking simvastatin chronically may experience minor elevations in serum ALT levels during therapy, but confirmed elevations to above three times the upper limit of normal (ULN) occur in only 1% to 2% of patients. These abnormalities are usually asymptomatic and self-limited even if therapy is continued. In some studies, ALT elevations have occurred no more frequently in simvastatin treated as in control subjects. Clinically apparent liver injury due to simvastatin is rare. The usual latency to onset of symptoms of liver disease ranges from one week to as long as 3 years, but most cases have a latency of 1 to 6 months. The pattern of injury is variable, hepatocellular, cholestatic or mixed patterns have been described. Immunoallergic symptoms of fever and rash are uncommon. Isolated cases of an autoimmune hepatitis-like syndrome associated with simvastatin therapy have been reported, some of which did not reverse completely with discontinuation, resulting in a chronic hepatitis requiring long term immunosuppressive therapy. In most cases, however, recovery occurs within 1 to 3 months. Rare cases of acute liver failure and death have been attributed to simvastatin. But in view of the wide use of simvastatin, clinically apparent liver injury is exceeding rare and is estimated to occur in 1 per 100,000 patient years of exposure.
Likelihood score: A (well known cause of clinically apparent liver injury).
Mechanism of Injury
The cause of hepatic injury from simvastatin is unknown. Simvastatin is metabolized to some extent in the liver (via CYP 3A4) and is excreted in bile. The mild, self-limited ALT elevations are likely due to a toxic intermediate of drug metabolism and the reversal of these elevations due to adaptation. Medications that inhibit cytochrome P450 activity (such as cyclosporine, ketoconazole, diltiazem, ciprofloxacin or amiodarone) may cause increases in simvastatin levels and potentiate its hepatic or muscle toxicity. The idiosyncratic, clinically apparent liver injury associated with simvastatin may be due to failure of adaptation.
Outcome and Management
The mild ALT elevations associated with simvastatin therapy are usually self-limited and do not require dose modification; simvastatin should be stopped if ALT levels rise above 10-fold the upper limit of normal, or persist in being above 5-fold elevated or are associated with symptoms. In the clinically apparent liver injury attributed to simvastatin, recovery is usually complete within 1 to 2 months. Vanishing bile duct syndrome has not been described in association with simvastatin. Rare instances of acute liver failure have been attributed to simvastatin, but in these cases the role of simvastatin was not completely clear. In view of the wide scale use of simvastatin, clinically apparent and severe liver injury is extraordinarily rare. Recurrence of injury with rechallenge has been reported and should be avoided. Switching therapy to another statin after simvastatin induced injury is apparently safe, but few instances have been reported, and it should be done with careful monitoring for recurrence.
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Case 1. Cholestatic hepatitis due to simvastatin.
[Modified from: Lata S, Chudy B. [Acute cholestatic hepatitis caused by simvastatin in a 67-year-old patient]. Przegl Lek 2006; 63 (suppl 7): 97-8. Polish. PubMed Citation
A 67 year old woman was admitted to the hospital with a 2 week history of jaundice, pruritus, right upper quadrant pain and fatigue that had arisen 10 months after starting simvastatin (10 mg daily for 8 months, 5 mg for 2) for hypercholesterolemia. She had suffered an ischemic stroke the year before and was taking nitroglycerin and aspirin chronically. She had no history of liver disease and drank little alcohol. On examination, she was jaundiced. Laboratory tests showed moderate elevations of aminotransferase and alkaline phosphatase levels (Table). Tests for hepatitis B and C were negative as were autoantibodies. Imaging of the abdomen showed no evidence of biliary obstruction. Simvastatin was stopped and she was treated with ursodiol, cholestyramine and prednisone (50 mg daily). She improved slowly and was discharged from the hospital 3 weeks later with no symptoms and minimal jaundice. In follow up 4 weeks later, her blood tests were normal.
|Medication:||Simvastatin (5-10 mg daily)|
|Pattern:|| Cholestatic (R=0.6→1.3)|
||3+ (jaundice, hospitalization)|
|Other medications:||Nitroglycerin, aspirin|
|Time After Starting
||Time After Stopping
||Alk P (U/L)
* Some values estimated from Table 1.
The latency to onset of liver injury due to simvastatin is quite variable, ranging from a few weeks to several years. Nevertheless, the acute cholestatic course, resolution with stopping simvastatin and lack of other diagnoses make it likely that this injury was due to simvastatin. The role of prednisone in managing acute cholestatic injury due to medications is unclear. While therapy may appear to improve jaundice and symptoms promptly, it is doubtful whether the ultimate outcome of the hepatic injury is changed by therapy and the risks of using high doses of prednisone are not negligible.
Case 2. Acute liver failure attributed to simvastatin/ezetimibe therapy.
[Modified from: Tuteja S, Pyrsopoulos NT, Wolowich WR, Khanmoradi K, Levi DM, Selvaggi G, Weisbaum G, et al. Simvastatin-ezetimibe-induced hepatic failure necessitating liver transplantation. Pharmacotherapy 2008; 28: 1188-93. PubMed Citation]
A 70 year old woman developed abnormal liver tests ten weeks after adding switching from simvastatin (40 mg) monotherapy to the combination of simvastatin (40 mg) and ezetimibe (10 mg) daily. She had a history of coronary artery disease, hypertension, depression and hypercholesterolemia and had been on simvastatin for one and a half years with normal serum enzymes (Table). Despite stopping both simvastatin and ezetimibe, she developed jaundice and progressive symptoms of liver failure. Tests for hepatitis A, B and C were negative as were autoimmune markers. A liver biopsy showed changes suggestive of drug induced liver injury and severe cholestasis. She developed progressive encephalopathy and worsening coagulation indices, and was listed and underwent successful liver transplantation approximately 4 weeks after stopping therapy. In follow up for two years after transplantation, liver enzymes were normal.
|Medication:||Simvastatin and ezetimibe|
|Pattern:|| Hepatocellular (R=25)|
||5+ (emergency liver transplantation)|
||10 weeks to liver test abnormalities, 12 weeks to jaundice
|Other medications:||Enalapril, escitalopram chronically|
|Weeks After Starting
||Weeks After Stopping
||Alk P (U/L)
||Before starting simvastatin
||On simvastatin before ezetimibe
||Simvastatin and ezetimibe stopped
|Emergency liver transplantation performed
|Post-op day 1
|Post-op day 23
|2 years after transplant
The onset of injury 10 weeks after starting ezetimibe suggests that it was the cause of the acute liver injury, but onset of hepatitis due to simvastatin can occur months to years after its initiation. This is one of the few case reports of acute liver failure due to a cholesterol lowering agent.
Clinical cases of drug-induced liver injury that have been submitted to LiverTox ("Submit a Case Report") are available for review. Most of these reference cases are from
the Drug-Induced Liver Injury Network, but others are from users of LiverTox who have submitted data from an actual clinical case. All cases have been reviewed and cleared
of personal identifiers and a brief comment added by the LiverTox editors. Click on the following link to view the submitted case reports that have been made publically available.
REPRESENTATIVE TRADE NAMES
Simvastatin – Generic, Zocor®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 05 August 2017
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Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002; 360: 7-22. PubMed Citation (Large controlled trial of simvastatin vs placebo; ALT levels >2 times ULN occurred in 1.3% of patients on simvastatin vs 1.8% on placebo; ALT >4 times ULN in 0.42% vs 0.31%, not significantly different).
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Ashar U, Desai D, Bhaduri A. Flutamide-induced hepatotoxicity with possible potentiation by simvastatin. J Assoc Physicians India 2003; 51: 75-7. PubMed Citation (65 year old man developed jaundice 1 month after starting flutamide while on simvastatin [bilirubin 33.5 mg/dL, ALT 646 U/L, Alk P 290 U/L]; role of simvastatin uncertain).
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~50,000 liver transplants done in the US between 1990 and 2002, 270
[0.5%] were done for drug induced acute liver failure, 3 of which were
attributed to statins including simvastatin in 1 and cerivastatin in
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Zhao XQ, Morse JS, Dowdy AA, Heise N, DeAngelis D, Frohlich J, Chait A, et al. Safety and tolerability of simvastatin plus niacin in patients with coronary artery disease and low high-density lipoprotein cholesterol (The HDL Atherosclerosis Treatment Study). Am J Cardiol 2004; 93: 307-12. PubMed Citation (Controlled trial of simvastatin and niacin vs placebo in 160 patients for up to 3 years; side effects were similar in the two groups, with AST elevations >3 times ULN in 2 patients on simvastastin/niacin and one on placebo).
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Jacobson TA. Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol 2004; 94: 1140-6. PubMed Citation (Pharmacokinetic studies of drug-drug interactions demonstrated that drugs that inhibit CYP 3A4, the major P450 drug metabolizing enzyme [itraconazole, clarithromycin, verapamil], cause increases in blood levels of simvastatin and atorvastatin, but have little effect on pravastatin levels).
Masana L, Mata P, Gagné C, Sirah W, Cho M, Johnson-Levonas AO, Meehan A, et al.; Ezetimibe Study Group. Long-term safety and, tolerability profiles and lipid-modifying efficacy of ezetimibe coadministered with ongoing simvastatin treatment: a multicenter, randomized, double-blind, placebo-controlled, 48-week extension study. Clin Ther 2005; 27: 174-84. PubMed Citation (Trial comparing addition of ezetimibe vs placebo to ongoing simvastatin therapy for hypercholesterolemia for up to 48 weeks; only one instance of ALT levels >3 times ULN and no case of clinically apparent liver injury in 355 patients on the combination).
Alsheikh-Ali AA, Karas RH. Adverse events with concomitant amiodarone and statin therapy. Prev Cardiol 2005; 8: 95-7. PubMed Citation (Review of MedWatch adverse event reports for proportion that included combination with amiodarone; 1.0% for simvastatin, 0.7% atorvastatin and 0.4% pravastatin; 77% muscle, 30% liver involvement).
Cokça F, Ozkan S, Nergisoglu G, Memikoglu O, Azap A. Statin toxicity: a situation that mimics viral hepatitis. Int J Clin Pharmacol Ther 2005; 43: 543-5. PubMed Citation (44 year old woman developed rhabdomyolysis 2 months after being switched from fluvastatin to simvastatin with clinical features suggesting viral hepatitis, but no jaundice [ALT 1,196 U/L, AST 1,200 U/L, CPK 119,300 U/L], myoglobin in serum resulting in renal failure requiring dialysis, but ultimate full recovery).
Charles EC, Olson KL, Sandhoff BG, McClure DL, Merenich JA. Evaluation of cases of severe statin-induced transaminitis within a large health maintenance organization. Am J Med 2005; 118: 618-24. PubMed Citation (Among 23,000 patients on statins in a health plan, 17 had ALT elevation >10 times ULN attributable to statin use; 10 on simvastatin, 5 lovastatin, and 2 atorvastatin; onset 2 days to 4 years after starting; 10 symptomatic; all resolved within 2-8 weeks, except one death; 3 of 7 recurred on rechallenge, 5 of 6 tolerated switching to another statin).
Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-Ruiz E, García-Muñoz B, et al.; Spanish Group for the Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005; 129: 512-21. PubMed Citation (Analysis of 461 cases of drug induced liver disease enrolled between 1984 to 2004 in a Spanish Registry; 11 cases were attributed to “statins”, but no specific agent caused more than 4 cases).
Ballantyne CM, Abate N, Yuan Z, King TR, Palmisano J. Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study. Am Heart J 2005; 149: 464-73. PubMed Citation (Controlled trial of ezetimibe/simvastatin vs atorvastatin in 1902 patients with hypercholesterolemia, ALT elevations >3 times ULN occurred in 1.1% on atorvastatin and none on ezetimibe/simvastatin).
Khorashadi S, Hasson NK, Cheung RC. Incidence of statin hepatotoxicity in patients with hepatitis C. Clin Gastroenterol Hepatol 2006; 4: 902-7. PubMed Citation (Electronic record review of rate of ALT elevations in patients with hepatitis C with or without statin therapy and controls on statin therapy found no differences between the three groups [20%, 24% and 17%]; severe abnormalities most frequent in patients with chronic hepatitis C not on statin [6.6% vs 1.2%]).
Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol 2006; 97 (8A): 52C-60C. PubMed Citation (Review of safety of statins; 38 cases of acute liver failure submitted to MedWatch by end of 1999, which gives an estimated rate of 1 per million person years of use; rate of confirmed ALT elevations >3 times ULN is 0.1% with statins and 0.04% with placebo).
Ricaurte B, Guirguis A, Taylor HC, Zabriskie D. Simvastatin-amiodarone interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity. Ann Pharmacother 2006; 40: 753-7. PubMed Citation (72 year old developed muscle pain and dark urine after 10 weeks of amiodarone and 4 weeks of simvastatin therapy [ALT 748 U/L, CK 19,620 U/L; no mention of bilirubin or Alk P], resolving within 3 months of stopping both drugs; enzyme elevations likely due to rhabdomyolysis rather than hepatitis).
Conforti A, Magro L, Moretti U, Scotto S, Motola D, Salvo F, Ros B, et al. Fluvastatin and hepatic reactions: a signal from spontaneous reporting in Italy. Drug Saf 2006; 29: 1163-72. PubMed Citation (Italian Pharmacovigilance Group review of 35,757 adverse reaction reports; 1260 due to statins of which 178 were hepatic: 69 [36%] fluvastatin, 37 [21%] atorvastatin, 50 [28%] simvastatin, 16 [9%] pravastatin, 6 [3%] rosuvastatin; proportion reporting rate based on number of prescriptions was highest for fluvastatin [~9] compared to other agents [~2-3]; 26 fluvastatin cases described as “hepatitis”, but no details given except that most cases occurred within 90 days of starting).
Goldberg RB, Guyton JR, Mazzone T, Weinstock RS, Polis A, Edwards P, Tomassini JE, et al. Ezetimibe/simvastatin vs atorvastatin in patients with type 2 diabetes mellitus and hypercholesterolemia: the VYTAL study. Mayo Clin Proc. 2006; 81: 1579-88. PubMed Citation (Controlled trial of atorvastatin vs simvastatin/ezetimibe in 1229 patients with diabetes and hypercholesterolemia; confirmed ALT elevations >3 times ULN occurred in 0.3% of atorvastatin vs no simvastatin/ezetimibe treated patient, and no clinically apparent liver injury).
Björnsson E, Olsson R. Suspected drug-induced liver fatalities reported to the WHO database. Dig Liver Dis 2006; 38: 33-8. PubMed Citation (In WHO database of fatal adverse drug reactions from 1968-2003 included 4690 reports of deaths from liver disease due to medications: none of the statins were in the top 20 suspected causes of acute liver failure due to medications).
Lata S, Chudy B. [Acute cholestatic hepatitis caused by simvastatin in a 67-year-old patient]. Przegl Lek 2006; 63 (suppl 7): 97-8. Polish. PubMed Citation (67 year old woman developed jaundice and pruritus 10 months after starting simvastatin [bilirubin 8.2 mg/dL, ALT 165 U/L, Alk P 502 U/L], resolving within 7 weeks of stopping: Case 1).
Silva MA, Swanson AC, Gandhi PJ, Tataronis GR. Statin-related adverse events: a meta-analysis. Clin Ther 2006; 28: 26-35. PubMed Citation (Meta analysis of adverse event rates in 18 placebo controlled trials of six statins in 71,108 patients; ALT elevations >3 times ULN occurred in 1.7% of statin vs 1.4% of placebo recipients; event rates highest with atorvastatin, lowest with fluvastatin).
Alla V, Abraham J, Siddiqui J, Raina D, Wu GY, Chalasani NP, Bonkovsky HL. Autoimmune hepatitis triggered by statins. J Clin Gastroenterol 2006; 40: 757-61. PubMed Citation (Three cases of autoimmune hepatitis arising after simvastatin or atorvastatin therapy 6, 20 and 20 weeks after starting [bilirubin 11.3, 3.4 and 5.5 mg/dL, ALT 1749, 1170 and 155 U/L, Alk P of 228, 160, and 203 U/L, all being ANA or SMA positive in titers of 1:40 to 1:160], all responding to prednisone/azathioprine and requiring long term mono-therapy with azathioprine or mycophenylate).
Dale KM, White CM, Henyan NN, Kluger J, Coleman CI. Impact of statin dosing intensity on transaminase and creatine kinase. Am J Med 2007; 120: 706-12. PubMed Citation (Meta analysis of rates of ALT and CPK elevations in nine controlled studies comparing low vs high doses of statins; ALT elevations >3 times ULN occurred in 1.5% of high- and 0.4% of low-intensity statin groups, effect particularly seen with hydrophilic [pravastatin and atorvastatin] compared to lipophilic agents [simvastatin and lovastatin]).
Silva M, Matthews ML, Jarvis C, Nolan NM, Belliveau P, Malloy M, Gandhi P. Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy. Clin Ther 2007; 29: 253-60. PubMed Citation (Meta analysis of rates of adverse events in 4 controlled trials in 108,049 patient years comparing standard to intensive-dose statin therapy; increased risk of ALT elevations >3 times ULN with intensive therapy [odds ratio 4.5; absolute risk 1.2%], but no mention of clinically apparent liver injury).
Alsheikh-Ali AA, Karas RH. Safety of lovastatin/extended release niacin compared with lovastatin alone, atorvastatin alone, pravastatin alone, and simvastatin alone (from the United States Food and Drug Administration adverse event reporting system). Am J Cardiol 2007; 99: 379-81. PubMed Citation (Analysis of MedWatch reports of adverse events found no excess in liver related adverse event reports per million prescription due to lovastatin alone [2.3] vs niacin alone [2.5] vs the combination [3.2], but slightly higher rates with atorvastatin [4.5], simvastatin [5.7] and pravastatin [4.9], but data relied upon spontaneous reporting).
Ose L, Johnson-Levonas A, Reyes R, Lin J, Shah A, Tribble D, Musliner T; Vytorin Extension Study Group. A multi-centre, randomised, double-blind 14-week extension study examining the long-term safety and efficacy profile of the ezetimibe/simvastatin combination tablet. Int J Clin Pract 2007; 61: 1469-80. PubMed Citation (Continuation of trial [Bayes 2004] with 1104 patients continuing in extension study of simvastatin vs simvastatin/ezetimibe in various dosages; confirmed ALT elevations >3 times ULN occurred in 1.3% on simvastatin alone and 1.5% on the combination; no cases of clinically apparent liver injury).
Bhardwah SS, Chalasani N. Lipid-lowering agents that cause drug-induced hepatotoxicity. Clin Liver Dis 2007; 11: 597-613. PubMed Citation (Review of hepatotoxicity of statins; reported rates of ALT or AST elevations >3 times ULN: atorvastatin 0.7%, fluvastatin 1.2%, lovastatin 0.6%, pravastatin 1.4%, rosuvastatin 0% and simvastatin 1.8%. Usually asymptomatic, individual case reports of autoimmune hepatitis).
Alsheikh-Ali AA, Maddukuri PV, Han H, Karas RH. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol 2007; 50: 409-18. PubMed Citation (Systematic review of relationship between LDL cholesterol lowering effects and adverse events in 23 statin treatment arms representing 309,506 person years of therapy; positive and graded relationship between statin dose [simvastatin, lovastatin and atorvastatin] and rates of ALT elevations, but no independent relationship to degree of LDL cholesterol decrease).
Escobar C, Echarri R, Barrios V. Relative safety profiles of high dose statin regimens. Vasc Health Risk Manag 2008; 4: 525-33. PubMed Citation (Review of efficacy and safety of use of higher doses of statins to achieve lower LDL cholesterol levels; ALT elevations are more frequent [2-3%] with higher than lower [~1%] doses).
Tuteja S, Pyrsopoulos NT, Wolowich WR, Khanmoradi K, Levi DM, Selvaggi G, Weisbaum G, et al. Simvastatin-ezetimibe-induced hepatic failure necessitating liver transplantation. Pharmacotherapy 2008; 28: 1188-93. PubMed Citation (70 year old woman developed acute liver failure 10 weeks after addition of ezetimibe to long term simvastatin therapy [1.5 years], with ALT 842→2595 U/L, Alk P 217 U/L, bilirubin 0.4→23.7 mg/dL, INR rising to 2.0 and emergency liver transplant: Case 2).
Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, 3 cases were attributed to atorvastatin, 3 to simvastatin/ezetimibe, and one each to pravastatin, fluvastatin, and simvastatin, but most cases were mild or not clearly attributable to the statin therapy).
Bays H. Safety of niacin and simvastatin combination therapy. Am J Cardiol 2008; 101 (8A): 3B-8B. PubMed Citation (Review of safety of the combination of niacin and simvastatin; ALT elevations associated mostly with slow release [SR], rather than the extended [ER] or intermediate [IR] release formulations of niacin).
Guyton JR, Brown BG, Fazio S, Polis A, Tomassini JE, Tershakovec AM. Lipid-altering efficacy and safety of ezetimibe/simvastatin coadministered with extended-release niacin in patients with type IIa or type IIb hyperlipidemia. J Am Coll Cardiol 2008; 51: 1564-72. PubMed Citation (Controlled trial comparing niacin alone vs simvastatin/ezetimibe vs the triple combination for 24 weeks in 1220 patients with hypercholesterolemia; confirmed ALT elevations >3 times ULN occurred in 0.4% on niacin, 0.4% on simvastastin/ezetimibe and 0.5% on all three).
Martin JE, Cavanaugh TM, Trumbull L, Bass M, Weber F Jr, Aranda-Michel J, Hanaway M, et al. Incidence of adverse events with HMG-CoA reductase inhibitors in liver transplant patients. Clin Transplant 2008; 22: 113-9. PubMed Citation (Retrospective review of adverse events associated with statin and fibrate use in 69 patients with liver transplants; myalgias problematic in 5, myopathy in 1, but none had significant ALT elevations or hepatitis related to medication).
Neuvonen PJ, Backman JT, Niemi M. Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin. Clin Pharmacokinet 2008; 47: 463-74. PubMed Citation (Review of literature on pharmacokinetics of statins; simvastatin and lovastatin are metabolized extensively by the P450 system and levels are affected by inhibitors or inducers of CYP 3A4 [itraconazole, erythromycin, verapamil, diltiazem, cyclosporine], whereas fluvastatin and pravastatin are minimally if at all affected).
MRC/BHF Heart Protection Study Collaborative Group, Armitage J, Bowman L, Collins R, Parish S, Tobert J. Effects of simvastatin 40 mg daily on muscle and liver adverse effects in a 5-year randomized placebo-controlled trial in 20,536 high-risk people. BMC Clin Pharmacol 2009; 9: 6. PubMed Citation (Analysis of muscle and hepatic adverse events in controlled trial of simvastatin [40 mg] vs placebo daily for 5 years in 20,536 UK patients; hepatitis occurred in 1 patient on simvastatin [ALT 257 U/L] at 7 months, 9 months later presenting with acute hepatitis and jaundice] and 1 on placebo [later attributed to septicemia]; ALT elevations >3 times ULN occurred in 0.75% on simvastatin and 0.63% on placebo).
Robinson JG, Ballantyne CM, Grundy SM, Hsueh WA, Parving HH, Rosen JB, Adewale AJ, et al. Lipid-altering efficacy and safety of ezetimibe/simvastatin versus atorvastatin in patients with hypercholesterolemia and the metabolic syndrome (from the VYMET study). Am J Cardiol 2009; 103: 1694-702. PubMed Citation (Controlled trial of ezetimibe/simvastatin versus atorvastatin alone in 1128 patients with metabolic syndrome and hypercholesterolemia; adverse event rates were similar in the two groups, but consecutive ALT or AST elevations >3 times ULN occurred in 0.3% of atorvastatin vs 1.4% of ezetimibe/simvastatin treated patients).
Abraldes JG, Albillos A, Bañares R, Turnes J, González R, García-Pagán JC, Bosch J. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology 2009; 136: 1651-8. PubMed Citation (Controlled trial of simvastatin [20-40 mg/d] vs placebo for 30 days assessing effects on hepatic venous pressure gradient [HVPG] in 59 patients with portal hypertension found slight decrease in HVPG and improvement in indocyanine green clearance; no changes in ALT levels or evidence of liver injury).
Russo MW, Scobey M, Bonkovsky HL. Drug-induced liver injury associated with statins. Semin Liver Dis 2009; 29: 412-22. PubMed Citation (Review of statin hepatotoxicity and the several forms of liver injury that they can cause, including silent aminotransferase elevations, cholestatic and hepatocellular hepatitis and autoimmune hepatitis-like syndromes, all of which are rare).
Björnsson E, Jacobsen EI, Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing. J Hepatol 2012; 56:374-80. PubMed Citation (Between 1988 and 2010, the Swedish registry received 217 adverse event reports possibly related to statins, 124 [57%] being liver related, 73 of which could be evaluated; 2 were fatal and one led to liver transplant; 3 had positive rechallenge; 43 [59%] were hepatocellular, 22 [30%] cholestatic and 8 [11%] mixed; 30 were due to atorvastatin, 28 simvastatin, 11 fluvastatin, 2 pravastatin and 2 rosuvastatin, arising after 30 to 248 days; simvastatin injury was hepatocellular in 75% of instances [one case was fatal, one led to transplant] and was estimated to occur in 0.9 per 100,000 person years of exposure).
H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-center
experience with drug-induced liver injury from India: causes, outcome,
prognosis, and predictors of mortality. Am J Gastroenterol 2010; 105:
2396-404. PubMed Citation (Among
313 cases of drug induced liver injury seen over a 12 year period at a large
hospital in Bangalore, India, 5 [2%] were attributed to atorvastatin, but no
other statin listed].
Idilman R, Bektas M, Cinar K, Toruner M, Cerit ET, Doganay B, Erden E, et
al. The characteristics and clinical outcome of drug-induced liver injury: a
single-center experience. J Clin Gastroenterol 2010; 44: e128-32. PubMed Citation (Among 170 patients
with drug induced liver injury seen at a single referral center in Turkey
between 2001 and 2007, 14 were attributed to statins which were hepatocellular
in 10 and cholestatic in 4; no details provided).
Reuben A, Koch DG, Lee WM; Acute Liver Failure
Study Group. Drug-induced acute
liver failure: results of a U.S.
multicenter, prospective study. Hepatology 2010;
52: 2065-76. PubMed Citation (Among 1198 patients with acute liver failure enrolled in a US
prospective study between 1998 and 2007, 133 [11%] were attributed to drug
induced liver injury, of which 6 were attributed to statins: 2 atorvastatin, 2
simvastatin [one with ezetimibe] and 2 cerivastatin).
Vaverkova H, Farnier M, Averna M, Missault L, Viigimaa M, Dong Q, Shah A,
et al. Lipid-altering efficacy of ezetimibe/simvastatin
10/20 mg compared to rosuvastatin 10 mg in high-risk patients with and without
type 2 diabetes mellitus inadequately controlled despite prior statin
monotherapy. Cardiovasc Ther 2012; 30: 61-74. PubMed Citation (In a randomized trial in patients with hypercholesterolemia, ALT or AST elevations >3 times ULN occurred in none 303 patients receiving rosuvastatin versus 0.7% of 312 on the combination of simvastatin and ezetimibe).
Xu CF, Xue Z, Bing N, King KS, McCann LA, de Souza PL, Goodman VL, et al. Concomitant use of pazopanib and simvastatin increases the
risk of transaminase elevations in patients with cancer. Ann Oncol 2012; 23: 2470-1. PubMed Citation (Retrospective analysis of ALT elevations in 895 patients with cancer enrolled in 22 studies of pazopanib; among those who were also receiving a statin, rates of ALT elevations above 3 times ULN were higher [17% to 21%] than in those not on a statin [14%]).
Bergmann OM, Kristjansson G, Jonasson JG, Björnsson ES. Jaundice due to
suspected statin hepatotoxicity: a case series. Dig Dis Sci 2012; 57: 1959-64.
PubMed Citation (3 women and 1 man,
ages 55 to 85 years, developed jaundice 3, 3, 11 and 30 months after starting
atorvastatin [n=3] or simvastatin [n=1], with hepatocellular or mixed injury
[peak bilirubin 4.0-7.4 mg/dL, ALT 446-2987 U/L, Alk P 174-716 U/L, ANA positive
in 1], all resolving spontaneously in 1-3 months).
Björnsson E, Jacobsen EI,
Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic
liver injury post-marketing. J Hepatol 2012; 56: 374-80. PubMed Citation (Between 1988 and 2010, the Swedish registry received 217 adverse event
reports possibly related to statins, 124 [57%] being liver related, 73 of which
could be evaluated: 2 were fatal and one led to liver transplant; 3 had positive
rechallenge; 43 [59%] were hepatocellular, 22 [30%] cholestatic and 8 [11%]
mixed; 30 were due to atorvastatin, 28 simvastatin, 11 fluvastatin, 2
pravastatin and 2 rosuvastatin, arising after 30-248 days; atorvastatin injury
was more likely to be cholestatic and was estimated to occur in 2.9 per 100,000
Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence,
presentation and outcomes in patients with drug-induced liver injury in the
general population of Iceland. Gastroenterology 2013; 144: 1419-25. PubMed Citation (In a population
based study of drug induced liver injury from Iceland, 96 cases were identified
over a 2 year period, including one case [without jaundice] attributed to simvastatin).
N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al.
Profile of idiosyncratic drug induced liver injury in Latin America. An analysis
of published reports. Ann Hepatol 2014; 13: 231-9. PubMed Citation (Systematic review
of literature of drug induced liver injury in Latin American countries published
from 1996 to 2012 identified 176 cases, none of which were attributed to statins
or lipid lowering agents).
MW, Hoofnagle JH, Gu J, Fontana RJ, Barnhart H, Kleiner DE, Chalasani N, et al.
Spectrum of statin hepatotoxicity: Experience of the drug-induced liver injury
network. Hepatology 2014; 60: 679-86. PubMed Citation (Among 1,188
cases of drug induced liver disease collected in the US between 2004 to 2012, 22
[2%] were attributed to statins, including atorvastatin , simvastatin ,
rosuvastatin , fluvastatin , pravastatin  and lovastatin ; median
age was 60 years and 68% were women; 9 cases were cholestatic and 12
hepatocellular [6 with autoimmune features]; the latency ranged widely, from 1
month to 10 years; only one case was fatal [a man with preexisting cirrhosis
presenting with acute-on-chronic liver failure]).
H, Cohen DE, Chalasani N, Harrison SA. An assessment by the Statin Liver Safety
Task Force: 2014 update. J Clin Lipidol 2014; 8 (3 Suppl): S47-57. PubMed Citation (Review of the
safety of statins including their use in patients with liver disease
recommending that liver tests be obtained before therapy, but that routine
monitoring is not necessary and that statins can be safety used in patients with
nonalcoholic liver disease, and are probably safe in other forms of chronic
liver disease and after liver transplantation).
N, Sato T, Wakana A, Orii T, Kitamura M, Kokan A, Kurata H, et al. A prospective
stratified case-cohort study on statins and multiple adverse events in Japan.
PLoS One 2014; 9: e96919. PubMed Citation (Among 6877 patients
started on statins between 2008 and 2010, 139 developed an increase in ALT or
AST deemed likely due to the drug with no significant differences among those
treated with pra-, ator-, flu-, pita- or rosu-vastatin).
AF, Taylor FC, Casas JP, Adler A, Prieto-Merino D, Ebrahim S. Unintended effects
of statins from observational studies in the general population: systematic
review and meta-analysis. BMC Med 2014; 12: 51. PubMed Citation (Systematic review
of 90 studies of 48 different "unintended effects" of statins with evidence of
an increased risk of myopathy [Odds Ratio: OR=2.6] and raised liver enzymes
for lipids. Treat Guidel Med Lett 2014; 12 (137): 1-6. PubMed Citation (Concise
recommendations on management of hyperlipidemia mentions that 1-2% of patients
on high doses of statins develop ALT elevations [above 3 times ULN], but that
there is not always cross sensitivity to this side effect and that patients with
mild-to-moderate ALT elevations can tolerate statins; no discussion of
clinically apparent liver).
C, Also MA, Pericas JM, Letang E, Tuset M, Miró JM. [Rhabdomyolysis and severe
hepatotoxicity due to a drug-drug interaction between ritonavir and
simvastatin]. Enferm Infecc Microbiol Clin 2014; 32: 579-82. Spanish. PubMed Citation (52 year old woman
with HIV infection on darunavir/ritonavir, lamivudine and raltegravir was
switched from atorvastatin [40 mg] to simvastatin [80 mg] daily and developed
rhabdomyolysis 3 weeks later [bilirubin 0.5 mg/dL, ALT 787 U/L, CK 34,960 U/L],
possibly due to drug-drug interactions between simvastatin and
EV, Medina-Cáliz I, Hernando S, Ortega A, Martín-Ocaña F, Navarro JM, Peláez G,
et al. Hepatotoxicity associated with statin use: analysis of the cases included
in the Spanish Hepatotoxicity Registry. Rev Esp Enferm Dig 2014; 106: 246-54.
PubMed Citation (Among 858 cases of
drug induced liver injury enrolled in a Spanish Registry between 1994 and 2012,
47 [5.5%] were attributed to statins [16 atorvastatin, 13 simvastatin, 12
fluvastatin, 4 lovastatin and 2 pravastatin] usually with a hepatocellular
pattern of injury, 8.5% with autoimmune features, chronic injury in 19%, and no
liver related deaths).
GL, Hsiao FY, Dong YH, Shen LJ, Wu FL. Statins and the risk of liver injury: a
population-based case-control study. Pharmacoepidemiol Drug Saf 2014; 23:
719-25. PubMed Citation (Among 2165
Taiwanese patients hospitalized for liver injury between 2002 and 2009, use of
statins was not more frequent than among 16,600 hospitalized controls, except
for use of high doses of rosuvastatin [adjusted odds ratio of
Á. [Drug-induced liver injury caused by simvastatin associated with antinuclear
antibodies]. Med Clin (Barc) 2015; 144: 189-90. Spanish. PubMed Citation. (66 year old woman
was found to have asymptomatic elevations of ALT [92 U/L] and AST [55 U/L] with
ANA positivity [1:320) 5 months after starting simuvastatin, the abnormalities
resolving 1 month after stopping).
N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.;
United States Drug Induced Liver Injury Network. Features and outcomes of 899
patients with drug-induced liver injury: The DILIN Prospective Study.
Gastroenterology 2015; 148: 1340-52.e7. PubMed Citation (Among
899 cases of drug induced liver injury enrolled in a US prospective study
between 2004 and 2013, 31 cases [3.4%] were attributed to statins, including 8
to atorvastatin, 8 simvastatin, 7 rosuvastatin, 4 pravastatin, 2 fluvastatin
and 2 lovastatin).
CH, Chang YC, Lee YC, Liu YC, Chuang LM, Lin JW. Severe hepatic injury
associated with different statins in patients with chronic liver disease: a
nationwide population-based cohort study. J Gastroenterol Hepatol 2015; 30:
155-62. PubMed Citation (Among 37,929
Taiwanese persons with chronic liver diesase started on statin therapy for
hyperlipidemia between 2005 and 2009, there were 912 incident cases of
hospitalization for liver injury, rates being similar for the 6 different
statins used [1.94-2.95 per 100,000 person-days], but higher in those on high
doses of atorvastatin [40 or 80 mg daily]).
AM, Damkier P, Rasmussen TB, Hellfritzsch M. Statin-associated rhabdomyolysis
triggered by drug-drug interaction with itraconazole. BMJ Case Rep 2016 Sep 7;
2016. PubMed Citation (47 year old woman
taking simvastatin [80 mg daily] for two years developed rhabdomyolysis 3 weeks
after starting a ten day course of itraconazole [CK 30,855 U/L, myoglobin 5,046 μmol/L], resolving
completely over the next month).
HS, Lee SH, Kim H, Lee SH, Cho JH, Lee H, Yim HW, et al. Statin-related
aminotransferase elevation according to baseline aminotransferases level in real
practice in Korea. J Clin Pharm Ther 2016; 41: 266-72. PubMed Citation (Among 21,233 Korean
patients starting statin therapy between 2009 and 2013, abnormal ALT or AST
values above 3 times ULN were more frequent among those with mild baseline
AT, Johnson PC, Hall GC, Ford I, Mills PR. High dose atorvastatin associated
with increased risk of significant hepatotoxicity in comparison to simvastatin
in UK GPRD cohort. PLoS One 2016; 11: e0151587. PubMed Citation (Analysis of the
Clinical Practice Research Database of UK patients initiating statin treatment
between 1997 and 2006 identified 71 of 76,411 developing liver dysfunction
while on atorvastatin [0.09%] vs 101 of 164,407 on simvastatin [0.06%], rates
being higher with higher [40 or 80 mg] vs lower [10 or 20 mg] doses of
atorvastatin [0.44% vs 0.07%], but not with higher vs lower doses of simvastatin
[0.09% vs 0.05%]).
LY, Huang YS, Perng CL, Huang B, Lin HC. Statin-induced liver injury in an area
endemic for hepatitis B virus infection: risk factors and outcome analysis. Br J
Clin Pharmacol 2016; 82: 823-30. PubMed Citation (Have).
FC, Brogan A, Boyle JG. Ciprofloxacin and statin interaction: a cautionary tale
of rhabdomyolysis. BMJ Case Rep 2016; 2016. pii: bcr2016216048. PubMed Citation (62 year old woman
on simvastatin for 13 years developed rhabdomyolysis 4 days after starting
ciprofloxacin [bilirubin not given, ALT 240 U/L, AST 870 U/L, CPK 24,514], which
resolved upon stopping; no mention of myoglobin levels).
ES. Hepatotoxicity of statins and other lipid-lowering agents. Liver
2017; 37: 173-8. PubMed Citation (Review of the
hepatotoxicity of statins mentions that atorvastatin has been the most
frequently implicated statin [accounting for 30-40% of cases] in drug induced
liver injury estimated to arise in 1 in 17,000 users, cholestatic in 56% and
with autoimmune features in 10% and rarely fatal).
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