The hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins, are the most potent, best tolerated and most widely used cholesterol lowering agents and represent some of the most commonly prescribed medications in the United States. HMG-CoA reductase is the rate limiting step in cholesterol synthesis by the liver and inhibition of its activity causes a significant decrease in total and LDL cholesterol levels. The statins also have minor effects on triglyceride and HDL levels. Seven statins are available in the United States (year of approval and brand name in parentheses): lovastatin (1987: Mevacor), pravastatin (1991: Pravachol), simvastatin (1991: Zocor), fluvastatin (1993: Lescol), atorvastatin (1996: Lipitor), rosuvastatin (2003: Crestor) and pitavastatin (2009: Livalo). All of the statins have been associated with mild-to-moderate serum aminotransferase elevations during therapy that are typically transient, asymptomatic and may resolve even with continuation without dose adjustment. All have also been associated rare instances of clinically apparent acute liver injury. Cases with autoimmune features have been reported with atorvastatin, simvastatin, rosuvastatin and fluvastatin, as well as with combinations of these agents with ezetimibe. The following medications are discussed individually:
References Last Updated:
03 Jan 2014
Zimmerman HJ. Drugs used in the treatment of hypercholesterolemia and hyperlipidemia. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 660-2. (Expert review of hepatotoxicity published in 1999; the statins have dose related hepatic effects in guinea pigs and rabbits, and transient elevations in aminotransferases occur in 1-5% of humans treated; several cases of clinically apparent liver injury from lovastatin and simvastatin have been published).
De Marzio DH, Navarro VJ. Hepatotoxicity of cardiovascular and antidiabetic
drugs. Lipid regulating agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced
liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 526-7. (Review of
hepatotoxicity of lipid lowering agents; elevations in serum enzymes occur in up
to 3% of patients, usually within first 3 months of therapy, apparently a class
Bersot TP. Drug therapy for hypercholesterolemia and dyslipidemia. In,
Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the
pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp.
877-908. (Textbook of pharmacology and therapeutics; “the statins
are the most effective and best-tolerated agents for treating dyslipidemia.” Act
by inhibition of the rate-limiting step in hepatic cholesterol
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 attributed to the statins were 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).
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, 4690 reports of drug induced liver fatality: none of the statins were in the top 20 suspected causes of acute liver failure due to medications).
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, statins represented 3% of cases overall including 3 cases attributed to atorvastatin, 3 simvastatin/ezetimibe, and one each to pravastatin, fluvastatin, and simvastatin).
Russo MW, Scobey M, Bonkovsky HL. Drug-induced liver injury associated with statins. Semin Liver Dis 2009; 29: 412-22. PubMed Citation (Report of two cases of hepatotoxicity attributed to statins, accompanied by a review of the literature. Most cases demonstrate a hepatocellular pattern of injury, and some manifest features of autoimmunity).
Calderon RM, Cubeddu LX, Goldberg RB, Schiff ER. Statins in the treatment of dyslipidemia in the presence of elevated liver aminotransferase levels: a therapeutic dilemma. Mayo Clin Proc 2010; 85: 349-56. PubMed Citation (Review of published articles and studies of statin use in patients with liver disease; the authors conclude that statins can be used in patients with elevated transaminase levels and/or stable liver disease).
Hippisley-Cox J, Coupland C. Unintended effects of statins in men and women in England and Wales: population based cohort study using the QResearch database. BMJ 2010; 340: c2197. PubMed Citation (Among 225,922 new users of statins followed in a large UK healthcare database, the risk of moderate-to-severe liver dysfunction [ALT >3 times ULN] was increased in statin users compared to controls, relative risk ranging from 1.31-2.53 in women and 1.21-1.97 in men being highest with fluvastatin and lowest with pravastatin, more common with higher doses and usually arising within 6 months of starting).
Russo MW, Scobey M, Bonkovsky HL. Drug-induced liver injury associated with statins. Semin Liver Dis 2009; 29: 412-22. PubMed 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).
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 were attributed to
drug induced liver injury including 2 due to atorvastatin, 2 simvastatin and 2
cerivastatin, but none to other statins).
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).