Lovastatin 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.
Lovastatin (loe" 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”), lovastatin lowers total serum cholesterol and low density lipoprotein (LDL) concentrations, thereby reducing the risk of atherosclerosis and its complications – myocardial infarction and stroke. Lovastatin is indicated for treatment of hypercholesterolemia in persons at high risk for coronary, cerebrovascular and peripheral artery disease. Lovastatin is available in tablets of 10, 20, 40 and 60 mg in generic forms and under the brand name Mevacor. Extended release forms (Altoprev) and fixed combinations with niacin (Advicor) are also available. The recommended adult dose is 10 to 80 mg daily in single or two divided doses based upon tolerability and lipid levels. Lovastatin was approved for use in the United States in 1987, the first of this class of drugs to be commercially available. Lovastatin is a widely prescribed drug with more than 7 million prescriptions filled yearly. Common side effects include muscle cramps, joint aches, headache and weakness.
Lovastatin therapy is associated with mild, asymptomatic and usually transient serum aminotransferase elevations. In summary analyses of large scale studies with prospective monitoring, ALT elevations above normal occurred in 3 to 5% of patients, but were above 3 times the upper limit of normal (ULN) in only 0.4% compared to 0.1% of placebo recipients. These elevations were more common with higher doses of lovastatin, being greater than 3 times ULN in 0.1% of patients receiving 20 mg daily, 0.9% with 40 mg and 1.5% with 80 mg daily. Most of these elevations were self-limited and did not require dose modification, although discontinuation is recommended for any elevation above 10 times and for persistent elevations above 5 times the ULN. Lovastatin is also associated with frank, clinically apparent hepatic injury, but cases are rare. The onset of clinical injury ranges from a few weeks to several years. The pattern of injury is typically cholestatic, but can be hepatocellular. Rash, fever and eosinophilia are uncommon as are autoimmune features. The injury usually resolves rapidly upon stopping lovastatin, but instances of prolonged cholestasis have been reported (Case 1).
The traditional Chinese medication known as red yeast rice which is used to treat hyperlipidemia has been shown to contain monacolin K, a natural component that is chemically identical to lovastatin, perhaps explaining its efficacy in reducing cholesterol levels. Red yeast rice has also been implicated in cases of acute liver injury and myopathies that are similar to those linked to lovastatin. In some instances cross-sensitivity to hepatic injury has been shown between red yeast rice products and lovastatin.
Likelihood score: B (likely cause of clinically apparent liver injury).
Mechanism of Injury
The cause of hepatic injury from lovastatin is unknown. Lovastatin is largely metabolized in the liver (via CYP 3A4) and metabolites are 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. The idiosyncratic, clinically apparent liver injury associated with lovastatin may be due to failure of adaptation.
Outcome and Management
The ALT elevations that occur with lovastatin therapy often resolve spontaneously within a few weeks without discontinuation. The product label for lovastatin mentions rare cases of acute liver failure due to lovastatin, some of which were fatal. There have not been fatal instances of acute liver injury attributable to lovastatin in the published literature. In the average case, recovery is expected within 1 to 2 months of stopping lovastatin, but instances of prolonged cholestasis and some degree of vanishing bile duct syndrome have been reported. In view of the wide scale use of lovastatin, 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 lovastatin induced injury is apparently safe, but few instances have been reported, and it should be done with careful monitoring for recurrence.
Case 1. Cholestatic hepatitis due to lovastatin therapy.
[Modified from: McQueen MJ. Cholestatic jaundice associated with lovastatin (Mevacor) therapy. Can Med Assoc J 1990; 142: 841-2.]
A 40 year old man developed fatigue, dark urine, jaundice and itching approximately 11 weeks after starting lovastatin (20 mg daily). He had no previous history of liver disease and drank little alcohol. He had a past history of kidney stones, hyperlipidemia and hypertension, and his other medications included allopurinol (100 mg daily) and the combination of hydrochlorothiazide and amiloride. Liver tests had been normal in the past. When he was finally seen and evaluated, 17 weeks after starting therapy, laboratory tests showed a mixed pattern of serum enzyme elevations. Tests for hepatitis A and B and for autoantibodies were negative. An ultrasound of the abdomen showed evidence suggestive of bile duct dilatation, but ERCP was normal. Lovastatin was stopped and he improved symptomatically. Liver tests had improved but were not completely normal six months later.
|Medication:||Lovastatin (20 mg daily)|
|Pattern:|| Mixed (R=4.7)|
||3+ (jaundice, hospitalization)|
||11 weeks to symptoms
|Other medications:||Allopurinol, hydrochlorothiazide, amiloride|
|Time After Starting
||Time After Stopping
||Alk P (U/L)
* Some values estimated from Figure 1.
The patient had symptoms of a cholestatic hepatitis with prominence of jaundice and itching. There was a delay in stopping lovastatin and the cholestatic hepatitis was prolonged. At the time of this report, lovastatin had been available for only approximately a year, and 3 cases of jaundice possibly related to lovastatin had already been reported to the Food and Drug Administration (MedWatch).
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
Lovastatin – Altoprev®, Mevacor®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 05 August 2017
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Raveh D, Arnon R, Israeli A, Eisenberg S. Lovastatin-induced hepatitis. Isr J Med Sci. 1992; 28: 101-2. PubMed Citation (50 year old woman developed enzyme elevations and marked pruritus 7 months after starting lovastatin [bilirubin 0.7 mg/dL, ALT 296 U/L, Alk P 626 U/L], with prompt disappearance of symptoms, but slow improvement in abnormal liver tests upon stopping lovastatin).
The Lovastatin Pravastatin Study Group. A multicenter comparative trial of lovastatin and pravastatin in the treatment of hypercholesterolemia. Am J Cardiol 1993; 71: 810-5. PubMed Citation (Controlled trial of lovastatin [20 to 80 mg] vs pravastatin [10 to 40 mg] daily for 18 weeks in 672 hypercholesterolemic patients; ALT elevations >3 times ULN occurred in 1 lovastatin and 2 pravastatin treated patients; no clinically apparent liver injury mentioned).
Grimbert S, Pessayre D, Degott C, Benhamou JP. Acute hepatitis induced by HMG-CoA reductase inhibitor, lovastatin. Dig Dis Sci. 1994; 39: 2032-3. PubMed Citation (64 year old man developed jaundice 12 weeks after starting lovastatin [bilirubin 11.7 mg/dL, ALT 8 times and Alk P 1.5 times ULN], resolving within 2 months of stopping).
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Gavilán Carrasco JC, Bermúdez Recio F, Salgado Ordóñez F, González Santos P. [Hepatitis due to lovastatin] Med Clin (Barc) 1996; 107: 557-8. PubMed Citation (51 year old with epilepsy on long term phenytoin, phenobarbital and valproate therapy developed jaundice 6 weeks after starting lovastatin [bilirubin 15 mg/dL, ALT 4000 U/L, Alk P 662 U/L], resolving within 2 months of stopping; restarted on phenobarbital and carbamazepine without recurrence).
Bruguera M, Joya P, Rodés J. [Hepatitis associated with treatment with lovastatin. Presentation of 2 cases] Gastroenterol Hepatol. 1998; 21: 127-8. PubMed Citation (Two women, ages 57 and 59 years, developed symptomatic but anicteric hepatitis 9 months and 3 years after starting lovastatin [bilirubin 0.8 and 1.3 mg/dL, ALT 244 and 273 U/L, Alk P 845 and 306 U/L], resolving rapidly on stopping).
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Tolman KG. The liver and lovastatin. Am J Cardiol 2002; 89: 1374-80. PubMed Citation (In premarketing controlled trials of lovastatin, 21% of patients had ALT elevations, but only 1.9% had ALT >3 times ULN and rates were similar to comparator statins).
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Bays HE, Dujovne CA, McGovern ME, White TE, Kashyap ML, Hutcheson AG, Crouse JR; Advicor Versus Other Cholesterol-Modulating Agents Trial Evaluation. Comparison of once-daily, niacin extended-release/lovastatin with standard doses of atorvastatin and simvastatin(the Advicor Versus Other Cholesterol-Modulating Agents Trial Evaluation [ADVOCATE]). Am J Cardiol 2003; 91: 667-72. PubMed Citation (Controlled trial comparing lovastatin combined with niacin to atorvastatin or simvastatin alone in 315 patients for 16 weeks; no patient had confirmed ALT elevation >3 times ULN).
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 1984 to 2004 in Spanish Registry; 11 cases [2%] were attributed to “statins”, but no specific agent caused more than 4 cases).
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Stein CA, Goel S, Ghavamian R. Hepatitis and rhabdomyolysis in a patient with hormone refractory prostate cancer on ketoconazole and concurrent lovastatin therapy. Invest New Drugs 2007; 25: 277-8. PubMed Citation (84 year old man on long term lovastatin developed muscle weakness 4 weeks after starting ketoconazole [bilirubin and Alk P normal, ALT 829 U/L, CPK 47,250 U/L], suspected to be rhabdomyolysis caused by effects of ketoconazole on lovastatin pharmacokinetics, resolving in 3 weeks after stopping both).
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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 [none attributed to lovastatin], but most cases were mild or not clearly attributable to the statin therapy).
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).
Avins AL, Manos MM, Ackerson L, Zhao W, Murphy R, Levin TR, Watson DJ, et al. Hepatic effects of lovastatin exposure in patients with liver disease: a retrospective cohort study. Drug Saf 2008; 31: 325-34. PubMed Citation (Analysis of electronic medical records on 93,106 patients, 14% of whom had received lovastatin; compared to controls, patients receiving lovastatin had lower rates of moderate ALT elevations and diagnosis of cirrhosis or liver failure compared to controls who did not receive lovastatin).
Roselle H, Ekatan A, Tzeng J, Sapienza M, Kocher J. Symptomatic hepatitis associated with the use of herbal red yeast rice. Ann Intern Med 2008; 149: 516-7. PubMed Citation (62 year old woman developed fever, nausea and fatigue 4 months after starting red yeast rice extract [ALT 211 U/L, bilirubin and Alk P not given], resolving within several months of stopping).
Grieco A, Miele L, Pompili M, Biolato M, Vecchio FM, Grattagliano I, Gasbarrini G. Acute hepatitis caused by a natural lipid-lowering product: when "alternative" medicine is no "alternative" at all. J Hepatol 2009; 50: 1273-7. PubMed Citation (63 year old woman with ALT elevations after 6 months of lovastatin use, developed fatigue 6 months after starting a cholesterol lowering herbal preparation containing red yeast rice extract [bilirubin 1.9 mg/dL, ALT 1760 U/L, Alk P 722 U/L], resolving over the next 6 months, but with persistence of ALT elevations).
Russo MW, Scobey M, Bonkovsky HL. Drug-induced liver injury associated with statins. Semin Liver Dis 2009; 29: 412-22. PubMed Citation (Case reports linked to fluvastatin and atorvastatin and review of literature on statin related hepatotoxicity).
Becker DJ, Gordon RY, Halbert SC, French B, Morris PB, Rader DJ. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial. Ann Intern Med 2009; 150: 830-9. PubMed Citation (Controlled trial of red yeast rice extract vs placebo in 62 patients who had stopped statin therapy because of myalgias, found similar rates of myalgias [7% vs 3%] and no change in ALT or AST levels in both groups).
Halbert SC, French B, Gordon RY, Farrar JT, Schmitz K, Morris PB, Thompson PD, et al. Tolerability of red yeast rice (2,400 mg twice daily) versus pravastatin (20 mg twice daily) in patients with previous statin intolerance. Am J Cardiol 2010; 105: 198-204. PubMed Citation (43 patients with myalgias due to statin use were treated with pravastatin or red rice extract for 24 weeks; discontinuation due to myalgias occurred in 5% on red yeast rice extract and 9% on pravastatin, and mean ALT levels were similar between the 2 groups).
Gordon RY, Cooperman T, Obermeyer W, Becker DJ. Marked variability of monacolin levels in commercial red yeast rice products: buyer beware! Arch Intern Med 2010; 170: 1722-7. PubMed Citation (Among 12 red yeast rice extracts commercially available in the US, total monacolin concentrations varied from 0.3-11.1 mg/capsule, monacolin K by 0.1-10.1 mg/capsule, and citrinin [which is nephrotoxic] was present in 4).
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 in a UK health care database, there was an increased risk of moderate or severe liver dysfunction [ALT >3 times ULN], usually within first 6 months and associated with higher doses of statins; relative risks were highest with fluvastatin [2.53 in women, 1.97 in men] and lowest with pravastatin [0.93 to 1.58]; there were too few persons treated with lovastatin for separate analysis).
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).
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; no mention of lovastatin).
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 2 cases attributed to atorvastatin and 1 to simvastatin, but none to lovastatin).
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).
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
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]).
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
G, Moro PA, Raschi E, Da Cas R, Menniti-Ippolito F. Adverse reactions to dietary
supplements containing red yeast rice: assessment of cases from the Italian
surveillance system. Br J Clin Pharmacol 2017; 83: 894-908. PubMed Citation (Among 1261
spontaneous adverse event reports made to an Italian surveillance system for
natural health products between 2002 and 2015, 55 were for red yeast rice,
including 10 for liver injury of which 6 were described as "hepatitis" and
required hospitalization, ALT elevations 315 to 3566 U/L, bilirubin normal or
minimalllly elevated, all resolving upon stopping
ES. Hepatotoxicity of statins and other lipid-lowering agents. Liver
2017; 37: 173-8. PubMed Citation (Review of the
hepatotoxicity of statins mentions that 12 cases of lovastatin induced liver injury have been published, but none were fatal or had a positive rechallenge).
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