The liver and lovastatin

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Abstract

The cholesterol-lowering agents, known as statins, have been in use for 15 years and are among the most commonly prescribed drugs. Animal studies and premarketing clinical trials have given signals of hepatotoxicity, primarily minor elevations in serum alanine aminotransferase enzyme (ALT) levels. For that reason, all of the cholesterol-lowering drugs have labeling that requires monitoring of liver enzymes. Postmarketing experience, however, suggests that hepatotoxicity is rare and thus it is timely to revisit the issue. The first of the statins, lovastatin, was approved in 1986 and has acquired 24 million patient-years of clinical experience. Minor elevations in liver enzymes, i.e., ALT 3 × the upper limit of normal (ULN) occur in 2.6% and 5.0% of patients on lovastatin doses of 20 and 80 mg/day, respectively. These elevations are reversible with continuing therapy, are dose related, and are probably related to cholesterol lowering per se. Rare cases of acute liver failure (ALF) have been reported with all of the cholesterol-lowering drugs. With lovastatin, the rate is approximately 1/1.14 million patient-treatment years, which is 9% of the background rate of all causes of ALF and approximately equal to the background rate of idiopathic ALF. Monitoring for hepatotoxicity has not been effective in preventing serious liver disease, largely because of its rarity and the poor predictive value of minor ALT elevations. In fact, it may increase patient risk because of needless discontinuation of cholesterol-lowering therapy for false-positive results in patients who are benefiting from treatment.

Section snippets

Animal toxicology studies

Chronic toxicology studies in dogs demonstrated that lovastatin caused slight elevations in ALT but no histologic liver damage.2 Lovastatin given to rodents induced HMG-CoA, did not lower cholesterol, and was not associated with cell injury. Lovastatin administered in high doses (100 to 200 mg/kg/day) to rabbits was associated with hepatic necrosis.3 The injury could be prevented by forcing adequate nutrition or coadministering mevalonic acid, suggesting that hepatocellular injury was related

Premarketing clinical trials

Mild increases in ALT <3 × the ULN were seen in 21% of patients in the initial clinical trials. Increases of ≥3 × the ULN were observed in 1.9% of patients in the phase IIb trials and appeared to be dose related (Figure 1).

Increased ALT was reported as a drug-related event in 3.1% of patients treated with lovastatin, 40 to 80 mg/day, in phase 3 trials. This was comparable to that seen with the comparator agents, cholestyramine (3.4%) and probucol (3.1%). Increases in aminotransferase enzymes

Postmarketing (phase IV) studies

Two phase IV studies involving almost 15,000 patients were conducted with lovastatin. The first, the EXpanded Clinical Evaluation of Lovastatin (EXCEL) study, was a multicenter, double-blind diet and placebo-controlled trial in 8,245 patients with hypercholesterolemia.5 The second study, the Air Force/Texas Coronary Arteriosclerosis Prevention Study (AFCAPS/TexCAPS) was a double-blind, randomized, placebo-controlled primary prevention trial involving 6,605 patients.6 Both studies were monitored

Spontaneous adverse event reports

The manufacturer of lovastatin maintains a record of all spontaneously reported adverse events, irrespective of assessment of causality. This is referred to as the Worldwide Adverse Experience Database (WAES). These records were reviewed by the investigator to assign causality. As of March 1999, 17 cases of “ALF” and 232 cases of “acute hepatitis,” exclusive of hepatitis A, B, C, or non-A, non-B, had been reported.

Acute liver failure

There are 17 reports of ALF. One report is an inquiry about whether lovastatin could cause ALF. Two reports are from patients who stated that their livers had “quit functioning.” One report is from a friend of a patient and does not provide specific clinical information. Another report is about a patient who developed liver failure secondary to metastatic carcinoma. Two reports appear to be cases of autoimmune hepatitis. Another is a case of decompensated primary biliary cirrhosis. Two patients

Acute hepatitis

There are 232 reports of “hepatitis” in the WAES database for a reporting rate of 9.7 cases/million patient-treatment years. In many of these cases, the only evidence of hepatitis was an elevated aminotransferase determination. The dose of lovastatin was known in 158 cases, and paralleled the known use of lovastatin. Fifty-six percent of patients were women. The average age was 56.4 years. Liver biopsy specimens were available in 60 cases and the results are summarized in Table 3. Twenty-four

Previous reports

There are 9 reported cases of lovastatin hepatotoxicity, with the most recent published in 1995 and 1996.9, 10 The WAES database includes 3 of these cases. The average age was 54 years. Five were men. The mean latency period from onset of dosing to the appearance of liver disease was 11 months. The dose of lovastatin when known ranged from 20 to 80 mg/day. Four of the reactions were cholestatic and 5 were hepatocellular. Recovery occurred in all patients but tended to be slow, ranging from a

Lovastatin in patients with undiagnosed liver disease

In AFCAPS/TexCAPS,6 266 of 6,605 participants had ALT greater than the ULN before initiation of treatment with lovastatin (n = 136) or placebo (n = 130). Ninety-four percent had peak pretreatment elevations ≤2 than the ULN. Independent of treatment, participants with pretreatment ALT elevation (3 of 266, 1.1%) were more likely than those without pretreatment (26 of 6,351, 0.4%) to have a confirmed increase >3 × the ULN. However, the presence of ALT elevation at baseline did not

Drug interactions

Lovastatin is metabolized primarily by the cytochrome P450 3A4 pathway. Thus, the potential for many drug interactions exists. Experimentally, there appears to be an interaction with acetaminophen, leading to increased ALT and hepatocyte swelling in mice.13 Acetaminophen, however, is metabolized primarily through CYP2E1 rather than CYP3A4. There are no data to suggest that such an interaction occurs in humans. The AFCAPS/TexCAPS database was searched for concomitant use of CYP3A4-inhibiting

Other cholesterol-lowering agents

ALT elevations of 3 × the ULN have occurred with all of the lipid-lowering drugs. These elevations have been transient, often dose related, and have typically reverted to normal levels with continuing therapy. None of these minor ALT elevations has been associated with hepatotoxicity, although hepatotoxicity has been reported with all of the drugs except cholestyramine.15, 16, 17, 18, 19 The reactions include jaundice, hepatitis, cholestasis, chronic active hepatitis, fatty liver, cirrhosis,

Liver function test monitoring

Monitoring of liver chemistries is a labeling requirement for all of the cholesterol-lowering drugs. Given the widespread use of those drugs and the very low incidence of serious liver disease, the need for monitoring needs to be revisited. The evidence that it prevents serious liver disease is lacking. For example, all of the patients in the preapproval clinical trials were monitored every 4 weeks. If the sensitivity limit were set at an ALT level of 3 × the ULN, 3 patients (20%) who were

Discussion

There appear to be 2 hepatic abnormalities associated with the use of lovastatin: a pharmacodynamic effect consisting of asymptomatic dose-related ALT elevations common to all of the lipid-lowering agents, and rare hepatotoxic reactions manifested primarily by cholestatic or mixed injury with very rare cases of ALF.

The aminotransferase elevations in the premarketing trials of lovastatin were characterized by minor elevations in ALT that were almost uniformly greater than aspartate transaminase

Acknowledgements

I acknowledge the editorial assistance of Rowan Tweedale and the secretarial assistance of Hollie Fletcher.

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