- Order liver function tests before starting statin therapy, 12 weeks after initiation, with any dose increase, and periodically for long-term maintenance therapy (C).
- Mild elevations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (<3 times the upper limit of normal [ULN]) following statin therapy do not appear to lead to significant liver toxicity over time (C).
- Other medications that lower low-density lipoprotein (LDL), and might be substituted for statins, may not improve morbidity and mortality (C).
Strength of recommendation (SOR)
- Good-quality patient-oriented evidence
- Inconsistent or limited-quality patient-oriented evidence
- Consensus, usual practice, opinion, disease-oriented evidence, case series
Are we more aggressive than ever when it comes to our use of statins? You bet.
Should this prompt a heightened attention to hepatic safety? In a word, no. The more detailed, evidence-based answer (which follows) makes 2 things clear:
1. Clinically significant hepatic injury following statin use is very rare.
2. While US Food and Drug Administration (FDA) labeling recommends routine monitoring of serum transaminase levels prior to and during statin therapy, the evidence suggests that such routine monitoring is not clinically necessary.
More potent statins, more combination therapy
Our prescribing has become more aggressive to keep pace with National Cholesterol Education Program (NCEP) recommendations. In 2001, the NCEP Adult Treatment Panel III indicated:
- LDL cholesterol should be the primary target of therapy.
- The LDL cholesterol goal should be based on the patient’s risk of cardiovascular disease.
- Statins are the most effective agents to achieve treatment goals.1
Three years later, the NCEP advised that in light of more recent clinical trials, even more aggressive (ie, lower) LDL goals should be considered for patients at very high risk, high risk, and moderately high risk for cardiovascular disease.2
As a result, we are prescribing higher doses of statins, more potent statins, and more combination therapies of statins with other lipid-altering agents. Not surprisingly, this trend has prompted concerns about the potential increase in toxicities/side effects of statins.
An interesting clinical question is whether statins are appropriate when the cause of hepatic enzyme elevation appears to be excess fat in the liver. There is some evidence that treatment of fatty infiltration of the liver may lower transaminase levels and improve histological findings.14 In general, though, no medications have been demonstrated to improve patient-oriented outcomes such as mortality or need for liver transplant.15
This review examines the hepatic safety profile of statins and details why there’s no need to stop treatment based on moderate elevations in liver function tests. The most common serious side effect of statins—muscle damage/rhabdomyolysis—is rare, and is not extensively discussed here.
Clinical trials: Risk is small
A review of 35 randomized clinical statin trials reported from 1966 to 2005, involving 74,102 patients, reported an absolute risk of transaminase (also referred to as aminotransferase) elevations from statin therapy of only about 4 per 1000 patients (risk difference [RD]=4.2; 95% confidence interval [CI], 1.5-6.9).3 The same researchers’ analysis of 28 clinical trials involving 62,184 patients showed a relative risk of increased transaminase of 1.3 (95% CI, 1.06-1.59), achieving statistical significance only for the fluvastatin and lovastatin trials.3
High-dose statin therapy. A review of clinical trials involving high-dose statin therapy found rates of hepatic enzyme elevation (defined as ALT or AST >3 times the ULN on 2 or more consecutive occasions) to be quite low (<1.3%).4 Higher statin doses were more likely to increase enzyme levels, though reduction in the dose or withdrawal of the statin resulted in normalization of the liver enzymes.
A study of patients ages 65 to 85 years who were treated with high-dose atorvastatin (80 mg per day) vs moderate dose pravastatin (40 mg per day) resulted in only 11 of 893 (1.23%) patients discontinuing the drug following abnormal liver function tests; most of these were in the high-dose treatment arm.5
Small risk in clinical practice, too
Clinical trials often have lower rates of adverse effects from medications than are seen in usual clinical practice.6 This may be because the stringent application of patient selection and exclusion criteria used in the administration of clinical trials does not occur in the “real world.”
However, the FDA database reported only 0.69 cases of hepatitis/liver failure per million statin prescriptions through 2004.4 A retrospective review of 1194 patients treated with a statin showed that 85% (1014) of patients had at least 1 monitoring test of transaminases performed during the year of the study. Of these, 10 (1.0%) had a significant elevation and 5 (0.5%) had a moderate elevation of transaminases. A review of the patient records demonstrated that none of these abnormalities appeared to be related to the use of statins, suggesting that routine monitoring of transaminases with statin therapy is not clinically necessary.7