Elevations of serum aminotransferase activity (up to three times normal) occur in some patients. This is often intermittent and usually not associated with other evidence of hepatic toxicity. Therapy may be continued in such patients in the absence of symptoms if aminotransferase levels are monitored and stable. In some patients, who may have underlying liver disease or a history of alcohol abuse, levels may exceed three times normal. This finding portends more severe hepatic toxicity. These patients may present with malaise, anorexia, and precipitous decreases in LDL. Medication should be discontinued immediately in these patients and in asymptomatic patients whose aminotransferase activity is persistently elevated to more than three times the upper limit of normal. These agents should be used with caution and in reduced dosage in patients with hepatic parenchymal disease, north Asians, and the elderly. Severe hepatic disease may preclude their use. In general, aminotransferase activity should be measured at baseline, at 1–2 months, and then every 6–12 months (if stable). Monitoring of liver enzymes should be more frequent if the patient is taking other drugs that have potential interactions with the statin. Excess intake of alcohol tends to aggravate hepatotoxic effects of statins. Fasting plasma glucose levels tend to increase 5–7 mg/dL with statin treatment. Long-term studies have shown a small but significant increase in the incidence of type 2 diabetes in statin-treated patients, most of whom had findings of prediabetes before treatment.
Minor increases in creatine kinase (CK) activity in plasma are observed in some patients receiving reductase inhibitors, frequently associated with heavy physical activity. Rarely, patients may have marked elevations in CK activity, often accompanied by generalized discomfort or weakness in skeletal muscles. If the drug is not discontinued, myoglobinuria can occur, leading to renal injury. Myopathy may occur with monotherapy, but there is an increased incidence in patients also receiving certain other drugs. Genetic variation in an anion transporter (OATP1B1) is associated with severe myopathy and rhabdomyolysis induced by statins. Variants in the gene (SLCO1B1) coding for this protein can now be assessed (see Chapter 5).
The catabolism of lovastatin, simvastatin, and atorvastatin proceeds chiefly through CYP3A4, whereas that of fluvastatin and rosuvastatin, and to a lesser extent pitavastatin, is mediated by CYP2C9. Pravastatin is catabolized through other pathways, including sulfation. The 3A4-dependent reductase inhibitors tend to accumulate in plasma in the presence of drugs that inhibit or compete for the 3A4 cytochrome. These include the macrolide antibiotics, cyclosporine, ketoconazole and its congeners, some HIV protease inhibitors, tacrolimus, nefazodone, fibrates, paroxetine, venlafaxine, and others (see Chapters 4 and 66). Concomitant use of reductase inhibitors with amiodarone or verapamil also causes an increased risk of myopathy.