Statin-Drug Interactions: Update on the Most Common and Clinically Significant

Statins (HMG-CoA reductase inhibitors) are the most effective drugs in the management of elevated low-density lipoprotein cholesterol (LDL-C) levels.1  Recent large clinical trials continue to demonstrate the remarkable efficacy of these agents, including improved outcomes.2,3 Our purpose here is to summarize some clinically relevant examples of statin-drug interactions. Appropriate management of these interactions can both minimize risks and ensure effective statin doses. The Table lists several examples of statin-drug interactions. Because of the limited scope of this review, the emphasis is on atorvastatin and simvastatin. These statins were selected because they were used in several landmark clinical trials, arecommonly prescribed, and are on many formularies. POTENTIAL RISKS OF STATIN THERAPY Although most patients tolerate statins quite well, myopathy is associated with this class of drugs. Myositis with rhabdomyolysis is rare, and the incidence of fatal rhabdomyolysis is 0.15 deaths per 1 million statin prescriptions.4 Advise patients who are receiving statin therapy to report promptly any unexplained muscle tenderness, pain, or weakness. Discontinue the statin if the creatine kinase level is more than 10 times the upper limit of normal; such an elevation indicates myopathy. The risk of myopathy is doserelated and is increased by concomitant use of cytochrome P-450 (CYP) 3A4 inhibitors,5  which raise serum concentrations of statins. Other agents such as gemfibrozil also increase the risk of myopathy, possibly by inhibiting the glucuronidation of statins.6  Inducers of CYP3A4, such as rifampin, decrease serum concentrations of statins; a higher statin dosage will probably be required.7  Sporadic case reports suggest that some statins can increase the response to warfarin.8 MANAGEMENT TIPS Interactions between statins and CYP3A4 inhibitors can be circumvented with pravastatin, because it is not metabolized by CYP3A4. However, many clinicians manage these interactions by lowering the dosage of atorvastatin and simvastatin because of the results of major outcomes trials that favor these statins, their great effectiveness in reducing LDL-C, and their inclusion in numerous formularies. Inhibitors of CYP3A4 generally have a greater effect on simvastatin than on atorvastatin metabolism, but both agents are susceptible to these interactions.9  Concomitant use of ezetimibe facilitates prescription of lower doses of statins by reducing the absorption of cholesterol from the intestine.10 Rosuvastatin is a relatively new statin that is not metabolized significantly by CYP3A4 and thus has less potential for drug interactions with CYP3A4 inhibitors.11  However, rosuvastatin is a substrate for the human hepatic uptake transporter organic anion transporter 2 (OATP2). Gemfibrozil inhibits OATP2, and has been shown to increase rosuvastatin plasma concentrations by about 2-fold.12 Myopathy, including rhabdomyolysis, and acute renal failure have been associated with rosuvastatin, as with other drugs in this class. Be vigilant when your patient is admitted to a hospital that has an automatic substitution policy associated with formulary restrictions. As was recently pointed out, “All statins are not created equal.”13 REFERENCES: 1. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239. 2. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352: 1425-1435. 3. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004; 350:1495-1504. 4. Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002; 346:539-540. 5. Thompson PD, Clarkson P, Karas RH. Statin-associated myopathy. JAMA. 2003;289:1681-1690. 6. Prueksaritanont T, Zhao JJ, Ma B, et al. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J Pharmacol Exp Ther. 2002; 301:1042-1051. 7. 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Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrob Agents Chemother. 2001;45:3445-3450. 27. Neuvonen PJ, Kantola T, Kivisto KT. Simvastatin but not pravastatin is very susceptible to interaction with CYP3A4 inhibitor itraconazole. Clin Pharmacol Ther. 1998;63:332-341. 28. Jacobson RH, Wang P, Glueck CJ. Myositis and rhabdomyolysis associated with concurrent use of simvastatin and nefazodone. JAMA. 1997;277:296-297. 29. Lipitor product literature. Physicians’ Desk Reference. 2004:2543,2606.