Clinical importance of the drug interaction between statins and SYP3A inhibitors

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DESCRIPTION (PROVIDED BY APPLICANT): National Cholesterol Education Program (NCEP) guidelines recommend aggressive cholesterol lowering in high risk patients including diabetics and the elderly (> 65 years old). Although statins are very safe drugs, they have the potential for minor and severe adverse reactions, especially when given to patients taking concomitant medications that prolong statin exposure. Specific Aim: To compare the relative incidence of myopathy and acute kidney injury following concomitant use of a CYP3A4 substrate statin [atorvastatin or simvastatin] and a CYP3A4 inhibitor to the incidence of myopathy and acute kidney injury following concomitant use of a non-3A4 substrate statin [fluvastatin, pravastatin, or rosuvastatin] and a CYP3A4 inhibitor. Background and significance: The potentially harmful combination of statins and drugs that inhibit the CYP3A4 isoenzyme are frequently used. This is particularly important since atorvastatin and simvastatin undergo oxidative metabolism by the cytochrome P450 3A4 isoenzyme. The concomitant use of CYP3A4 substrate statins (atorvastatin & simvastatin) and CYP3A4 inhibitors results in increased statin exposure and the potential for increased statin related adverse events. Given the potential for increased statin exposure and related statin adverse events when given concomitantly with a CYP3A4 inhibitor, I propose to expand on previously conducted descriptive studies by conducting a case-cohort study to evaluate the relative rate of actual adverse events for patients exposed to a CYP3A4 substrate statin and a concomitant 3A4 inhibitor (exposed) vs. a non-CYP3A4 substrate statin and a concomitant 3A4 inhibitor. Data source: The Health Improvement Network. Research design and methods: A case-cohort study will be used to evaluate the incidence of adverse events between concomitant exposure to a statin and a CYP3A4 inhibitor. Adverse events will be attributed to either the CYP3A4 substrate statin group or the non-CYP3A4 substrate statin group. Incidence rates and hazard ratios will be determined using Cox proportional hazard regression and incidence rate ratios using person-time Poisson regression. Impact: The results from the proposed study will provide evidence that will guide appropriate selection of concomitant medications to reduce the risk for adverse events. Additionally, the study should elucidate the impact of differential oxidative metabolism of statins, specifically regarding competitive utilization of the CYP3A4 isoenzyme. The benefits to clinical practice include providing physicians with increased knowledge about statin-related drug interactions with frequently used drugs via a common metabolic pathway. If the results support the hypothesis, physicians should be able to identify high-risk drug combinations and potentially prevent serious adverse drug reactions. If not, these warnings should be removed. This study has the capacity to reveal the true potential of an underrated and preventable drug interaction. Although statin-related adverse events are uncommon, the medical and financial burden of such events can be considerable, due to the widespread use of these drugs. Despite the well-documented pharmacokinetic drug interaction between statins and CYP3A4 inhibitors, the available data, including our pilot data (see below), suggest that this potentially harmful combination is either disregarded or misunderstood. Indeed, what makes this study important is that physicians are not practicing as if they recognize this interaction. Thus, either we should stop warning about it, or warn much more emphatically.