SOURCE: Lee JW, et al. Grapefruit juice and statins. Am J Med 2016;129:26-29.
FDA labeling for simvastatin changed several years ago because of the recognition that high doses of simvastatin were associated with a meaningful increase in risk for rhabdomyolysis. Drugs known to interact with the CYP450 hepatic enzyme system — specifically, CYP3A4 — were singled out since CYP3A4 is the primary metabolic pathway for many of the statins. Many patients with dyslipidemia also suffer hypertension, and drugs like amlodipine, which can also influence CYP3A4 metabolism, were promptly added to the list of agents that could potentially interact with simvastatin.
About 3 years ago, new FDA labeling for simvastatin spoke to the issue of grapefruit juice, suggesting patients should avoid large quantities. Why grapefruit juice?
Grapefruit juice has been known for more than a decade to be a prompt, potent, and persistent inhibitor of the CYP3A4 enzyme, and it doesn’t take a lot: As little as 8 oz. of grapefruit juice (or one whole grapefruit) taken with simvastatin 40 mg elevates the simvastatin area under the curve by almost 400%.
In evaluating the effect of grapefruit juice on risk, Lee et al extrapolated from data that link changes in low-density lipoprotein to cardiovascular outcomes. They also suggested that the combination of grapefruit juice with simvastatin would indeed increase simvastatin blood levels, but at the same time would possibly reduce cardiovascular event levels to a degree that would far counterbalance any increased risk of rhabdomyolysis. While their notion is intriguing, in the absence of prospective data corroborating that the simvastatin + grapefruit juice combination is safe and actually reduces cardiovascular events, clinicians would be wise to continue observing labeling restrictions.
Research suggests the combination of grapefruit juice with simvastatin would increase simvastatin blood levels, but at the same time would possibly reduce cardiovascular event levels to a degree that would counterbalance any increased risk of rhabdomyolysis.
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