Statin Safety Test: From Fruit Juice to Fibrates

Question 1 

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Answer: D. All of the above. 

Grapefruit juice can inhibit CYP3A4 and OAT for up to 24 hours. CYP3A4 and OAT are membrane transporters involved in the metabolism of certain statins. Sweet orange (citrus sinensis) may inhibit OATP, which helps mediate hepatic uptake and facilitates statin metabolism. Tangerines are related to sweet orange and may also inhibit OATP. Patients should either avoid these juices altogether or limit consumption to 60 mL per serving. Separating consumption of these juices from statin administration by 4 hours may also limit the interaction.¹

Question 2

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Answer: A. Higher

Serum statin levels are often higher in Asians compared to whites, because of genetic differences in the expression of membrane transporter proteins that play a role in statin metabolism. In particular, the FDA has cautioned against treating Chinese patients with simvastatin doses higher than 20 mg/day, when combined with niacin. Rosuvastatin labeling also includes information about higher blood levels of statins in Asians. Labeling for pitavastatin, atorvastatin and fluvastatin does not include a special population warning for Asians. However, experts recommend starting Asians and Asian-Americans on low doses of all statins.¹

Question 3

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Answer: B. Fenofibrate

Fenofibrate is generally the fibrate of choice, when combined with a statin. Gemfibrozil can increase the maximum statin concentration of most agents except fluvastatin. The maximum concentration is generally not affected when statins are combined with fenofibrate.¹ In 2013, the American College of Cardiology/American Heart Association made a strong statement against using gemfibrozil with any statin. Clofibrate is similar to gemfibrozil.²

Question 4

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Answer: A. Lovastatin

Both simvastatin and lovastatin are more dependent on CYP3A4 for elimination and so the likelihood of drug-drug interactions is higher than with other drugs in the class. Because atorvastatin is less dependent on CYP3A4, it may be less susceptible to interactions mediated by that enzyme system, but may nevertheless interact with similar drugs. Rosuvastatin, pravastatin, pitavastatin, and fluvastatin are metabolized through different enzyme pathways and may potentially have fewer severe drug-drug interactions than the previously mentioned statins. However, the following may need to be avoided with any statin: gemfibrozil, grapefruit (and related fruit juice), St. John’s Wort, red yeast rice.¹

Question 5

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Answer: C. Fluvastatin

In 2014, the FDA issued a warning³ about the use of statins with protease inhibitors and non-nucleoside reverse transcriptase inhibitors. For these drugs, interactions are usually specific to the statins via the CYP3A4 pathway. Current guidelines from the National Institutes of Health⁴ recommended using fluvastatin, pitavastatin, and pravastatin over lovastatin and simvastatin with these drugs, and using atorvastatin and rosuvastatin with caution. The efficacy of some statins will increase while that of other will decrease when taken in combination with non-nucleoside reverse transcriptase inhibitors.

References:

1. Kellick KA, Bottorff M, Toth PP, The National Lipid Association's Safety Task Force. A clinician's guide to statin drug-drug interactions. J Clin Lipidol. 2014;8:S30-46. 

2. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2013;63:2889-2934.

3. US Food and Drug Administration. FDA Drug Safety Communication: interaction between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury. http://www.fda.gov/Drugs/DrugSafety/ucm293877.htm. Published March 1, 2012. Acessed May 8, 2018. 

4. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. US Department of Health and Human Services. Available at https://aidsinfo.nih.gov/contentfiles/adultandadolescentgl003093.pdf. Accessed May 18, 2018.