Top 5 Statin Drug Interactions

Statins are one of the most commonly prescribed medications to help manage hyperlipidemia and reduce the risk of cardiovascular events. However, statins are notorious for their drug interactions which can pose a significant risk to patients if not taken into consideration. Working in a retail pharmacy, I frequently encounter cases involving statin drug interactions that require intervention by either contacting the provider and/or educating patients on monitoring parameters. In this article, I want to focus on the most common statin drug interactions you’ll see in the ambulatory pharmacy setting.

Grapefruit Juice

Probably the most well-known drug interaction with statins. Grapefruit (or grapefruit juice) is a strong CYP3A4 inhibitor, the major enzyme responsible for the breakdown of atorvastatin, simvastatin, and lovastatin. The inhibition of this enzyme can lead to increased plasma statin concentrations, increasing the patient’s risk for developing adverse side effects such as myalgia and rhabdomyolysis. Grapefruit is best avoided in patients taking these three statins. So if a patient is a big fan of grapefruit and really does not want to give it up, it’s best to change to an alternative statin such as rosuvastatin or pravastatin to avoid this drug interaction. If you are looking for more information about grapefruit interactions, you must listen to this podcast episode.

Azole Antifungals

Azole antifungals are also a class of medications known for their statin drug interactions. Depending on the specific azole, there are varying degrees of inhibition of CYP2C19, CYP2C9, and most importantly CYP3A4. Like with grapefruit, this enzyme inhibition increases statin concentrations in the body, leading to an increased risk of adverse effects. While short courses of azole antifungals taken in combination with statins are not likely to cause major issues, long-term use could pose a greater risk to the patient.

Gemfibrozil

Statins do a good job of reducing total cholesterol, but some patients require additional therapy to help further lower cholesterol and triglycerides. Fibrates are very effective in lowering triglycerides while also providing some total cholesterol lowering effects. However, depending on the specific fibrate used, there are varying degrees of interactions with statins. While fenofibrate is generally considered safer in combination with statins, gemfibrozil should be avoided. Gemfibrozil is an inhibitor of OATP1B1, a transporter that statins use to enter the liver. When this transporter is inhibited, plasma statin concentrations increase, and the patient’s risk for adverse effects like myalgia and rhabdomyolysis also increase.

Paxlovid

Paxlovid is a newer drug on the market used for the treatment of COVID-19 that has gained a lot of popularity. Paxlovid is a combination medication composed of two drugs, nirmatrelvir and ritonavir. Ritonavir is used in this formulation specifically for its strong CYP3A4 inhibitory properties to help enhance the effects of nirmatrelvir. Due to this strong inhibition, the majority of statins need to be held during the 5-day treatment course and for several days after. It is especially important to reiterate this dosing modification to patients to avoid adverse reactions related to elevated plasma statin levels.

Calcium Channel Blockers and Statin Drug Interactions

Verapamil and diltiazem are both non-dihydropyridine calcium channel blockers that are metabolized by CYP3A4. Although these medications do not directly inhibit this enzyme, they compete against statins for metabolism. This competition reduces the amount of statin metabolized, increasing the risk for adverse effects due to high statin levels. The statins most affected by this interaction include atorvastatin, simvastatin, and lovastatin. Currently there are maximum daily dose recommendations for simvastatin and lovastatin when used in combination with diltiazem or verapamil.

Amlodipine is a dihydropyridine calcium channel blocker that deserves an honorable mention (excellent board exam question!). It has a significant interaction with simvastatin and can increase concentrations.

Major Takeaways

Overall, a common theme amongst these drug interactions is that atorvastatin, simvastatin, and lovastatin are the statins most likely to have significant drug interactions. When plasma statin concentrations remain elevated for an extended period, the risk of developing adverse side effects also increases, with myalgia and rhabdomyolysis being the most notable.

This article was written by Kelly Cheis, PharmD Candidate, in collaboration with Eric Christianson, PharmD, BCPS, BCGP

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