Why can't gemfibrozil (fibrate) be used concurrently with a statin (HMG-CoA reductase inhibitor)?

From the Guidelines

Gemfibrozil should not be used concurrently with a statin due to the increased risk of muscle symptoms and rhabdomyolysis. This is because gemfibrozil inhibits the metabolism of statins in the liver, causing statin levels to rise dramatically in the bloodstream and increasing the risk of myopathy and potentially life-threatening rhabdomyolysis 1. The combination of gemfibrozil and statins can increase statin concentrations by 2-10 times normal levels, depending on the specific statin, and is particularly dangerous with simvastatin, lovastatin, and rosuvastatin.

Some key points to consider when using fibrates with statins include:

• Gemfibrozil should not be initiated in patients on statin therapy because of the increased risk for muscle symptoms and rhabdomyolysis 1
• Fenofibrate may be considered concomitantly with a low- or moderate-intensity statin only if the benefits from ASCVD risk reduction or triglyceride lowering when triglycerides are ≥500 mg/dL are judged to outweigh the potential risk for adverse effects 1
• The FDA-approved product labeling recommends that the combined use of gemfibrozil with certain statins should be avoided, and gemfibrozil is contraindicated with simvastatin 1

It is essential to note that patients taking any statin should immediately report unexplained muscle pain, tenderness, or weakness to their healthcare provider, especially if accompanied by fever or malaise, as these could be early signs of serious muscle damage. If a patient needs both fibrate and statin therapy, fenofibrate is the preferred fibrate option as it has significantly less interaction with statins 1.

From the FDA Drug Label

The concomitant administration of gemfibrozil with simvastatin is contraindicated (see CONTRAINDICATIONS and WARNINGS) The risk of myopathy and rhabdomyolysis is increased with combined gemfibrozil and HMG-CoA reductase inhibitor therapy. Myopathy or rhabdomyolysis with or without acute renal failure have been reported as early as three weeks after initiation of combined therapy or after several months (see WARNINGS)

• Gemfibrozil cannot be used concurrently with a statin (HMG-CoA reductase inhibitor) because the risk of myopathy and rhabdomyolysis is increased with combined therapy.
• This increased risk is due to the potential for severe myopathy and kidney damage, which can occur as early as three weeks after initiation of combined therapy or after several months.
• The FDA drug label explicitly states that the concomitant administration of gemfibrozil with simvastatin is contraindicated 2.

From the Research

Risk of Myopathy and Rhabdomyolysis

• The combination of gemfibrozil (a fibrate) and a statin (HMG-CoA reductase inhibitor) may raise the risk of myopathy and rhabdomyolysis 3, 4.
• Gemfibrozil interferes with statin glucuronidation, which may increase the risk of myopathy due to elevations in statin serum levels 3.
• Fenofibrate is considered a more appropriate choice than gemfibrozil when combined with statins due to its lower myopathic potential 3, 5.

Mechanism of Increased Risk

• The increased risk of myopathy is thought to be due to the direct toxic effect of gemfibrozil on muscles, as well as its effect on statin metabolism 4.
• Predisposing factors to the development of myopathy from the combination include use of medications affecting statin metabolism, higher doses of statins, renal insufficiency, diuretics, and hypothyroidism 4.

Clinical Considerations

• Combination therapy with a fibrate and a statin should be used with caution and reserved for high-risk patients with a mixed hyperlipidaemia 6.
• Patients should have normal renal, liver, and thyroid function tests and should not be receiving therapy with cyclosporine, protease inhibitors, or drugs metabolized through cytochrome P450 (especially 3A4) 6.
• Regular monitoring of liver function and creatine kinase is required when using combination therapy 6.