What is the interaction between Gemfibrozil and Atorvastatin?

From the Guidelines

Gemifibrozil and atorvastatin should not be used together due to a significant drug interaction that increases the risk of severe muscle damage (rhabdomyolysis). This combination can lead to a modest increase in atorvastatin blood levels because gemifibrozil inhibits the OATP2-mediated hepatic uptake of atorvastatin, with the AUC values of atorvastatin and its active metabolites increased by 1.2- to 1.4-fold when coadministered with gemfibrozil 1. If lipid-lowering combination therapy is needed, fenofibrate is a safer fibrate option to pair with atorvastatin, though caution is still warranted 1. The dose of atorvastatin should be reduced if combination therapy is necessary. Patients on any statin-fibrate combination should be monitored for muscle pain, weakness, or dark urine, which could indicate muscle damage. These symptoms require immediate medical attention and possible discontinuation of the medications. Alternative approaches for mixed dyslipidemia might include using a statin with omega-3 fatty acids, ezetimibe, or PCSK9 inhibitors instead of fibrates.

Some key points to consider when managing patients on statin and fibrate combination therapy include:

• The increased risk of muscle-related toxicity, including rhabdomyolysis, with gemfibrozil and statin combination therapy 1
• The potential for increased atorvastatin blood levels when coadministered with gemfibrozil, which may increase the risk of muscle damage 1
• The safer alternative of using fenofibrate with atorvastatin, if combination therapy is necessary 1
• The importance of monitoring patients for signs of muscle damage, such as muscle pain, weakness, or dark urine, and taking prompt action if these symptoms occur.

In terms of specific management strategies, the following may be considered:

• Avoiding the use of gemfibrozil with atorvastatin, due to the increased risk of muscle-related toxicity 1
• Using fenofibrate as a safer alternative, if combination therapy is necessary 1
• Reducing the dose of atorvastatin if combination therapy is necessary, to minimize the risk of muscle damage 1
• Monitoring patients closely for signs of muscle damage, and taking prompt action if these symptoms occur.

From the FDA Drug Label

Atorvastatin calcium is a substrate of CYP3A4 and transporters (e.g., OATP1B1/1B3, P-gp, or BCRP). Atorvastatin calcium plasma levels can be significantly increased with concomitant administration of inhibitors of CYP3A4 and transporters Table 2 includes a list of drugs that may increase exposure to atorvastatin and may increase the risk of myopathy and rhabdomyolysis when used concomitantly and instructions for preventing or managing them Cyclosporine or Gemfibrozil Clinical Impact:Atorvastatin plasma levels were significantly increased with concomitant administration of atorvastatin calcium and cyclosporine, an inhibitor of CYP3A4 and OATP1B1 . Gemfibrozil may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium. Intervention:Concomitant use of cyclosporine or gemfibrozil with atorvastatin calcium is not recommended

The concomitant use of Gemifibrozil and Atorvastatin is not recommended due to the increased risk of myopathy and rhabdomyolysis 2, 2, 2.

From the Research

Gemifibrozil and Atorvastatin Combination Therapy

• The combination of gemfibrozil and atorvastatin has been studied for its efficacy and safety in treating mixed lipid disorders 3.
• A study published in the American Heart Journal found that the combination of gemfibrozil and an HMG-CoA reductase inhibitor, such as atorvastatin, resulted in improved long-term control of lipid abnormalities in mixed lipid disorders 3.
• The study reported a low incidence of toxicity, with only one episode of myopathy and one episode of aminotransferase level elevation occurring in 252 patients over a mean of 2.36 years 3.

Safety Considerations

• The use of statin-fibrate combination therapy, including gemfibrozil and atorvastatin, has been associated with an increased risk of myopathy and hepatic toxicity 4, 5.
• However, the risk of myopathy is considered to be lower with fenofibrate than with gemfibrozil 4.
• Regular monitoring of liver function and creatine kinase is recommended for patients receiving combination therapy 5.

Comparison with Other Treatments

• A study comparing gemfibrozil and fenofibrate in patients with dyslipidemic coronary heart disease found that fenofibrate produced significantly greater reductions in total cholesterol, LDL, and triglycerides, and significantly greater increases in HDL 6.
• Another study found that fenofibrate therapy had substantially better effects on lipoprotein and metabolic profiles in patients with hypertriglyceridemia compared to omega-3 fatty acids 7.