What is the interaction between statin (HMG-CoA reductase inhibitor) and fenofibrate (fibric acid derivative)?

From the Guidelines

Statin and fenofibrate can be used together for patients with mixed dyslipidemia, particularly those with elevated LDL cholesterol and triglycerides, but the combination requires careful monitoring for potential side effects, especially myopathy, as noted in the 2016 study 1. The combination therapy is generally safe but requires monitoring for potential side effects. Typical statin options include atorvastatin (10-80mg daily), rosuvastatin (5-40mg daily), or simvastatin (10-40mg daily), while fenofibrate is typically dosed at 145mg daily. Before starting combination therapy, baseline liver function tests and creatine kinase levels should be checked, as recommended by the 2002 study 1. During treatment, patients should be monitored for muscle pain, weakness, or tenderness, as the combination slightly increases the risk of myopathy compared to statin monotherapy, as noted in the 2012 study 1. Liver function tests should be monitored periodically, especially in the first year of treatment. This combination works through complementary mechanisms - statins inhibit HMG-CoA reductase to reduce cholesterol synthesis, while fenofibrate activates peroxisome proliferator-activated receptor alpha (PPAR-α) to enhance triglyceride clearance and increase HDL production. The combination is particularly beneficial for patients with diabetes or metabolic syndrome who often have complex lipid abnormalities requiring dual-targeted therapy, as recommended by the 2012 study 1. Some key points to consider when using statin and fenofibrate together include:

• The use of moderate statin doses combined with fibrate appears to have a relatively low incidence of myopathy, especially when used in persons without multisystem disease or multiple medications, as noted in the 2002 study 1.
• Fibrates, particularly fenofibrate, may be useful, not only for decreasing high triglyceride concentrations and increasing low HDL cholesterol, but can further lower LDL cholesterol when applied together with a statin, as recommended by the 2012 study 1.
• Other drugs metabolized through cytochrome P450 should be avoided when this combination is prescribed, as recommended by the 2012 study 1.
• Patients have to be instructed about warning symptoms (myalgia) even though these adverse effects are very rare, as noted in the 2012 study 1.
• Avoiding the addition of gemfibrozil to a statin regimen is advised, as recommended by the 2012 study 1 and the 2016 study 1. However, fluvastatin may be used in combination with gemfibrozil, fenofibrate, or fenofibric acid, as noted in the 2016 study 1.

From the FDA Drug Label

Myopathy and Rhabdomyolysis: Have been reported in patients taking fenofibrate. Risks are increased during co-administration with a statin (with a significantly higher rate observed for gemfibrozil), particularly in elderly patients and patients with diabetes, renal failure, or hypothyroidism. (5.3)

The combination of statin and fenofibrate may increase the risk of myopathy and rhabdomyolysis, especially in certain patient populations such as the elderly, those with diabetes, renal failure, or hypothyroidism. Therefore, caution is advised when co-administering these medications. 2

From the Research

Statin and Fenofibrate Combination Therapy

• The combination of statin and fenofibrate has been shown to be effective in managing mixed dyslipidemia, a common lipid disorder characterized by the presence of an atherogenic lipoprotein phenotype 3, 4.
• Fenofibrate exerts a favorable effect on the atherogenic lipid profile of mixed dyslipidemia and can effectively reduce cardiovascular disease in patients with mixed dyslipidemia 3.
• The addition of fenofibrate to statin therapy may be a useful strategy for the management of mixed dyslipidemia in patients with or at risk for cardiovascular disease 4.

Efficacy and Safety

• Studies have shown that the combination of fenofibric acid and statin therapy can achieve individual and combined lipid and lipoprotein/biomarker targets in patients with mixed dyslipidemia 5.
• Alternate day therapy with atorvastatin and fenofibrate combination has been shown to be an effective and safe alternative to daily therapy in mixed dyslipidemia, with significant cost savings and reasonable reduction in the incidence of adverse events 6.
• However, combining a statin with either niacin or a fibrate may increase the risk for myopathy, and therefore requires careful monitoring and evaluation of the risk-benefit ratio for each patient 7.

Treatment Guidelines

• National guidelines recommend the addition of either niacin or a fibrate to statin therapy in patients with mixed dyslipidemia to achieve better overall lipid control 4.
• Fenofibrate may be the fibrate of choice for use in combination with a statin, due to its favorable safety profile and efficacy in reducing cardiovascular disease 4.
• The role of fenofibrate-statin therapy and of other therapies involving fenofibrate in cardiovascular risk reduction strategies remains to be established 3.