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Abstract & Commentary
Synopsis: Combining a fibrate with a statin increases the risk of rhabdomyolysis by more than 10 times the use of a statin alone. A large study of more than 250,000 patients found that this combination had greater risk than the use of cerivastatin (Baycol), which was removed from the market. For patients needing intensive drug therapy for dyslipidemia, high-dose statins or other combination therapy should be used.
Source: Graham DL, et al. JAMA. 2004;292:2585-2590.
The new guidelines for lowering lipid levels, especially in high risk patients, call for intensive drug therapy. While statins are the mainstay of treating dyslipidemia, another drug may be needed to achieve recommended lipid levels. This is especially true for patients with metabolic syndrome or genetic hyperlipidemias. Statins alone have limited value in lowering triglycerides and raising HDL cholesterol. Fibrates have a specific indication for elevated triglycerides and low HDL cholesterol, so combining either fenofibrate or gemfibrozil with a statin may seem like an attractive option.
Graham and colleagues studied a database of 252,460 patients in 11 managed care health plans that were treated for dyslipidemia with drug therapy for at least 6 months between 1998 and 2001. Patients were either on monotherapy with a statin, a fibrate, or a combination of both. 24 patients were hospitalized with rhabdomyolysis, a very low rate. However, among these patients, a much higher risk of rhabdomyolysis occurred in the patients receiving combination therapy.
The risk of rhabdomyolysis requiring hospitalization in patients taking atorvastatin, pravastatin, or simvastatin was found to be 0.44 per 10,000 person years, a very low risk. The risk in patients taking a fibrate as monotherapy was 2.82 per 10,000 person years. Since this study was started before the removal of cerivastatin (Baycol) from the market, a comparison with this agent was made. The risk of rhabdomyolysis with monotherapy with cerivastatin was 5.34 per 10,000 person years, more than 10 times higher than the other statins, and about 2 times higher than using a fibrate alone. The risk of combination therapy with a fibrate and one of the safe statins was 5.98 per 10,000 years. The risk of rhabdomyolysis in patients using cerivastatin and a fibrate was a whopping 1035 per 10,000 person years, or more than 1 in 10 persons.
Comment by Joseph E. Scherger, MD, MPH
I have seen 2 patients disabled from rhabdomyolysis due to the use of a statin with a fibrate. This is a heavy price to pay for treating an asymptomatic, albeit important, disease. This study from a large population shows that combined therapy with a statin and fibrate is as dangerous as using a drug that has been withdrawn from the market. This combination therapy should only be used in clinical practice for patients with severe, genetic hyperlipidemia, especially with very high triglycerides and very low HDL cholesterol.
Niacin and ezetimibe are effective medications which can be used with a statin. Niacin has similar beneficial effects as fibrates, and while side effects may be troublesome in effective therapeutic doses, they are not as serious as rhabdomyolysis. Major lifestyle modification with very low fat nutrition may prevent the need for multiple drug treatment in some patients. We should treat dyslipidemia aggressively, but also as safely as possible.
Dr. Scherger, Clinical Professor, University of California, San Diego, is Associate Editor of Internal Medicine Alert.