Fenofibric Acid (TRILIPIX) May Not Lower Heart Attack/Stroke Risk

The Food and Drug Administration (FDA) announced on Nov. 9, 2011, that the cholesterol-lowering drug fenofibric acid (TRILIPIX) might not lower the risk of having a heart attack or stroke.

The FDA now requires the product label for fenofibric acid to contain the following statement in the “Important Limitations of Use” section:

No incremental benefit of TRILIPIX on cardiovascular morbidity and mortality over and above that demonstrated for statin monotherapy has been established. Fenofibrate at a dose equivalent to 135 mg [milligrams] of TRILIPIX was not shown to reduce coronary heart disease morbidity and mortality in 2 large, randomized controlled trials of patients with type 2 diabetes mellitus.

Fenofibric acid was approved in the U.S. in December 2008 and is now a top-selling product, with more that 3.6 million prescriptions written and almost $500 million in sales in 2010.

Fenofibric acid is the active breakdown product (metabolite) of fenofibrate (TRICOR). The FDA noted that there is no reason to expect that at comparable doses fenofibric acid and fenofibrate would be any different in terms of safety and efficacy. (Fenofibrate and fenofibric acid can be considered the same drug.)

Fenofibrate was approved by the FDA in February 1998, and Public Citizen’s Health Research Group lists it as a “Do Not Use” drug, suggesting niacin extended (intermediate) release as an alternative. This “Do Not Use” warning extends to fenofibric acid as well.

The FDA has approved fenofibric acid to treat cholesterol by lowering low-density lipoprotein (LDL) cholesterol (or “bad cholesterol”) and increasing high-density lipoprotein (HDL) cholesterol (or “good cholesterol”). Fenofibric acid also is approved to lower very high levels of fat (triglycerides) in the blood to help reduce the risk of pancreatitis (inflammation of the pancreas). It also can be used in combination with statins, such as simvastatin (ZOCOR), in patients at high risk for cardiovascular disease.

Label change and fenofibrate trials

The FDA’s decision to require the labeling change for fenofibric acid was based in part on the results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial. Published in the April 29, 2010, New England Journal of Medicine, this trial evaluated the efficacy and safety of a fenofibrate-plus-simvastatin combination treatment versus a simvastatin-plus-placebo treatment in patients with type 2 diabetes.

The ACCORD Lipid trial was a gold-standard randomized, double-blind, placebo-controlled trial. The researchers tracked cases of major adverse cardiovascular events: nonfatal heart attack, nonfatal stroke and cardiovascular disease death.

The study followed 5,518 subjects for an average of 4.7 years. Results showed that use of fenofibrate plus simvastatin was associated with a non-statistically significant 8 percent relative risk reduction in major adverse cardiovascular events compared to treatment with simvastatin plus a placebo. The absolute risk difference between the two groups at the end of the study was less than 1 percent (0.76 percent).

When men and women were analyzed separately, the risk of major adverse cardiovascular events was higher in women than in men. This unexpected study result was not statistically significant.

The authors of the ACCORD Lipid trial concluded:

These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes.

The authors of a second study, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, published their results in the November 2005 Lancet medical journal. This was also a gold-standard randomized clinical trial. The study included 9,795 patients who had type 2 diabetes and were treated with fenofibrate or a placebo over a period of five years. The researchers measured cases of coronary heart disease death and nonfatal heart attack, which defined the primary outcomes of the study coronary events.

The results showed an 11 percent relative reduction in coronary heart disease deaths and nonfatal heart attacks in those taking fenofibrate compared to those taking a placebo. This difference was not statistically significant. The absolute risk of coronary events was 6.1 percent and 5.4 percent in the placebo and fenofibrate groups, respectively. This is an absolute difference of only 0.7 percent.

The authors of the FIELD study concluded:

Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events [coronary heart disease death and nonfatal heart attack].

Evidence from the ACCORD Lipid and FIELD studies, both large gold-standard randomized clinical trials, has failed to show a significant benefit for fenofibric acid.

Fenofibric acid and risk of rhabdomyolysis

In addition to requiring the recent label change, the FDA also mandates fenofibric acid to be dispensed with an FDA-approved Medication Guide written specifically for consumers in nontechnical language. The FDA has the authority to require Medication Guides for drugs that present serious public health concerns, including fenofibric acid.

One of the main safety messages in the fenofibric acid Medication Guide is that using fenofibric acid in combination with a statin drug can increase the risk of an adverse drug reaction called rhabdomyolysis. The breakdown of muscle in rhabdomyolysis can cause kidney damage and death. Symptoms include muscle pain, tenderness or weakness.

Below is a list of the statin drugs currently on the market in the U.S.

• atorvastatin (LIPITOR, CADUET)
• fluvastatin (LESCOL, LESCOL XL)
• lovastatin (ALTOPREV, MEVACOR, ADVICOR)
• pitavastatin (LIVALO)
• pravastatin (PRAVACHOL)
• rosuvastatin (CRESTOR)
• simvastatin (ZOCOR, SIMCOR, VYTORIN)

The Medication Guides for fenofibric acid and other drugs can be obtained from the FDA’s website at www.fda.gov/Drugs/DrugSafety/ucm085729.htm, or from a pharmacist.

What You Can Do

If you are currently taking fenofibric acid in combination with a statin drug, you should consult your health care provider to discuss the evidence that adding fenofibric acid to a statin does not improve outcomes.

Consumers may report serious adverse events with drugs or product quality problems to the FDA’s MedWatch Adverse Event Reporting program online or by regular mail, fax or phone.

• Online: www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
• Regular mail: Use postage-paid, pre-addressed FDA form 3500 and mail to MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787
• Fax: (800) FDA-0178
• Phone: (800) FDA-1088