Fenofibrate and fenofibric acid are used as adjuncts to dietary therapy in the management of primary hypercholesterolemia and mixed dyslipidemia. The drugs also are used as adjuncts to dietary therapy in the management of severe hypertriglyceridemia. In addition, fenofibric acid is used in combination with a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) for the treatment of mixed dyslipidemia in patients with coronary heart disease (CHD) or CHD risk equivalents who are receiving optimal statin therapy; however, no additional benefit on cardiovascular morbidity and mortality has been demonstrated with such combination therapy beyond that already established with statin monotherapy. (
See Primary Hypercholesterolemia and Mixed Dyslipidemia under Uses: Dyslipidemiasand also see Effects on Morbidity and Mortality under Cautions: Warnings/Precautions.)
The American College of Cardiology (ACC)/American Heart Association (AHA) guideline for management of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults states that nondrug therapies (i.e., lifestyle modifications), which include adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight, are the foundation of atherosclerotic cardiovascular disease (ASCVD) prevention. Drug therapy is not a substitute for, but an adjunct to, these nondrug therapies and measures, which should be continued when drug therapy is initiated. For additional details on lifestyle modifications, consult the most recent AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk (available at http://www.cardiosource.org or http://my.americanheart.org).
The effects of fenofibrate and fenofibric acid on cardiovascular morbidity and mortality or noncardiovascular mortality have not been established.
Primary Hypercholesterolemia and Mixed Dyslipidemia
Fenofibrate and fenofibric acid are used as adjuncts to dietary therapy to decrease elevated serum total and low-density lipoprotein (LDL)-cholesterol, triglyceride, and apolipoprotein B (apo B) concentrations, and to increase high-density-lipoprotein (HDL)-cholesterol concentrations in the management of primary hypercholesterolemia and mixed dyslipidemia, including heterozygous familial hypercholesterolemia and other causes of hypercholesterolemia. Fenofibric acid also is used in combination with a statin to decrease triglyceride concentrations and increase HDL-cholesterol concentrations in patients with mixed dyslipidemia and CHD (or CHD risk equivalents) who are receiving optimal statin therapy; CHD risk equivalents include diabetes mellitus, multiple risk factors that confer a 10-year risk of CHD exceeding 20%, or other types of atherosclerotic disease such as peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease. The addition of fenofibrate to statin therapy has not been shown to provide an incremental benefit on cardiovascular morbidity and mortality beyond that already established with statin monotherapy.
(See Effects on Morbidity and Mortality under Cautions: Warnings/Precautions.)
The ACC/AHA cholesterol management guideline states that nonstatin therapies (e.g., fibric acid derivatives) do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. The guideline states that nonstatin drugs may be useful as adjuncts to statin therapy in certain high-risk patients (e.g., patients with ASCVD, patients with LDL-cholesterol concentrations of 190 mg/dL or higher, patients 40-75 years of age with diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate even a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy. However, because the addition of fenofibrate to simvastatin therapy has not been shown to provide an incremental benefit on cardiovascular morbidity and mortality beyond that already established with statin monotherapy, the ACC/AHA cholesterol management guideline states that the combination of fenofibrate (or fenofibric acid) and low- or moderate-intensity statin therapy may be considered only if the benefits from ASCVD risk reduction or triglyceride lowering (when triglyceride concentrations exceed 500 mg/dL) outweigh the potential risks of adverse effects and drug interactions. and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).
Efficacy and safety of fenofibrate and fenofibric acid in the management of hypercholesterolemia were established in 4 randomized, double-blind, placebo-controlled studies of 3-6 months' duration in patients with primary hypercholesterolemia or mixed dyslipidemia. In these studies, patients who received fenofibrate in dosages equivalent to 90 mg (as Antara micronized capsules), 120 mg (as Fenoglide tablets), 150 mg (as Lipofen capsules), 160 mg (as Triglide tablets), 200 mg (as micronized Lofibra capsules), or 145 mg (as Lofibra or TriCor tablets) daily or fenofibric acid at dosages equivalent to 135 mg once daily (as Trilipix capsules) had mean reductions of about 17-22% in total cholesterol, 20-31% in LDL-cholesterol, 24-36% in triglyceride, and (in a subset of patients) 25% in apo B concentrations; mean increases of 10-15% in HDL-cholesterol concentrations also were reported.
Efficacy and safety of fenofibric acid in combination with a statin were established in 3 randomized, double-blind studies of 12 weeks' duration and a long-term (52-week) open-label extension study in patients with mixed dyslipidemia. In these studies, the combination of fenofibric acid (135 mg daily) and a statin (atorvastatin 20 or 40 mg daily, rosuvastatin 10 or 20 mg daily, or simvastatin 20 or 40 mg daily) substantially increased HDL-cholesterol and reduced triglyceride concentrations compared with the corresponding statin monotherapy and substantially reduced LDL-cholesterol concentrations compared with fenofibric acid monotherapy. Patients who received the combination antilipemic regimens in these studies had mean increases of about 18% in HDL-cholesterol concentrations and mean decreases of about 42-44 and 33-35% in triglyceride and LDL-cholesterol concentrations, respectively. In the 52-week extension study, patients continued to receive fenofibric acid in combination with a moderate dosage of statin; reductions of about 48% in triglyceride concentrations, 35% in total cholesterol concentrations, 38% in LDL-cholesterol concentrations, 44% in apo B concentrations, and 46% in non-HDL-cholesterol concentrations were observed, in addition to an increase of approximately 24% in HDL-cholesterol concentrations. Such effects were observed within 4 weeks and sustained throughout the duration of the study.
Use of fenofibrate in combination with a statin was evaluated in another randomized, controlled study (the Action to Control Cardiovascular Risk in Diabetes [ACCORD Lipid] study). In this study, the combination of fenofibrate (160 mg daily) and a statin (simvastatin at dosages up to 40 mg daily) was compared with statin therapy alone in patients with type 2 diabetes mellitus at high risk for cardiovascular disease. Despite a favorable effect on serum lipid concentrations (e.g., increased HDL-cholesterol, reduced triglycerides), the addition of fenofibrate to simvastatin therapy did not substantially reduce the rate of cardiovascular events (i.e., nonfatal myocardial infarction, nonfatal stroke, death from cardiovascular causes) compared with simvastatin monotherapy over a mean follow-up period of 4.7 years.
(See Effects on Morbidity and Mortality under Cautions: Warnings/Precautions.)In general, routine use of fenofibrate in combination with a statin is not recommended to further reduce cardiovascular risk in patients with type 2 diabetes mellitus; while subgroup analyses indicate that such a combination may provide some benefit in certain groups of patients (e.g., those with type 2 diabetes mellitus and atherogenic dyslipidemia), further study is required to confirm these findings.
While few studies are available on the comparative efficacy of fenofibrate and other antilipemic agents, limited data suggest that fenofibrate may have more favorable effects on serum total cholesterol and LDL-cholesterol concentrations than gemfibrozil. Fenofibrate appears to be more effective than statins in lowering triglyceride and increasing HDL-cholesterol concentrations but generally is less effective in reducing LDL-cholesterol concentrations.
Data from several studies indicate that combination therapy with fenofibrate and other antilipemic agents (e.g., colesevelam, ezetimibe) may produce additive antilipemic effects. In one study, the addition of colesevelam hydrochloride (3.8 g daily) to current fenofibrate therapy (160 mg daily as micronized formulations) in patients with mixed dyslipidemia further reduced total and LDL-cholesterol concentrations by 8 and 12%, respectively, but increased triglyceride concentrations by 9%. In another study in patients with mixed dyslipidemia, combination therapy with fenofibrate (160 mg daily as micronized formulations) and ezetimibe was superior to fenofibrate monotherapy in reducing total cholesterol (22 versus 11%), LDL-cholesterol (20 versus 6%), apo B (26 versus 15%), and non-HDL-cholesterol concentrations (30 versus 16%) following up to 60 weeks of therapy; effects on triglyceride and HDL-cholesterol concentrations in patients receiving combination therapy were comparable to those in patients receiving fenofibrate monotherapy.
Fenofibrate and fenofibric acid are used as adjuncts to dietary therapy in the management of severe hypertriglyceridemia. Efficacy of the drugs in reducing the risk of pancreatitis in patients with marked elevations in triglyceride concentrations (i.e., exceeding 2000 mg/dL) has not been established. In patients with diabetes mellitus who have fasting chylomicronemia, improving glycemic control usually will reduce fasting triglycerides and eliminate the need for pharmacologic therapy.
Efficacy and safety of fenofibrate and fenofibric acid in the management of hypertriglyceridemia were established in 2 randomized, double-blind, placebo-controlled studies of 8 weeks' duration in patients with type IV or V hyperlipoproteinemia. In these studies, patients who received fenofibrate in dosages equivalent to 90 mg (as Antara micronized capsules), 120 mg (as Fenoglide tablets), 150 mg (as Lipofen capsules), 145 mg (as Lofibra or TriCor tablets), 200 mg (as Lofibra micronized capsules), or 160 mg (as Triglide tablets) daily or fenofibric acid at a dosage equivalent to 135 mg daily (as Trilipix capsules) had mean reductions of 46-55 and 45-49% in triglyceride and very low-density lipoprotein (VLDL)-cholesterol concentrations, respectively; mean increases of 20-23% in HDL-cholesterol concentrations also were reported.
Treatment of patients with type IV hyperlipoproteinemia and elevated triglycerides with fenofibrate often is associated with increases in LDL-cholesterol concentrations. In clinical studies with fenofibrate, LDL-cholesterol concentrations were increased by 15 or 45% in patients with baseline triglyceride concentrations of 350-499 or 500-1500 mg/dL, respectively.