INDICATIONS

• Hypertriglyceridemia: To prevent cardiovascular disease and events (Buse)
• Mixed dyslipidemia: To prevent cardiovascular disease and events (Buse)

• Prevention of acute pancreatitis secondary to severe hypertriglyceridemia

MECHANISM

• Activation of PPAR alpha reduces the synthesis of apo AIII, an inhibitor of the action of lipoprotein lipase (van Dijk), the enzyme that breaks down circulating triglycerides. (Hertz)
• Activation of PPAR alpha also stimulates the formation of apoAV, which lowers blood levels of triglycerides. (Prieur)

USUAL ADULT DOSING

• Fenofibrate (Tricor) 48 to 145 mg daily
• Fenofibrate (Fenoglide) 20 to 120 mg daily
• Fenofibrate, micronized (Antara, Lofibra): Antara 43 to 130 mg daily; Lofibra 67 to 200 mg daily; Tripilix 45 to 135 mg daily. Administer with food.
• Gemfibrozil (Lopid) 120 mg twice daily
• Start with maximal dose in patients with triglycerides > 500 mg/dL
• In others, dose titrations are based on patient responses when assessed at the end of 4 to 6 weeks.

FORMS

*Costs (rounded to the nearest dollar) are based on usual adult dosing per day, are representative of "Average Wholesale Price" (AWP), and are current within the prior three months.

^Dosage is indicated in mg unless otherwise noted.

DOSING IN SPECIAL POPULATIONS

• Contraindicated with severe renal disease (GFR < 30 mL/min) or on dialysis
• Reduce dose with moderate renal disease, GFR between 30 and 60 mL/min

• Contraindicated for active liver disease or primary biliary cirrhosis

• Category C

• Contraindicated

ADVERSE DRUG REACTIONS

• Major concern is development of severe myositis and rhabdomyolysis when used in combination with a statin.

• There are no common side effects.

• Abnormal liver function tests
• Abdominal pain
• Upset stomach
• Myositis
• Headache, dizziness

• Severe myositis, rabdomyolysis, and renal failure when used in combination with a statin.
• Gallstones
• Bone marrow suppression

DRUG INTERACTIONS

• Statins: may increase risk of rhabdomyolysis. Monitor for sign and symptoms of rhabdomyolysis. Gemfibrozil increases rosuvastatin AUC by 90% (use fenofibrate with rosuvastatin).
• Warfarin: may increase INR. Monitor closely with co-administration.
• Bile acid sequestrants can reduce fibrate absorption. Fibrates should be taken 1 hour before or 4 to 6 hours after a sequestrant.
• Glyburide: case report of increased hypoglycemic effect with glyburide and gemfibrozil co-administration. Use with close monitoring.
• Repaglinide: gemfibrozil increased repaglinide serum concentrations 8.1-fold increase; therefore, co-administration is contraindicated. No significant interaction between fenofibrate and repaglinide.
• Pioglitazone and rosiglitazine: co-administration with fibric acid derivatives may increase hypoglycemic effect. Gemfibrozil increases pioglitazone and rosiglitazone AUC by 226% and 130%, respectively.
• Ursodiol: efficacy may be decreased.

PHARMACOKINETIC

COMMENTS

• Fibrates lower triglycerides by 25 to 50% and raise HDL cholesterol by about 8%, but may raise LDL cholesterol in patients with triglycerides > 500 mg/dL.
• Severe myositis occurs most commonly when a fibrate is taken in combination with a statin.
• The risk of myositis is greater with gemfibrozil than with fenofibrate.
• When triglyceride levels are between 200 and 500 mg/dL and LDL is elevated, begin treatment with a statin. If triglycerides are still greater than 200 mg/dL, consider adding fenofibrate. The target is a non-HDL cholesterol <100 mg/dL (non HDL cholesterol = total cholesterol - HDL cholesterol. (Expert panel ...)
• Fibrates can be used as monotherapy in patients with normal LDL cholesterol and triglycerides between 200 and 500 mg/dL and in patients with triglycerides > 500 mg/dL. (Expert panel ...)
• Fenofibrate has not been shown to reduce coronary heart disease mortality or morbidity in a large trial of patients with type 2 diabetes. (Keech)
• Fenofibrate lowers the incidence of laser treatment for diabetic retinopathy. (Keech)
• Weight loss and improved glycemic control lower triglyceride levels and should always be attempted before and during treatment with a fibrate.
• Recent RCT (ACCORD) tested effect of fenofibrate added to simvastatin in 5,518 people with diabetes at high risk for cardiovascular events. LDL-cholesterol was low (about 80 mg/dl) in both fenofibrate and placebo groups, and fenofibrate had no additional benefit to simvastatin alone (Ginsberg).

References

1. ACCORD Study Group, Ginsberg HN, Elam MB, et al.; Effects of combination lipid therapy in type 2 diabetes mellitus.; N Engl J Med; 2010; Vol. 362; pp. 1563-74;
   ISSN: 1533-4406;
   PUBMED: 20228404
   Comments:The ACCORD Study tested the effect of intensive glucose control, intensive blood pressure control and this, addition of fenofibrate. In this report, patients starting with triglyceride >200 mg/dl had benefit from fenofibrate. Not surprising, since the fibrates are generally used to tread hypergriglyceridemia.
   
   
2. Buse JB, Ginsberg HN, Bakris GL, et al.; Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association.; Circulation; 2007; Vol. 115; pp. 114-26;
   ISSN: 1524-4539;
   PUBMED: 17192512
   Comments:Recommendations from AHA and ADA for the primary prevention of cardiovascular heart disease in patients with diabetes.
   
   
3. Keech AC, Mitchell P, Summanen PA, et al.; Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial.; Lancet; 2007; Vol. 370; pp. 1687-97;
   ISSN: 1474-547X;
   PUBMED: 17988728
   Comments:Treatment with fenofibrate in individuals with type 2 diabetes mellitus reduced the need for laser treatment for diabetic retinopathy.
   
   
4. Sarwar N, Danesh J, Eiriksdottir G, et al.; Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies.; Circulation; 2007; Vol. 115; pp. 450-8;
   ISSN: 1524-4539;
   PUBMED: 17190864
   Comments:Prospective studies in Western populations consistently indicate moderate and highly significant associations between triglyceride values and coronary heart disease risk.
   
   
5. Keech A, Simes RJ, Barter P, et al.; Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.; Lancet; 2005; Vol. 366; pp. 1849-61;
   ISSN: 1474-547X;
   PUBMED: 16310551
   Comments:Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reduce total cardiovascular events.
   
   
6. Grundy SM, Vega GL, Yuan Z, et al.; Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial).; Am J Cardiol; 2005; Vol. 95; pp. 462-8;
   ISSN: 0002-9149;
   PUBMED: 15695129
   Comments:The combination of a statin and fenofibrate is beneficial in the treatment of combined hyperlipidemia.
   
   
7. van Dijk KW, Rensen PC, Voshol PJ, et al.; The role and mode of action of apolipoproteins CIII and AV: synergistic actors in triglyceride metabolism?; Curr Opin Lipidol; 2004; Vol. 15; pp. 239-46;
   ISSN: 0957-9672;
   PUBMED: 15166778
   Comments:Apo CIII raises triglyceride levels by inhibiting lipoprotein lipase activity. Apo AV lowers plasma triglyceride levels.
   
   
8. Prieur X, Coste H, Rodriguez JC; The human apolipoprotein AV gene is regulated by peroxisome proliferator-activated receptor-alpha and contains a novel farnesoid X-activated receptor response element.; J Biol Chem; 2003; Vol. 278; pp. 25468-80;
   ISSN: 0021-9258;
   PUBMED: 12709436
   Comments:Apo AV formation is stimulated by activation of PPAR alpha.
   
   
9. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults; Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).; JAMA; 2001; Vol. 285; pp. 2486-97;
   ISSN: 0098-7484;
   PUBMED: 11368702
   Comments:General guidelines for management of blood lipid abnormalities: Risk factors, normal and abnormal cholesterol levels, when to initiate treatments, targets for treatment.
   
   
10. Hertz R, Bishara-Shieban J, Bar-Tana J; Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III.; J Biol Chem; 1995; Vol. 270; pp. 13470-5;
    ISSN: 0021-9258;
    PUBMED: 7768950
    Comments:Fibrates exert their effects by activating PPAR alpha which inhibits the formation of apo CIII.
    
    

RELATED MODULES

• Elderly and Diabetes