Fibrates

Fibrates activate peroxisome proliferator-activated receptor alpha, increasing lipoprotein lipase activity and fatty acid oxidation and reducing hepatic VLDL production. They lower triglycerides by 30% to 50%, raise HDL cholesterol by 5% to 20% and have variable effects on LDL cholesterol. Their main role is prevention of pancreatitis in severe hypertriglyceridaemia, and mixed dyslipidaemia in selected patients.

Members. Fenofibrate, bezafibrate, gemfibrozil, ciprofibrate. Pemafibrate is a selective agent available in some regions.

Mechanism. PPAR alpha activation increases transcription of lipoprotein lipase and apolipoproteins A-I and A-II, and reduces apolipoprotein C-III.

Pharmacokinetics. Fenofibrate is a prodrug (fenofibric acid) taken with food, with a half-life of about 20 hours. Gemfibrozil has a half-life of 1.5 hours. Elimination is renal, so accumulation occurs in renal impairment. Gemfibrozil inhibits glucuronidation, which causes statin interactions.

• Fenofibrate: most used; can be combined with a statin; raises creatinine without kidney injury.
• Bezafibrate: modified-release once-daily option; used in some cholestatic liver conditions.
• Gemfibrozil: avoid with statins; used when other options are unavailable.
• Ciprofibrate: similar to bezafibrate.

• Severe hypertriglyceridaemia (over 10 mmol/L, or over 5.6 mmol/L with pancreatitis history): fenofibrate 145 mg daily (nanocrystal) or 160 mg daily, or micronised 200 mg daily, with diet, alcohol restriction and glucose control.
• Mixed dyslipidaemia, diabetes, on a statin: may be considered when triglycerides stay at 2.3 mmol/L or over with low HDL cholesterol, accepting limited evidence of event reduction.
• Bezafibrate: 400 mg modified release at night.
• Gemfibrozil: 600 mg twice daily before meals, avoided with statins.
• Selection: use after secondary causes are treated and a statin is started, and add omega 3 fatty acids if triglycerides stay over 5.7 mmol/L.

Contraindications. Severe renal impairment (eGFR under 30 mL/min/1.73 m2), active liver disease, gallbladder disease with gallstones, photosensitivity or phototoxicity to fibrates or ketoprofen, and pregnancy and breastfeeding. Gemfibrozil is contraindicated with statins and repaglinide.

Adverse effects. Gastrointestinal upset, rash, raised creatinine (reversible), liver enzyme rise, gallstones, myopathy (higher with statins, mainly gemfibrozil), pancreatitis, and venous thromboembolism.

Interactions. Fibrates potentiate warfarin (reduce the warfarin dose by about 30% and recheck INR). Gemfibrozil raises statin exposure markedly. Ciclosporin and fibrates raise creatinine and nephrotoxicity. Fibrates increase sulphonylurea effect.

Monitoring. Lipid profile, liver function and creatinine at baseline, 3 months, then every 6 to 12 months. Creatine kinase if muscle symptoms. INR with warfarin.

Referral and escalation. Triglycerides over 20 mmol/L, recurrent pancreatitis, or abdominal pain with high triglycerides needs urgent assessment.

Special groups. Kidney disease: reduce fenofibrate to 48 to 67 mg daily if eGFR is 30 to 59, and avoid under 30. Older adults: renal dosing. Pregnancy: avoid; severe hypertriglyceridaemia in pregnancy needs specialist care.