Using Fibrates in Primary Care

Currently licensed fibrates in the UK are bezafibrate,¹ ciprofibrate,² fenofibrate³ and gemfibrozil.⁴

Fibrates are one of the oldest groups of drugs used to treat dyslipidaemias. Their use has lessened over the years because of unimpressive results in major clinical trials, safety concerns, and the emergence of statins.⁵ They are used only infrequently in primary care now and tend to be prescribed under advice of a specialist, particularly if used in combination with a statin.

Fibrates activate the α-subclass of peroxisome proliferator-activated receptors (PPARs). PPARs have multiple and complex effects on the control of glucose and lipid metabolism, regulation of cholesterol levels, oxidation of fatty acid and adipogenesis and may also be modulators of vascular inflammation. Potentially favourable metabolic effects include:⁶

• Increased plasma high density lipoprotein (HDL) cholesterol by 9% on average.
• Decreased very low-density lipoprotein (VLDL) cholesterol.
• Decreased total plasma cholesterol (TChol) by 8% on average.
• Decreased plasma triglyceride (TG) by approximately 30%.

Compared to statins, fibrates produce significantly greater reductions in TG levels and increases in HDL levels, but less favourable reductions of LDL and TChol levels.

The clinical effect of a fibrate in lowering TG appears to be modulated by genetic polymorphisms - for example, fibrates are more effective in individuals with certain lipoprotein lipase haplotypes.⁷

Bezafibrate, ciprofibrate, fenofibrate and gemfibrozil are licensed for the treatment of hyperlipidaemias of type IIa, IIb, III, IV and V (not ciprofibrate) where patients have not responded adequately to lifestyle measures. Gemfibrozil alone is licensed for primary CVD prevention in men with hyperlipidaemias that have not responded to other measures.

Primary and secondary prevention of cardiovascular disease

Isolated hypertriglyceridaemia

Current clinical guidelines tend to recommend them as the treatment of choice for severe isolated hypertriglyceridaemia (TG >10 mmol/l), but where this co-exists with hypercholesterolaemia (i.e. in mixed hyperlipidaemia), LDL-reduction remains the priority and thus statins tend to remain first line.⁸

Diabetic dyslipidaemia

TChol levels do not substantially vary between those with type 2 diabetes and sex and age-matched individuals without diabetes but diabetics frequently have lower HDL and higher TG levels, which are independent risk factors for coronary heart disease. The use of fibrates which can, theoretically, correct this pattern of dyslipidaemia (also seen in metabolic syndrome), has consequently been of research interest.

• There is limited evidence for macrovascular benefit: The Fenofibrate Intervention and Event Lowering in Diabetes study (FIELD)⁹ was an RCT looking at the effects of long-term fenofibrate therapy on cardiovascular events in almost a thousand people with type 2 diabetes mellitus. Fenofibrate did not significantly reduce the risk of coronary events or stroke. Some have argued that the higher proportion of placebo patients starting statins during the study, compared to the treatment group, may have masked a larger treatment benefit.
• There is some evidence of microvascular benefit: treatment with fenofibrate reduced the need for laser treatment for diabetic retinopathy in type 2 diabetics (NNT 67).¹⁰ Similarly, the rate of progression of proteinuria was slowed with fenofibrate.¹¹
• One observational study suggested that the use of bezafibrate was associated with delayed or even prevented onset of type 2 diabetes in high risk individuals and that it had a stronger antidiabetogenic effect compared to other fibrates.¹² This remains to be elucidated.

The exact role of fibrates in the treatment of diabetes and metabolic syndrome continues to be unclear. Currently, it is suggested that fibrates can be used in diabetes where:^13,14

• Statins are not tolerated or are contraindicated for primary or secondary prevention.
• In addition to statin therapy, where target lipid level is not reached (TChol <4 mmol/l or LDL <2 mmol/l) on statins alone.
• In addition to statin therapy, where the individual is at high cardiovascular risk and triglyceride is 2.3–4.5 mmol/l despite treatment with a statin and optimal glycaemic control.

Include:¹⁵
• Severe hepatic impairment (including biliary cirrhosis)
• Severe renal impairment
• Gallbladder disease
• Known photoallergy or phototoxic reaction to a fibrate
• Chronic or acute pancreatitis (except where due to severe hypertriglyceridaemia)
• Pregnancy and lactation

As with statins, myotoxicity is the most important adverse effect of this class of drugs. Risk is increased by:

• Concomitant treatment with statins
• Concomitant treatment with ciclosporin
• Renal insufficiency
• Older age
• Female sex

Include:

• Myopathy (approximately 1%) and rhabdomyolyis - rare but serious
• Gastrointestinal side-effects - more common
• Hypersensitivity reaction (urticaria, pruritus, photosensitive rash)

For individual drug side-effect profiles see specific drug monographs.

Drug choice

NICE do not recommend any particular fibrate for use in CVD prevention in those intolerant of a statin.¹⁶ Clinical Knowledge Summaries suggest the use of bezafibrate and fenofibrate, in preference to gemfibrozil (based on risk of drug interactions and expense) and ciprofibrate (based on difficulty of titration) but there is inadequate evidence to choose between them based on efficacy.¹⁵

Combination treatment⁸

Combination treatment (statin + fibrate) may be used when statin therapy alone has not reduced triglycerides (or raised HDL) to target levels.

• Robust evidence for the benefit of a combination approach is lacking and there is an increased risk of myopathy and rhabdomyolysis so the likely risk/benefit ratio needs careful consideration. Whether or not this increased risk of myotoxicity in combination with statins is a class effect is debatable.¹⁷
• Do not exceed 10 mg simvastatin and 20 mg rosuvastatin when combined with a fibrate.
• Gemfibrozil should not be used with a statin as the risk of myotoxicity is 15 times that with fenofibrate.¹⁸
• There is a theoretical risk of cholelithiasis and gallbladder diseases when ezetimibe and fenofibrate are combined.

Monitoring¹⁵

• Check U & Es prior to treatment, particularly if using in combination with a statin, as renal insufficiency increase the risk of myotoxicity. Adjust dose if evidence of renal insufficiency. Routine on-going monitoring of creatinine levels etc. is not required.¹⁹
• Discontinue the fibrate if serum aminotransferases are three or more times the upper limit of the normal.
• Check creatine kinase only if myopathy or rhabdomyolysis is suspected: stop treatment if the creatine kinase level is five times the upper limit of normal or more.

Patient information

Serious muscular side-effects are rare but seek medical advice and stop the fibrate if they develop unexplained muscle symptoms such as pain, tenderness, weakness.