Fibrates

Fibrates (bezafibrate, ciprofibrate, fenofibrate and gemfibrozil) are lipid lowering drugs. They were introduced in 1962 and were widely used before the statins arrived. Please also refer to the related article on hyperlipidaemia.

Fibrates work by lowering elevated levels of cholesterol (raising HDL cholesterol, lowering LDL and VLDL cholesterol levels) and reducing triglycerides. Recent studies have shown that the triglyceride-lowering effect occurs due to stimulation of lipoprotein lipase-mediated lipolysis and suppression of apoprotein C-III production. The HDL-increasing effect is a result of stimulation of the synthesis of apoprotein A-I and apoprotein A-II.^1,2 (The apoproteins are lipid-binding proteins, lipoprotein A being found in HDL cholesterol).

Fibrates are not first line treatment in primary or secondary prevention of cardiovascular disease, statins should be used first. They are mainly used:

• To reduce elevated triglyceride levels¹
• In patients who cannot tolerate statins
• In patients with mixed hyperlipidaemias with very high triglyceride levels or low HDL-Cholesterol levels. Fibrates are first-line treatment if triglyceride levels are > 10 mmol/litre.
• In a patient with type 2 diabetes who has had 6-months of treatment with a statin and who also has optimal glycaemic control, consider adding a fibrate to the statin if triglyceride levels remain > 2.3 mmol/litre.

• Pregnancy or breast feeding.
• Severe renal insufficiency. Dose adjustment may be needed in mild/moderate renal impairment.
• Gallbladder disease (some fibrates).
• Patients known to have photoallergic or phototoxic reactions or hypersensitivity to fibrates.
• Nephrotic syndrome (presumably due to the increased risk of rhabdomyolysis with concomitant use of fibrates in renal disease).
• Significant hepatic disease (other than fatty infiltration of the liver associated with raised triglyceride levels).
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption should not take ciprofibrate and fenofibrate should be used with caution.
• Chronic or acute pancreatitis, with the exception of acute pancreatitis due to severe hypertriglyceridaemia (fenofibrate).
• Hypothyroidism should be corrected before fibrate treatment is started as hypothyroidism may increase the risk of rhabdomyolysis.

• Fibrates are generally well tolerated - only 5% get GI upset.
• Muscle toxicity: Fibrates should be used with caution in existing muscle disorders. As with statins there is a risk of myositis, especially if there is co-existing impaired renal function. The Committee on Safety of Medicines advises that concomitant treatment with a fibrate and a statin may be associated with an increased risk of serious muscle toxicity. Some fibrates (not gemfibrozil) can be given with statins - but only on specialist advice if statin monotherapy is insufficient.⁶ The efficacy and safety of using a statin and a fibrate together is currently being investigated in the ACCORD trial which is due to report in 2010.⁷

• Which fibrate: Gemfibrozil has the added advantage of also being licensed for primary prevention of CHD in men aged 40-55 (but statins should still be the first line treatment).⁸ However, fenofibrate and bezafibrate have the most evidence from randomised controlled trials to support their use.^9,10
• The starting dose of fibrates is generally also the maintenance dose.
• Warn the patient to report any muscle pains. Stop the drug and check creatine kinase levels. Refer to Summary of Product Characteristics to see at what creatine kinase level the drug should be discontinued.
• Warn the patient to report any pain which could be related to gallbladder disease. The fibrates can cause cholelithiasis.
• Check lipids, renal and liver function before starting treatment and at 3 months. Withdraw if creatinine rises progressively, or if abnormal liver enzymes persist.
• Consider specialist referral if there is any renal impairment. Do not use slow-release preparations if there is any renal impairment.
• Monitor INR carefully if the patient is also on warfarin, as the dose may need reducing by up to 50%.
• Patients should not drive or use machines if they are affected by dizziness when taking fibrates.
• The fibrates may interact with oral hypoglycaemics causing possible hypoglycaemia.

Three major trials, the Helsinki Heart Study (HHS),⁸ the Bezafibrate Infarction Prevention (BIP Study) ¹ and the Veterans Affairs HDL Intervention Trial (VA-HIT) ¹¹ have shown that fibrates can raise HDL cholesterol by approximately 10-15%. They can also reduce triglycerides by 25-50%.¹²

In the HHS, gemfibrozil was shown to reduce the risk of a first coronary event by 34%. The BIP Study showed no significant reduction in fatal and non-fatal myocardial infarction or sudden death but in a subgroup of patients with higher baseline triglyceride levels, there was a significant decrease in coronary morbidity and mortality. In the VA-HIT trial, gemfibrozil treatment significantly lowered fatal and non-fatal MI as well as reducing cerebrovascular events and transient ischaemic attacks.

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study¹³ looked at the effect of fenofibrate on cardiovascular disease events in diabetic patients. Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events but it did reduce total cardiovascular events. However, the study did not allow a direct comparison between fibrates and statins. Therefore, the evidence from FIELD is not sufficient to warrant a change in the current guidelines and statins remain the first choice treatment for primary and secondary prevention of cardiovascular disease.¹⁴