Fibrates

Introduction

Fibrates are among the earliest cholesterol drugs evaluated in cardiovascular outcomes trials. Clofibrate was tested in the Coronary Drug Project and the World Health Organization (WHO) study. Clofibrate-treated patients had higher total mortality, did not experience a reduction in coronary artery disease (CAD) events and had an excess of adverse events and non-cardiovascular deaths, including cancer, thromboembolism, gallstones, pancreatitis, angina, claudication and arrhythmias. Clofibrate is no longer marketed in the United States.

Gemfibrozil was subsequently shown to reduce cardiovascular events in selected populations of men, with a reasonable safety profile. Gemfibrozil is available as a generic.

Fenofibrate has been shown to reduce cardiovascular events in primary prevention diabetic patients and also has a reasonable safety profile. However, fenofibrate did not reduce cardiovascular events when added to a statin in well-controlled diabetic patients, Fenofibrate is available as a generic.

Fenofibric acid is the pharmacologically active metabolite of fenofibrate and has similar efficacy and safety. It has not been evaluated in a randomized cardiovascular outcomes trial. It is available as a generic.

Bezafibrate is not approved for use in the United States. It has been shown to reduce cardiovascular events in primarily men with CAD who had triglycerides ≥200 mg/dL.

In the absence of randomized trial data showing a clear cardiovascular risk reduction benefit when added to a statin, and only modest reductions in cardiovascular events when used as monotherapy, fibrates have been relegated to a minor role in the statin era. The 2018 multi-society cholesterol guideline does not recommend the routine use of fibrates for atherosclerotic cardiovascular disease (ASCVD) risk reduction as it does not consider them effective low-density lipoprotein cholesterol (LDL-C)-lowering drugs, although they can be considered for selected patients with severe hypertriglyceridemia >500 mg/dL (to prevent acute pancreatitis).

Appropriate Uses

Triglyceride Lowering

The Food and Drug Administration (FDA) has approved fenofibrate and fenofibric acid for adults as an adjunct to diet to 1) treat patients with severe hypertriglyceridemia, and 2) reduce elevated LDL-C, total cholesterol, triglycerides and apoB and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia. The FDA has not approved fenofibrate for cardiovascular risk reduction.

The FDA has approved gemfibrozil for the treatment of adults with: 1) very high triglyceride levels (typically >2,000 mg/dL; Type IV and V hyperlipidemia) who have pancreatitis and are unresponsive to diet. Patients with triglycerides <1,000 mg/dL are at low risk for pancreatitis. Gemfibrozil may be considered in patients with triglycerides 1,000-2,000 mg/dL and a history of pancreatitis or recurrent abdominal pain suggestive of pancreatitis, and for reducing the risk of coronary artery disease (CAD) only in patients with Type IIb hyperlipidemia (e.g., familial combined hyperlipidemia) who have had an inadequate response to lifestyle modification and other lipid-modifying drugs. Due to concerns about toxicity, unclear benefit and increased non-cardiovascular mortality observed with clofibrate, the FDA cautions against the use of gemfibrozil in Type IIA patients or patients with isolated low HDL-C.

The 2018 multi-society cholesterol guideline does not recommend the routine use of fibrates for ASCVD risk reduction. Fibrates have been tested in only a few, limited study populations. Gemfibrozil and fenofibrate used as monotherapy have been shown to reduce cardiovascular events, and in the era of greater availability of more efficacious nonstatins, are rarely appropriate.

Pancreatitis Prevention

The 2018 multi-society guideline states that initiating fibrate therapy, if necessary to prevent acute pancreatitis, is reasonable (Class of Recommendation [COR] IIb) in patients with fasting triglycerides ≥500 mg/dL, and especially fasting triglycerides ≥1,000 mg/dL and if triglycerides are persistently elevated or increasing. The 2021 American College of Cardiology and American Heart Association (ACC/AHA) Expert Consensus Decision Pathway on hypertriglyceridemia agrees with this recommendation. No randomized trials are available to support this use.

ASCVD Prevention

Gemfibrozil has been shown to reduce CAD events in primary prevention among men with severe hypercholesterolemia (Helsinki Heart Study) and CAD and stroke in secondary prevention among men with CAD, low LDL-C, low HDL-C and high triglycerides (VA-HIT). Gemfibrozil does not lower LDL-C. The risk reduction with gemfibrozil is independent of triglyceride changes and has been largely attributable to the use of gemfibrozil itself.

Gemfibrozil and fenofibrate used as monotherapy have been shown to reduce cardiovascular events, and so may be appropriate for some patients who cannot tolerate any statin. Gemfibrozil is contraindicated in statin-treated patients due to the excessive risk of serious muscle adverse effects.

Fenofibrate monotherapy modestly reduces cardiovascular risk to the degree expected from the magnitude of its modest LDL-C and non–HDL-C changes. Fenofibrate does not appear to reduce cardiovascular events when added to background statin therapy in the large majority of well-treated diabetic patients. In the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, fenofibrate added to moderate dose simvastatin therapy did not result in additional cardiovascular risk reduction. Subgroup analysis did suggest a trend toward benefit in the 17% of patients with elevated triglycerides and low HDL-C levels. This may have been related more to the reduction in non–HDL-C than to HDL-C or triglyceride changes. However, this finding was counterbalanced by a significantly greater harm in women.

In contrast, high-intensity statin therapy reduces cardiovascular risk compared to moderate-dose statin therapy across all subgroups of patients, and is the preferred therapy for ASCVD prevention.

Clinical Highlight I

• Triglycerides >500 mg/dL after lifestyle modification and treating secondary causes
  • Consider fibrate therapy to prevent acute pancreatitis in select patients (especially if fasting triglycerides are ≥1000 mg/dL); if the patient is taking a statin, fenofibrate is preferred to gemfibrozil.

Mechanism of Action

Fibrates are nuclear peroxisome proliferator-activated (PPAR) receptor-α agonists. They upregulate the gene for lipoprotein lipase and downregulate the gene for apolipoprotein C-III, an inhibitor of lipoprotein lipase. Lipoprotein lipase increases triglyceride hydrolysis (which decreases VLDL-C secretion) and increases catabolism of triglyceride-rich particles (Figure 27-1). Fibrates modestly raise HDL-C by lowering triglycerides and by increasing synthesis of apolipoproteins A-I and A-II. Fibrates variably influence LDL-C levels depending on the type of dyslipidemia and which fibrate is used.

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Metabolism

Gemfibrozil

Gemfibrozil undergoes glucuronidation in the liver and is 70% renally excreted. Gemfibrozil potently inhibits glucuronidation of other drugs, including all statins and concomitant use should be avoided.

Fenofibrate and Fenofibric Acid

Fenofibrate and fenofibric acid are also metabolized via glucuronidation and primarily excreted by the kidney. However, fenofibrate and fenofibric acid, its active metabolite, are much less potent inhibitors of glucuronidation than gemfibrozil and have little effect on statin levels.

Dosing

The usual dose of gemfibrozil is 600 mg twice a day, taken 30 minutes before the morning and evening meals.

The usual dose of fenofibrate or fenofibric acid is 145 mg daily. Generic formulations may come in doses of up to 200 mg daily that are considered to have equivalent efficacy.

Renal

Adjust the dose of fenofibrate and fenofibric acid to one third the usual dose for patients with mild to moderate renal impairment. Do not use any fibrate if renal function is severely impaired.

Efficacy

Lipid effects may vary substantially depending on the type and severity of the dyslipidemia present. As monotherapy, fenofibrate is slightly more effective than gemfibrozil for lowering LDL-C (11% vs 1%, respectively) and non–HDL-C (18% vs 13%), although all fibrates may increase LDL-C levels in hypertriglyceridemic patients. Both drugs lower triglycerides by up to 50%, with greater efficacy in severe hypertriglyceridemia. Effects on LDL-C are variable, depending on triglyceride (LDL-C increases with triglycerides >1000 mg/dL) and LDL-C levels themselves (decreases when LDL-C >160 mg/dL) (Table 27-1).

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Cardiovascular Outcomes Trials

Fibrate cardiovascular outcomes trials are summarized in Table 27-2.

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ACCORD

In patients with well-controlled diabetes with or without cardiovascular (CV) disease, fenofibrate did not further reduce CV events when added to background moderate-intensity statin therapy in the ACCORD trial (Figure 27-2). Mean achieved LDL-C was approximately 80 mg/dL at year 3 in both treatment groups (Figure 27-3). HDL-C increased by about 1 mg/dL at year 1, and triglycerides were reduced by about 17% at year 3 in the fenofibrate group. A trend toward a cardiovascular event reduction benefit was observed in the subgroup of patients with HDL-C <34 mg/dL and triglycerides ≥204 mg/dL (P=.06). However, there was evidence of significant harm in women (P=.01).

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FIELD

Fenofibrate monotherapy reduced cardiovascular events and reduced progression of albuminuria and retinopathy in diabetic patients in the FIELD trial. However, the cardiovascular risk reduction was observed only in the subset of primary prevention patients (Figure 27-4). This was likely due to the greater crossover to statin therapy in patients with previous cardiovascular disease. A slight excess of pancreatitis and pulmonary embolism was observed in the fenofibrate group.

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VA-HIT

In the VA-HIT trial, men with CAD, LDL-C ≤140 mg/dL, HDL-C ≤40 mg/dL and elevated triglycerides had a 24% reduction in coronary death and nonfatal MI, and a 31% reduction in stroke with gemfibrozil monotherapy vs placebo (Figure 27-5). LDL-C did not differ between the two treatment groups (Figure 27-6). HDL-C was only modestly increased to 34 mg/dL with gemfibrozil (vs 32 mg/dL in the placebo group) and triglycerides were reduced by 31% with gemfibrozil (111 mg/dL vs 166 mg/dL with placebo). The majority of the cardiovascular risk reduction benefit was attributable to the treatment with gemfibrozil rather than to specific lipid changes.

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Helsinki Heart Study

In the primary prevention Helsinki Heart Study, gemfibrozil monotherapy reduced CAD events by 37% in men 40-55 years of age without CAD or heart failure and non-HDL-C ≥200 mg/dL. Gemfibrozil reduced LDL-C by 10% and triglycerides by 43%, and increased HDL-C by 10%. The gemfibrozil group had increased rates of skin cancer, gastrointestinal surgery and severe upper gastrointestinal symptoms, especially in the first year. There was no difference in the incidence of diarrhea, constipation, nausea, or vomiting. Total mortality was not reported.

Contraindications

Gemfibrozil

• Hepatic dysfunction, including primary biliary cirrhosis
• Severe renal dysfunction
• Gallbladder disease
• Hypersensitivity to gemfibrozil
• Combination of gemfibrozil with simvastatin
• Combination of gemfibrozil with repaglinide
• Combination of gemfibrozil with dasabuvir
• Combination of gemfibrozil with selexipag
• Nursing mothers.

Fenofibrate and Fenofibric Acid

• Severe renal dysfunction, including hemodialysis
• Active liver disease
• Gallbladder disease
• Nursing mothers
• Known hypersensitivity to fenofibrate or fenofibric acid.

Safety

There is evidence of fetal toxicity in animal studies. Fibrates should not be used in nursing mothers.

Fibrates increase the risk of myopathy, abnormal transaminase levels and creatinine elevations. Fenofibrate has been more extensively evaluated in long-term trials than fenofibric acid, its active metabolite. Fenofibrate’s adverse effect profile should be extended to fenofibric acid.

Muscle

Fenofibrate monotherapy increases the risk of myopathy 5-fold over statins alone. The risk for gemfibrozil monotherapy is 2-fold higher than for fenofibrate.

When used with a statin, gemfibrozil has a 33-fold higher risk of myopathy than fenofibrate, in part due to greater inhibition of glucuronidation. Gemfibrozil increases blood levels of all statins, with a lesser impact on fluvastatin. Fenofibrate appears to have little impact on statin blood levels, and is the drug of choice for combination with low to moderate-intensity statins. Fenofibrate has not been evaluated with the highest doses of statins. Although fenofibrate-statin combinations have acceptable muscle safety, it should be noted that their value has not yet been demonstrated in clinical outcomes trials.

In patients at increased risk for myopathy, the potential benefits of fibrates should be carefully weighed against their risks, especially in combination with a statin. Myopathy risk characteristics include advancing age, female sex, renal or hepatic dysfunction, hypothyroidism, debilitation, surgery, trauma, excessive alcohol intake, or heavy exercise. Extensive patient education and regular creatine kinase monitoring should be considered in such cases. For severely hypertriglyceridemic patients for whom the safety of fibrates is a concern, high doses of marine omega-3 fatty acids (>3 g) should be strongly considered.

Renal

Rises in creatinine levels can occur in patients taking fenofibrate, although the clinical significance of this is unclear. Fenofibrate often improves proteinuria with long-term use, and no cases of renal failure have been reported. However, the dose of fenofibrate should be reduced if creatinine rises above the normal range, and the patient should be carefully monitored for adverse effects. Fenofibrate dose should be reduced to one third the regular dosage in patients with glomerular filtration rates <60 mL/min/1.73 m², and fenofibrate completely avoided when it is <15 mL/min/1.73 m². Fenofibrate is nondialyzable and must be avoided in dialysis and used with caution in renal transplant patients. A reduced dose of gemfibrozil can be used in these patients, as can high doses of omega-3 fatty acids.

Gemfibrozil also has significant renal excretion, and concomitant use with statins with renal clearance should be avoided.

Elderly

The maximum dose of fenofibrate or fenofibric acid for elderly patients should be determined based on renal function.

Liver

Although gemfibrozil more frequently increases hepatic transaminase levels than fenofibrate, the rates of hepatic and total adverse events are lower for gemfibrozil than fenofibrate. Both fibrates are contraindicated in the setting of severe liver disease.

Gallbladder Disease

Fibrates increase cholesterol excretion in the bile and may increase the risk of cholelithiasis. Fibrates should be avoided in patients with active gallbladder disease.

Thromboembolism

Increased risk of deep vein thrombosis and pulmonary embolism has been observed in some fibrate trials, but no increase was observed when fenofibrate was added to simvastatin in the ACCORD trial.

Coronary Mortality

Unlike the earlier FIELD trial of fenofibrate monotherapy, no increase in coronary mortality was noted in ACCORD.

Other Adverse Effects

Gemfibrozil—mild decreases in hemoglobin, hematocrit and white blood cell count.

Drug-Drug Interactions

Statins

Fibrates can raise the blood levels of statins by inhibiting their glucuronidation. Gemfibrozil should not be used concomitantly with a statin. Fenofibrate has little effect on statin levels.

Warfarin

Fibrates may substantially increase prothrombin time and international normalized ratios in patients receiving warfarin. INR should be closely monitored after starting a fibrate. Warfarin dose may need to be decreased by 25-35%.

Bile Acid Binding Resins

Fibrates may be bound by bile acid binding resins and should be administered at least one hour before or 4-6 hours after resin administration.

Immunosuppressants

Cyclosporine and tacrolimus can cause nephrotoxicity and decreased creatinine clearance. This may raise fibrate levels due to impaired renal excretion.

Colchicine

Rhabdomyolysis has been reported with concomitant use of fenofibrate and colchicine.