Fibric Acid Antilipemic Agents

Mechanism of Action

Fibric acids are peroxisome proliferator-activated receptor alpha (PPAR-alpha) agonists. Fibric acids act as ligands that bind to PPAR-alpha. PPAR-alpha is a ligand-activated transcriptional factor belonging to the nuclear receptor family. Once activated, PPAR-alpha is responsible for several biological functions, including fatty acid beta-oxidation and lipid metabolism. By binding to PPAR-alpha, fibric acids reduce blood cholesterol by increasing fatty acid oxidation, eliminating triglyceride-rich particles, and the catabolism of very low-density lipoproteins (VLDL). The decrease in VLDL can cause plasma triglyceride levels to decrease by 30% to 60%. Additionally, fibric acids have been shown to work at the vascular wall in an anti-inflammatory and anti-thrombotic capacity. Fibric acids have pleiotropic effects that reduce atherosclerotic plaque formation, thereby decreasing the incidence of cardiovascular complications, including coronary heart disease.[19]

Pharmacokinetics

Absorption: Gemfibrozil is rapidly and nearly completely absorbed after oral administration, with peak plasma concentrations achieved within 1 to 2 hours. Food enhances absorption, and administration 30 minutes before meals is recommended. Fenofibrate is a prodrug with variable absorption depending on formulation; micronized and nanocrystal forms exhibit improved bioavailability. Food increases absorption for most fenofibrate formulations, necessitating administration with meals. Fenofibric acid, the active metabolite of fenofibrate, can also be administered directly; food intake does not significantly influence its absorption.

Distribution: Gemfibrozil is approximately 95% bound to plasma proteins, primarily albumin. Fenofibrate and fenofibric acid exhibit high protein binding (>99%), predominantly to albumin. The fenofibrate distribution volume is approximately 0.89 L/kg, indicating limited extravascular distribution.

Metabolism: Gemfibrozil undergoes extensive hepatic metabolism via oxidation and inhibits cytochrome P450 2C8, increasing the risk of drug interactions.[20][21] Fenofibrate is a prodrug. Esterases hydrolyze fenofibrate to fenofibric acid, which is subsequently metabolized by glucuronidation.[22] Fibric acid and its derivatives are metabolized primarily via glucuronidation and have minimal impact on cytochrome P450 activity.

Excretion: Gemfibrozil and its metabolites are excreted primarily in the urine, accounting for approximately 70% of the administered dose. The elimination half-life is approximately 1.5 hours. Fenofibric acid is mainly eliminated via renal excretion in both free and conjugated forms; the elimination half-life is approximately 20 hours.

Administration

Available Dosage Forms and Strengths

There are 3 agents of choice in the fibric acid drug class: fenofibric acid, fenofibrate, and gemfibrozil. All of these agents are administered orally as either tablets or capsules. Fenofibric acid and fenofibrate are marketed under several trade names and are available in various strengths. Regarding the difference, fenofibrate is the choline salt of fenofibric acid. Fenofibric acid is more hydrophilic and has better bioavailability than its choline salt counterpart.[22]

Fenofibrate and fenofibric acid are each dosed once daily without regard to meals. Fenobiric acid is available in 35 and 105 mg doses as an immediate-release tablet. The delayed-release capsule is available in 45 and 135 mg formulations. Fenofibrate is available as oral tablets and capsules in various strengths. Tablet strengths include 40, 48, 54, 120, 145, and 160 mg.

Capsule formulations are available in 50 and 150 mg strengths. The formulations differ in particle size—micronized, nonmicronized, or nanoparticle—which affects their bioavailability and food requirements. Some formulations, such as Tricor tablets, can be taken without regard to meals, while others, like Lipofen capsules, must be taken with food. These products are not interchangeable, and prescribing should be formulation-specific to ensure therapeutic consistency.

Dosage

Gemfibrozil: The recommended adult dose is 1200 mg administered as 2 divided doses, 30 minutes before morning and evening meals. Worsening renal insufficiency is an issue upon adding gemfibrozil therapy in patients with a baseline serum creatinine of 2.0 mg/dl. This is contraindicated if there is severe renal impairment. Worsening renal insufficiency is an issue upon adding gemfibrozil therapy in patients with a baseline serum creatinine of 2.0 mg/dL.

Fenofibrate

The initial dose for hypercholesterolemia or mixed dyslipidemia is 145 mg once daily. For severe hypertriglyceridemia, the starting dose is 48 to 145 mg once daily. Doses should be individualized based on patient response and adjusted as necessary following lipid measurements at 4- to 8-week intervals. For mild to moderate renal impairment, the dose should be initiated at 48 mg and increased only after evaluating the effects on renal function and lipid levels. This is contraindicated if there is severe renal impairment.

Fenofibric Acid

This should be coadministered with statins for treating mixed dyslipidemia at 135 mg once daily. For severe hypertriglyceridemia, the initial dose is 45 to 135 mg once daily. For primary hyperlipidemia or mixed dyslipidemia, the dose is 135 mg once daily, and for mild to moderate renal impairment, the dose should be initiated at 45 mg and increased only after evaluating the effects on renal function and lipid levels. This is also contraindicated if there is severe renal impairment.

Specific Patient Populations

Hepatic impairment: The use of fibrates in active liver disease is contraindicated.

Renal impairment: Please see above.

Pregnancy considerations: According to the American Heart Association, the 2 most common conditions in which dyslipidemia should be addressed during pregnancy are severe hypertriglyceridemia and familial hypercholesterolemia; however, treatment is restricted because of fetal risks. Pregnancy-related complications like preeclampsia and gestational diabetes mellitus are associated with triglyceride levels over 250 mg/dL. Patients with high triglyceride levels (>500 mg/dL) are at risk for pancreatitis and may benefit from pharmacological treatment with omega-3 fatty acids with fenofibrate/gemfibrozil during the second trimester. The risk of premature atherosclerosis is elevated in patients with familial hypercholesterolemia. During pregnancy, this risk may be further exacerbated by elevated atherogenic lipoproteins when the patient is not on statin therapy.[23]

Breastfeeding considerations: No relevant published information exists on using fibrates during breastfeeding. Due to concerns about disrupting infant lipid metabolism, fenofibrate is generally avoided during breastfeeding. An alternate medication is preferred, especially while nursing a newborn or preterm infant. The manufacturer recommends avoiding breastfeeding during fibrate treatment and for 5 days after the final dose.[24][25]

Pediatric patients: There is a lack of significant safety and efficacy data for fibric acid derivatives in pediatric populations.[26] Fibrates are not FDA-approved for use in pediatric populations. Still, they may be used off-label to manage severe hypertriglyceridemia in children and adolescents, particularly to reduce the risk of pancreatitis. Although their effects on low-density lipoprotein cholesterol vary, fibrates can reduce triglyceride levels by 40% to 60%, depending on baseline concentrations.

Adverse effects are similar to those observed with statins. Given the limited pediatric safety and dosing data, fibrates and niacin should be used under the supervision of a lipid specialist.[27] There is a lack of safety and efficacy data in the pediatric population, and fenofibric acids are not recommended for use in pediatric patients with lipid disorders.[26] 

Older patients: Use a statin-fibrate combination with caution in older adults, as there is an increased risk of myopathy in patients aged 70 years or older.[28] Adjust the dosage of individual fibrates based on renal function.

Adverse Effects

The adverse effects of fibric acids vary depending on the particular agent selected for the patient. Some of the most common include headache, dizziness, back pain, diarrhea, dyspepsia, nasopharyngitis, sinusitis, and abnormal liver function tests.[29][30] Comparatively, gemfibrozil is associated with a significant percentage of gastrointestinal reactions (34.2%), including dyspepsia, abdominal pain, and acute appendicitis. Fenofibrate may be a more suitable agent in patients with a past medical history significant for gastrointestinal diseases. However, fenofibrate is associated with a statistically significant increase in liver transaminases (7.5%), which requires monitoring in patients initiating therapy.

Gemfibrozil

• Gastrointestinal reactions (34.2%)
• Dyspepsia (19.6%)
  • Abdominal pain (9.8%)
  • Acute appendicitis (1.2%)
• Atrial fibrillation (0.7%)

Adverse events reported without statistical significance vs placebo:

• Diarrhea (7.2%)
• Fatigue (3.8%)
• Nausea/vomiting (2.5%)
• Eczema (1.9%)
• Rash (1.7%)
• Vertigo (1.5%)
• Constipation (1.4%)
• Headache (1.2%)

Fenofibrate

• Body, overall
• Abdominal pain (4.6%)
• Back pain (3.4%)
• Headache (3.2%)
• Digestive
• Nausea (2.3%)
• Constipation (2.1%)
• Metabolic and Nutritional Disorders
• Abnormal liver function tests (7.5%)
• Increased alanine aminotransferase, ALT (3.0%)
• Increased creatine phosphokinase (3.0%)
• Increased aspartate aminotransferase, AST (3.4%)
• Respiratory
• Respiratory disorder (6.2%)
• Rhinitis (2.3%)

Fenofibric acid

• Gastrointestinal disorders
  • Constipation (3.3%)
  • Diarrhea (3.9%)
  • Dyspepsia (3.7%)
  • Nausea (4.3%)
• General disorders and administration site conditions
  • Fatigue (2.0%)
  • Pain (3.5%)
• Investigations
  • ALT increased (1.2%)
• Musculoskeletal and connective tissue disorders
  • Arthralgia (3.9%)
  • Back pain (6.3%)
  • Muscle spasms (1.6%)
  • Myalgia (3.3%)
  • Pain in extremity (4.5%)
• Infections and infestations
  • Nasopharyngitis (3.5%)
  • Sinusitis (3.3%)
  • Upper respiratory tract infection (5.3%)
• Nervous system disorders
  • Dizziness (4.1%)
  • Headache (12.7%)

Drug-Drug Interactions

• Statins: Rhabdomyolysis and myopathy have been reported when fibric acids are administered in combination with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or colchicine, and patients with hypothyroidism, diabetes mellitus, or renal failure. The only fibric acid with FDA approval for use in combination with an HMG-CoA reductase inhibitor (statin) is fenofibric acid.[31]
• Bile acid sequestrants: The concomitant administration of bile acid sequestrants (colestipol) with gemfibrozil reduces the absorption of gemfibrozil. No change in absorption was noticed when gemfibrozil was administered 2 hours before or after colestipol.
• Colchicine: Myopathy, including rhabdomyolysis, may occur with chronic colchicine use. Gemfibrozil can increase this risk, particularly in older patients with renal impairment. Caution is advised when prescribing gemfibrozil with colchicine for these patients.
• CYP2C8 inhibitors: CYP2C8 metabolizes amodiaquine and daprodustat; coadministration with CYP2C8 inhibitors such as gemfibrozil is not recommended.[32][33] Dasabuvir has an increased risk of corrected QT interval prolongation associated with increased exposure, particularly when used concomitantly with gemfibrozil.[34] Concurrent administration of CYP2C8 inhibitors such as gemfibrozil with repaglinide or selexipag should be avoided.[35][36]
• Organic anion-transporting polypeptide 1B1 inhibitors: Elagolix is an oral gonadotropin-releasing hormone receptor antagonist; the use of elagolix is contraindicated with potent organic anion-transporting polypeptide 1B1 (OATP1B1) inhibitors, such as gemfibrozil.[37] Elbasvir/Grazoprevir use is contraindicated with gemfibrozil. Gemfibrozil may significantly increase Grazoprevir levels by inhibiting OATP1B1 and OATP1B3, thereby increasing the risk of hepatotoxicity.[38]
• Oral anticoagulants: Caution is necessary when using anticoagulants with fibrates due to the risk of increased prothrombin time/international normalized ratio (PT/INR). The anticoagulant dosage should be adjusted to maintain the PT/INR within the desired range, thereby preventing bleeding complications.

Contraindications

Contraindications for using fibric acids include a history of hypersensitivity to the drugs in the class, patients with active liver disease, severe renal dysfunction, and preexisting gallbladder disease. In addition, they are contraindicated in primary biliary cirrhosis. Also, gemfibrozil is contraindicated with simvastatin, repaglinide, dasabuvir, and selexipag. Fibric acids are excreted in breast milk and may interfere with infant lipid metabolism. Therefore, fibrates are contraindicated in women who are breastfeeding. Fibric acids are excreted in breast milk and may interfere with infant lipid metabolism; fibrates are contraindicated in breastfeeding women.[24][25]

Warnings and Precautions

• Hepatotoxicity: Hepatotoxicity has been associated with fibrates. Documented hepatic effects include elevations in serum transaminases such as AST and ALT. Reports of hepatocellular injury, active hepatitis, and cholestatic hepatitis have been observed. In rare instances, cirrhosis has been reported in the context of chronic active hepatitis. Liver function tests should be monitored periodically during fibrate therapy, and treatment should be discontinued if transaminase levels persist at more than three times the upper limit of normal.[29][30]
• Pregnancy: As a class, fibric acid derivatives are classified as pregnancy category C. There is a documented case of a 30-year-old woman who received fenofibrate for the treatment of hypertriglyceridemia. The patient was on fenofibrate therapy for 1 year. Afterward, it was discovered during a gynecologic visit that this patient had an unplanned pregnancy at 8 weeks of gestation, and abruptly, fenofibrate therapy was discontinued. Notably, the patient delivered a healthy male infant without congenital malformation.[39] However, fibric acids should only be considered in pregnancy if the benefit outweighs the risk of potential toxicity to the fetus.
• Cholelithiasis: Cholelithiasis may occur with fenofibrate and gemfibrozil due to increased cholesterol excretion into bile. If cholelithiasis is clinically suspected, diagnostic evaluation of the gallbladder is warranted. The discovery of gallstones should prompt the discontinuation of fibrate therapy.
• Myopathy: Myopathy, including myositis and rhabdomyolysis, has been rarely reported with monotherapy using fibrates.[40] Patients presenting with muscle pain, tenderness, or weakness should be evaluated promptly, including assessment of serum creatine kinase levels. If a diagnosis of myopathy or myositis is made or strongly suspected, fibrate therapy should be discontinued immediately.
• Hypersensitivity reactions: Hypersensitivity reactions to fibrates have included dermatologic adverse drug reactions, some of which have required hospitalization.[41] According to product labeling, rare but severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

Monitoring

Patients who start fibric acid therapy require close monitoring for adverse effects. Fibric acid derivatives should only be a therapy consideration in patients receiving treatment with low or moderate-intensity statin therapy if the benefits from reducing the risks of atherosclerotic cardiovascular disease or the benefits of lowering triglyceride levels are higher than 500 mg/dL and outweigh the potential risks of adverse effects. Monitoring parameters include a lipid profile, blood counts, serum creatine phosphokinase levels (particularly if the patient has a history of muscular issues on a statin), and liver function tests.

The treatment should cease if there is no adequate response within 2 to 3 months of initiating fibric acid therapy.[42] If there is suspicion of pancreatitis, serum lipase should be obtained. Pregnancy testing is necessary for women of childbearing age. If cholelithiasis is suspected, ultrasound, computed tomography scans, and magnetic resonance cholangiopancreatography can be used for diagnosis. Before any major surgery, the Revised Cardiac Risk Index should be obtained.[43] The need to monitor the International Normalized Ratio when administering fibric acid agents to patients on long-term warfarin therapy remains unclear.[44]

Toxicity

Signs and Symptoms of Overdose

Signs and symptoms of overdose may include abdominal pain, diarrhea, joint and muscle pain, nausea, and vomiting. Laboratory investigations may reveal increased creatine phosphokinase and abnormal liver function tests.

Managing Overdose

Fibric acids are highly protein-bound, which rules out the use of hemodialysis. Managing an overdose of fibric acids is primarily symptomatic. Gastric lavage may be used in cases of overdose, provided the usual precautions for airway maintenance are in place.[45] If rhabdomyolysis is suspected during fibrate therapy, the medication should be discontinued immediately. Supportive care includes aggressive intravenous resuscitation with isotonic saline to preserve renal function and promote myoglobin clearance. Nephrology consultation is required for oliguric renal failure or rising azotemia. Urinary alkalinization with sodium bicarbonate remains a valuable treatment option in severe metabolic acidosis and hyperkalemia cases.[46]

Enhancing Healthcare Team Outcomes

Managing dyslipidemia requires input and interprofessional communication from all healthcare team members, including physicians, nurses, pharmacists, and other healthcare professionals. Without question, clinicians and pharmacists need to be current on the guidelines detailing the management of blood cholesterol. Cholesterol is one of the primary risk factors for cardiovascular disease—one of the costliest disease states to manage. The Centers for Disease Control and Prevention estimated in 2010 that $444 billion, or approximately $1 out of every $6 spent on healthcare, can be attributed to cardiovascular disease.[47] 

Clinicians need to manage dyslipidemia in the outpatient setting to prevent hospitalization due to cardiovascular disease. The pharmacist's role is to verify orders for lipid-lowering agents and contact prescribers if a medication-related error is detected. For instance, many commercially available lipid-lowering agents exist, including HMG-CoA reductase inhibitors, niacin, bile acid sequestrants, and fibric acids. Suppose the pharmacist receives an order and identifies a more suitable agent for the patient than the one prescribed. In that case, it is the pharmacist's responsibility to contact the prescriber and relay that information. 

The cardiologist assesses cardiovascular risk and determines whether triglyceride lowering with fibric acid derivatives provides added benefit beyond statins. The lipidologist evaluates complex cases of dyslipidemia and guides therapy for severe hypertriglyceridemia or mixed disorders. The endocrinologist treats patients with diabetes or metabolic syndrome who are at higher risk for dyslipidemia and pancreatitis, often coordinating fibrate use when glycemic and lipid goals are unmet. Advanced practice clinicians play a crucial role in prescribing and monitoring adherence to therapy. In the hospital setting, nurses have several responsibilities, including patient monitoring. For that reason, nurses need to have a basic understanding of the adverse effect profiles of commonly used lipid-lowering agents. Nurses play a frontline role in identifying adverse drug reactions and managing associated symptomatology in patients.

Additionally, adverse events should be reported to the medical team, including physicians, nurse practitioners, physician associates, and pharmacists, to initiate appropriate action. All healthcare team members play a crucial role in optimizing drug therapy for patients, and the common denominator in the ideal scenario is effective interprofessional communication. By doing so, healthcare professionals can manage a patient's blood cholesterol in the outpatient setting, prevent unnecessary hospitalizations, and save the healthcare system billions of dollars in costs. An interprofessional team approach and effective communication among clinicians, specialists, pharmacists, and nurses are crucial for decreasing potential adverse effects and improving patient outcomes related to fibric acid antilipemic agents.