Continuing Education Activity

Fibric acids are FDA indicated to treat patients with primary hypercholesterolemia or mixed dyslipidemia. In adults, they reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, and apolipoprotein B and increase high-density lipoprotein cholesterol (HDL-C). Fibric acids should be used in conjunction with restricting cholesterol and fat intake and exercise if the response to diet and nonpharmacological interventions alone has been inadequate. This activity outlines the indications, mechanism of action, significant adverse effects, contraindications, monitoring, and toxicity of fibrate drugs so that providers can direct patient therapy to optimal outcomes.

Objectives:

• Summarize the indications for using fibric acid derivatives.
• Outline the mechanism of action of fibric acid derivatives.
• Review the potential adverse events and contraindications when initiating therapy with fibric acid derivatives.
• Explain the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving a fibric acid derivative drug.

Indications

Fibric acids are FDA indicated to treat patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson types IIa and IIb). In adults, they reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, and apolipoprotein B and increase high-density lipoprotein cholesterol (HDL-C). Fibric acids should be used in conjunction with restricting cholesterol and fat intake and exercise if the response to diet and nonpharmacological interventions alone has been inadequate. The clinician should rule out secondary causes of hyperlipidemia before initiating therapy with a fibric acid. The patient should receive the drug for at least 2 to 3 months before assessing for efficacy. Fibric acid derivatives are also FDA indicated to treat adults with high serum triglycerides (Fredrickson types IV and V). Hypertriglyceridemia manifests itself in cardiovascular disease and pancreatitis.[1] 

Mechanism of Action

Fibric acids are peroxisome proliferator-activated receptors alpha (PPAR-alpha) agonists. Fibric acids act as ligands that bind to PPAR-alpha. PPAR-alpha is a ligand-activated transcriptional factor that belongs to the family of nuclear receptors. Once activated, PPAR-alpha is in charge of 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 exert their effects to reduce atherosclerotic plaque formation and, thus, decrease the incidence of cardiovascular complications, including coronary heart disease (CHD).[2] 

Administration

There are three 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 both marketed under several different trade names and are available in various strengths. Regarding the difference between the two, fenofibrate is the choline salt of fenofibric acid. Fenofibric acid is more hydrophilic and has better bioavailability than its choline salt counterpart.[3] Fenofibrate and fenofibric acid are each dosed once daily without regard to meals.

Gemfibrozil

• The recommended adult dose is 1200 mg administered as two 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.

For Severe Renal Impairment: Contraindicated

Fenofibrate

For Hypercholesterolemia or Mixed Dyslipidemia: 

• The initial dose is 145 mg once daily. 

For Severe Hypertriglyceridemia  

• The starting dose is 48 to 145 mg once daily.

• Doses should be individualized according to patient response and adjusted if necessary following lipid determinations at 4 to 8-week intervals.   

For Mild to Moderate Renal Impairment: Dose should be initiated at 48 mg and increased only after evaluating the effects on renal function and lipid levels. 

For Severe Renal Impairment: Contraindicated

Fenofibric Acid

Co-administration Therapy with Statin for the Treatment of Mixed Dyslipidemia

• The dose is 135 mg once daily, taken simultaneously as a statin.

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.

For Mild to Moderate Renal Impairment: Dose should be initiated at 45 mg and increased only after evaluating the effects on renal function and lipid levels. 

For Severe Renal Impairment: Contraindicated

Adverse Effects

The adverse effects of fibric acids vary depending on the particular agent selected for the patient. Some of the most common adverse effects include headache, dizziness, back pain, diarrhea, dyspepsia, nasopharyngitis, sinusitis, and abnormal liver function tests. Comparatively, gemfibrozil is associated with a more 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 as a Whole
• 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 ALT (3.0%)
• Increased CPK (3.0%)
• Increased 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%)

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. Fibric acids are excreted in breast milk and may interfere with infant lipid metabolism. Therefore, fibric acids are contraindicated in women who are breastfeeding. Fibric acids, as a class, are pregnancy category C. There is a documented case of a 30-year-old female who received fenofibrate for the treatment of hypertriglyceridemia. The patient was on fenofibrate therapy for one year. Afterward, it was discovered during a gynecologic visit that this patient had an unplanned pregnancy at eight weeks gestation, and abruptly, fenofibrate therapy was discontinued. It is worth noting that the patient delivered a healthy male infant without congenital malformation.[4] However, fibric acids should only be considered in pregnancy if the benefit outweighs the risk of potential toxicity to the fetus; there is a lack of safety and efficacy data in the pediatric population; fenofibric acids are not recommended for use in pediatric patients with lipid disorders.[5] 

Fibric acids may also interact with other drugs and require dose or frequency adjustments. Monitoring and/or selection of a new therapy should also be considered in such cases. Rhabdomyolysis and myopathy have been reported when fibric acids are administered in combination with 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.[6] Combination therapy of gemfibrozil with repaglinide is also contraindicated.

Monitoring

Patients who start fibric acid therapy require close monitoring for adverse effects. Fibric acids 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 outweigh the potential risks of adverse effects. Monitoring parameters include a lipid profile, blood counts, serum CPK levels (particularly if the patient has had 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.[7]

The need to monitor INR when giving fibric acid agents to patients on long-term warfarin therapy is unclear.[8]

Toxicity

Management of an overdose of fibric acids is primarily symptomatic. Signs and symptoms of overdose may include increased CPK, abnormal liver function tests, abdominal pain, diarrhea, joint and muscle pain, nausea, and vomiting. Fibric acids are highly protein-bound, which rules out the use of hemodialysis. Emesis or gastric lavage may be used in cases of fibric acid overdose so long as the usual precautions for airway maintenance are in place.[9]

Enhancing Healthcare Team Outcomes

The management of dyslipidemia requires input and interprofessional communication from the healthcare team members, including physicians, nurses, pharmacists, and other healthcare professionals. Without question, physicians and pharmacists need to be up to date on the guidelines detailing the management of blood cholesterol. Cholesterol is one of the primary risk factors for cardiovascular disease. Cardiovascular disease is one of the costliest disease states to manage. In fact, the CDC estimated in 2010 that $444 billion, or $1 out of every $6 spent on health care, can be attributed to cardiovascular disease.[10] 

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 there is a medication-related error. For instance, there are many commercially available lipid-lowering agents, including HMG-CoA reductase inhibitors, niacin, bile acid sequestrants, and fibric acids. If the pharmacist receives an order and identifies a more suitable agent for the patient than the agent prescribed, then it is the responsibility of the pharmacist to contact the prescriber and relay that information. This interprofessional team approach to patient care will yield improved outcomes, not only with fibric acid therapy but also in treating the patient as a whole. [Level 5]

In the hospital setting, nurses have several responsibilities, including patient monitoring. For that reason, nurses need to have a basic understanding of the side effect profiles of commonly used lipid-lowering agents. If a patient is suffering a medication-related adverse event, nurses are on the frontline to identify the problem and manage the patient's symptomatology. Additionally, adverse events should be reported to the medical team, including physicians, nurse practitioners, and pharmacists, to initiate appropriate action to control the patient's blood cholesterol. All health care team members play an important role in optimizing drug therapy for the patient, and the common denominator in the ideal scenario is interprofessional communication. In doing so, health care professionals can manage a patient's blood cholesterol in the outpatient setting, prevent unnecessary hospitalizations, and save the health care system billions of dollars in costs.