Introduction
Gemfibrozil is a fibric acid derivative (fibrate) medication primarily used for the management of dyslipidemia. First approved by the FDA in 1981, it remains an important therapeutic option for specific lipid disorders, particularly in patients with hypertriglyceridemia. As a lipid-modifying agent, gemfibrozil works through multiple mechanisms to reduce triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C).
Mechanism of Action
Gemfibrozil exerts its effects through activation of peroxisome proliferator-activated receptor-alpha (PPAR-α). This nuclear receptor activation leads to:
- Increased lipoprotein lipase activity, enhancing clearance of triglyceride-rich particles
- Reduced hepatic production of very-low-density lipoprotein (VLDL)
- Increased synthesis of apolipoproteins A-I and A-II, contributing to HDL formation
- Promotion of fatty acid oxidation in the liver and muscle
The drug does not significantly affect LDL cholesterol levels and may paradoxically increase LDL in some patients with hypertriglyceridemia.
Indications
FDA-approved indications:
- Treatment of severe hypertriglyceridemia (Type IV and V hyperlipidemia) in patients at risk of pancreatitis
- Reduction of coronary heart disease risk in Type IIb hyperlipidemia patients with low HDL-C, elevated LDL-C and triglycerides, who have failed diet and other pharmacologic therapy
Off-label uses may include combination therapy in specific dyslipidemias, though this requires careful monitoring due to interaction risks.
Dosage and Administration
Standard dosing: 600 mg orally twice daily, 30 minutes before morning and evening meals Special populations:- Renal impairment: Use with caution in CrCl <60 mL/min; contraindicated in end-stage renal disease
- Hepatic impairment: Contraindicated in primary biliary cirrhosis, severe hepatic dysfunction
- Geriatric patients: Consider reduced dose based on renal function
- Pediatric use: Safety and effectiveness not established
Dosage adjustments may be necessary based on therapeutic response and tolerability.
Pharmacokinetics
Absorption: Well absorbed from GI tract; bioavailability >90%; food decreases rate but not extent of absorption Distribution: Volume of distribution: 0.15 L/kg; highly protein bound (>95%) Metabolism: Extensive hepatic metabolism via CYP2C8, CYP2C9, and CYP3A4; undergoes glucuronidation Elimination: Half-life: 1.5 hours; primarily renal excretion (70%) as unchanged drug and metabolites; fecal excretion (6%)Contraindications
- Hypersensitivity to gemfibrozil or any component
- Hepatic dysfunction including primary biliary cirrhosis
- Severe renal impairment
- Pre-existing gallbladder disease
- Concurrent use with repaglinide or simvastatin
Warnings and Precautions
Black Box Warning: Concomitant use with simvastatin increases risk of rhabdomyolysisAdditional precautions:
- Monitor for myopathy and rhabdomyolysis, especially in elderly and patients with renal impairment
- Risk of cholelithiasis; discontinue if gallstones are detected
- May increase serum transaminases; monitor liver function
- Use caution in patients with anticoagulant therapy (enhances warfarin effect)
- May cause hematologic abnormalities; monitor CBC periodically
Drug Interactions
Major interactions:- Statins: Increased risk of myopathy (particularly simvastatin)
- Repaglinide: Contraindicated due to increased hypoglycemia risk
- Warfarin: Enhanced anticoagulant effect; requires INR monitoring and dose adjustment
- CYP2C8/2C9 substrates: May alter concentrations of drugs metabolized by these enzymes
- Bile acid sequestrants: May decrease gemfibrozil absorption; administer 2 hours apart
Adverse Effects
Common (≥5%):- Dyspepsia (19.6%)
- Abdominal pain (9.8%)
- Diarrhea (7.7%)
- Nausea (4.5%)
- Fatigue (3.8%)
- Rhabdomyolysis (<0.1%)
- Severe hepatotoxicity (0.1-1%)
- Cholelithiasis (1-5%)
- Hematologic abnormalities (anemia, leukopenia)
- Stevens-Johnson syndrome (rare)
Monitoring Parameters
Baseline:- Complete lipid profile
- Liver function tests (ALT, AST)
- Renal function (BUN, creatinine)
- CBC with platelets
- CPK if muscle symptoms occur
- Lipid profile at 3-6 month intervals
- LFTs every 3-6 months initially, then annually
- CPK if myalgias develop
- INR frequently if on warfarin
- Symptoms of gallstones (right upper quadrant pain)
Patient Education
- Take medication 30 minutes before meals for optimal absorption
- Report any unexplained muscle pain, tenderness, or weakness immediately
- Be aware of potential stomach upset; take with food if tolerated
- Maintain prescribed dietary modifications and exercise regimen
- Inform all healthcare providers about gemfibrozil use, especially before new prescriptions
- Report any signs of bleeding (if on warfarin) or yellowing of skin/eyes
- Do not discontinue without medical supervision
- Attend all scheduled follow-up appointments and laboratory monitoring
References
1. Rubins HB, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341(6):410-418. 2. FDA Prescribing Information: Lopid (gemfibrozil). Revised 2021. 3. Grundy SM, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. J Am Coll Cardiol. 2019;73(24):e285-e350. 4. Bays H, et al. Fibrates: where are we now? Am J Cardiol. 2007;100(11A):n69-n75. 5. Davidson MH, et al. Efficacy and safety of fibrates in the management of dyslipidemia. Am J Cardiovasc Drugs. 2007;7(1):31-41. 6. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases; 2012.