Generic Name

Gemfibrozil

Mechanism

Gemfibrozil is a *fibrate* that exerts its lipid‑lowering effects primarily through activation of Peroxisome Proliferator‑Activated Receptor‑α (PPAR‑α). This nuclear receptor modulates the transcription of genes involved in lipid metabolism.
• ↑ Lipoprotein lipase activity → hydrolyzes triglycerides in VLDL → ↓ plasma triglycerides.
• ↑ Hepatic fatty acid oxidation → reduces hepatic triglyceride synthesis.
• ↓ Gene expression of apolipoprotein C‑III → less inhibition of lipoprotein lipase.
• ↑ HDL‑cholesterol (increased synthesis and maturation).

Result: marked reduction in triglycerides and modest increases in HDL‑C with a lesser effect on LDL‑C.

Pharmacokinetics

• Absorption: ~50‑70 % orally; peak plasma levels ~1–2 h post‑dose.
• Distribution: highly protein‑bound (~80 % to albumin, <10 % to α‑1‑acid glycoprotein).
• Metabolism: primarily hepatic via CYP2C9 to inactive metabolites; minor involvement of CYP2C19.
• Elimination: ~60 % renal excretion (urine) of metabolites; ~30 % fecal.
• Half‑life: 12–20 h (depends on renal/hepatic function); steady state achieved in 5–7 days.
• Drug interactions: limited by CYP2C9; significant inhibitors (e.g., fluconazole) may elevate plasma gemfibrozil.

Indications

• Mixed dyslipidemia / hypertriglyceridemia (≥200 mg/dL).
• Primary prevention of pancreatitis in patients with severe hypertriglyceridemia (>1000 mg/dL).
• Adjuncts to diet/exercise therapy in *metabolic syndrome* when lipid levels remain inadequately controlled.

Contraindications

• Severe hepatic dysfunction (ALT/AST >10× ULN).
• Severe renal disease (CrCl *Warning*: Potential for hepatotoxicity (elevated transaminases ≤3× ULN) and myopathy (CK >10× ULN).

Dosing

• Adult regimen: 600 mg orally twice daily (BID) with meals to improve absorption.
• Adjustment for renal impairment: consider half‑dose (300 mg BID) if CrCl 30–49 mL/min; avoid if <30 mL/min.
• Duration: Chronic; self‑titration to maintain triglycerides <150 mg/dL and LDL <100 mg/dL.
• Food note: Consistency with meals helps prevent GI upset.

Adverse Effects

• Common
• Gastro‑intestinal: nausea, abdominal pain, dyspepsia, diarrhea.
• Headache, rash, arthralgia.
• Serious
• Hepatotoxicity → ↑ transaminases, jaundice, cholestatic picture.
• Myopathy / rhabdomyolysis → CK elevation, muscle pain, weakness (especially with statins).
• Gallstone formation (biliary sludge).
• Increased D‑dimers → caution in thromboembolic conditions.

Monitoring

• Baseline
• LFTs (ALT, AST, ALP, bilirubin).
• CK, serum creatinine, eGFR.
• Lipid panel (triglycerides, LDL, HDL).
• Follow‑up
• LFTs: 2–4 weeks post‑initiation, then every 3–6 months.
• CK: if myalgias or statin co‑therapy, at 2–4 weeks, then 3–6 months.
• Lipids: every 3 months until therapeutic goal achieved, then 6‑12 month intervals.
• Special
• INR for patients on warfarin—check every 2–3 weeks initially.

Clinical Pearls

1. Avoid concomitant use with high‑dose simvastatin (>20 mg) to reduce the risk of *myopathy*—combine at most *20 mg statin + gemfibrozil* with caution.
2. Cholestyramine or bile‑acid sequestrants significantly lower gemfibrozil absorption; stagger dosing by ≥4 h or consider alternative lipid‑lowering agents.
3. Warfarin interaction: gemfibrozil may potentiate anticoagulation; start with a low INR target and titrate slowly.
4. Renal dosing: when CrCl 30–49 mL/min, a single 600 mg dose may be permissible but monitor for drug accumulation.
5. Pregnancy precautions: a single‑dose cohort study in 1996 found minimal placental transfer (≈1 %), yet clinical guidelines still contraindicate due to limited safety data.
6. Lifestyle synergy: maintain a low‑fat, low‑sodium diet and exercise ≥150 min/week to maximize lipid‑lowering benefit.
7. Non‑statin combinations: gemfibrozil is effective when added to statins for patients with very high triglycerides; however, prescribing *statin + fibrate* combo should be limited to 12 months if possible, with close monitoring.

*References available on request.*