Fibric acid derivatives

Introduction
Fibric acid derivatives, commonly known as fibrates, are a class of lipid-modifying agents primarily used to manage hypertriglyceridemia, low HDL cholesterol, and mixed dyslipidemia. They exert their therapeutic effects by activating the peroxisome proliferator-activated receptor alpha (PPAR-α), a nuclear receptor that regulates lipid metabolism genes. Although they are not first-line agents for lowering LDL cholesterol, fibrates are particularly effective in patients with elevated triglycerides (TG ≥ 200 mg/dL), low HDL-C (<40 mg/dL in men, <50 mg/dL in women), and in select patients with atherogenic dyslipidemia, such as those with metabolic syndrome or type 2 diabetes mellitus.

Fibrates have been in clinical use since the 1960s. Over time, their formulations and pharmacokinetics have improved, but the class remains essential in the management of dyslipidemia in both primary and secondary cardiovascular disease (CVD) prevention when triglycerides are markedly elevated or when patients are statin-intolerant.

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1. Members of the Fibric Acid Derivatives Class

The most widely used and FDA-approved fibrates include:

1. Fenofibrate

   • Brand names: Tricor, Lipofen, Triglide, Antara, Fenoglide, Lofibra

   • Available in multiple formulations with different bioavailability profiles

2. Gemfibrozil

   • Brand name: Lopid

3. Bezafibrate (not FDA-approved in the US)

   • Used in Europe, Asia, and parts of Latin America

4. Ciprofibrate (not FDA-approved in the US)

5. Clofibrate (obsolete due to safety concerns)

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2. Mechanism of Action

Fibrates activate PPAR-α, a nuclear transcription factor predominantly expressed in liver, heart, kidneys, and skeletal muscle. Activation of PPAR-α leads to:

• ↑ Expression of lipoprotein lipase (LPL) → enhanced TG clearance

• ↓ Expression of apolipoprotein C-III (apoC-III) → disinhibition of LPL

• ↑ Expression of apolipoprotein A-I and A-II → increased HDL production

• Enhanced β-oxidation of fatty acids in liver and muscle

Net effects:

• ↓ Plasma triglycerides (20–50%)

• ↑ HDL cholesterol (10–20%)

• Modest ↓ LDL cholesterol (5–20%) or even ↑ LDL in very high TG states

• ↓ Small dense LDL particles (atherogenic subtype)

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3. Pharmacokinetics

Parameter	Fenofibrate	Gemfibrozil
Prodrug	Yes (converted to fenofibric acid)	No
Absorption	Enhanced with food	Enhanced with food
Peak plasma	~4–8 hours (fenofibric acid)	~1–2 hours
Half-life	~20 hours	~1.5 hours
Protein binding	>99% (albumin)	~98%
Metabolism	Hepatic (non-CYP)	Hepatic (oxidation, conjugation)
Excretion	Renal (mainly unchanged)	Renal (as conjugates)

Note: Fenofibrate has a longer half-life, allowing for once-daily dosing. Both drugs require dose adjustment in renal impairment.

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4. Clinical Indications

A. Hypertriglyceridemia

• Primary indication for fibrates (TG ≥ 200 mg/dL; especially ≥ 500 mg/dL)

• Used to prevent pancreatitis in severe hypertriglyceridemia

B. Mixed dyslipidemia

• Patients with elevated LDL-C, TG, and low HDL-C, particularly those intolerant to statins

C. Atherogenic dyslipidemia in diabetes/metabolic syndrome

• Characterized by high TG, low HDL, small dense LDL

• Fibrates may be used as adjuncts in patients not at non-HDL goals with statins alone

D. Statin intolerance

• Monotherapy in patients unable to tolerate statins

E. Combination therapy (selected cases)

• Fenofibrate may be cautiously combined with moderate-intensity statins in high-risk patients with persistent hypertriglyceridemia

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5. Lipid-Lowering Efficacy

Parameter	Gemfibrozil	Fenofibrate
↓ TG	30–50%	20–50%
↑ HDL-C	10–20%	10–25%
↓ LDL-C	5–15% (may increase in high TG states)	5–20%
↓ ApoB	Mild	Moderate
↓ Non-HDL-C	Moderate	Moderate

6. Major Clinical Trials

• Helsinki Heart Study (1987) – Gemfibrozil reduced CHD events in middle-aged men with dyslipidemia.

• VA-HIT (1999) – Gemfibrozil lowered risk of cardiovascular events in men with CHD and low HDL-C.

• FIELD (2005) – Fenofibrate did not significantly reduce CHD events in type 2 diabetes but reduced progression of microvascular complications.

• ACCORD-Lipid (2010) – Fenofibrate + simvastatin did not significantly reduce CV events overall but benefited a subgroup with high TG and low HDL-C.

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7. Adverse Effects

A. Common

• Dyspepsia

• Nausea

• Diarrhea

• Myalgia

• Headache

• Elevated liver transaminases (ALT, AST)

B. Serious

• Myopathy and rhabdomyolysis

  • Higher risk when combined with statins (especially with gemfibrozil)

  • Fenofibrate + statin is safer than gemfibrozil + statin

• Cholelithiasis

  • Due to increased cholesterol excretion in bile

• Pancreatitis (rare)

• Reversible creatinine elevation (especially fenofibrate)

  • Monitor renal function

• Hypersensitivity reactions

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8. Contraindications

• Severe renal impairment (eGFR <30 mL/min/1.73 m²)

• Active liver disease (including biliary cirrhosis)

• Gallbladder disease

• Hypersensitivity to fibrates

• Nursing mothers (avoid use)

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9. Precautions and Monitoring

• Monitor:

  • Liver function tests (baseline and periodically)

  • Renal function (especially fenofibrate)

  • Lipid panel (4–12 weeks after initiation or dose changes)

  • CPK (in patients with muscle symptoms)

• Use cautiously in:

  • Elderly patients

  • History of gallstones

  • Diabetes with CKD (dose adjust or avoid if eGFR <30 mL/min)

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10. Drug Interactions

Interaction	Clinical Relevance
Statins	↑ risk of myopathy (especially gemfibrozil)
Oral anticoagulants (warfarin)	↑ INR, risk of bleeding → monitor closely
Bile acid sequestrants	↓ absorption of fibrates – separate by 1–4 hrs
Cyclosporine	↑ nephrotoxicity → avoid or monitor renal function
Sulfonylureas	↑ risk of hypoglycemia

Fenofibrate is generally preferred for combination with statins due to lower interaction potential.

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11. Dosage Overview

Fenofibrate (varies by brand and formulation)

• Typical adult dose: 48–145 mg once daily

• Administer with food for certain formulations

• Adjust in renal impairment

Gemfibrozil

• 600 mg orally twice daily, 30 minutes before breakfast and dinner

• Avoid combination with statins unless benefits outweigh risks

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12. Role in Combination Therapy

• Not routinely recommended as add-on to statins unless:

  • TG ≥ 200–499 mg/dL despite statin therapy

  • HDL-C remains low

  • Patient has type 2 diabetes or metabolic syndrome

  • ASCVD risk is elevated

Combination Guidelines (per ACC/AHA):

• Statin + fenofibrate may be considered in men >50 years or women >60 years with:

  • TG 200–499 mg/dL

  • HDL-C <35 mg/dL

  • On statin therapy and controlled LDL-C

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13. Comparison with Other Lipid Agents

Parameter	Statins	Fibrates	Niacin	Omega-3 FA
↓ LDL-C	Strong	Mild	Moderate	Minimal
↓ TG	Moderate	Strong	Strong	Strong
↑ HDL-C	Mild	Mild to moderate	Strong	Minimal
↓ CV events	Proven	Modest	Limited evidence	Limited evidence