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Dyslipidemia & Hypertriglyceridemia: Drugs and Mechanisms of Action

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Overview of Dyslipidemia

• Borderline high: 150–199 mg/dL
• High: 200–499 mg/dL
• Very high: ≥500 mg/dL (pancreatitis risk)

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1. Statins (HMG-CoA Reductase Inhibitors)

Mechanism of Action

• Structural analogs of the HMG-CoA intermediate — they competitively inhibit HMG-CoA reductase, the rate-limiting enzyme in hepatic cholesterol biosynthesis (mevalonate pathway)
• Reduced hepatic cholesterol → upregulation of LDL receptors on hepatocytes → increased fractional catabolism of LDL and clearance of VLDL remnants/IDL from plasma
• Modest reductions in TG (significant when TG >250 mg/dL, with % TG reduction ≈ % LDL reduction)
• Small increases in HDL (~5–10%)
• Pleiotropic effects: reduced prenylation of Rho and Rab proteins → anti-inflammatory, endothelial-stabilizing effects

Key Toxicities

• Myopathy/rhabdomyolysis (dose-dependent; risk ↑ with CYP3A4 inhibitors, gemfibrozil, cyclosporine)
• Hepatotoxicity (rare)
• CYP3A4 interactions (lovastatin, simvastatin, atorvastatin); CYP2C9 (fluvastatin, rosuvastatin)

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2. Fibrates (Fibric Acid Derivatives) ⭐ Primary for Hypertriglyceridemia

Mechanism of Action

Clinical Use

• First-line for severe hypertriglyceridemia (TG ≥500 mg/dL) and chylomicronemia syndrome (prevents pancreatitis)
• Most effective in Type III hyperlipoproteinemia (dysbetalipoproteinemia)
• Fenofibrate preferred over gemfibrozil when combined with a statin (gemfibrozil inhibits statin glucuronidation → ↑ myopathy risk by 38%)

Toxicity

• Myopathy (especially with statins + gemfibrozil)
• Cholelithiasis (↑ biliary cholesterol secretion)
• GI symptoms; ↑ transaminases
• Avoid in hepatic/renal dysfunction

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3. Niacin (Nicotinic Acid)

Mechanism of Action

1. GPR109A agonism in adipose tissue → ↓ cAMP → inhibits hormone-sensitive lipase → ↓ lipolysis of stored TG → ↓ free fatty acid (FFA) flux to liver → ↓ hepatic TG synthesis
2. In liver: directly inhibits FFA synthesis and esterification → ↓ Apo B synthesis and degradation → ↓ VLDL production
3. ↑ LPL activity → enhanced clearance of chylomicrons and VLDL
4. ↑ HDL-C: decreases fractional catabolism of Apo A-I in HDL (most effective agent for raising HDL)
5. ↓ Lp(a) (unique among lipid drugs)
6. ↓ Fibrinogen; ↑ tissue plasminogen activator

Toxicity

• Cutaneous flushing (prostaglandin-mediated; blunted by aspirin 81–325 mg taken 30 min prior) — most common
• Hyperglycemia, insulin resistance
• Hyperuricemia / gout
• Hepatotoxicity (particularly with sustained-release preparations)
• GI symptoms

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4. Omega-3 Fatty Acids

Mechanism of Action

• ↓ Hepatic VLDL-TG synthesis: EPA/DHA reduce availability of fatty acid substrates for hepatic TG assembly; EPA may also activate PPARα
• ↑ β-oxidation of fatty acids in liver and muscle (PPARα-mediated)
• ↓ VLDL secretion from hepatocytes
• Icosapent ethil (pure EPA): additional anti-inflammatory, anti-platelet, and membrane-stabilizing effects; reduces cardiovascular events (REDUCE-IT trial) — at 4 g/day in patients with TG 135–499 mg/dL on statins

Clinical Use

• Indicated when TG ≥500 mg/dL or as adjunct for moderate hypertriglyceridemia (135–499 mg/dL with ASCVD risk — icosapent ethil only for CV benefit)
• DHA-containing formulations may modestly ↑ LDL-C; pure EPA (icosapent ethil) does not

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5. Ezetimibe

Mechanism of Action

• Inhibits NPC1L1 (Niemann-Pick C1-Like 1) transporter in intestinal brush border → blocks dietary and biliary cholesterol absorption
• Reduced intestinal cholesterol → ↓ hepatic cholesterol → upregulation of LDL receptors
• Primarily lowers LDL (~20%); modest TG reduction
• No direct effect on TG synthesis

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6. Bile Acid Sequestrants (Resins)

Mechanism of Action

• Anion exchange resins that bind bile acids in intestine → interrupt enterohepatic circulation → ↑ conversion of hepatic cholesterol to bile acids → upregulate LDL receptors
• ⚠️ Contraindicated in hypertriglyceridemia: resins cause reflex ↑ in hepatic VLDL production → can worsen TG levels significantly (TG >400 mg/dL is a contraindication)

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7. PCSK9 Inhibitors

Mechanism of Action

• PCSK9 binds the LDL receptor at the hepatocyte surface and escorts it to lysosomal destruction
• Humanized antibodies block PCSK9–LDL receptor interaction → LDL receptor recycles to cell surface → ↑ LDL clearance
• LDL-C ↓ up to 70%; also reduces TG and Apo B-100; Lp(a) ↓ ~25%
• Inclisiran: small interfering RNA (siRNA) that silences hepatic PCSK9 mRNA → ↓ PCSK9 protein production; reduces LDL-C ~50%; given twice yearly (SC)

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8. MTP Inhibitor — Lomitapide

Mechanism of Action

• Inhibits Microsomal Triglyceride Transfer Protein (MTP) — essential for loading TG onto nascent VLDL in liver and chylomicrons in intestine
• → ↓ VLDL and chylomicron assembly and secretion → ↓ LDL (downstream)
• LDL-C ↓ up to 50%
• Approved only for homozygous familial hypercholesterolemia (HoFH)
• Major ADR: hepatic steatosis, ↑ transaminases, GI symptoms (diarrhea); requires REMS program

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9. Bempedoic Acid (ATP Citrate Lyase Inhibitor)

Mechanism of Action

• Inhibits ACL (ATP Citrate Lyase): blocks conversion of citrate → oxaloacetate + acetyl-CoA
• ↓ Acetyl-CoA → ↓ HMG-CoA → ↓ hepatic cholesterol synthesis (proximal to statin target)
• Active only in liver (requires hepatic enzyme ACSL1 for activation) → no myopathy risk
• LDL-C ↓ ~15–25%; additive with statins
• ADR: hyperuricemia, tendon rupture (rare)

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Summary Table: Drugs & Key Effects on Lipids

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Drug Priority for Hypertriglyceridemia Specifically

⚠️ Bile acid sequestrants are contraindicated in hypertriglyceridemia as they worsen TG levels.

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