OVERVIEW OF LIPID-LOWERING AGENTS

  • Main Classes:
    1. Cholesterol absorption inhibitors
    2. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins)
    3. Bile acid sequestrants
    4. Nicotinic acid
    5. Fibric acid derivatives
    6. Fish oil (omega-3 fatty acids)
  • Key Overall Benefits:
    • Lowering harmful lipids (LDL cholesterol, triglycerides)
    • Potentially reducing atherosclerosis and stabilizing plaques
    • Improving endothelial function
    • Decreasing thrombogenesis

1. CHOLESTEROL ABSORPTION INHIBITORS

  • Example: Ezetimibe
  • Mechanism:
    • Blocks cholesterol absorption at the brush border of the intestine
    • Targets Niemann-Pick C1–like 1 (NPC1L1) proteins
  • Effect:
    • Lowers serum low-density lipoprotein (LDL) cholesterol by ~17%
    • Has additive LDL-lowering effects when combined with statins
  • Selectivity:
    • Does not affect absorption of triglycerides or fat-soluble vitamins

2. HMG-CoA REDUCTASE INHIBITORS (STATINS)

  • Mechanism:
    • Competitive inhibitors of the enzyme HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis
    • Decreased intracellular cholesterol → upregulation of LDL receptor turnover
  • Lipid Effects:
    • Lowers serum LDL cholesterol by 30–60%
    • Decreases small dense LDL (more atherogenic)
    • Typically lowers triglycerides by 20–40%
    • Increases HDL cholesterol by 5–10%
  • Examples:
    • Lovastatin, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin, Pitavastatin, Rosuvastatin

3. BILE ACID SEQUESTRANTS

  • Examples: Cholestyramine, Colestipol, Colesevelam
  • Mechanism:
    • Bind bile acids in the intestine → interrupt normal (90%) reabsorption
    • Depleted bile acids = increased LDL receptor expression in hepatocytes
  • Effects:
    • Reduce serum LDL cholesterol by 10–24%
    • Additive effects with statins (can further lower LDL)
  • Specific Consideration:
    • May affect absorption of other drugs or nutrients if taken simultaneously

4. NICOTINIC ACID (NIACIN)

  • Mechanism:
    • Decreases hepatic production of very low-density lipoproteins (VLDL)
    • Reduces lipolysis to LDL
    • Enhances HDL cholesterol by inhibiting its clearance
  • Effects:
    • Increases HDL by up to 35%
    • Lowers LDL and triglycerides to varying degrees
  • Formulations:
    • Immediate-release (crystalline)
    • Sustained-release
  • Clinical Note:
    • Common side effect: Flushing (can be mitigated with aspirin pre-treatment)

5. FIBRIC ACID DERIVATIVES

  • Examples: Gemfibrozil, Fenofibrate
  • Mechanism:
    • Activate peroxisome proliferator–activated receptor-α (PPAR-α)
    • Decrease hepatic VLDL secretion
    • Stimulate lipoprotein lipase (LPL) activity
    • Downregulate apolipoprotein (apo) CIII expression
  • Effects:
    • Lower triglycerides by 35–50%
    • Increase HDL by 15–25%
    • May modestly lower LDL or have variable LDL effects depending on the baseline lipid profile

6. FISH OIL (OMEGA-3 FATTY ACIDS)

  • Active Components:
    • Eicosapentaenoic acid (EPA, 20:5n-3)
    • Docosahexaenoic acid (DHA, 22:6n-3)
  • Mechanism:
    • Exact action not fully clarified
    • Decrease hepatic secretion of triglycerides (likely by reducing VLDL production)
  • Effects:
    • Lowers serum triglycerides by 20–50% (at doses ~3–4 g/day)
    • Can slightly raise HDL
    • May shift LDL toward less dense forms

ADDITIONAL NOTES

  • Combination therapy:
    • Certain agents (e.g., ezetimibe + statin, or bile acid sequestrant + statin) have additive LDL-lowering effects.
  • Beyond Lipid Lowering:
    • Many lipid-lowering drugs (especially statins) have pleiotropic effects:
      • Plaque stabilization
      • Anti-inflammatory properties
      • Improved endothelial function

OVERVIEW oF TREATMENT GOALS

  • Lifestyle modifications (for all patients with elevated LDL cholesterol):
    • Regular aerobic exercise
    • Prudent diet (low in saturated fat, high in fiber)
    • Weight loss in overweight individuals
  • Pharmacologic therapy depends on:
    • Primary prevention (no coronary heart disease [CHD])
    • Secondary prevention (presence of CHD or CHD risk equivalent)

PRIMARY PREVENTION

  • When to Treat:
    • If LDL remains high despite lifestyle measures
    • If CHD risk assessment (e.g., Framingham) indicates pharmacologic treatment
  • First-Line Therapy:
    • HMG-CoA reductase inhibitors (statins)
    • Statins lower CHD risk by 20–30%
  • Typical Statin Doses:
    • Atorvastatin 10 mg
    • Lovastatin, Pravastatin, or Simvastatin 20 mg
  • Expected Lipid Changes:
    • LDL ↓ by 30–60%
    • Some statins (e.g., atorvastatin, rosuvastatin) also lower triglycerides
  • Adverse Effects:
    • Potential hepatic enzyme elevations
    • Rare diffuse myalgias
    • Rhabdomyolysis (1 per 15 million prescriptions), more common if combined with:
      • Fibrates (notably gemfibrozil > fenofibrate)
      • Cyclosporine

SECONDARY PREVENTION

  • Patient Population:
    • Individuals with CHD or CHD equivalent (e.g., diabetes)
    • Risk of future myocardial infarction is 20× higher in these patients
  • Benefits of Cholesterol Lowering in CHD:
    • 13–16% reduction in mortality
    • Slows progression and may induce regression of coronary atherosclerosis
    • Greatest benefit when LDL <100 mg/dL
  • Treatment Approach:
    • Statins (titrate every 6 weeks to achieve LDL <100 mg/dL)
    • In acute MI setting: high-dose statin (e.g., atorvastatin 80 mg/d) to target LDL <70 mg/dL
    • If LDL goal not met with statin alone:
      • Add cholesterol absorption inhibitor (ezetimibe)
      • Or add bile acid sequestrant
    • Statin intolerance (myopathy):
      • Consider alternative agents or pravastatin (lower myopathy risk)

RAISING HIGH-DENSITY LIPOPROTEIN (HDL) CHOLESTEROL

  • Low HDL is common in patients with premature CHD
  • Lifestyle Measures to increase HDL:
    • Exercise
    • Weight loss (if obese)
    • Smoking cessation
  • Medications that may help increase HDL by 15–30%:
    • Nicotinic acid
    • Gemfibrozil
    • Estrogen replacement therapy in postmenopausal women
  • Drugs that lower HDL (e.g., androgens, benzodiazepines, β-blockers) should be discontinued if possible

HYPERTRIGLYCERIDEMIA

  • Rationale:
    • Triglyceride-rich lipoproteins (VLDL, chylomicrons) also transport cholesterol
    • Managing hypertriglyceridemia helps correct hypercholesterolemia
  • Combined High LDL + High Triglycerides:
    • Statins often first choice
  • Triglycerides >1000 mg/dL:
    • Risk of chylomicronemia syndrome (pancreatitis, eruptive xanthomas, lipemia retinalis)
    • Immediate therapy (e.g., fibrates, nicotinic acid) to prevent pancreatitis

MONITORING

  • Frequency:
    • Every 6–8 weeks until LDL goal is achieved
    • Every 6–12 months thereafter
  • Liver Function Tests:
    • Check at time of blood sampling with each dose change (especially for statins)

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