See also Lipid transport

Statins

• The only first-line medication for dyslipidemia, significantly reducing the risk of mortality in patients suffering from CAD.
• Competitive inhibition of HMG-CoA reductase renders this enzyme unable to convert HMG-CoA to mevalonate (the rate-limiting step of cholesterol synthesis) → reduced intrahepatic cholesterol biosynthesis → upregulation of expression of LDL receptor gene via sterol regulatory element-binding protein (SREBP) → increased LDL recycling and:
  • ↓↓ LDL cholesterol
  • ↑ HDL cholesterol
  • ↓ Triglyceride level
• Adverse effects
  • Statin-associated myopathy
    • Muscle pain and weakness, especially when used alongside fibrates or niacin
    • Myositis: ↑ CK
    • Statins are metabolized by CYP3A4. This enzyme can be inhibited by macrolide antibiotics (eg, erythromycin, clarithromycin), leading to increased statin drug levels and subsequent statin myopathy. See Cytochrome P450.
    • May progress to rhabdomyolysis: rare but severe side-effect that may lead to myoglobinuria → AKI (↑ BUN and ↑ creatinine)
    • Treatment must be discontinued if myopathy/rhabdomyolysis occurs.

Ezetimibe

• Mechanism of action: selective inhibition of cholesterol reabsorption at the brush border of enterocytes (cholesterol transporter NPC1L1) → ↓↓ LDL, little effect on HDL (slight ↑) and triglycerides (slight ↓)
• Adverse effects: ↑ Liver enzymes

Fibrates

• Agents: bezafibrate, fenofibrate, and gemfibrozil
• Mechanism of action: activation of the peroxisome proliferator-activated receptor alpha (PPAR–α) → ↑ lipoprotein lipase activity → more rapid degradation of TGs circulating in chylomicrons and VLDLs into fatty acids and glycerine, which can be taken up by cells; and induction of HDL synthesis → ↓ LDL, ↑ HDL, ↓↓↓ triglyceride
• Adverse effects
  • Dyspepsia
  • Myopathy, especially in combination with statins
  • Cholelithiasis: fibrates inhibit cholesterol 7α hydroxylase → decreased bile acid synthesis → supersaturation of bile with cholesterol (↑ cholesterol:bile acid ratio)
  • ↑ LFTs (reversible)

Niacin (Vitamin B3)

• Mechanism of action: inhibits lipolysis and fatty acid release in adipose tissue through blockade of hormone-sensitive lipase and ↓ hepatic VLDL synthesis → ↓ triglyceride, ↓↓ LDL synthesis, ↑↑ HDL
• Indication: high LDL cholesterol and lipoprotein(a) levels (> 50 mg/dL) despite statin and ezetimibe therapy (or if statins are contraindicated)
• Adverse effects, see Vitamin B3#Vitamin B3 toxicity
  • Flushing and pruritus
  • Hyperglycemia
  • Hyperuricemia and gout
    • Niacin decreases renal uric acid excretion.

Bile acid resins

• Drugs: cholestyramine, colestipol, colesevelam
• Mechanism of action
  • Ion exchange resin binds bile acids in the intestine → interruption of enterohepatic circulation (↓ bile acid absorption and ↑ bile acid excretion) → ↑ conversion (compensatory) of cholesterol to bile → lowers cholesterol pool in the liver and promotes synthesis of LDL receptors and ↑ LDL receptor recycling → ↓↓ unbound LDL, slightly ↑ HDL, and slightly ↑ triglycerides
• Indications
  • Combination treatment with statins in hypercholesterolemia
  • Digitoxin overdose
• Adverse effects
  • Gastrointestinal: nausea, abdominal bloating and cramping