L40: Lipid Lower Drugs

Question 1

Risk factors of atherosclerosis

Answer 1

• Age
• Family history
• Diabetes
• Hypertension
• ↓HDL, ↑LDL, ↑TAG
• ↑Coagulation factors
• ↑Inflammation
• Lifestyle

Question 2

IDL, LDL, Chylomicron uptake by liver

Answer 2

IDL: Apo E mediated

Chylomicron remnant: Apo E mediated

LDL: Apo B100 mediated

Question 3

Risk assessment of CVD risk

Answer 3

• 10 year Coronary Heart Disease risk (CHD risk)
• Primary target: LDL-C
• Secondary target: Non-HDL-C (for patients with fasting TAG > 200 mg/dL)
• Risk ↑ —> goals for LDL-C ↑ (lower threshold)
• TC:HDL-C ratio for treatment of low HDL-C patients

Question 4

Managment of lipoprotein disorder

Answer 4

1. ↓ cholesterol intake
   - dietary restriction
   - cholesterol absorption inhibitor
2. ↓ LDL plasma level
   - statins
   - niacin
   - resins (bile acid sequestrants)
   - PCSK9 inhibitor
3. ↓ VLDL plasma level (TAG)
   - omega-3
   - fibrates
   - niacin
4. ↑ HDL plasma level
   - niacin

Question 5

Statins

Answer 5

HMG CoA reductase inhibitor

• ↓ LDL (due to ↓ cholesterol synthesis in liver)
• ↓ LDL (due to ↑ LDL receptor synthesis —> ↑ LDL clearance)
• small ↑ HDL (due to LDL clearance)
• little ↓ TAG

Use:
- prevention of atherosclerosis in elevated LDL
- NOT for pregnancy, nursing, children
- homozygous familial hypercholesterolaemia: Attenuated response
- Short half life (1-4 hours): Pravastatin (taken at bed)
- Intermediate half life (12 hours): Simvastatin (taken at bed)
- Long half life (20 hours): Atorvastatin, Rosuvastatin (taken anytime)
(Hepatic cholesterol synthesis is maximal between 12am to 2am)

Adverse effects:

• Safe (GI disturbance)
• Hepatotoxicity (↑ALT, malaise, anorexia)
• Myopathy / Rhabdomyolysis —> Renal failure (↑creatine kinase)

Factors increasing statin plasma level:

• age
• hepatic and renal dysfunction
• small body size
• drugs inhibit hepatic uptake (Gemfibrozil)
• drugs inhibit CYP450 enzymes / glucuronidase (Gemfibrozil, Warfarin, Erythromycin, Itraconazole)

Question 6

Niacin

Answer 6

Vitamin B3

• ↓ VLDL (inhibition of hormone-sensitive lipase in adipose tissue —> ↓ fatty acids to liver —> ↓ hepatic synthesis of TAG; ↑VLDL clearance by enhancing LPL activity)
• ↓ LDL (due to ↓ VLDL)
• ↑ HDL (due to ↓ clearance of Apo A1 in liver)

Use:

• Most effective in ↑ HDL
• Hypertriglyceridemia —> Effective in ↓ TAG
• Normalize LDL level irrespective of LDL-R level
• limited by adverse effects
• NOT for pregnancy

Adverse effects:

• flushing (reversed by aspirin, tachyphylaxis)
• skin rash
• GI disturbance (avoid in peptic disease)
• Hepatotoxicity
• birth defects
• ↓ glucose tolerance, ↑ uric acid

Question 7

Fibrates

Answer 7

PPAR-α activator (clofibrate, fenofibrate, gemfibrozil)

• ↓ VLDL (↑ LPL synthesis, ↑ fatty acid oxidation by liver —> ↓ TAG)
• **- ↓/↑ LDL (due to ↓ VLDL / ↑ TAG —> fatty acid)
• little ↑ HDL (↑ Apo A1, A2 production)

Use:

• Hypertriglyceridemia
• NOT for pregnancy, children

Adverse effects:

• Safe (GI disturbance)
• Myopathy (caution with statin)
• ↑ Liver enzyme
• ↑ cholesterol gallstone (caution with biliary tract disease)
• ↑ Warfarin action

Question 8

Resins (Bile acid sequestrant)

Answer 8

(cholestyramine, colesevelam)

• ↑ Bile acid excretion (by binding to bile acid —> ↓ reabsorption —> ↑ liver conversion of cholesterol into bile acid)
• ↓ LDL (by ↑ LDL receptor synthesis in liver, offset by up-regulation of HMG CoA reductase —> ↑ cholesterol synthesis)

Use:

• conditions with ↑ LDL
• may cause ↑ hepatic TAG
• relieve pruritis (in cholestasis)
• bind digoxin (in digoxin toxicity)

Adverse effects:

• no systemic toxicity
• GI disturbance (diverticulitis, relieved by increase fibre intake)
• ↓ fat-soluble vitamin and drug absorption in GI tract (1 hour before, 3-4 hours after)

Question 9

Cholesterol absorption inhibitor

Answer 9

Ezetimibe

• ↓ cholesterol absorption (by binding to NPC1L1 + inhibit ACAT2)
• ↓ LDL (by ↑ LDL receptor synthesis in liver, offset by up-regulation of HMG CoA reductase —> ↑ cholesterol synthesis)

Use:
- plasma concentration increased by fibrates, decreased by resins

Adverse effects:
- Safe

Question 10

PCSK9 inhibitor

Answer 10

Monoclonal Ab against PCSK9 (Alirocumab, Evolocumab)
- ↓ LDL (by binding to PCSK9 —> prevent binding to LDL receptor —> ↓ LDL receptor degradation —> ↑ LDL clearance)

Use:

• 2nd line in refractory to diet change / maximum statin therapy
• familial hypercholesterolaemia
• CVD —> prevent cardiovascular events

Adverse effects:
- Safe

Question 11

Combination therapy

Answer 11

• Lowest effective dose
• Close monitoring for potential toxicity
• Statin + Fenofibrate (Myopathy, Hepatotoxicity)

Question 12

Summary of all lipid lowering drugs

Answer 12

Statin:

• ↓ cholesterol synthesis in liver —> ↓ LDL
• ↑ LDL receptor synthesis —> ↓ LDL

Niacin:

• ↓ Apo A1 clearance —> ↑ HDL
• ↓ hepatic TAG synthesis —> ↓ VLDL

Fibrates:
- ↑ LPL synthesis + ↑ fatty acid oxidation in liver —> ↓ VLDL

Resins:
- ↑ bile acid excretion —> ↑ cholesterol utilisation —> ↓ LDL

Ezetimibe:
- inhibit NPC1L1 —> ↓ cholesterol absorption —> ↓ LDL

PCSK9 inhibitor:
- ↓ degradation of LDL receptor —> ↓ LDL