Hyperlipidemia Drugs

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Statins

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• Competitive inhibitor of HMG CoA reductase
o ↓ Cholesterol synthesis → ↑ Liver LDL receptors → ↑ LDL Clearance
• Effects:
o ↓ LDL (Primary use)
o ↑ HDL (moderate)
o ↓ triglycerides (moderate)
o ↓ CRP → ↓ risk for atherosclerosis
• Largest ↓ LDL is initial dose, each doubling of dose thereafter → 5-7% further ↓
• Adverse Effects:
o Dose related myopathy - myalgia, myositis (↑ CK) and rarely rhabdomylysis
o Elevation of liver enzymes may occur (monitor these)
• Contraindication:
o Liver disease, pregnancy, and breast feeding

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Drug Interactions of Statins:

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• Lovastatin & Simvastatin are metabolized by Cyp3A4 – subject to inhibitors or inducers
• Concamitant use with fibrates (Gemfibrozil) and possible nicotinic acid may ↑ risk of myopathy

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Order of Strength of Statins:

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• 20% ↓ you can use any, 50% ↓ you have to use of the more efficacious one

1. Rosuvastatin – most effective (↓ Cholesterol 50%)
2. Atorvastatin
3. Simvastatin
4. Pravastatin – non metabolized by P450s so less likely to have drug interaction

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Atorvastatin (Lipitor)

Back 4

• Statin

Front 5

Fluvastatin

Back 5

• Statin
• Metabolized by Cyp2C9 – no major drug interactions

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Lovastatin

Back 6

• Statin
• Metabolized by Cyp3A4 – subject to inhibitors or inducers

Front 7

Provastatin

Back 7

• Statin
• Metabolized by Cytochrome system – no major drug interactions

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Rosuvastatin

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• Statin
• Metabolized by Cyp3A4 – subject to inhibitors or inducers

Front 9

Cholestyramine

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• Bile Acid Resin – (+) Charged resin
• Results in:
1. ↑ Bile acid excretion (blocks enterohepatic circulation)
2. ↓ Cholesterol Absorption → ↓ Hepatoc Cholesterol →
• ↑ Cholesterol Synthesis & Triglyceride Synthesis
• ↑ LDL Receptor → ↓ plasma LDL
• Major Use: Lower LDL alone or with a Statin
• Adverse Effects:
1. GI side-effects: Bloating, gas, constipation (seen less with Colesevelam)
2. Contraindicated in patients with high triglycerides (>400mg/dL) – can cause an ↑ in triglycerides
• Drug Interactions
o Can impair absorption of: warfarin and digoxin
o Impaired absorption of Vitamins A, D, E, K possible (take 2-4 hrs b4 resin)

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Colesevelam

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• Bile Acid Resin – hyprophilic gel (easier to ingest)
• Results in:
1. ↑ Bile acid excretion (blocks enterohepatic circulation)
2. ↓ Cholesterol Absorption → ↓ Hepatoc Cholesterol →
a. ↑ Cholesterol Synthesis & Triglyceride Synthesis
b. ↑ LDL Receptor → ↓ plasma LDL
• Major Use: Lower LDL alone or with a Statin
• Adverse Effects:
1. GI side-effects: Bloating, gas, constipation (seen less with Colesevelam)
2. Contraindicated in patients with high triglycerides (>400mg/dL) – can cause an ↑ in triglycerides
• Drug Interactions
o Can impair absorption of: warfarin and digoxin
o Impaired absorption of Vitamins A, D, E, K possible (take 2-4 hrs b4 resin)

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Ezetimibe

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• Inhibits intestinal NPC1L1 cholesterol transporter → ↓ Cholesterol absorption
• Effects:
o ↓ Cholesterol delivery to liver → ↓ SS Cholesterol (↑ clearance from blood) → ↑ LDL Receptors
o ↓ LDL (major effect), ↑ HDL, ↓ TG
• Uses:
o Hypercholesterolemia (inherited and non-inherited)
o Other inherited hypercholesterol disorders
• Adverse Effects:
o Diarrhea
o Depression
• Precautions:
o Myalgia-Rhabdomyolysis: adding a statin to ezetimibe → ↑ risk
o Liver Enzymes: when given with a statin must monitor liver function
• Contraindicated in patients with liver disease
o Geriatrics: Doses reach high [ ] in elderly
o Pregnancy and nursing: benefit to risk weighing

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Drug Interactions of Ezetimide:

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• Fibrates may ↑ bioavailability of ezetimibe
• Cholestyramine can ↓ absorption of ezetimibe

Front 13

Fenofibrate

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• Fibrate
• Mechanism: Agonist for αPPAR → TF to nucleus → ↑ FA metabolism → ↓ TG → ↓ VLDL → ↑ LPL → clear lipids from circulation
• LDL remodeling (less dense), ↑ HDL, ↓ VLDL, ↓ TG
• Major use: Triglyceridemia (also ↑ HDL)
• Adverse Effects:
o Headache, nausea, diarrhea
o Myalgia (especially if combined with statins; fenofibrate less than genfibrozil – do not use this with a statin!)
o Gallstones
• Drug Interactions
o Fenofibrate may prolong warfarin INR

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Fenofibric Acid

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• Fibrate
• Mechanism: Agonist for αPPAR → TF to nucleus → ↑ FA metabolism → ↓ TG → ↓ VLDL → ↑ LPL → clear lipids from circulation
• LDL remodeling (less dense), ↑ HDL, ↓ VLDL, ↓ TG
• Major use: Triglyceridemia (also ↑ HDL)
• Adverse Effects:
o Headache, nausea, diarrhea
o Myalgia (especially if combined with statins; fenofibrate less than genfibrozil – do not use this with a statin!)
o Gallstones

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Nicotinic Acid (Niacin; Vit. B3)

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• Mechanism: Binds nicotinic acid receptor (GPR109A) → inhibits adenylate cyclase → ↓cAMP → ↓ FFA → ↓ VLDL synthesis → ↓ LDL and ↑ HDL
o Receptor is found in adipocytes
o cAMP – regulates lipolysis by activating PKA → phosphorylate HSL (active) → HSL hydrolyse TAG
o ↓ cAMP → ↓ lipolysis
• Effects: ↓ LDL; ↑ HDL (most effective drug); ↓ TG ; ↓LP(a) – risk factor in CAD
• Use: Broad spectrum agent to ↓ LDL & TG, ↑ HDL
• Adverse Effects:
o Flushing (upper face & body) – via vasodilation (PGE mediated) → onset usually within an hour. With itching & tingling. Give aspirin b4 dose
o ↑ Insulin resistance (hyperglycemia) and induce hyperuricemia (gout)
o Has been associated with hepatotoxicity
o Headache, heartburn, indigestion, nausea, diarrhea, stomach pain
• Drug Interactions: Possible myopathy with statin
• Contraindications: Liver disease, peptic ulcers, gouty arthritis, diabetes (relative)

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Omega-3 PUFA

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• Combo of EPA & DHA from fish oil
• ↓ Liver production of TG and VLDL
• ↑ LDL (remodeling effect – so less dense, thought to be non-atherogenic)
• Main use is to lower TG
• Used with statins to further lower TGs
• Have some anti-platelet effect (↓ MI & stroke in eskimos)
• Adverse Effects:
o Impaired hemostasis
o Primarily minor GI (burp, fart, taste)
o Worsening glycemic control

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Orlistat

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• Not on Block exam
• Used for weight control
• Mechanism – inhibits lipases in GI tract → do not absorb fat → ↓ caloric intake, fat is excreted
• Not used for hyperlipidemia

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Metabolic Syndrome:

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• 3/5 of the following:
1. Hypertension (>130/85 or on anti-HTN meds)
2. Low HDL (<40mg/dL)
3. Obesity (BMI > 25)
4. Hyperglycemia
5. Hyperlipidemia

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Comparing Statins to Fibrates: (4)

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1. Fibrates are more effective than statins at lowering TG and raising HDL
2. Fibrates are much less effective at lowering LDL than statins → stating are better for lowering LDL
3. Adding a statin to fibrate will further ↓ TG levels
4. Adding a statin to fibrate does not raise HDL any further