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What are primary chylomicronemia and familial hypertriglyceridemia?

- Primary chylomicronemia (PC):

1. Defective removal of CM (ApoCII, LPL defect) 

2. Manifestations: chylomicrons, VLDL elevated, pancreatitis 

- Familial hypertriglyceridemia (FH):

1. Defective metabolism of VLDL (LPL defect)

2. Manifestations: TG, VLDL elevated, pancreatitis; not as severe as PC (above) 

- NOTE: as a general rule, if TG’s exceed 1,000, there are probably chylomicrons present: 

    1) Extremely high TG’s (8-10,000 or above) -> PC

    2) If TG’s are moderately to highly elevated -> FH


What are familial dysbetalipoproteinemia, familial combined hyperlipidemia, and familial hypercholesterolemia?

Familial dysbetalipoproteinemia

1. Defective metabolism of VLDL, chylomicrons (ApoE defect; E2 allele)

2. Manifestations: VLDL and CM remnants (IDL) up; chol and TG up 1:1 (atherosclerosis) 

3. You'll give a statin to these pts, and nothing happens 

- Familial combined hyperlipidemia

1. Overproduction of ApoB (VLDL) 

2. Manifestations: variable phenotype; VLDL, LDL, or both up -> premature atherosclerosis

- Familial hypercholesterolemia:

1. LDL receptor, ApoB defect; DEC receptor-mediated removal of LDL from plasma 

2. Manifestations: LDL increased; premature atherosclerosis 


What are ApoA1 and ApoA2?

- A1: intestine, liver 

1. HDL, chylomicrons 

2. Structural protein for HDL; activates LCAT, which converts chol into chol ester 

- A2: liver 

1. HDL, chylomicrons 

2. Structural protein for HDL 


What is ApoA-V?

- Primary source is liver 

- VLDL, chylomicrons 

- Promotes LPL-mediated TG breakdown, release of FFA (free fatty acids)

- Has been associated with reduced CV risk 



What is Apo(a)?

- Primary source is the liver 

- Lp(a), LDL 

- Aberrant form of thromboplastin that adheres to LDL (atherogenic)


What are ApoB-48 and ApoB-100?

- B-48: intestine

1. Chylomicrons

2. Structural protein

- B-100: liver

1. VLDL, IDL, LDL, Lp(a) 

2. Structural protein 

- NOTE: high ApoB an adverse finding -> atherogenic proteins 


What are ApoC-II and ApoC-III?

- ApoC-II: liver 

1. Chylomicrons, VLDL, HDL

2. Co-factor for LPL (accelerates hydrolysis, reducing TG's

- ApoC-III: liver 

1. Chylomicrons, VLDL, HDL 

2. Inhibits lipoprotein binding to receptors (promotes hyperTGemia)


What is ApoE?

- Liver 

- Chylomicron remnants, IDL, HDL 

- Ligand for binding LDL receptor (acts like ApoB-100)

1. If you have defect, you have accumulation of all these particles -> hyperlipidemia (FD) 


Why can patients with diabetes present with hyperTGemia?

- Insulin is an activator of LPL

- T1D and T2D can have hyperTGemia if they quit taking their meds

- They can develop pancreatitis too



What is the order (from least to most dense) of the lipid particles discussed in this lecture? How does this reflect the TG:chol ratio?

- Chylomicrons (10:1)

- VLDL (5:1)

- IDL (1:1)

- LDL (<5%)

- HDL (<5%)

- TG's (10:1) highest in chylomicrons, and decrease going on down to HDL (<5%)


Know this. What other factors influence "target" numbers?

- Recommendations based on general pop, but high-risk patients need even less 

1. Ex: For someone w/coronary disease, or high risk, even a level of 100-130 is too high for LDL; ideal would be less than 70, or close to 50 

- Women tend to have higher HDL to begin with

- Arbitrary definition of hyperlipidemia about 90th percentile (but even levels that aren’t at that level increase risk of CV disease) 


What are the current recommendations for dietary management of hyperlipoproteinemia?

- Dietary measures initiated first, or in some cases concurrently, with pharmacologic therapy

- Chol, saturated, trans fats are principle factors that increase LDL-C (red meat, dairy products, cheeses, pastries, baked goods)

- Simple sugars, carbs, alcohol, and excess caloric intake all increase syn and secretion of VLDL, leading to hyperTGemia

- Use of complex carbs, limiting saturated fat intake, use of cis-mono unsaturated fats recommended  


Many drugs, including macrolide antibiotics, calcium channel blockers, Azole antifungals, and HIV protease inhibitors are potent inhibitors of CYP3A4. What statin is completely dependent upon this enzyme for metabolism? 

Simvastatin (Lova + methyl group) or Lovastatin


A patient is admitted with acute onset of abdominal pain, nausea and intractable vomiting. Plasma TGs are markedly elevated at 1,200 mg/dl, indicating likely TG-related pancreatitis. What drug would be most likely to reduce triglyceride to a safe level? 



A 62 year old man has recently experienced a heart attack. His LDL-C is 170 mg/dl. What cholesterol lowering medication would most effectively reduce his risk of a second heart attack? 

Atorvastatin (80mg)


What is the MOA of the statins?

- HMG-CoA reductase inhibitors: inhibits rate-limiting step of cholesterol biosyn

1. When cholesterol levels fall, signal to make more LDL receptors, which reduces chol in the plasma (SREBP from ER to Golgi to nucleus to upregulate transcription of LDL receptor protein) 

2. SREBP also upregulates HMG-CoA reductase, but statins are inhibiting it 

- Lowers LDL by 25-60% 



What is the MOA of the bile acid resins?

- Bind to bile acids 

- Prevent reabsorption and re-use of bile acid cholesterol 

- Lowers LDL by up to 20% 



What is the MOA of Ezetimibe?

- Inhibits absorption of dietary chol by small intestine (50%); localizes to brush border of sm intestine epi

1. Reduces delivery of cholesterol to liver

2. Reduced hepatic chol upregulates LDL receptors, INC clearance of LDL from plasma 

- No affect on plasma levels of fat-soluble vitamins (A, D, E, K)

- Lowers LDL by up to 20%

- Could use with a bile acid sequestrant because different MOA


What is the MOA of Niacin?

- Inhibits mobilization of FFA from adipocytes 

1. Reduces hepatic TG synthesis 

2. Reduces hepatic ApoB syn, secretion (VLDL)

3. Enhances ATP cassette-mediated transfer of chol from macro to HDL; promotes reverse cholesterol transport

4. Promotes conversion of VLDL to LDL via enhanced Lipoprotein Lipase (LPL)

- Lowers LDL by up to 20% 


What is the common mechanism of the cholesterol-limiting drugs? What is the most effective combo?

- All work through the same mechanism, so they can be administered together, and work synergistically 

1. LDL receptor upregulation (and LDL uptake) is common mech of ezetimibe, bile acid resins, and statins 

- Most effective (70-80% reduction in LDL) combo is HMG-CoA reductase inhibitor with eze or bile resin



What are the tx guidelines for statins?

- Potent statins (Atorvastatin, Rosuvastatin) produce greatest reduction in LDL (80mg A or 40mg R in pts with existing cardiac disease or high-risk diabetes)

1. Strong relationship b/t reduction of LDL and reduced cardiac events: 1% LDL reduction = 1% reduction in CV events

- Statins are primary therapy in all high-risk patients due to strong and consistent reduction in coronary events and stroke

1. Only exceptions: 1) pts w/heart failure, 2) on dialysis, 3) pts above 75 (most of these cases will be on statins too, but not as clear cut)


Your patient has hypercholesterolemia and hypertension. Her antihypertensive medications include the calcium channel blocker verapamil which is a known inhibitor of CYP3A4. What statins are dependent on CYP3A4 for metabolism and whose dose should be reduced when co-administered with calcium channel blockers? 

Simvastatin and Lovastatin


What are the distinguishing characteristics of the 5 statins we need to know?

- Lovastatin, Simvastatin: lipid soluble 

1. Inactive lactone pro drugs
2. Metabolized by CYP3A4
3. Intermediate potency and efficacy

- Pravastatin: water soluble

1. Active, open lactone ring; low potency, low efficacy

- Atorvastatin, Rosuvastatin:

1. Flourine containing congeners; active as given
2. Long plasma T/2 (14-19 hr)
3. High potency, high efficacy

- All are used to reduce LDL, reduce CHD risk


Know this.

Good job!


Which statins are metabolized by CYP2C9?

Fluvastatin, Rosuvastatin (minimal)


Which statins are metabolized by CYP3A4?

Simvastatin, Lovastatin, Atorvastatin


What statins is NOT metabolized by glucuronidation? Why does this matter?

- Fluvastatin

- Gemfibrozil also metabolized by UGT-1, so pharmacokinetic interactions result in increased statin in the body (for all statins except Fluva)


Which statin has the highest systemic bioavailability?

Fluvastatin (then Rosuvastatin)


What are the common statin drug interactions?

- Drugs that inhibit CYP3A4:

1. Macrolide ABs: erythromycin, clarithromycin

2. Azole antifungals: keto-, itraconozole (oral not topical)

3. Selected SSRI’s: nefazodone

4. Ca channel blockers: verapamil, diltiazem > dihydropyridines

5. Grapefruit juice (>1 quart/day)

6. HIV protease inhibitors: Indinavir, ritonavir

7. Immunosuppresants: cyclosporine

- Drugs that inhibit p-glycoprotein mediated intestinal reabsorption: cyclosporine, grapefruit juice

- Drugs that inhibit other pathways in statin metab: gemfibrozil (gluconlyltransferase; UTGT1A1) 


What are the AE's of the statins?

- Generally well tolerated; mild transient GI distress

- Increased liver enzymes (hepatitis rare)

- Sleep disturbance, reduced daytime vigilance, memory loss (temporary)

- Teratogenic Potential: Pregnancy Category X!

- Myalgia: muscle pain/weakness, no CPK rise

- Myositis: muscle weakness + increased CPK

- Rhabdo: marked INC CPK, renal failure, death