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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


Why do lipid soluble statins have increased risk of adverse effects? Which ones?

- Because they penetrate muscle 

- Simvastatin, Lovastatin 


Why is it good that statins are metabolized in the liver?

- This is also the site of action of statins, so very little statin ever leaves the liver, making these drugs pretty safe under normal circumstances 

- Dangerous at periphery -> myositis 



Why is the OATP transporter important for statin metabolism?

Primary method of liver uptake of statins



How dose renal insufficiency affect statin tx?

- Should reduce dosage in pts with renal insufficiency

- EXCEPT Atorvastatin, which is primarily secreted by fecal mechanisms 


What are the bile acid sequestrants?

- Anionic (+ charge) ion exchange resins: interrupt enterohepatic recycling of cholesterol by binding (-) charged bile acids in the gut

- Among the oldest (and safest) hypolipidemic drugs

- Non-systemic (not absorbed from intestine), so can be safely used in children, pts with liver disease

- Available in both powder and pill formulations

- Lowers LDL-cholesterol by up to 25% at max doses

- Modest effect on HDL-C, but does NOT decrease TGs (may increase)

- GI side effects (bloating, constipation) can limit use


Which bile acid sequestrants are given only as a tablet, only as a powder, or both?

- Only tablet: Colesevelam (should be taken w/liquid)

- Only powder: Cholestyramine 

- Both: Colestipol (powder should be mixed with OJ or applesauce)


What are the common AE's of bile acid sequestrants?

- Gritty texture (slurried powder, “sand”)

- GI: bloating, nausea, flatulence, constipation (premix-refrigerate), fecal impaction (take with water!)

- Paradoxical hypertriglyceridemia 


What are the drug interactions and contraindications for the bile acid sequestrants?

- Drug interactions:

1. Prevents absorption of other drugs: digoxin, b-blockers, thyroxine, Warfarin

2. Take other meds 1 hour before or 3-4 hours after bile acid sequestrant

- Contraindications:

1. Hypertriglyceridemia

2. Complex drug regimens, critical meds

3. History of constipation (elderly patients) 


What drugs lower TG's and raise HDL?

- Fibric Acid Derivatives (Fibrates)

- Nicotinic Acid (Niacin)

- Omega-3 Polyunsaturated fatty acids (Fish Oil) 


What are the fibric acid derivatives? What is their MOA?

- Gemfibrozil, Fenofibrate

- MOA: ligand for the ligand-activated PPAR-alpha nuclear receptor (mimic fatty acids, the natural ligand)

1. INC transcription of LPL, DEC syn of ApoC-III, and ApoA-1 and -2 syn INC (increased HDL) 

2. Increased oxidation of fatty acids bc enzymes involved also regulated by PPAR -> less FA available for synthesis of TG’s

3. Whole series of metabolic genes with this binding site on them 


What are the lipoprotein effects of fibrates?

- Reduce VLDL, increase HDL 

- TG's reduced up to 50% 

- HDL-C increased up to 15% 

- LDL-C unchanged or decreased modestly (may also increase) 


What are the AE's of the fibrates?

- Gastroesophageal reflux, diarrhea, increased liver enzymes

- Fenofibrate: increased creatinine (reversible DEC in GFR; though to be related to PG syn), paradoxical HDL lowering

- Lithogenic bile: gallstones

- Teratogenic/Embryocidal in animals (no human data)

1. Pregnancy category C (use only if benefit outweighs risk) 


What are the dosage, metabolism, and excretion differences between Gemfibrozil and Fenofibrate?

- Gemfibrozil (generic): 600 mg tablet

1. Extensively metabolized by liver (oxidation, glucuronidation by UGT1A1) -- UGT1A1 also used for statins -> reduces statin metabolism, so contraindicated or dosage of statin limited

2. Can be safely given to pts w/renal disease.

- Fenofibrate (Tricor®)

1. Hepatic metabolism: active metabolite fenofibric acid dependent on renal excretion

2. Accumulates with renal insufficiency (GFR < 50 ml/min) -> dosage reduction recommended

3. NOT recommended for advanced renal disease ie GFR < 30 ml/min


What are the chemistry and preparations of nicotinic acid?

- Pyridine-3-carboxylic acid (vitamin B3, aka niacin)

- Preparations:

1. Immediate Release (IR) (Niacor®): requires slow up-titration to minimize flushing

2. Extended-Release (ER) (Niaspan®): less flushing, better tolerated


What are the adverse effects of nicotinic acid?

- Cutaneous flushing (common): give ASA; start low, INC slowly, use extended-release niacin (Niaspan)

- Elevated transaminases, hepatitis, hepatic failure (older slow release preps: SR dose limited to 2 g/d)

- GI irritation: nausea, activation of peptic ulcer disease, hyperuricemia, gout

- Conjunctivitis, cystoid macular edema, retinal detachment 

- Myositis (rare)

- Dry skin, pruritis, icthyosis, acanthosis nigricans (if you give Niacin several times, you deplete mast cells of histamine)

- Insulin resistance: glu intolerance, hyperglycemia

- Pregnancy category C: use if benefit exceeds risk 


HyperTGemia and low HDL are powerful risk predictors, but are they risk factors?

- When you do multivariate analysis, looking at risk with these, and take everything else out, very little risk remaining that can be attributed solely to these

Somehow this moderates risk, however 

- No trials showed added benefit of using these with statin therapy, which are main line of tx (exception people with high TG, low HDL, who did improve)

- Considered unproven add-on therapy


What are N-3 FA's, and how do they reduce TG's and CV risk?


What are some dietary sources of Omega-3 and -6 FA's?

- 3: walnuts, flaxseed, fatty fish, canola oil, fish oil, soybean 

- 6: corn, cottonseed, sunflower oils, black currant seed oil, 


How do N-3 FA's affect lipids?

- Reduce plasma TG's up to 35% and hepatic TG syn

- INC FA oxidation via PPAR


What are the potentially beneficial effects of N-3 FA's?

- Antiplatelet, hypotensive, hypolipidemic effects

- Dietary intake of one or more servings of fish/week reduces risk of heart attack or stroke

- Intake of fish oil capsules has not yet been shown to reduce risk 

- Studies using concentrated fish oil (EPA and/or DHA) currently underway 


How does HDL affect CHD risk?

- Epi observations: 

1. CHD risk decreases by 50% for each 0.52 mmol/L INC in HDL-C 

2. Epi association b/t low HDL-C level and CAD consistent across pops, and has been validated in all major epi studies 

3. Still just an ASSOCIATION (does NOT imply causality)


What is CETP?

- Plasma protein that catalyzes transfer of CE (chol ester) from HDL to ApoB-containing lipoproteins (VLDL and LDL) in exchange for TG's 


Will CETP inhibitors work?

- Higher HDL-C is good, but benefit of HDL-C raising has been harder to prove 

- Anacetrapib and Evacetrapib dramatically increase HDL-C (10x that seen in HPS2), AND lower LDL by 30-40% 

- Anacetrapib lowers Lp(a) by 35% 



A 55 year old male has Type II Diabetes and Coronary Heart Disease. His LDL-C is 105 mg/dl, TG is 300 mg/dl and HDLC is 32 mg/dl. What drug would be considered PRIMARY treatment to reduce his risk of recurrent coronary disease events? 



What did the PROVE-IT study show?

That while there is a benefit to using intensive statin therapy, there is still residual risk