Atherosclerosis Treatment

Question 1

reasons for using statins over other cholesterol lowering therapies

Answer 1

Proven effective based on large number (21) of randomized clinical trials (RCTS)

More intensive statin therapy reduces rates of CHD, stroke and death more than less intensive therapy (5 RCTs)

Inexpensive (5 of 7 generic)

Safe when given as directed

Question 2

statin benefit groups

Answer 2

clinical ASCVD

LDL-C >/= 190 mg/dL without secondar ycause

primary prevention/diabetes - ages 40-75, LDL-C 70-189 mg/dL

primary prevention/no diabetes - ages 40-75, LDL-C 70-189 mg/dL, ASCVD risk >/= 7.5%

Question 3

When do results of stain treatment become the most prominent?

Answer 3

years 4-5

Question 4

mechanism of action of statins

Answer 4

structurally similar to HMG-CoA and act as a competitive inhibitor of HMG-CoA reductase, thereby reducing synthesis of cholesterol

leads to increased LDL receptors

small elevations in HDL-c is also seen

Question 5

drugs that lower LDL-C

Answer 5

statins

bile acid sequestrants

niacin

fibrates

omega-3’s

Question 6

What happens to mean % change from baseline LDL-C every time the dose of statin is doubled?

Answer 6

there will be an extra 6% decrease

Question 7

non-LDL effects of statins

Answer 7

endothelial function

reduction of inflammatory response

plaque stability

thrombus formation

Question 8

statins with long half lives

Answer 8

rosuvastatin (19-20 hrs) and atorvastatin (15-30 hrs)

Question 9

statins with short half lives

Answer 9

fluvastatin, lovastatin, pravastatin, simvastatin

Question 10

toxicity of statins

Answer 10

liver enzyme rises (transaminases)

muscle myositis

interacts with cyclosporine, gemfibrozil (glucuronidation affected), grapefruit juice (P450), erythromycin

decrease in ischemic stroke but slight increase in hemorrhagic stroke

Question 11

statins and diabetes

Answer 11

may raise blood sugar, 1 to 2 excess cases per year per 1000 patients

Question 12

metabolism of statins

Answer 12

CYP3A4 for lovastatin, simvastatin, and atorvastatin

CYP2C9 for fluvastatin and rosuvastatin

pravastatin has no CYP activty

all statins undergo glucuronidation

Question 13

lovastatin

Answer 13

fungal derivative

used for over a decade

moderate potency

has similar properties as red yeast rice, which has mevilonin

Question 14

simvastatin

Answer 14

fungal derivative

at high doses, best at raising HDL-c and Apo A1

very inexpensive

Question 15

pravastatin

Answer 15

fungal derivative

not metabolized by P450 system, sulfated

inexpensive

Question 16

fluvastatin

Answer 16

synthetic

not as potent

Question 17

atorvastatin

Answer 17

synthetic

potent, long half life of 14 hours

Question 18

cerivastatin

Answer 18

synthetic

removed from market due to myositis risk with high dosages and with gemfibrozil

Question 19

rosuvastatin

Answer 19

synthetic

most potent due to low lipophilicity and high hepatocyte selectivity because of large polar side chain

19 hour half life

Question 20

pitavastatin

Answer 20

synthetic

can be used for those who don’t tolerate other statins

Question 21

GI active drugs

Answer 21

bile acid sequestrants

stanols, sterols

Eztimibe (cholesterol absorbtion inhibitor)

Question 22

bile acid sequestrants

Answer 22

cholestyramine and colestipol - resins

colesevelam - gel

binds bile acids in the gut and causes depletion of hepatic cholesterol pools

increased production of more LDL receptors

non-systemic, not absorbed

Question 23

Ezetimibe

Answer 23

cholesterol absorption inhibitor

hepatic glucuronidation and then intestinal villi

decreased absorption of biliary and dietary cholesterol

acts at brush borders of small intestins

helpful in sitosterolemia

only one year of SHARP trial data for safety and additive effect with statins

Question 24

plant/sterol esters

Answer 24

inhibit micellar cholesterol absorption

not additive to Ezetimibe therapy

Question 25

efficacy of GI active drugs

Answer 25

sequestrants and Ezetimibe lowers LDL-C about 20% stanol ester about 10-14%

Question 26

combinint statin and GI active drugs

Answer 26

same result as 3 doublings of dosage of statins alone

Question 27

niacin (vitamin B3) mode of action

Answer 27

a. Potent **inhibitor of adipose tissue lipolysis** (G-coupled receptor) - Suppression of lipolysis in adipocytes by niacin activating its receptor GPR109A b. Decreases flux of FFA used by liver for VLDL production c. **Inhibits VLDL synthesis**; see decrease in large TG rich VLDL d. Decrease in assembly of apo B containing lipoproteins e. See decreased small dense LDL f. See increased HDL Apo A-1 (prolongs half-life) - Inhibits hepatic removal, best drug for raising HDL-C g. Reduces Lp(a) (only lipid drug to do this)

Question 28

clinical usage of niacin

Answer 28

Patients with high cholesterol and high triglyceride and low HDL-c Raises HDL at low dose; less potent in lowering LDL c at low dose than statins

Question 29

niacin toxicity

Answer 29

1) **Cutaneous vasodilation** and flushing due to effects of receptors in the dermis 2) **Hepatotoxicity**; more prominent with Niacin than it is with statins. 3) Niacin **raises blood sugar**; increases hepatic glucose output-use carefully in diabetics 4) **Elevates uric acid**--can lead to gouty arthritis 5) Exacerbates **peptic ulcer disease**

Question 30

forms of niacin

Answer 30

sustained release (more GI side effects, hepatic toxicity) intermediate release (bed time only, linear kinetics, best balance between flushing and liver concerns) immediate release (cheapest, most flushing)

Question 31

fibrates - Gemfibrozil and Fenofibrate mechanism of action

Answer 31

**Triglyceride rich lipoproteins** – major effect on lowering TG levels, done through PPAR alpha effects on ApoCII (decrease) and LPL (increase) **LDL**: Differing effects depending on LDL and TG levels - best LDL lowering if high LDL alone, paradoxical increases in LDL-C if LDL is not elevated fenifibrate lowers LDL-C more thatn Gemfibrozil **HDL**: increase if baseline levels are low, increase in ApoAI and AII Fenofibrate lowers uric acid and raises homocystein

Question 32

efficacy of fibrates

Answer 32

reduce progression of coronary lesions reduce major coronary events in primary and secondary prevention trials, bu tnot in trials of diabetics

Question 33

toxicity of fibrates

Answer 33

cholelithiasis mild GI symptoms myositis when combined with HMG CoA reductase inhibitors

Question 34

omega 3 fatty acids mode of action

Answer 34

Lower TG in a dose –related fashion (lipid reason to use omega 3 fatty acids) Don’t use to lower LDL-c Can see slight increase in HDL-c Reduced CHD death in survivors of MI

Question 35

efficacy of omega 3 fatty acids

Answer 35

In those with very high TG; can lower TG up to 50% In those with mild-moderate TG, can lower TG about 25%

Question 36

side effects of omega 3 fatty acids

Answer 36

well tolerated can raise LDL-C if combined with hyperlipidemia see increasing bruising can be used in combined hyperlipidemia with statins

Question 37

therapies to increase HDL-C

Answer 37

apo A1 milano like IV preparations CETP inhibitors –Torcetrapib caused increase in CHD and total mortality