Lipids Physiology, Pathophysiology and Atherosclerosis

What is/are the main function(s) of cholesterol?

cell membrane formation and production of steroid hormones

What is the primary function of lipoproteins?

Transportation of TG and cholesterol from liver to tissues or vice versa

Lipoproteins vary…

in size, TC and TG content, and function

Normal homeostasis

Cholesterol part of all cell membranes

Lipoproteins

transport TGs(triglycerides) and cholesterol from liver to tissues and back

lipoproteins are composed of

apolipoproteins and phospholipids

with too much LDL in the tissues

HDL can scavenge (reverse cholesterol transport)

Apo A1 function

atheroprotective (on the surface)

Apolopoproteins can be either

atheroprotective or atherogenic

General risk factors for ASCVD

hypertension, hyperlipidemia, DM, smoking

smoking increases ASCVD risk

30%

pathophysiology of atherosclerosis

lipids, inflammatory cells, and cellular debris accumulate in the arterial walls, forming plaques

Small, dense LDL

increase ASCVD (more atherogenic)

Why do we treat Hyperlipidemia?

TO PREVENT MI AND STROKE, PAD, angina, CABG and stent

Larger, less dense (“fluffy”) LDL

less increase of ASCVD risk

Which of the following best describes the pathophysiology of hyperlipidemia and ASCVD?

Excess LDL becomes oxidized in vasculature, causing atherosclerotic plaques, which rupture and cause ASCVD events

Adhering to heart healthy diet

LDL (decrease) 10-15% and ASCVD (decrease) up to 25%

Therapeutic Lifestyle Choices (TLC)

Foundation to ASCVD Risk

smoking (decrease) HDL

15-20%

first line hyperlipidemia agents

HMG coA (statins), ezetimibe, PCSK9i mABs

second line hyperlipidemia agents

bile acid, bempedoic acid, PCSK9 siRNA

third line hyperlipidemia agents

MTP inhibitors, ANGPTL3 inh, niacin, peroxisome

General Counseling

STRESS ADHERANCE, heart attack, stroke

statins moa

first line therapy, inhibits production of cholesterol by inhibiting HMG coA, reduces LDL 10-60%

Statin associated side effects (SASEs)

 intolerant to at least 2 different statins with 1 attempt at the lowest daily dose and a trial of alternative regimens

ASCVD at very high risk, ASCVD not very high risk, no ASCVD but LDL >190

first line: ezetimibe and PCSK9i, 2nd line: bempedoic acid or inclisiran

no ASCVD but with DM, no ASCVD nor DM

first line ezetimibe, second line bile acid, third line bempedoic acid

do not exceed 10mg simvastatin with

amiodarone, verapamil, diltiazem

do not exceed 20mg simvastatin with

amlodipine and grape fruit juice

Rhabdomyolysis

condition resulting in muscle cell breakdown and release into bloodstream, may cause renal failure

what to do with muscle pain before therapy

Obtain history of muscle symptoms to establish baseline

what to do with muscle pain during therapy

meausure CK if muscle symptoms

if unexplained muscle symptoms or fatigue develop…

DC statin and check CK, SCr, and a UA for myoglobinuria

muscle pain management

original or decrease dose of same statin or different statin

low

daily dose lowers LDL-C by <30%

moderate

daily dose lowers LDL-C by 30%-<50%

high

daily dose lowers LDL-C by >50%

Which of the following is/are toxic monitoring parameters for atorvastatin?

cratine kinase, AST/ALT

ezetimibe moa

impairs absorption of cholesterol and increases LDL receptor activity - reduces LDL 15-25%

PCSK9i moa

reduces LDL 45-60% or 50% in siRNA, blocks effects of PCSK9 to destroy LDL receptors

Bempedoic acid (Nexletol) moa

inhibitor of ATP-citrate lyase to decrease cholesterol synthesis, it is a pro drug

Bile Acid Sequestrants: MOA

Exchange chloride ion for bile acid in intestine, disrupt recycling of bile acids, reduces LDL 15-25%

MTP inh. moa

reduces LDL 50%, inhibits mtp in liver, preventing assembly of apo B containing lipoproteins

The earlier you are diagnosed with hyperlipidemia

the earlier you could develop atherosclerosis

ANGPTL3 inh moa

targets mRNA to block angiopoietin like protein 3, lowers LDL 50%

Niacin moa

inhibits TG synthesis, causes apoB degradation , reduces LDL 5-15%

Niacin safety

flushing of skin

fibric acid derivatives moa

activates PPAR alpha- activates lipoprotein lipase, which increases lipolysis and TG removal, reduces LAL 5-15% and TG 20-50%

Doubling a statin would be how lowering of LDL

6%

the lower the LDL

the lower the ASCVD risk

primary prevention next steps

10-yr risk score, risk enhancers, DM

secondary prevention next steps

ASCVD very high risk?

ASCVD includes

MI, ACS, angina, CVA, CBG, PTCA, stent

prevent risk low

<3%

prevent risk borderline

3-<5%

prevent risk intermediate

5-<10%

prevent risk high

>10%

Patient is considered very high risk if

multiple major ASCVD events OR 1 majotr ASCVD event with multiple high risk conditions

high risk conditions

age>65yr, DM, HF, HTN, LDL >100, smoker, coronary bypass

if 10 year risk over 10%…

start statin - moderate intensity

not very high risk initial treatment

TLC + statin - high intensity

No drugs 2 hrs before or 4 hrs after taking

bile acids