Lipid/Atherosclerotic Disorders and Lipid lowering drugs

exam 2

LDL

delivers to cholesterol cells

excess LDL→ atherosclerosis

1. excess enters the cell walls

2. becomes oxidized

3. Oxidized LDL→ inflammation→macrophages engulf LDL→ foam cells

4. cells accumulate →plaque → atherosclerosis (narrowed arteries )→ increased cardiovascular risk (heart attack and stroke)

HDL

removes cholsterol from arteries

protective agaisnt atherosclerosis and

Low HDL → increased risk Coranary artery disease (CAD)

picks up excess

cholesterol from tissues

and returns it to the liver

￫ protective.

Triglycerides

stored blood fats/energy

High levels→ increased risk of pancreatitis and cardiovascular risk

Total cholesterol

LDL + HDL + other lipoproteins -total cholesterol in blood, includes cholesterol carried in LDL, HDL and other lipoproteins -

Liver

• Makes cholesterol

(and triglycerides).

• Removes excess

cholesterol from blood.

VLDL

Carries triglycerides (TG)

from liver ￫ tissues.

• After releasing TG,

becomes LDL

LDL Receptors

Remove LDL from

• Picks up cholesterol

circulation (mainly

in liver).

Thyroid hormone

T LDL receptors

￫ \ LDL

insulin

increases TG storage -Insulin promotes the storage of triglycerides (fat) in adipose tissue

Insulin can increase LDL receptor activity in the liver, helping the liver remove LDL cholesterol from the blood

More LDL is taken out of the bloodstream, so blood LDL levels can decrease

decreases lipolysis

decreases circulating TG

Cortisol

is released during stress, such as fasting, illness, or prolonged exercise. It helps make energy available to the body→lipolysis

Lipolysis

stored triglycerides in fat cells break down into fatty acids and glycerol

What does cortisol do to lipolysis?

Can ↑ lipolysis- mobilizes fat for energy, but too much cortisol over time can also promote fat accumulation.

What happens during lipolysis?

TG breaks down into fatty acids and glycerol

What can chronically high cortisol do to blood TG?

What can chronically high cortisol do to blood TG?

thyroid

hormones help the liver clear LDL from the blood

LDL-C

less than 100= good

greater than or equal to 160= high

greater than or equal to 190 = very high

HDL

great than or equal to 60 = lower risk

less than 40 = risk for ASCVD

Triglycerides (TG)

less than 150 = good

greater than or equal to 150= elevated ASCVD risk

greater than or equal to 500 = markedly elevaated and increased pancreatitis risk

total cholesterol

less than 200 = good

greated than 200 = elevated

Non-HDL-C

less than 130= good

greater than or equal to 130

Dyslipidemia

abnormal levels of fats in your blood.

Dyslipidemia . Primary causes : genetic (inherited)

These are caused by the genes you inherit from your parents.

our body has an inherited problem clearing LDL from the blood.

Remember: LDL clearance decreases → LDL increases, often from birth.

Dyslipidemia . Primary cause: Polygenic risk

Many different genes contribute to abnormal cholesterol or triglycerides.

Remember: multiple genes → increased risk of high LDL and/or TG.

Dyslipidemia Secondary causes = acquired (develop during life)- Diet high in saturated/trans fats

↑ LDL

Unhealthy fats can raise LDL.

Dyslipidemia Secondary causes = acquired (develop during life)- excess sugar

Extra sugar can be converted into fat by the liver.

Dyslipidemia Secondary causes = acquired (develop during life)- Obesity/inactivity

↑ TG, ↓ HDL; LDL may increase

Fat metabolism becomes less healthy.

Dyslipidemia Secondary causes = acquired (develop during life)- Diabetes

↑ TG, ↓ HDL

Insulin resistance makes it harder to manage blood fats.

Dyslipidemia Secondary causes = acquired (develop during life)- Hypothyroidism

↑ LDL

Low thyroid hormone means the liver clears less LDL

Dyslipidemia Secondary causes = acquired (develop during life)- Chronic kidney disease (CKD)

Often ↑ TG

Kidney disease disrupts fat metabolism

Dyslipidemia Secondary causes = acquired (develop during life)- Alcohol

Can ↑ TG

The liver processes alcohol and can produce more TG.

Dyslipidemia Secondary causes = acquired (develop during life)- Some medications

May ↑ TG

Steroids and some beta-blockers can affect lipid levels.

Dyslipidemia Secondary causes = acquired (develop during life)- Smoking

↓ HDL and ↑ LDL oxidation

Smoking damages blood vessels and makes LDL more harmf

Lipoprotein(a) — Lp(a)

A cholesterol-carrying particle whose level is largely determined by genetics.

Lipoprotein(a) — Lp(a) Why measure it?

• high level indicates additional inherited cardiovascular risk.

• Usually measured at least once in adulthood.

Apolipoprotein B (ApoB)

Reflects the number of atherogenic (plaque-forming) particles in the blood, including LDL, VLDL and IDL particles.

• Higher ApoB = more particles capable of contributing to plaque buildup.

• Can help guide decisions about lifestyle changes and cholesterol-lowering medication.

IDL = Intermediate-Density Lipoprotein.

It forms when VLDL loses triglycerides and can then be converted into LDL.

Remember the sequence:

VLDL → IDL → LDL

Coronary Artery Calcium (CAC) Score

A CT scan detects calcified plaque in the coronary arteries.

• CAC = 0: No detectable calcified coronary plaque; medication may sometimes be deferred, depending on the patient's overall risk.

• CAC greater than 0: Calcified plaque is present, indicating coronary atherosclerosis.

Remember: CAC = Coronary Artery Calcium, showing evidence of plaque.

Borderline/intermediate risk, no known ASCVD

< 100 mg/dL

High risk, no known ASCVD

< 70 mg/dL

Established ASCVD, not very high risk

< 70 mg/dL

Established ASCVD, very high risk

< 55 mg/dL

ASCVD

atherosclerotic cardiovascular disease, such as a heart attack or ischemic stroke caused by atherosclerosis.

 dyslipidemia.-first-line therapy

Statins —

examples: atorvastatin and rosuvastatin.

They inhibit HMG-CoA reductase in the liver, reducing cholesterol production and increasing LDL removal from the blood.

trtm. - dyslipidemia-add if needed

Nonstatin medications 

Examples: ezetimibe, PCSK9 inhibitors, and bempedoic acid.

These may be added when statins alone do not achieve the appropriate LDL reduction or when statins are not tolerated.

dislypidemia lifestyle mods

Diet: DASH, Mediterranean, and other diets that reduce saturated/trans

fats, increase fiber.

• Exercise: ≥150 minutes/week moderate intensity.

• Weight: Support a weight that promotes overall health

• Smoking cessation

Dyslipidemia Monitoring:

Check lipid panel 4–12 weeks after starting therapy

• Then every 3–12 months.

Atherosclerosis:

• Chronic inflammation

of arterial walls ￫

lipid plaque buildup ￫

narrowed, stiff arteries

￫ blood flow to tissues.

Atherosclerosis:Pathophysiology (Progression) 1

Normal artery Healthy endothelium

and normal blood flow

Atherosclerosis:Pathophysiology (Progression) 2

Endothelial Injury -LDL enters arterial wall

after endothelial injury

(e.g., HTN, smoking hyperglycemia )

Atherosclerosis:Pathophysiology (Progression) 3

. Fatty Streak Macrophages take up LDL

￫ foam cells ￫ fatty streak

(early lesion).

Atherosclerosis:Pathophysiology (Progression) 4

Fibrous Plaque- Smooth muscle cells and

collagen form a fibrous cap

(stable plaque).

Atherosclerosis:Pathophysiology (Progression) 5

Complicated Plaque -Plaque rupture ￫ clot

formation ￫ can acutely

block blood flow

(e.g., Mi, stroke).

Atherosclerosis Complications heart

Coronary artery disease → less blood to heart

→ angina or heart attack

Atherosclerosis Complications Brain;

Cerebrovascular disease → less blood to brain

→ TIA or stroke

Atherosclerosis Complications Gut

Mesenteric ischemia → less blood to intestines →

abdominal pain, poor digestion, bowel damage

Atherosclerosis Complications Carotid artery disease

→ reduced

blood flow → TIA or stroke

Atherosclerosis Complications Limbs

Peripheral artery disease → less blood to

legs/arms → pain, ulcers, gangrene

Atherosclerosis Complications aorta

Aneurysms → weak artery walls → bulging →

risk of rupture and bleeding

Atherosclerosis Management

Medications: Statins, ezetimibe, PCSK9 inhibitors

▪ Lifestyle: Diet, exercise, quit smoking, weight control

▪ Control comorbidities: BP, diabetes

HMG-CoA Reductase Inhibitors “Statins” ex

Atorvastatin (prototype), rosuvastatin, simvastatin, pravastatin

HMG-CoA Reductase Inhibitors “Statins” moa

 inhibit HMG-CoA reductase → ↓ cholesterol synthesis in liver → ↑ LDL receptors → ↑ LDL

removal from blood → ↓ LDL-C

HMG-CoA Reductase Inhibitors “Statins” use

first-line drug therapy for lowering LDL-C and reducing ASCVD risk

HMG-CoA Reductase Inhibitors “Statins” Benefits

↓ Risk of MI (myocardial infarction) & stroke

▪ Stabilize arterial plaques→ ↓ risk of plaque rupture

HMG-CoA Reductase Inhibitors “Statins” ADR

Muscle pain/weakness, GI upset, ↑ liver enzymes; serious: rhabdomyolysis

HMG-CoA Reductase Inhibitors “Statins” nursing and clincial point

Monitor lipid panel; assess for muscle pain/weakness and liver problems

▪ Severe muscle pain/weakness + dark urine → report immediately

▪ Statins are generally avoided during pregnancy

Cholesterol Absorption Inhibitor ex

Ezetimibe [prototype]

Cholesterol Absorption Inhibitor Ezetimibe MOA

↓ cholesterol absorption in small intestine → ↑ hepatic LDL receptors

→ ↓ LDL-C

Cholesterol Absorption Inhibitor Ezetimibe Use

often added when statin alone does not achieve the LDL-C goal or used

when statins are not tolerated

Cholesterol Absorption Inhibitor Ezetimibe Benefits

Provides additional LDL-C lowering

▪ When added to statin therapy in appropriate high-risk patients → further ↓

cardiovascular events

Cholesterol Absorption Inhibitor Ezetimibe ADR

Diarrhea, abdominal pain, fatigue; may ↑ liver enzymes; rare myopathy

Cholesterol Absorption Inhibitor Ezetimibe nursing and clincial point

Monitor lipid panel; monitor liver enzymes when combined with a

statin; assess for muscle pain

▪ Commonly combined with a statin when additional LDL-C lowering is needed

PCSK9 Inhibitors ex

 Alirocumab [prototype], evolocumab (Repatha)

PCSK9 Inhibitors Alirocumab [prototype], evolocumab (Repatha) moa

Block PCSK9 → prevent LDL receptor destruction → ↑ LDL removal from blood

→ ↓↓ LDL-C

PCSK9 Inhibitors Alirocumab [prototype], evolocumab (Repatha) Use

additional LDL lowering for selected patients with ASCVD or severe

hypercholesterolemia who remain above their LDL-C goal

PCSK9 Inhibitors Alirocumab [prototype], evolocumab (Repatha) Benefits

Powerful LDL-C reduction

▪ In appropriate high-risk patients → ↓ risk of cardiovascular events, including MI &

stroke

PCSK9 Inhibitors Alirocumab [prototype], evolocumab (Repatha) ADR

Injection-site reactions, flu-like symptoms, nasopharyngitis

PCSK9 Inhibitors Alirocumab [prototype], evolocumab (Repatha) nursing and clinical point

dminister subcutaneously; monitor lipid panel and injection sites

▪ Clinical Point:

▪ Think PCSK9 = more LDL receptors available → much lower LDL-C

Bile Acid Sequestrants

ex.

(cholestyramine, colesevelam)

Bile Acid Sequestrant (cholestyramine, colesevelam) moa

Bind bile acids in the intestine

￫ I LDL-C

Bile Acid Sequestrants

(cholestyramine, colesevelam) adr and nursing

Constipation, bloating

• May increase T TGs

Encourage fluids/fiber

• Separate from other

medications as directed

Niacin (Vitamin B3) moa

decrease TGs and LDL-C;

may increase T HDL-C

Niacin (Vitamin B3) adr and nursing

Flushing

• increase blood glucose

• Liver toxicity

Monitor liver function

and blood glucose Note: Rarely used for cholesterol

management today.

hypertriglycerdemia pathogenesis

increase tg in blood- increase tg production/clearence leading to VLDL/chylomicrons

Hypertriglyceridemia Causes

obesity/insulin resistance, diabetes,

diet/alcohol, hypothyroidism, medications, genetics

Hypertriglyceridemia risk and trt

↑ ASCVD; very high TG → pancreatitis

lifestyle changes and statins and for severe cases fibrate

Fibrates — TG Lowering Drugs ex

Fenofibrate (prototype), gemfibrozil (Lopid)

Fibrates — TG Lowering Drugs Fenofibrate (prototype), gemfibrozil (Lopid) moa

Activate PPAR-α → ↑ breakdown/removal of triglycerides → ↓↓ TG

Fibrates — TG Lowering Drugs Fenofibrate (prototype), gemfibrozil (Lopid) use

Severe hypertriglyceridemia→ helps reduce risk of pancreatitis

Fibrates — TG Lowering Drugs Fenofibrate (prototype), gemfibrozil (Lopid) benefits

▪ Significantly ↓ triglycerides

▪ May ↑ HDL

▪ Helps reduce pancreatitis risk when TG are severely elevated

Fibrates — TG Lowering Drugs Fenofibrate (prototype), gemfibrozil (Lopid) ADR and nursing

GI upset, ↑ liver enzymes, gallstones; serious: myopathy/rhabdomyolysis

Monitor TG levels and liver function; assess for muscle pain/weakness

▪ Interactions: Combining with statins ↑ risk of myopathy/rhabdomyolysis

▪ Fenofibrate is generally preferred over gemfibrozil with a statin because

gemfibrozil has a greater risk of statin-associated muscle toxicity.

Peripheral Artery Disease (PAD)

Narrowing or blockage

of peripheral arteries

(most often in legs) due to

atherosclerosis.

reduced blood flow to the

extremities.

Peripheral Artery Disease (PAD) Pathogenesis

• Atherosclerosis → plaque buildup in peripheral arteries (most often legs).
  Narrowing/occlusion →
  J blood flow to the extremities.

• Can lead to tissue ischemia with activity or at rest.

Peripheral Artery Disease (PAD) signs and symptoms

Intermittent claudication

(calf pain with activity

that resolves with rest).

• Cool extremities

• Decreased or absent

peripheral pulses

• Hair loss, shiny skin

• Slow-healing wounds or ulcers

Peripheral Artery Disease (PAD) Diagnostic Testing

ankle bracial index, doppler, CT angiography

ME angiography

conventional angiography

Peripheral Artery Disease (PAD) management

lifestyle changes

antiplatelet

statins

Carotid Artery Stenosis

Narrowing of the carotid artery

(usually internal carotid) due

to atherosclerosis, leading

to decreased blood flow to

the brain and increased risk

for transient ischemic attack

(TIA) or ischemic stroke.

Carotid Artery Stenosis pathogenisis

Atherosclerotic plaque

accumulates in the carotid

artery (intima).

• Progressive narrowing

and turbulent flow.

• Can lead to reduced

cerebral perfusion or

plaque rupture with

thromboembolism to the

brain (TIA or ischemic stroke)

Carotid Artery Stenosis Risk Factors

Older age (≥65 years)

Hypertension Diabetes mellitus

Hyperlipidemia Smoking (strongest modifiable risk factor)

Coronary artery disease or other

atherosclerotic disease

Male sex

Family history of stroke or atherosclerosis

brain (TIA or ischemic stroke

Carotid Artery Stenosis Signs & Symptoms

Often asymptomatic

If symptomatic (TIA or stroke)

• Detected by screening

• Transient neurological

(e.g., carotid bruit).

deficits (e.g., unilateral

weakness or numbness,

facial droop, speech

changes, vision loss).

• Symptoms are usually

brief (TIA) or persistent

(stroke).