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Cardio Week 3 > ICL 5.9: Clinical Hyperlipidemia Management > Flashcards

ICL 5.9: Clinical Hyperlipidemia Management Flashcards

1
Q

elevated levels of what substance correlates with increased/decreased incidence of atherosclerosis and coronary artery disease?

A

elevated levels of LDL correlate with increased incidence of atherosclerosis and coronary artery disease

elevated levels of triglycerides (which measures triglyceride-rich lipoproteins such as VLDL and IDL) are also implicated in development of atherosclerosis

markedly elevated levels of triglycerides (>500 mg/dl) are associated with a higher risk of pancreatitis

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2
Q

what are lipoproteins? what is their structure?

A

lipoproteins ship cholesterol and triglycerides since they’re insoluble in water

lipoprotein particles consists of lipid and apolipoprotein –> the lipid component has a hydrophobic core of triglycerides and cholesteryl esters and a surface monolayer of phospholipids and free (unesterified) cholesterol

the apolipoprotein function as a cofactor and ligand for receptors

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3
Q

what are the classes of lipoproteins?

A
  1. chylomicrons
  2. VLDL
  3. LDL
  4. HDL
  5. IDL

the major plasma lipoproteins are distinguished by their lipid content and density and their constituent proteins

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4
Q

what is the exogenous pathway of lipid metabolism?

A

chylomicrons are formed within the intestine from dietary fat and are rich in triglycerides

chylomicrons undergo hydrolysis by lipoprotein lipase in the muscle and adipose tissue to form chylomicron remnants –> free fatty acids are taken up by tissue

the liver then clears chylomicron remnants using the LDL receptor on hepatocytes

cholesterol is also removed exogenously through secretion of cholesterol into bile or conversion of cholesterol into bile salts.

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5
Q

which apolipoproteins do chylomicrons have? what is their function?

A

ApoC, ApoE and ApoB-48

ApoC is required cofactor for metabolism by lipoprotein lipase. It is then removed after it is converted to a chylomicron remnant

ApoE is a ligand for the LDL receptor and facilitates binding of the chylomicron remnant particles and uptake by the liver

ApoB48 is an essential protein needed for the assembly & secretion of chylomicrons

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6
Q

what is the endogenous pathway of lipid metabolism?

A

the liver produces lipoprotein, they circulate and deposit and then are re-uptaken by the liver

VLDL is produced by the liver and is also triglyceride rich

VLDLs undergo hydrolysis by lipoprotein lipase in the muscle and adipose tissue to form IDL

IDL undergoes further metabolism to form LDL particles

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7
Q

which apoproteins do VLDL, IDL and LDL have? what is their function?

A

VLDL, IDL and LDL have ApoB-100 particles!!

VLDL and IDL also have ApoC and ApoE proteins

ApoC is required cofactor for VLDL metabolism by lipoprotein lipase. It is then removed after it is converted to IDL

ApoE is a ligand for the LDL receptor, facilitates binding of the IDL and LDL particles and uptake by the liver

ApoB100 is an essential protein needed for the assembly & secretion of VLDL, IDL and LDL. It is also another ligand for the LDL receptor facilitating hepatic uptake.

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8
Q

which cholesterol is the bad cholesterol?

A

LDL accounts for approximately 70% of the total plasma cholesterol and is cleared by the liver

elevated levels of LDL correlate with increased incidence of atherosclerosis and coronary artery disease (“bad cholesterol”)

a major mechanism for LDL cholesterol removal is uptake by the LDL receptor on hepatocytes

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9
Q

how is cholesterol eliminated/removed?

A

HDL is secreted by both the liver and the intestines and readily accepts cholesterol from macrophages and other peripheral cells and it is then taken up by the liver

since it removes cholesterol from cells and returns it to the liver, it is considered cardioprotective (“good cholesterol”)

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10
Q

which apoproteins does HDL have?

A

HDL has ApoA-1 proteins

these are essential structural proteins for HDL and also activate hepatic lipase when HDL is taken up by the liver

HDL and ApoA-1 proteins have multiple additional properties including anti-inflammatory properties

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11
Q

how do the exogenous and endogenous pathways work together to control cholesterol?

A

EXOGENOUS PATHWAY
involves dietary intake of fats and cholesterol, uptake in intestines, transport in blood via chylomicrons, unloading of TGs at muscle and fat via lipoprotein lipase, liver uptake of chylomicron remnants, and bile acid secretion

ENDOGENOUS PATHWAY
involves secretion of VLDL by the liver, circulation and metabolism of VLDL, IDL, and LDL particles, deposition of LDL into peripheral tissues, and re-uptake of LDL by the liver. It also involves reverse cholesterol transport by HDL to the liver

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12
Q

which particles are atherogenic particles?

A

LDL, IDL and VDL

they are all apoB-100 containing particles

LDL is the most atherogenic of them all

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13
Q

on a lipid panel, how do you measure chylomicrons, VLDL, LDL, IDL and HDL?

A

chylomicrons are measured by triglyceride levels

VLDL are measured by triglyceride levels

LDL and HDL are directly measured

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14
Q

what is the etiology of dyslipidemia?

A

combination of factors cause dyslipidemia:

  1. obesity
  2. inactivity
  3. dietary habits
  4. genetic predisposition
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15
Q

what are genetic syndromes of dyslipidemia?

A

aka primary dyslipidemia

primary dyslipidemia results from genetic mutations in lipid metabolism genes

there are 5 primary dyslipidemias: hyperlipoproteinemias type I-V

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16
Q

what is the cause of hyperlipoproteinemias type I and V?

A

type I and V result from genetic defects in lipoprotein lipase

this results in an accumulation of unhydrolyzed chylomicrons and VLDL leading to severely elevated triglyceride levels

normal triglyceride levels are under 100 but these people have over 1000!!

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17
Q

what is the cause of hyperlipoproteinemias type II?

A

result from defects in the LDL receptor so this is what we mean when we say familial hyperlipidemia! can be heterozygous or homozygous

type IIb also associated with increased VLDL secretion

these result in an severely increased LDL and VLDL particles since they cannot be effectively taken up by hepatocytes

this results in predominately LDL but also triglyceride elevations on serum lipid measurements

LDL >200 and total cholesterol > 300

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18
Q

what is the cause of hyperlipoproteinemias type III?

A

results from a defective/nonfunctional apoE protein

these result in an accumulation of chylomicron remnants and IDL which cannot be taken up by hepatocytes also causing elevations in triglycerides only

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19
Q

what is the cause of hyperlipoproteinemias type IV?

A

result from an increase in VLDL production

results in elevated circulating levels of VLDL and elevated triglycerides

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20
Q

what are some of the secondary causes of hypercholesterolemia?

A
  1. high fat diet
  2. obstructive liver disease
  3. nephrotic syndrome
  4. hypothyroidism
  5. medications = corticosteroids, progestins

these are conditions can produce elevated lipoprotein levels in the absence of an underlying genetic defect

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21
Q

what are some of the secondary causes of hypertriglyceridemia?

A
  1. type II DM
  2. obesity
  3. hypothyroidism
  4. alcohol use
  5. medications = B blockers, diuretics, estrogen

these are conditions can produce elevated lipoprotein levels in the absence of an underlying genetic defect

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22
Q

how do we diagnose dyslipidemias?

A

a fasting lipid profile

many patients have no specific signs or symptoms

a fasting lipid profile is indicated in all patients > 35 years of age or in those >/= 20 years of age with coronary artery disease (CAD) risk factors

these should be repeated every 5 years or sooner if lipid levels are elevated

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23
Q

what is the Friedewald equation?

A

LDL-C = TC - HDL - TG/5

Friedewald equation is used to calculate LDL from Total cholesterol (TC), triglycerides (TG), and HDL cholesterol

the problem with this equation is that if triglyceride levels are >400 mg/dL, calculated LDL is inaccurate because you’re subtracting a huge number and you would underestimate the patient’s LDL-C levels

24
Q

what are the clinical manifestations of dyslipidemia?

A

for most people dyslipidemia is asymptomatic until a symptomatic CVD event occurs like MI, angina, stroke, or claudication

in extreme and genetic cases, there can be symptomatic presentations such as:

  1. severe hypertriglyceridemia may present with acute pancreatitis (common in type V dyslipidemia = LPL mutation)
  2. cutaneous manifestations
25
Q

in addition to a lipid profile, which major risk factors for CAD should be identified?

A
  1. cigarette smoking
  2. hypertension
  3. diabetes
  4. age (men > 45 years, women >55 years)
  5. family History of premature CAD - male < 55 years, female < 65 years (first degree relative)
  6. HDL <40 mg/dL (HDL >60 mg/dL is considered protective)
26
Q

in patients with severe dyslipidemias, which physical exam findings may be present?

A
  1. xanthoma and xanthelasma: abnormal deposits of cholesterol material under the skin
  2. corneal arcus: abnormal deposits of cholesterol material at the periphery of the cornea

these are rarely seen in children except in those with homozygous familial hypercholesterolemia (FH)

  1. tendon xanthomata are the most common in the Achilles tendons and dorsum of the hands, but can occur at the other sites

these are present in type IIA dyslipidemia

  1. palmar xanthomas may occur on the palms of the hand and are often painful

commonly present in the type III dyslipidemia

27
Q

what physical exam findings are most often present in homozygous familial hypercholesterolemia (FH)?

A
  1. xanthoma and xanthelasma: abnormal deposits of cholesterol material under the skin
  2. corneal arcus: abnormal deposits of cholesterol material at the periphery of the cornea
28
Q

what physical exam findings are most often present in type IIA dyslipidemia?

A

tendon xanthomata

most common in the Achilles tendons and dorsum of the hands, but can occur at the other sites

29
Q

what physical exam findings are most often present in type III dyslipidemia?

A

palmar xanthomas

may occur on the palms of the hand and are often painful

30
Q

how do you treat dyslipidemia?

A
  1. therapeutic lifestyle changes

smoking cessation, maintaining healthy diet, weight control, exercise

  1. patient who have had a cardiovascular event should be referred to cardiac rehabilitation to help in implementing therapeutic lifestyle changes
  2. medications
31
Q

what type of diet is best for dyslipidemia treatment?

A

mediterranean diet

fruits and vegetables, nuts, legumes, olive oil, lean protein

32
Q

what is the MOA of statins?

A

HMG-CoA reductase inhibitors –> statins are competitive inhibitors of the enzyme HMG-CoA reductase, a rate-limiting step in cholesterol synthesis

  1. the liver needs cholesterol for synthesizes of bile and other functions but statins inhibit liver cholesterol synthesis by inhibiting HMG-CoA reductase which is a key enzyme in cholesterol production –> so now, the liver is “starved” of cholesterol and upregulates LDL receptors! this leads to increased clearance of LDL-C –> serum LDL cholesterol reduced as liver takes up more cholesterol (:
  2. reduced inrahepatic cholesterol also results in a reduction of hepatic VLDL synthesis because in the endogenous pathway, the liver sends out VLDL but since there’s less cholesterol, less VLDL is sent out
33
Q

how effective are statins at reducing cholesterol?

A

reduce LDL levels by 20-50%

reduce TG levels by 7-30%

increase HDL levels by 5-15%

the lowering of LDL reduces the lipid content of atherosclerotic lesions and promotes plaque stability reducing the likelihood of thrombus formation and vascular occlusion

34
Q

how do statins effect adverse cardiovascular events and mortality rates?

A

major clinical trials evaluating statin therapy have demonstrated reduction in major adverse cardiovascular events and mortality rates in patients both with and without a history of coronary artery disease

35
Q

what dose of statin should you give to different patients?

A

ASCVD already present or LDL >190 or diabetics with LDL70-189 = high intensity statin

non diabetics without clinical ASCVD but with 10 year cardiac risk = moderate to high intensity statin

36
Q

what is the ACC 10 year risk calculator?

A

age, gender, race, total cholesterol, HDL-C, BP, diabetes, smoker

over 7.5% you should be on a high intensity statin

37
Q

what is a high intensity vs. low intensity statin?

A

high intensity statin will result in >50% LDL reduction

medium/low intensity statin will result in 30-50% LDL reduction

atorvastatin 40-80 mg daily or Rosuvastatin 20-40 mg daily is considered “high intensity”

38
Q

what are the side effects of statins?

A

statins are well-tolerated drugs

  1. however, sometimes a side effect is myopathy –> vague aches to intense myalgias and muscle weakness

can very rarely lead to rhabdomyolysis

  1. hepatotoxicity is dose related and occurs in <1% of patients – usually it’s just asymptomatic with elevation in LFTs
39
Q

what are some non-statin therapies for dyslipidemia?

A

these are used in patients who do not tolerate statins or when risk reduction or LDL cholesterol reduction is not adequate on statin therapy

  1. PCSK9 inhibitors
  2. cholesterol absorption inhibitors
  3. bile acid binding resins
  4. fibrates
  5. icosapent ethyl
40
Q

what are PCSK9 inhibitors?

A

class of agents that reduces LDL cholesterol

PCSK9 protein binds to the LDL receptors and targets them for destruction in lysosomes which leads to reduced LDL clearance and higher LDL levels

so PCSK9 inhibitors are monoclonal antibodies that target PCSK9 and prevent them from destroying LDL receptors

Inhibition of PCSK9 leads to LDL receptor recycling, higher LDL receptor density, and more effective removal of LDL cholesterol from the blood

41
Q

which drugs are PCSK9 inhibitors?

A
  1. evolucumab

2. alirocumab

42
Q

what is the efficacy of PCSK9 inhibitors?

A

these drugs reduce LDL cholesterol by 50-60% even in those patients already on statin therapy

43
Q

which drugs are cholesterol absorption inhibitors?

A

ezetimibe

it is the only drug in the class of absorption inhibitors

44
Q

what is the MOA of cholesterols absorption inhibitors?

A

it is a selective inhibitor of cholesterol uptake at the small intestine

it competitively inhibits a transporter called the Niemann-Pick-like 1 protein

by reducing cholesterol uptake ezetimibe results in reduced chylomicron production and less cholesterol delivery to the liver

the reduced cholesterol content stimulates compensatory hepatic production of LDL receptors, augmenting clearance of LDL particles

45
Q

what is the efficacy of ezetimibe?

A

Ezetimibe reduces LDL cholesterol by 18% and minimal effects on HDL and triglyceride levels

so statins and PCSK9 inhibitors are a lot better they have like 50% efficacy but Ezetimibe has been proven to reduce cardiovascular events when added to statin therapy

46
Q

which drugs are bile acid binding resins?

A
  1. cholestyramine
  2. colestipol
  3. colesevelam

not really used much clinically because the other classes are better

47
Q

what is the MOA of bile acid binding resins?

A

these drugs bind bile acids in the intestines and prevent normal reabsorption to the liver through the enterohepatic circulation

normally the liver secretes bile acids through the intestines which increase absorption of fats

by removing bile acids from enterohepatic circulation, more hepatic cholesterol is converted into newly produced bile acids –> this action depletes intrahepatic cholesterol stores and stimulated production of LDL receptors leading to a greater amount of circulating LDL

however, new hepatic cholesterol production is also stimulated resulting in greater vLDL production and greater triglyceride levels

48
Q

what are fibrates and niacin used for?

A

fibrates and Niacin are drugs that are most effective in reducing triglyceride levels

although elevated triglycerides are associated with higher risk of cardiovascular events, the clinical evidence for lowering triglycerides to improve cardiovascular outcomes is not strong

therefore these agents are mainly used to treat severe hypertriglyceridemia (>500 mg/dL) when the risk of pancreatitis is high or after LDL lowering therapies have been initiated

49
Q

which drugs are fibrates?

A
  1. gemfibrozil

2. fenofibrate

50
Q

what are the side effects of fibrates?

A

you should know that fibrates can increase the risk of myopathy especially when combined with a statin!!

also cholesterol gallstones

51
Q

what is icosapent ethyl?

A

it’s a new formulation of high purified EPA (omega-3 fatty acid)

it’s the first omega 3 product to be proven to reduce cardiovascular events including MI and death

it’s indicated for secondary prevention in patients with TG > 150 mg/dL and also for primary prevention in patients with multiple risk factors

52
Q

Which of the following lipoprotein particles contain apolipoprotein B48?

A.VLDL

B.LDL

C.Chylomicrons

D.IDL

E.HDL

A

C.Chylomicrons

53
Q

Which of the following best describes the mechanism of action of HMG-CoA Reductase Inhibitors (“statins”)?

A. Bind and inactivate a protein that targets the LDL receptors for destruction resulting in increased LDL receptors and increase in LDL clearance.

B. Selectively inhibits cholesterol uptake in the small intestine.

C. Increases synthesis of lipoprotein lipase.

D. Reduces intrahepatic cholesterol synthesis which causes an increase in number of hepatic LDL receptors and increases LDL and & IDL clearance

A

D. Reduces intrahepatic cholesterol synthesis which causes an increase in number of hepatic LDL receptors and increases LDL and & IDL clearance

54
Q

What is the most common side effect observed with HMG-CoA Reductase Inhibitors?

A.Myalgias

B. Diarrhea

C.Flushing

D.Hypersensitivity reaction – rash, pruritis

E.Hyperglycemia.

A

A.Myalgia

55
Q

match the following: statins, PCSK9 inhibitors, ezetimibe, fibrates

A. Bind and inactivate a protein that targets the LDL receptors for destruction resulting in increased LDL receptors and increase in LDL clearance.

B. Selectively inhibits cholesterol uptake in the small intestine.

C. Increases synthesis of lipoprotein lipase.

D. Reduces intrahepatic cholesterol synthesis which causes an increase in number of hepatic LDL receptors and increases LDL and & IDL clearance.

A

A. Bind and inactivate a protein that targets the LDL receptors for destruction resulting in increased LDL receptors and increase in LDL clearance –> PCSK9 inhibitors

B. Selectively inhibits cholesterol uptake in the small intestine –> ezetimibe

C. Increases synthesis of lipoprotein lipase –> fibrates

D. Reduces intrahepatic cholesterol synthesis which causes an increase in number of hepatic LDL receptors and increases LDL and & IDL clearance –> statins

Cardio Week 3 (13 decks)

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