lipid disorders Flashcards
leading cause of death in the US
heart disease
High cholesterol puts you at risk of heart disease
High cholesterol is ____ until chronic disease has developed
asymptomatic
The 2 main lipids are:
cholesterol
triglycerides
an essential element of all animal cell membranes and forms the backbone of steroid hormones and bile acids synthesis
cholesterol
lipid that assist in the transfer of energy into cells
Triglycerides
- proteins required for the assembly, structure, function and metabolism of lipoproteins
- activates enzymes for lipoprotein metabolism and acts as ligand for cell surface receptors
Apolipoproteins
Apolipoproteins are synthesized where
liver
small intestines
- complex molecules made up of lipids and apolipoproteins
- Transportation of cholesterol, triglycerides and fat-soluble vitamins to and from tissues
Lipoproteins
Lipoproteins are classified based upon ?
density
what is determined by the presence of triglycerides and apolipoproteins
density
apolioporoteins > triglycerides
5 types of Lipoproteins
- chylomicrons
- VLDL - Very-low-density
- IDL - Intermediate-density
- LDL - Low-density
- Lp (a) - (Lipoprotein A) - HDL - High-density
Lipoprotein Composition
- Core of hydrophobic lipids
- triglyceride (aka triglycerols)
- cholesterol esters - Shell of hydrophilic lipids
- phospholipids
- unesterified cholesterol
- apolipoproteins (apo)
Lipoprotein Metabolic Pathways
- Exogenous lipid pathway
- absorption of dietary lipids and formation of chylomicrons - Endogenous lipid pathway
- secretion of VLDL by the liver, transition to IDL and LDL
steps of Transportion of Dietary (Exogenous) Lipids
- Dietary TG’s, cholesterol, fatty acids and retinol (vit. A) are absorbed in small intestine combined with apolipoproteins (apoC, apoE, apoB-48) = chylomicrons
- Chylomicrons are absorbed into capillaries where they are used in peripheral tissue via apoCs.
- TG’s are broken down by LPL for energy to muscles and adipose tissue (aka - lipolysis) - Chylomicrons (smaller remnant) travel to the liver and are taken up by LDL receptors (LDLR) via apoE
steps of Transportation of Hepatic (Endogenous) Lipids
- VLDL is derived in the liver with a similar composition as chylomicrons with the substitution of apoB-100 (loses ApoB-48)
- Upon leaving the liver VLDL acquires apoE and apoC via transfer from HDL molecules
- VLDL is utilized in the peripheral tissues (apoC) as TG’s are broken down by LPL for energy (lipolysis) and now are referred to as IDL
- 40-60% of IDL is taken up by the liver (via apoE and the LDLR), the remaining IDL is further broken down by hepatic lipase (HL) during systemic circulation to form LDL
- 70% of the LDL is removed from circulation by the liver (via apoB & LDLR), the remaining 30% is used up by the peripheral tissues (lipolysis)
- LDL removed from circulation by the liver is broken down and the cholesterol is excreted in the bile
describe the HDL Metabolism & Reverse Cholesterol Transport
- Immature HDL is synthesized in the liver and intestines
- HDL recruits cholesterol from peripheral cells, macrophages and other lipoproteins (VLDL & chylomicrons)
- The recruited cholesterol is converted to cholesterol ester by a dietary enzyme, lecithin-cholesterol acyltransferase (LCAT), forming a mature HDL which allows for more efficient transport through the bloodstream
- HDL transport of cholesterol to liver (2 ways):
- HDL is directly taken up by hepatocytes
OR
- transfer of cholesterol for TGs with less dense lipoproteins (LDL & chylomicrons) - In the liver HDL is broken further down into smaller HDL molecules to allow for faster catabolism and excretion
which cholesterol
deposits cholesterol in the blood vessel wall
build-up of cholesterol in the vessel can impede blood flow
LDL - “bad”
which cholesterol
can “sweep” cholesterol out of the blood vessel keeping them clear of build-up
HDL - “good” cholesterol
A disorder that results in an increase in plasma cholesterol, triglycerides or both and is often accompanied by a low HDL
Dyslipidemia
(genetic predisposition and environmental factors)
Dyslipidemia increases risk for what disease?
atherosclerotic cardiovascular disease (ASCVD)
causes/pathways of dyslipidemia
- Excessive hepatic secretion of VLDL
- Impaired lipolysis of triglyceride-rich lipoproteins
- chylomicrons and VLDL - Impaired hepatic uptake of ApoB containing lipoproteins
- all lipoproteins except HDL - Inherited low levels of HDL-C
what is the MC cause of dyslipidemia
Excessive hepatic secretion of VLDL
for Excessive hepatic secretion of VLDL
what does fasting TGs and HDL-C levels look like?
elevated fasting TG’s
low HDL-C levels
Factors that increase VLDL secretion
- Obesity
- Insulin resistance
- High-carb diet
- Nephrotic syndrome
- ETOH use
- Cushing’s Syndrome
- Exogenous estrogens
- Genetics
- Familial Combined Hyperlipidemia
- Lipodystrophy
Pathophysiology varies with each cause
results from a dysfunction in lipoprotein lipase
Impaired Lipolysis of Triglyceride-Rich Lipoproteins
how does Impaired Lipolysis of Triglyceride-Rich Lipoproteins affect TGs and HDL-C levels?
elevated TGs
low HDL-C
cause of Impaired Lipolysis of Triglyceride-Rich Lipoproteins
genetic disorders
insulin resistance
a down regulation of the LDL receptor in the liver leads to elevated serum LDL-C
Impaired Hepatic Uptake of apoB-containing Lipoproteins
cause of Impaired Hepatic Uptake of apoB-containing Lipoproteins
- saturated fat intake reduces LDL activity
- hypothyroidism
- estrogen deficiency
- chronic kidney and liver disease
- multiple drugs
- thiazides, cyclosporin, carbamazepine - genetic disorders
accelerated catabolism of HDL and its apoA
Disorders of Low HDL Cholesterol
causes of Disorders of Low HDL Cholesterol
obesity
insulin resistance
genetic disorders
majority of pts with dyslipidemia are ___ and diagnosis is made on routine laboratory screening
asx
yellow, pink, brown, or skin-colored
can be pruritic or painful
patches on skin (MC -buttock) due to lipid deposition
extremely high chylomicrons (TG’s) or VLDL
eruptive xanthomas
lipid deposit nodules in the tendons of the hands, feet, and heel
seen with high LDL
tendinous xanthomas
milky appearance of the veins and arteries of the retina
seen with extremely high triglycerides
lipemia retinalis
serum changes with dyslipidemia
opalescent or milky serum
seen with high triglycerides
serum changes with dyslipidemia
opalescent or milky serum
seen with high triglycerides
what are the screening recommendations for dyslipidemia
- ACC/AHA 2018
- all at age 20
- children beginning at age 2 if (+) FMHx of early CVD or significant primary hypercholesterolemia
ASCVD Risk Factors
- Tobacco use
- DM
- HTN
- Obesity (BMI ≥ 30)
- Fhx of premature heart disease
- 55 y/0 in males
- 65 y/0 in females - Personal hx of CAD or non-coronary atherosclerosis
- abd aortic aneurysm, peripheral artery disease, carotid artery stenosis
preferred initial testing for dyslipidemia
Total cholesterol (TC) and HDL
Fasting (preferred) or non-fasting (acceptable) samples can be used for initial screening
Confirm abnormal results with a fasting sample
Fasting full lipid panel is needed if
TC > 250 or HDL-C is < 40
non-fasting may result in higher TG’s leading falsely elevated results
you must fast for how long for fasting lipid panel
9-12 hour fast prior to collection
How often should we screen for dyslipidemia
- 5 years for the average adult
- 3 years for lipid levels close to those warranting therapy
- Longer intervals are acceptable for low risk patients with repeated normal lipid levels
Interval for screening is not definitive
what changes do you see with lipid levels with age?
- Lipid levels stabilize in older adults but CVD increases with age
- Lipid levels are not likely to increase after age 65
- Screening can likely cease between 65-79 years of age
if lipid levels are elevated, what is next?
R/o secondary causes
1. hyperglycemia - blood glucose
2. nephrotic syndrome/chronic renal insufficiency - urine protein and serum creatinine
3. hepatitis/cholestasis - LFT’s
4. hypothyroidism - TSH
indications for statin therapy (Hyperlipidemia Management)
- clinical ASCVD
- LDL ≥ 190 mg/dL
- DM
- Primary Prevention with
ASCVD risk of ≥7.5%
clinical ASCVD management
- Hx + determine risk stratification
- statin therapy
- High intensity statin - Very high risk or ≤75 y/o
- Moderate intensity statin - Not “Very High Risk” and 75+
what are major ASCVD events for risk stratification
- ACS within past 12 months
- hx of MI (other than ACS above)
- hx of ischemic stroke
- Symptomatic PAD
what are the high-risk conditions for risk stratification
- Age ≥ 65 years
- CKD (GFR 15-59 mL/min)
- Coronary bypass or percutaneous intervention
- Current smoker
- DM
- Hereditary Familial Hyperlipidemia
- hx of heart failure
- HTN
- LDL-C ≥ 100 mg/dL despite max tolerated statin + ezetimibe
what makes a pt very high risk for ASCVD
2 Major ASCVD Events
OR
1 Major ASCVD Events + ≥2 high-risk conditions
what are the high-intensity statins?
moderate-intensity?
high
atorvastatin (40 mg++) 80 mg
rosuvastatin 20 (40 mg)
moderate
atorvastatin 10 mg (20 mg)
rosuvastatin (5 mg)
what is the goal for Clinical ASCVD management
- Goal #1 - 50% reduction in LDL-C
- Reassess lipid panel after 4-12 weeks then every 3-12 months - Goal #2 based upon risk factors
- ASCVD + Very High Risk = < 55 mg/dL
- ASCVD + Not Very High Risk = < 70 mg/dL
- ASCVD + baseline LDL-C ≥ 190 w/o FH = < 70 mg/dL
- ASCVD, a baseline LDL-C ≥ 190 w/ FH = < 55 mg/dL
Primary elevation of LDL cholesterol ≥ 190 mg/dL management (hyperlipidemia management)
- Start high intensity statin
- Reassess lipid panel after 4-12 weeks then every 3-12 months
- Goal
- Goal #1 50% reduction in LDL-C
- Goal #2 - LDL-C of <100 mg/dL
management for hyperlipidemia for Age 40–75 with DM and LDL 70-190 mg/dL
- Calculate estimated 10-year ASCVD risk
- review diabetes-specific high-risk features
- long duration (≥10 years for DM2 or ≥20 years for DM1)
- albuminuria ≥30 mcg of albumin/mg creatinine
- eGFR <60 mL/min/1.73 m2
- retinopathy
- neuropathy
- ankle-brachial index <0.9. - statin goals depend on risk factor
Predicts 10-year risk for first ASCVD event among patients who are between 20 and 79 years of age
ASCVD Risk Estimator Plus Calculator
ASCVD Risk Estimator Plus Calculator is based upon the following info:
Sex, Age, Race
TC/HDL
SBP
Tx for HTN/DM
Smoking status
what are the high risk factors for Age 40–75 with DM and LDL 70-190 mg/dL to determine statin indications
- 10 year risk ≥ 7.5%
- (+) Diabetes specific risk enhancers
what are the high intensity statin indications/goals for Age 40–75 with DM and LDL 70-190 mg/dL
Goal #1 - 50% reduction in LDL-C
Goal #2 - LDL-C of <70 mg/dL
what are the moderate intensity statin indications/goals for Age 40–75 with DM and LDL 70-190 mg/dL
Goal #1 - 30-49%% reduction in LDL-C
Goal #2 - LDL-C of <100 mg/dL
if the pt has no high risk factors present for Age 40–75 with DM and LDL 70-190 mg/dL for hyperlipidemia, what management do they receive?
moderate intensity statin
having at least 1 high risk factor = high intensity
management for Aged 40–75 without clinical ASCVD or DM and whose LDL-C is between 70–189 mg/dL for hyperlipidemia management
Calculate an estimated 10-year ASCVD risk
1. low risk (<5%) = risk discussion - lifestyle changes
2. borderline risk (5-7%) = risk discussion + discussion of moderate-intensity statin if risk enhancer present
3. intermediate risk (7.5-20%) = start moderate-intensity statin to reduce LDL-C by 30-40% (if risk estimate+enhancers favor statin use)
4. high risk (+20%) = start statin to reduce LDL-C +50%
borderline + intermediate:
Goal 1: 30-49% reduction of LDL
Goal 2: LDL < 100 mg/dL
high risk:
Goal 1: ≥ 50 % reduction of LDL
Goal 2: LDL < 70 mg/dL
how do you manage Aged 40–75 without clinical ASCVD or DM and whose LDL-C is between 70–189 mg/dL
with ASCVD risk of ≥7.5% to 19.9% and decision about statin therapy is uncertain
measure coronary artery calcium (CAC)
1. CAC ≥100 - consider statin
2. CAC 1-99 - consider statin if age ≥ 55 y/o
3. CAC = 0 - focus on lifestyle modifications
- reassess in 5-10 years
- indicates low 10-15 year risk
utilizes a low dose CT scan of the heart, assessing the amount of calcium plaque build up on the vascular walls.
Score ranges from 0-400.
coronary artery calcium (CAC)
no therapy is initiated for pts Aged 40–75 without clinical ASCVD or DM and whose LDL-C is between 70–189 mg/dL
1. what is the next step
2. what about for when Statin therapy is initiated
- recalculate the 10-year ASCVD risk every 4 to 6 years
- Reassess lipid panel after 4-12 weeks then every 3-12 months
management for hyperlipidemia
- Lifestyle Modification for all patients
- Aerobic exercise
- wt loss in overweight patients
- Diet changes - can reduce LDL by up to 30% (3-6 months) - pharm
- 1st line - statin
- 2nd line - ezetimibe, PCSK9 inhibitors, bempedoic acid, inclisiran
- 3rd line - bile acid sequestrants, fenofibrate, niacin - referral to a lipid specialist and/or dietician is also appropriate in these patients
what hyperlipidemia med
- inhibits HMG-CoA, a key enzyme in cholesterol synthesis in the liver
- increases the number of LDL receptors on the hepatocyte cell membrane
- stimulates LDL catabolism
statin
HMG CoA reductase inhibitors
rosuvastatin (Crestor)
atorvastatin (Lipitor)
simvastatin (Zocor)
lovastatin (Mevacor)
pravastatin (Pravachol)
fluvastatin (Lescol)
pitavastatin (Livalo)
- statin
SE of statins
- Myalgias - muscle pain with normal CK
- Myopathy/Rhabdomyolysis
- muscle pain with elevated CK
- Risk Factors: older age/frailty, renal insufficiency, drug interaction - Hepatotoxicity / liver failure
- check LFT’s before therapy, 2-3 months after initiation/dose titration & annually
- d/c if LFT’s are 3x ULN or less if sx - hyperglycemia - new onset DM
- Occurs in those predisposed to DM and use of high intensity statin
which statins are seen to have less Myopathy/Rhabdomyolysis
pravastatin
fluvastatin
risk factors of new onset DM when taking statin
- BMI ≥30
- fasting BS ≥100 mg/dL
- metabolic syndrome or A1c ≥6% are present
Occurs in predisposed DM and use of high intensity statin
CI with statins
- active liver disease
- pregnancy, women who may become pregnant, nursing mothers - risk of delayed fetal development
DI with statins
CYP450s
1. erythromycin and related antibiotics
2. antifungals
3. immunosuppressive drugs
4. fibric acid derivatives - gemfibrozil
the only drug class to demonstrate clear improvements in overall mortality in primary and secondary prevention for hyperlipidemia
statins
which statins are most likely to be tolerated
fluvastatin, pravastatin
what hyperlipidemia med
blocks appx 60% of dietary cholesterol absorption
Reduces LDL by 18% alone; synergistic with statin
No effect on HDL or TG
ezetimibe - Cholesterol Absorption Inhibitor
indication for Cholesterol Absorption Inhibitors
Adjunct to statin for hyperlipidemia
Not recommended monotherapy unless unable to tolerate statins
SE of ezetimibe
generally well tolerated
myalgias (when used with statin), diarrhea, fatigue
monitoring for ezetimibe
LFT at baseline if adding to statin
pregnancy caution with ezetimibe
weigh risk/benefit - skeletal abnormalities noted in animal studies at “higher than human” doses
what hyperlipidemia med
monoclonal antibodies inhibit PCSK9 from binding to LDL receptors decreasing LDL receptor degradation and increasing LDL clearance
PCSK9 inhibitors
- alirocumab
- evolocumab
route of PCSK9 inhibitors
SC injection q 2 wks (Reptha can be given qmo at a higher dose)
SE of PCSK9 inhibitors
injection site reactions, URI symptoms, gastroenteritis, dizziness, myalgias
No known limitation in renal or liver impairment
what hyperlipidemia med
- inhibits adenosine triphosphate-citrate lyase (ACL) inhibiting cholesterol synthesis in the liver
- increases the number of LDL receptors on the hepatocyte cell membrane
- stimulates LDL catabolism
bempedoic acid (Nexletol)
indications for bempedoic acid (Nexletol)
Need for additional LDL reduction after maximally tolerated statin therapy
- Lowers LDL approx. 16% when on max statin
- Lowers LDL approx. 23% alone
- Lowers LDL approx. 36% if combined with ezetimibe.
which hyperlipidemia med MC causes gout/hyperuricemia
bempedoic acid (Nexletol)
other SE: cold/flu symptoms, myalgias (worse when combined with statin), tendon rupture, muscle spasms, abdominal pain
monitoring needed for bempedoic acid (Nexletol)
lipids every 8-12 weeks, S/S of gout, uric acid as needed
Inclisiran (Leqvio)
PCSK9 Small Interfering RNA Agent
indications for Inclisiran (PCSK9 Small Interfering RNA Agent)
not controlled on max statin and unable to tolerate PCSK9
SE of Inclisiran
Injection site reaction, arthralgia
which hyperlipidemia med
blocks the physiologic production of the mRNA for PCSK9.
Less PCSK9 leads to less breakdown of the LDL receptor allowing for greater uptake of LDL from the circulation
PCSK9 Small Interfering RNA Agent - Inclisiran (Leqvio)
if pt cannot tolerate statins or other 2nd line therapies, what is the next line?
Bile Acid Sequestrants
- cholestyramine
- colestipol
- colesevelam
which hyperlipidemia med
binds bile acids in the intestines requiring the liver to excrete more bile. The liver uses hepatic cholesterol to make bile which results in the liver taking up more LDL-C from the systemic circulation
Bile Acid Sequestrants
- cholestyramine
- colestipol
- colesevelam
Lipid reduction is dose dependant ranging from 10-24% reduction in LDL
SE of Bile Acid Sequestrants
GI - nausea, bloating, cramping, hepatotoxicity, increase TG’s (avoid with hypertriglyceridemia)
DI with Bile Acid Sequestrants
- bind to and impair the absorption of other drugs
- take other drugs 1 hr before or 4 hr after bile acid sequestrants
which hyperlipidemia med is safe in kids and women who are pregnant or lactating
Bile Acid Sequestrants
Causes of hypertriglyceridemia
- Acquired
- obesity
- DM
- nephrotic syndrome
- hypothyroidism
- pregnancy
- oral estrogen therapy
- tamoxifen
- B-blockers
- HIV antiretroviral agents
- oral retinoids
- excessive alcohol use - Hereditary disorders
- chylomicronemia
- familial hypertriglyceridemia
- familial combined hyperlipidemia
- familial dysbetalipoproteinemia
Complication with severe hypertriglyceridemia is called what?
pancreatitis
management for Age ≥ 20 y/o with a moderate hypertriglyceridemia between 175-499 mg/dL
- Lifestyle modifications only
- Treat underlying conditions
- Avoid medications that worsen lipid levels
- Very low fat diet
- Avoid refined carbohydrates, saturated and trans fatty acids
- Avoid alcohol
what indications get statin therapy and lifestyle modifications in hypertriglyceridemia management
- 40-75 y/o with severe hypertriglyceridemia ≥ 500 mg/dL with an ASCVD risk of ≥ 7.5%
- Severe hypertriglyceridemia >1000 mg/dL alone
what med
stimulate LPL activity (enhances TG clearance from blood)
reduce apoC-III synthesis (enhances lipoprotein remnant clearance)
promote breakdown of fatty acids
may reduce VLDL-TG production
Fibrates (fibric acid derivatives)
- gemfibrozil (Lopid)
- fenofibrate (Trilipix, Tricor)
Can reduce TG’s by as much as 50%
SE of Fibrates (fibric acid derivatives)
dyspepsia, increase risk of gallstones, myopathy, hepatotoxicity
Caution in CKD: excreted by the kidneys - dose reduction required
myopathy most often occurs with fibrates when used in combination with ?
statin
less likely when fenofibrate is used
DI with fibrates
warfarin
what med
inhibit the release of TG’s from the liver (reducing VLDL). Stimulates LPL (increases clearance of TG’s from the plasma)
Omega 3 Fatty Acids
naturally found in fish and flaxseed, OTC supplement
effectiveness of omega 3 fatty acids
can reduce TG’s by 50% or more - requires up to 4 grams a day to be beneficial
SE of Omega 3 Fatty Acids
GI - diarrhea, N/V, dyspepsia, prolonged bleeding time
caution with omega 3 fatty acids
shellfish allergy, coadministration of anticoagulants
which med
- inhibits breakdown of TG in adipose tissue
- increases LPL activity (increases clearance of TG’s)
- inhibits synthesis of TG in liver (reduces VLDL secretion and subsequently LDL levels)
- reduces clearance of apoA-I
Nicotinic Acid (Niacin) (Vitamin B3)
SE of Nicotinic Acid (Niacin) (Vitamin B3)
- Flushing (MC)
- reduced if ASA 81 mg given 30 minutes prior to niacin - elevates uric acid levels - avoid hx of gout
