12/22/2022

‫الصيدلة‬

Dyslipidemia

Dr. Loai Saadah, BS, MS, PharmD

‫ممارسة الصيدلة في المستشفيات‬--- : ‫اسم المادة‬ --- - -‫الدكتور لؤي سعادة‬-- : ‫مدرس المادة‬
--- - --- - --- -

Outline
➢Introduction
➢Pathophysiology
➢Clinical Presentation
➢Diagnosis
➢Nonpharmacologic Treatment
➢Pharmacologic Treatment

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Introduction
➢DLP is elevated TC, LDL-C, or TG ; or low HDL-
C; or combo of these abnormalities.

Pathophysiology

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Pathophysiology I
• Cholesterol, TGs, & phospholipids are
transported in blood as complexes of lipids &
proteins (lipoproteins). ↑ TC & LDL-C & ↓
HDL-C associated with development of CHD.
• Risk factors e.g. oxidized LDL, mechanical
injury to endothelium, and excessive
homocysteine can lead to endothelial
dysfunction and cellular interactions
culminating in atherosclerosis. Eventual
clinical outcomes may include angina, MI,
arrhythmias, stroke, PAD, abdominal aortic
aneurysm, and sudden death.
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Pathophysiology II
• Atherosclerotic lesions arise from transport and
retention of plasma LDL through the
endothelial cell layer into the extracellular
matrix of the subendothelial space. Once in the
artery wall, LDL is chemically modified through
oxidation and nonenzymatic glycation. Mildly
oxidized LDL recruits monocytes into the artery
wall, which transform into macrophages that
accelerate LDL oxidation. Oxidized LDL
provokes an inflammatory response mediated
by chemoattractants and cytokines.

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Pathophysiology III
• Repeated injury and repair within an
atherosclerotic plaque eventually lead to a
fibrous cap protecting the underlying core of
lipids, collagen, calcium, and inflammatory
cells. Maintenance of the fibrous plaque is
critical to prevent plaque rupture and
coronary thrombosis.

Pathophysiology IV
• Primary or genetic lipoprotein disorders are
classified into six categories: I (chylomicrons),
IIa (LDL), IIb (LDL + very-low-density
lipoprotein [VLDL]), III (intermediate-density
lipoprotein), IV (VLDL), and V (VLDL +
chylomicrons). Secondary forms of
dyslipidemia also exist, and several drug
classes may elevate cholesterol levels (eg,
progestins, thiazide diuretics, glucocorticoids,
β-blockers, isotretinoin, protease inhibitors,
cyclosporine, mirtazapine, and sirolimus).
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Pathophysiology V
• The primary defect in familial
hypercholesterolemia is inability to bind LDL
to the LDL receptor (LDL-R). This leads to a
lack of LDL degradation by cells and
unregulated biosynthesis of cholesterol.

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Clinical Presentation
➢Most pts asymptomatic for many years.
Symptomatic pts may complain of chest
pain, palpitations, sweating, anxiety, SOB, or
abdominal pain. May also have difficulty
speak & movement or loss of consciousness.
➢Depending on the lipoprotein abnormality,
signs on physical examination may include
cutaneous xanthomas, peripheral
polyneuropathy, high blood pressure, and
increased body mass index or waist size.
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Diagnosis
✓Measure fasting (preferred) lipoprotein
profile (TC, LDL-C, HDL-C, & TG) in all adults
≥ 20 years old at least once every 5 years.
✓Measure plasma levels after a 12-hr fast as
TG may be ↑↑ in nonfasting; TC modest ↑.
✓Two determinations, 1 to 8 weeks apart
minimize variability & obtain a reliable
baseline. If TC > 200 mg/dL (>5.17 mmol/L),
another determination recommended
average all 3
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✓Hx & PE should assess: (1) presence or

absence of CV risk factors or definite CVD;
(2) FHx of premature CVD or lipid disorders;
(3) presence or absence of secondary causes
of DLP, including concurrent medications; &
(4) presence or absence of xanthomas,
abdominal pain, or pancreatitis, renal or
liver dx, PVD, abdominal aortic aneurysm, or
cerebral vascular disease (carotid bruits,
stroke, or TIA).
✓DM is a CHD (CVD) risk equivalent
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✓Lipoprotein electrophoresis is sometimes

performed to determine which class of
lipoproteins is involved. If TG < 400 mg/dL
(4.52 mmol/L), and neither type III
dyslipidemia nor chylomicrons are detected
by electrophoresis, then one can calculate
VLDL & LDL concentrations: VLDL = TG ÷ 5;
LDL = total cholesterol – (VLDL + HDL).
✓Pooled cohort equations (PCE) recommend
to predict individual's risk of 1◦ ASCVD (see
http://tools.acc.org/ASCVD-Risk-Estimator/).
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Goals of Therapy
1. Reduce CV morbidity and mortality
2. Achieve LDL-C goals, when appropriate

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Nonpharmacologic Therapy I
1. Lifestyle is cornerstone of initially
2. Recommend healthy diets such as the
Dietary Approaches to Stop Hypertension
(DASH) diet or the Mediterranean Diet
3. Emphasize consumption of fruits,
vegetables, whole grains, low-fat dairy
products, skinless poultry and fish, nuts
and legumes, and nontropical vegetable
oils

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Nonpharmacologic Therapy II
4. Limit sweets, sugar-sweetened beverages,
and red meats
5. Lower intake of saturated fats and replace
with unsaturated fats (especially
polyunsaturated fats)
6. Regular exercise
7. Engage in moderate-to-vigorous intensity
aerobic physical activity 3-4 times per week
for an average of 40 minutes per session
8. Smoking cessation
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Pharmacologic Therapy
Therapy recommendations are divided into
patient management groups:
➢Secondary ASCVD prevention
➢Severe hypercholesterolemia (LDL-C ≥190
mg/dL)
➢Diabetes mellitus (DM)
➢Primary prevention
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General Principles
1. First, initiate statin therapy if indicated.
Optimize statin therapy (high intensity or
maximally tolerated dose) before adding
nonstatin therapy
2. Second, add ezetimibe if indicated
3. Third, consider PCSK9-inhibitors (PCSK9-I)

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Secondary ASCVD
1. If multiple ASCVD events: high intensity
2. If one ASCVD & risk factors: high intensity
3. If no risk factors but age ≤ 75: high intensity
4. No risks & age > 75: moderate or high int
5. Consider ezetimibe as add on to statin if
LDL-C above 70 mg/dl
6. Consider PCSK9-inhibitor as add on to
statin and ezetimibe if LDL-C > 70 mg/dl
7. If > 75 yr and have functional decline or
multiple comorbidity may dc statin
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Severe Hypercholestrolemia
1. LDL ≥ 190 mg/dl and age 20 – 75 years
2. Give maximally tolerated statin dose
3. Add ezetimibe if LDL-C reduction is less
than or equal to 50% from baseline or LDL
remains above or equal to 100 mg/dL
4. Add PCSK9-inhibitor if age 30 to 75 years &
homozygous familial hypercholesterolemia
5. Also add PCSK9-inhibitor if age 40 to 75
years with baseline LDL-C of above or equal
to 200 mg/dl and LDL-C is still above 100
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Diabetes Mellitus
1. Age 20 – 39 yr with multiple risk factors or
risk enhancers may start statin
2. 40 – 75 yr moderate intensity but if with
multiple ASCVD risk factors high intensity
3. > 75 continue previously initiated statin or
may start if benefits outweigh risks
4. If 20 year ASCVD risk is more than or equal
20% can add ezetimibe

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Primary Prevention
1. Age 40 – 75 & LDL 70 to 189 mg/dL
2. Calculate PCE equation ASCVD risk and if:
3. < 5%: Lifestyle modify, reassess q4-6 years
4. Borderline (5 – 7.5%), if risk enhances
(Next) present use moderate intens statin
5. Intermediate (7.5 – 19.9%) moderate intens
if benefits>risks goal LDL-C ↓ 30-49%
6. High risk (>=20%) use high intensity statin
with goal LDL-C ↓ ≥50%
7. If additional LDL-C needed add ezetimibe
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Risk Enhancers I
1. FHx premature ASCVD (M <55 yr, F < 65 yr)
2. Primary hypercholesterolemia (LDL-C 160-
189 mg/dL or non-HDL-C 190-219 mg/dL)
3. Metabolic syndrome
4. Chronic kidney disease
5. Chronic inflammatory conditions such as
psoriasis, rheumatoid arthritis, HIV/AIDS
6. History of premature menopause (age <40)
7. History of preeclampsia

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Risk Enhancers II
8. High-risk race/ethnicity (e.g., South Asian
ancestry)
9. Elevated TG ≥175 mg/dL
10.Elevated biomarkers such as high-
sensitivity C-reactive protein, lipoprotein
(a), apolipoprotein B
11.Ankle-brachial index <0.9

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Coronary Artery Calcium Score

✓If risk decision is uncertain (especially
borderline and intermediate risk patients),
consider measuring coronary artery calcium
using computed tomographic angiography
scan (CT angio)
✓Score = 0: consider no statin (unless DM,
family history of premature coronary heart
disease, or cigarette smoking present)
✓Score = 1-99: favors statin if age ≥55
✓Score ≥100 or ≥75th percentile: favors statin
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Hypertriglyceridemia I
✓Primary goal is to prevent pancreatitis
✓Evaluate for secondary causes (Table Next)
✓Moderate hyperTG ( TG 175-499 mg/dL)
✓(a) Address and treat lifestyle factors,
comorbidities, and medications which
increase TGs
✓(b) If persistently elevated and ASCVD risk
≥7.5%, consider initiation or
intensification of statin therapy

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Hypertriglyceridemia II
✓Severe hypertriglyceridemia (TG ≥ 500
mg/dL)
✓(a) If persistently elevated and ASCVD risk
≥7.5%, consider initiation or intensification
of statin therapy
✓(b) Reasonable to initiate fibrate therapy to
prevent acute pancreatitis, especially if
fasting TG ≥ 1000 mg/dL
✓Expected changes in TG concentrations with
drug therapy (Table 2nd Next Slide)
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Secondary Increase LDL-C or TG

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Effect of Drugs on TG

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Monitoring
✓Measure fasting lipids 4-12 weeks after
therapy initiation
✓Measure fasting lipids every 3-12 months
thereafter
✓Periodically re-assess risk factors for ASCVD

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General Approach to Start Statin

✓3-Hydroxy-3-methylglutaryl coenzyme A
(HMG-CoA) reductase inhibitors (statins)
✓If baseline LDL-C > 190 mg/dL, evaluate for
2◦ causes. If 1◦, screen for familial type.
✓If baseline TG > 500 mg/dL, treat hyperTG
✓Evaluate pts with unexplained ALT > 3 X ULN
✓Hemoglobin A1C
✓Creatine kinase (if indicated)
✓Evaluate for secondary causes or conditions
that may affect statin safety
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Statin Efficacy & Benefits

✓First line for high LDL-C or CHD risk
✓Consider statin intensity (Table given)
✓Reduce LDL-C by 24%–60%, Reduce TG by
7%–30%, Raise HDL-C by 5%–15%.
✓Reduce major coronary events, Reduce CHD
mortality, Reduce coronary procedures
(percutaneous coronary intervention [PCI]
or coronary artery bypass grafting), Reduce
stroke, Reduce total mortality.

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MOA & Monitoring

✓Inhibits enzyme responsible for converting
HMG-CoA to mevalonate (rate limiting step
in production of cholesterol)
✓Main ADE & monitoring: a. Myopathy (can
check CK at baseline and then only if muscle
symptoms occur; no regular monitoring) b.
Elevated liver enzymes i. Obtain LFTs at
baseline in all patients ii. Perform repeated
LFTs only when clinically indicated. iii.
Monitor for symptoms of hepatic injury.
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Absolute Contraindications
✓Active liver disease, unexplained persistent
elevations in hepatic transaminases
✓Pregnancy
✓Nursing mothers
✓Certain meds (agent-specific; e.g. erythro- &
clarithro ↑ atorva (max dose 20 mg atorva)
✓Fibrates: ↑ myopathy. Risk with gemfibrozil
> fenofibrate, Avoid use with gemfibrozil.
✓Niacin: Doses > 1 g/day ↑ myopathy avoid
statin with such doses risk < fibrates
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Ezetimibe
✓Efficacy: a. Lowers LDL-C by 18%–20% b. Can
raise HDL-C by 1%–5% c. Lowers TG by 5%–
10%
✓MOA: Inhibition of cholesterol absorption
✓Adverse effects and monitoring: Diarrhea,
upper respiratory tract symptoms; no
monitoring necessary
✓Data suggest combination with simvastatin
is superior to simvastatin alone in
prevention of CV events.
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PCSK9 Inhibitors I
✓Efficacy: ↓ LDL-C by additional 45%–68%
and ↓ CV events both above statin alone
✓MOA: Monoclonal Ab inhibit a protein called
PCSK9, ↑ cholesterol clearance from liver
✓Both indicated for HeFH or clinical ASCVD;
evolocumab also indicated for homozygous
familial hypercholesterolemia (HoFH)
✓PCSK9-I only indicated for pts with maximal
tolerated statin & ezetimibe with very high
ASCVD risk or severe hypercholesterolemia
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PCSK9 Inhibitors
✓Adverse effects: Injection-site reactions,
respiratory infections
✓Dose: a. Evolocumab: i.Heterozygous familial
hypercholesterolemia or clinical ASCVD: 140
mg SC Q 2 wks or 420 mg SC once monthly
ii. HoFH: 420 mg SC once monthly
✓Alirocumab: Initial dose, 75 mg SC Q 2 wks
or 300 mg SC Q 4 wks; if LDL-C reduction
inadequate, can adjust dose to 150 mg
subcutaneously every 2 weeks
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Assessment Q1 Stem
➢M.M. 63-yr-old white woman just finished 6
mos of diet & exercise for DLP. PMH: HTN, DM,
& asthma. Smokes 1 ppd & drinks 3 beer daily.
Mother had HTN & MI at age 42 years. Father
HTN & DM. Meds: albuterol MDI, lisinopril,
metformin, linagliptin, & CaCO3 antacids. BP
134/84 & HR 75. HDL-C 38 mg/dL, LDL-C 134
mg/dL, TG 186 mg/dL, TC 209 mg/dL, and
HbA1C 8.6%. PCE estimates a 10-year ASCVD
risk of 27.8%. What most appropriate txx?
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Assessment Q1 Continued

A. Initiate a low-intensity statin

B. Initiate a moderate-intensity statin
C. Initiate a high-intensity statin
D. Initiate a high-intensity statin plus
ezetimibe

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Assessment Q1 Explanation
➢Pt falls into management group of DM and
age 40-75 years. Has multiple ASCVD risk
factors including smoking, low HDL-C, and
HTN, so would benefit from high-intensity
statin therapy (answer C). Answer B would be
correct if no additional ASCVD risk factors.
Low-intensity statins are not recommended
for initial therapy for any patient (answer A).
Pt should receive maximal tolerated statin txx
& assess before add ezetimibe (Answer D).
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Assessment Q2
➢According to the ACC/AHA blood cholesterol
guidelines, which is best described as a high-
intensity statin dose?
A. Pravastatin 20 mg/day.
B. Lovastatin 20 mg/day.
C. Atorvastatin 40 mg/day.
D. Rosuvastatin 10 mg/day.

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Assessment Q3
➢Which best describes a potential secondary
cause of high TG concentrations?
A. Amiodarone.
B. Biliary obstruction.
C. Sirolimus.
D. Saturated fats.

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Assessment Q4
➢J.T. 58-yr-old man presents for first time in 10
years. Smoked 2 ppd for past 30 years & takes
no meds. TC 222 mg/dL, LDL-C 105 mg/dL, TG
330 mg/dL, & HDL-C 51 mg/dL. BP 140/75 HR
80. His PCE reveals a 10-yr ASCVD risk of
14.6%. Which would be the best
pharmacologic therapy to initiate in J.T.?

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Assessment Q4 Continue
A. Initiate simvastatin 20 mg/day and
gemfibrozil 600 mg twice daily.
B. Initiate rosuvastatin 2.5 mg/day.
C. Initiate pravastatin 20 mg/day and
fenofibrate 160 mg/day.
D. Initiate atorvastatin 20 mg/day

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Assessment Q4 Explanation
➢Pt falls into management group (age 40–75
with an LDL-C of 70–189 & 10-year ASCVD risk
of 7.5-19.9% without DM or ASCVD) & thus
should be initiated on moderate statin txx.
Although simvastatin 20 mg is moderate,
gemfibrozil C/I combined with statin; TG < 500
mg/dL and need not be specifically targeted
(Answer A). Pravastatin 20 mg & Rosuvastatin
2.5 mg is a low-intensity. Atorvastatin 20 mg is
considered a moderate-intensity dose
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Assessment Q5
➢J.S. 43-year-old man with HTN who presents
for an annual physical examination. His family
history is significant for his father having HTN.
His only medication is lisinopril 10 mg/day. His
BP is 145/90 mm Hg. A fasting lipid profile
shows TC 238 mg/dL, TG 95 mg/dL, LDL-C 176
mg/dL, and HDL-C 43 mg/dL. His calculated
10-year ASCVD risk according to the pooled
cohort equation is 3.9%. Which best describes
the next step for management in J.S.?
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Assessment Q5
A. Initiate high-intensity statin therapy.
B. Do not initiate statin therapy and reevaluate
risk in 1–3 years.
C. Initiate moderate-intensity statin therapy.
D. Do not initiate statin therapy and reevaluate
risk in 4–6 years.

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Assessment Q5 Explanation
➢Calculated 10-year ASCVD risk of 3.9%;
therefore, not in any patient management
group. Thus, statin therapy would be
inappropriate. According to the cholesterol
guidelines, patients who are 40–75 years old,
without ASCVD or DM, and have an LDL-C of
70–189 mg/dL should have their 10-year risk
score recalculated every 4–6 years, making
Answer D correct and Answer B incorrect.

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Assessment Q6
➢J.C. 62-yr-old man (Ht 70 in, WT 135 kg [1
month ago 143 kg]) PMH: DM, CKD, bipolar
disorder, CHD, & hyperTG, pancreatitis. Father
had CHD & HyperTG. Pt not smoker, but drinks
6-pack of beer daily. HbA1C of 11.6% & SCr 2.6
mg/dL. Meds: atorva 40 mg Qpm, ASA 81
mg/day, metformin 1000 mg BID, olanzapine
10 mg/day, metoprolol tartrate 50 mg BID,
and coenzymeQ10 200 mg/day. TC 402 LDL-C
??, HDL-C 48, & TG 1500. Others WNL.
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Assessment Q6 Continue
➢Which best describes potential secondary
causes of HyperTG here?
A. Obesity, poorly controlled diabetes,
olanzapine, metoprolol, coenzyme Q10.
B. Alcohol consumption, poorly controlled
diabetes, weight loss, β-blockers.
C. Obesity, calcium channel blockers,
hyperthyroidism, alcohol consumption.
D. Alcohol consumption, obesity, poorly
controlled diabetes, olanzapine, metoprolol.
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Assessment Q6 Explanation
➢coenzyme Q does not affect TG; therefore,
Answer A is incorrect. weight loss does not
increase TG. Weight loss can actually lower
LDL-C and TG; therefore, Answer B is incorrect.
neither CCBs nor hyperthyroidism are
expected to have this effect (Answer C is
incorrect). All the conditions, medications, or
disease states in Answer D can increase TG,
making this option correct.

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References
1. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/
AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management
of blood cholesterol: executive summary: a report of the American College of
Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J
Am Coll Cardiol 2019;73(24): 3168–3209.
2. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/
ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention,
detection, evaluation, and management of high blood pressure in adults: executive
summary: a report of the American College of Cardiology/American Heart
Association Task Force on Clinical Practice Guidelines. Hypertension 2018
June;71(6):e13–e115.
3. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle
management to reduce cardiovascular risk: a report of the American College of
Cardiology American/Heart Association Task Force on Practice Guidelines.
Circulation 2014;129:S76–S99.

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References
4. Jensen MD, Ryan DH, Apovian CM, et al. 2013 ACC/AHA/TOS guideline for the
management of overweight and obesity in adults: a report of the American College
of Cardiology/American Heart Association Task Force on Practice Guidelines, and
The Obesity Society. J Am Coll Cardiol 2014;63:2985–3023.
5. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy
after acute coronary syndromes. N Engl J Med 2015;372:2387–2397.
6. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in
patients with cardiovascular disease. N Engl J Med 2017;376:1713–1722.
7. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes
after acute coronary syndrome. N Engl J Med 2018;379:2097–2107.
8. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent
ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22.
9. BCPS Prep course Chapter on Chronic Cardiology Section on Dyslipidemia
. 58

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References
10. BCPS Prep Course Chapter on Anticoagulation (DVT Part)

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Answer Key
1. C
2. C
3. C
4. D
5. D
6. D

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