Dyslipidemias

Abdullah Al-Dahbali, MPharm, PhD

Blood Lipoproteins (Transporters of Lipids)
Chylomicron VLDL LDL HDL
Physiologic Intestine Intestine & From VLDL Liver &
Origin liver catabolism intestine

Physiologic Transport Transport Transport Transport

Function dietary Chol endogenous endogenous Chol from
& TG to liver TG & Chol ……. Chol to cells cells to liver

Cholesterol (%) 3-7 20-30 51-58 18-25

TG (%) 85-95 50-65 4-8 2-7

Types of Cholesterol in the Blood:

1) VLDL-Cholesterol (VLDL-C) is a harmful because it is atherogenic
2) LDL-Cholesterol (LDL-C) is a harmful cholesterol because it is atherogenic
3) HDL-Cholesterol (HDL-C) is a beneficial cholesterol because it decreases
harmful cholesterol
Dr. Abdullah Al-dahbali 2
 Abnormalities in Lipid Metabolism
Metabolic Lipid Main Lipid Diagnostic
Disorder Defect Effect Parameter Features
Polygenic ↓LDL clearance ↑LDL-C LDL-C: None distinctive,
hypercholes- 130–250 environmental
terolemia mg/dL (poor
nutrition,
TG: 150–500 sedentary
mg/dL lifestyle) & genetic
factors
Atherogenic ↑VLDL secre on, ↑TG HDL-C: Frequently
dyslipidemia <40 mg/dL accompanied by
↑C-III synthesis ↑ Remnant VLDL central obesity or
↓LPL ac vity (Atherogenic) diabetes
↓VLDL removal
↓HDL

↑Small, dense LDL

(Atherogenic)
Dr. Abdullah Al-dahbali 3
 Rationale of Treating Dyslipidemia
• Cholesterol critical role in the pathogenesis of
atherosclerosis is Evidence-Based
– For every 1%↑in Chol., CHD incidence ↑ by 1%–2%
– For every 1%↓ in HDL-C, CHD incidence ↑ by 1%–2%
• Beneficial effect of lowering blood cholesterol on CHD
is Evidence-Based
– Lowering blood cholesterol for Secondary
Prevention of CHD is Evidenced-Based
– Lowering blood cholesterol for Primary Prevention
of CHD is Evidenced-Based

Dr. Abdullah Al-dahbali 4

 CHD & CHD Risk Equivalents
CHD is present if Hx of CHD equivalents
• Myocardial ischemia • Carotid artery disease
(angina, ACS) – Hx of Stroke
– Hx of Transient Ischemic
• Coronary angioplasty Attack (TIA)
and/or stent placement – Carotid artery stenosis >50%
• Coronary bypass graft • Peripheral arterial disease
– Claudication
– Ankle:brachial systolic BP
index (ABI) >0.9 (by Doppler)
• Abdominal aortic aneurysm
• Diabetes Mellitus

Dr. Abdullah Al-dahbali 5

Risk Factors & Global Risk Assessment of ASCVD
Positive Risk Factors Negative Risk Factor
(↑Risk, predisposing) (↓Risk, protec ve)
1) Age
• Male ≥45 yrs, Female: ≥55 yrs
2) Family Hx of a premature CHD: defined as a definite
MI or sudden death before age of:
• 55 yrs in a male 1st degree relative (e.g, father), or
• 65 yrs in a female 1st degree relative (e.g, mother)
3) Current Smoking
4) Hypertension: defined as BP ≥140/90 mmHg, or
on antihypertensive drug(s)
5) Overweight or Obesity
6) Low HDL-C (<40 mg/dL) or LDL-C >100 mg/dL High HDL-C: (≥60 mg/dL
Risk Assessment:
1) Low Risk of ASCVD if <2 risk factors.
2) Moderate-High Risk of ASCVD if >2 risk factors. In this case Framingham Risk
Score should be calculated. Dr. Abdullah Al-dahbali 6
Classifications of Blood Lipids
Item Value Interpretation
Total Cholesterol <200 mg/dL Desirable
(TC) 200–239 mg/dL Borderline high
≥240 mg/dL High

HDL-Cholesterol <40 mg/dL (men) or Low

(HDL-C) <50mg/dL (women)

LDL-Cholesterol <100 mg/dL Optimal

(LDL-C) 100–129 mg/dL Near optimal or above optimal
130–159 mg/dL Borderline high
160–189 mg/dL High
≥190 mg/dL Very high

Triglycerides <150 mg/dL Normal

(TG) 150–199 mg/dL Borderline high
200–499 mg/dL High
>500 mg/dL Very high
Dr. Abdullah Al-dahbali 7
 Treatment Goals & Tools
• Decreasing CV-associated morbidity & mortality
o By reducing the risk & the complications of atherosclerotic
cardiovascular diseases (ASCVD), including
revascularization procedures, MI, ischemic stroke
 By achieving & maintaining the target values of lipids
(cholesterol (TC, LDL-C, HDL-C) & TG) in the blood
By nondrug (therapeutic lifestyle changes, life style
modifications) therapy
» Smoking Cessation
» Weight Reduction (BMI 18- <25 kg/m2)
» Increasing Physical Activities
At least 30 minutes of aerobic exercise daily
for 5 days/week or 2.5 hrs once weekly
By drug therapy
Dr. Abdullah Al-dahbali 8
 LDL-C Goals & Cutpoints for Therapeutic Lifestyle Changes (TLC) & Drug Therapy
LDL-C at which LDL-C at which to
Risk Category LDL-C Target to Initiate TLC Consider Drug Therapya
CHD or CHD risk <100 mg/dL >100 mg/dL >100 mg/dL (<100 mg/dL,
equivalents (10-year (Reasonable target<70 consider drug options)b
risk >20%) mg/dL)c
>2 risk factors (10- <130 mg/dL >130 mg/dL >130 mg/dL (100-129
year risk 10%-20%) (Optional target<100 mg/dL) mg/dL; consider drug
options)d
>2 risk factors (10- <130 mg/dL >130 mg/dL >160 mg/dL
year risk <10%)
<2 risk factorse <160 mg/dL >160 mg/dL 190 mg/dL (160–189
mg/dL, LDL-C lowering
drug therapy is optional)
a For all patients without CHD: LDL-C lowering drugs should be initiated at a dose that produces at least a
30%-40% reduction in LDL-C. The use of lower doses just to barely attain the LDL-C goal would not be a
prudent use of medications.
b The clinician may select niacin or fibrate therapy if patient has high TG and/or low HDL-C. The

decision to lower LDL-C with drug therapy is optional based on available clinical trial evidence.
c All patients with CHD: When LDL-C <70 mg/dL is not achievable because high baseline LDL-C, it is possible

to achieve reductions of >50% by either statins or LDL-C lowering drug combinations.

d The decision to lower LDL-C with drug therapy to achieve an LDL-C <100 mg/dL is optional based on

available clinical trial evidence.

e Patients with <two risk factors usually have a 10-year risk of <10%, and therefore do not need a 10-year

risk assessment. Dr. Abdullah Al-dahbali 9

 Key Recommendations to Reduce ASCVD Risk in Adults
Prevention Type Risk Level Age Recommendations
Heart-healthy lifestyle for everyone
Patient Groups Likely to Benefit from Statin Therapy
Secondary @ very All High-intensity or maximally tolerated statin therapy (Class
Prevention (i.e., high riskc I)
Clinical ASCVDb Not @ <75 High-intensity statin therapy (Class I). If high-intensity not
already present) very high tolerated, use moderate-intensity statin therapy (Class I)
risk >75 Moderate/high-intensity statin is reasonable (Class IIa)
Primary prevention: 20– Maximally tolerated statin therapy (ClassI)
severe hypercholeste- 75
rolemia LDL-C ≥190
Primary prevention: 40– Moderate-intensity statin therapy (Class I). High-intensity
DM, LDL-C 70–189 75 statin is reasonable if multi ASCVD risk factors (Class IIa)
Primary prevention: High 20% High-intensity statin therapy (Class I)
LDL-C 70–189 Intermed- Consider moderate-intensity statin therapy (Class I)
iate 7.5%
Borderlin- Discuss moderate-intensity statin therapy (Class IIb)
e <7.5%
Low <5% Emphasize heart-healthy lifestyle (Class I)
20-39 Consider statin if FHx of premature ASCVD & LDL-C ≥160
b includes nonfatal MI, CHD death, and nonfatal and fatal stroke, TIA, PAD of atherosclerotic origin.
c includes Hx >1 major ASCVD event OR one major ASCVD event PLUS multiple high-risk conditions: >65 yrs,

familial hypercholesterolemia, Hx of coronary bypass graft surgery, DM, HTN, CKD, smoking, LDL-C >100
despite maximally tolerated statin & ezetimibe, HF.
 Therapeutic Lifestyle Change Diet

• Total calories/day= 2500 (men) & 1800 (women)

• One gram of fats= 9 calories
• Try TLC diet & other life style modifications for 6-12 weeks before
considering drug therapy Dr. Abdullah Al-dahbali 11
Drug
Class
Members
Drugs
of Antidyslipidemic
Effects
Classes
Comments, SEs, Disadvantage
HMG-CoA Prava, Lova, 20-40% ↓ LDL-C GI SEs
synthase Simva,Atorva, 35-60% ↓ LDL-C Myositis (Myalgia, soreness,
Inhibitors (Rosuva & Pitava: (w max. Dose) weakness & CPK ×10) &
(Statins) < hepatic 15-45% ↓ TG rhabdomyolysis
acc.org/statini metabolism) ↑transaminases ×3 (so?!!)
ntoleranceapp Many DDIs (at CYP450), (so?!!)
Cholesterol Ezetimibe (Not 20% ↓ LDL-C Maximizes effect of low dose of
Absorption absorbed) ↔ HDL-C statins & more ↓ LDL-C w max. dose
Inhibitors ↔ TG statins
Proprotein Monoclonal 60% ↓ LDL-C Inj. site rxns: ↓by allowing the inj. 30’
Convertase antibodies when added to in room temp. & icing the site.
Subtilisin/ Kexin (Alirocumab statins↓CV Flue-like Sx after the inj.
Type 9 (PCSK9) Evolocumab)↓ event These SEs are less with achieving LDL-
Inhibitors. clearance, ↑LDL recurrence C<20mg/dL.
SC 2/wk or hepatic receptors Evolocumab-FDA approved for 1ry
1/mo & degradation, hyperlipidemias (geneticssignificant
↓blood ↑Chol premature ASCVD).
clearance What are 2ry (acquired) dyslip?
Bile Acid Resins Cholestyramine 20% ↓ LDL-C DDIs, GI SEs (Colesevelam is less), the
(Not absorbed) Colestipol ↑ TG dose is large 12
Colesevelam Dr. Abdullah Al-dahbali
Drug Members of Antidyslipidemic Classes
Class Drugs Effects Comments
Fibrates Clofibrate 10-25% ↓ LDL-C (or ↑) Myositis & rhabdomyolysis
(Prevent Bezafibrate 20-50% ↓ TG (more w gemfibrozil)
pancreatitis d/t Fenofibrate 10-15% ↑HDL-C (in GI SEs (w gemfibrozil)
hyperTG) Gemfibrozil hyperTG) Rash (w fenofibrate)
Cholelithiasis
↑warfarin effect (monitor INR)

Omega-3 fatty HA&EPA ↔ LDL-C as part of a low-fat diet, ↓

acids, Polyuns- 30–60% ↓ TG CHD after MI even if w statins,
aturated FAs take before meal ↓ fishy taste
(PUFA)
Niacin Crystalline 15-25% ↓ LDL-C (linear) 2 metabolic pathways:
(improves all (Immediate 30-60%↓TG (curvilinear) Flushing metabolites (can ↓?)
lipids), Release) 20-35% ↑HDL-C Hepatotoxic metabolites (dose-
prevents related)
pancreatitis d/t
Niacin (Sustained ↓Flushing
hyperTG Release) ↑Hepatotoxicity (50% of pts)
Niaspan (Niacin A bit < effective than Better tolerated w <2 g daily
Extended Release) niacin
Dr. Abdullah Al-dahbali dose 13
 Bempedoic acid-Quick Takes
• a novel nonstatin drug that inhibits cholesterol
biosynthesis in the same pathway as statins
• administered as a prodrug and is only converted to active
drug in the liver and not muscles
• Phase II & III clinical trials have demonstrated promising
results regarding its safety and efficacy either as
monotherapy or in combination with statins or ezetimibe
among different patient profiles including patients with
statin intolerance
• currently FDA approved as an adjunct to diet & maximally
tolerated statin therapy for treatment of hyperlipidemia
& cardiovascular outcomes trials evaluating the impact of
bempedoic acid on hard cardiovascular endpoints are
currently ongoing Dr. Abdullah Al-dahbali 14
 Drugs of Choice for Dyslipidemias
Lipid Disorder Drug of Choice Alternatives Combinations
Polygenic Statin Resin, ezetimibe, Statin-ezetimibe, Statin-
hypercholesterolemia niacin resin, Resin-niacin,
Statin-niacin

Familial Mipomersen
hypercholesterolemia Lomitapide
or
severe polygenic Statin (high dose)
hypercholesterolemia
Atherogenic Statin Statin Statin-niacin,
dyslipidemia Niacin Niacin Niacin-resin,
Fibrate Fibrate Niacin-fibrate
Isolated low HDL Statin to ↓LDL-C Niacin Statin-niacin
Hypertriglyceridemia fibrates, omega-
TG 200–499 3 PUFA, niacin
Hypertriglyceridemia Statin if ASCVD fibrates, omega-
Fasting TG >500 risk≥7.5% 3 PUFA, niacin
Dr. Abdullah Al-dahbali 15