Definition:

Abnormally high level of total cholesterol (TC), triglycerides (TG), low

density lipoprotein cholesterol (LDL-C) or an abnormally low amount of
high density lipoprotein cholesterol (HDL-C) in the serum

Dyslipidemia

Dr. Dina Qa’adan

2022

Epidemiology
— A national population based household sample was selected
from north, middle, and south regions of Jordan in 2017. A
total sample of 4056 aged between 18 and 90 years were
included, and fasting blood samples were collected for
biochemical measurements.
— Results: the prevalence rates of hypercholesterolemia,
hypertriglyceridemia, high LDL, and low HDL were 44%, 42%,
76%, and 60%, respectively
Causes
— Hyperlipidemia is due to a combination of genetic and
environmental factors.
— Obesity is one of the strongest secondary factors
Classification :
— Primary hyperlipidemia: genetically determined.
— Secondary hyperlipidemia: due to underlying diseases,
drugs, or dietary anomalies.
 Drugs that affect lipid:
Secondary causes of dyslipidemia:
↑LDL-C: ↑ LDL-C: ↑ TG:
↑TG: •Thiazide.
•Hypothyrodisim. •Type 2 DM. •Glucocorticoids.
•Carbamazepine •Estrogen.
•Nephrotic syndrom. •smoking.
•Cyclosporine •B-blocker.
•Cholestasis. •Hypothyroidism •Furosemide.
•Anorexia nervosa. •Glycogen storage disease. •Retinoic acid.
• hepatoma.
↓ HDL-C: •Atypical antipsychoyic.
•Hepatitis. •HIV protease inhibitors
•Anabolic steroids.
•Acute intermittent porphyria. •Renal failure.
•B-blocker.
↓HDL-C: •Sepsis.
•Tobacco abuse. •Stress.
•Type 2 DM. •Cushing.
•Obesity. •Pregnancy.
•Gaucher disease •Acromegaly.
•Malnutrition. •SLE.

Screening
issuing Organization Year Populations to be Screened Screening Measurement Screening Interval

— Familial Hypercholesterolemia (FH)

• Men ≥35 years: Universal
screening
• Men 20-34 years: if at
USPSTF 2008 (update in progress) increased risk for coronary
heart disease (CHD)
• Women ≥20 years: if at
increased risk for CHD
ACC/AHA 2013 Adults 20-78 years
NHLBI (ATP-III) 2002
Adults ≥20 years: Universal
Screening
Men 20-44 years and Women
AACE 2012 20-54 years: Universal
screening as part of global risk mother or first-degree female
assessment for CHD
Uncertain; every 5 years, with
shorter intervals for individuals
Fasting or non-fasting lipid with elevated lipid levels and
panel longer intervals for those not at ◦ Individuals should be screened for FH when there is a family history
increased risk with normal lipid
levels of: Premature ASCVD (definite MI or sudden death before age 55
years in a male first-degree relative or before age 65 years in a female
None given Every 4-6 years if free of ASCVD
first-degree relative).
Fasting lipid panel; Calculation
of non-HDL-C when
TG>200mg/dL
Every 5 years — Children and Adolescents
Every 5 years; more frequent ◦ In children at risk for FH (e.g., family history of premature
assessment for patients with
Fasting lipid panel; family history of CHD before cardiovascular disease or elevated cholesterol), screening should
Calculation of non-HDL-C more age 55 for father or first-degree
accurate if TG >200 and < 500 male relatives or age 65 for
be performed at 3 years of age, then at 9 years, and again at age
mg/dL, diabetes, insulin
resistance, or established CAD relatives 18.
Annually for adults with
diabetes
Approach to patient with hyperlipidemia: Examination:
•General exam.
•Weight and height.
History: •Neck exam.
•Signs of Cushing.
•Identify co-morbidities as DM, HTN, CHD, obesity •Abdomen exam.
•Assessing CHD risks. •Signs of chronic liver disease.
•Exclude secondary causes.
Specific signs in dyslipidemia:
•Ask about any drugs. •Corneal arcus and xanthelasma.
•Review of past medical history. •Lipimia retinalis: opaque white blood vessels (retinal arteries and veins) on
fundoscope.
•Family history of hyperlipidemia.
•Eruptive xanthoma: yellow red raised waxy-appearing papules in the truck, arms,
•Social history : smoking , alcohol. and legs.
•Tuberous xanthoma : plaque on elbows and knees.
•Tendenous xanthoma: on patella, achillis, dorsum of hand.
•Planar xanthoma : orange streaks on palmar creases

Lipimia retinalis
Xanthelasma
Corneal arcus
Eruptive xanthomas Tuberous xanthomas Tendenous Xanthomata

Labs:
Planar xanthoma Standard lab measurement of lipid profile involves direct measure of
•total cholesterol
•HDL-C
•TG
•and then LDL-C by Friedewald equation:
LDL-C(mg/dl)=(total cholesterol)-(HDL-C)-(TG/5)

LDL calculation by this equation is valid only for values obtained during the fasting state and
becomes inaccurate when TG levels are greater than 200 mg/dL, and invalid when TG levels are
greater than 400 mg/dL

*Note:
TG measurement :fasting at least 12 hrs.
Total cholesterol and HDL: non fasting.
Direct measurement of LDL-C: non fasting.

Non-HDL-C
Non-HDL-C (total cholesterol minus HDL-C) should be calculated to assist risk stratification in
individuals with moderately elevated TG (200 to 500 mg/dL), diabetes, and/or established
ASCVD
 Classification of Triglyceride Levels
Lipid treatment goals

— High-Density Lipoprotein Cholesterol HDL-C

HDL-C should be greater than 40 mg/dL, but also as high as possible,
primarily through the use of lifestyle interventions (e.g., weight loss, physical
activity, and tobacco cessation).
— Non–High-Density Lipoprotein Cholesterol
For most individuals, a non–HDL-C goal (total cholesterol minus HDL-C) 30
mg/dL higher than the individual’s specific LDL-C goal is recommended
— Triglycerides
TG goals of less than 150mg/dL are recommended
— Total cholesterol
TC goals of less than 200 mg/dl are recommended

— Step 1: obtain a fasting lipid profile.

— Step 2: calculations of individual patients’ risk for a future
cardiovascular event, to determine the risk category that
established the LDL goal.
Approach…. Ø An elevated total cholesterol (TC) or low density
lipoprotein (LDL) cholesterol level and/or a reduced high
density lipoprotein (HDL) cholesterol level are traditional
risk factors for cardiovascular disease (CVD); when
cholesterol elevations occur in combination with other risk
factors, a much higher risk for CVD is predicted.
 Major Atherosclerotic Cardiovascular Disease
Basic Categories of Risk Factors for Future (ASCVD) Risk Factors
Cardiovascular Events
— Advancing age (>45 years for males, >55 years for females)
Category Risk Factors
— Hypertension
Age, sex, family history, genetic — Cigarette smoking
Nonmodifiable risk factors
predisposition
— Family history of ASCVD
Smoking, atherogenic diet, alcohol intake, When the HDL-C is > 60 mg/dL, one risk factor should be
— Low HDL-C (<40 mg/ dl) subtracted from an individual’s overall risk profile.
Modifiable risk factors physical activity, dyslipidemias, hypertension,
obesity, diabetes, metabolic syndrome — Diabetes mellitus
— Stage 3 or 4 chronic kidney disease
Elevation in C-reactive protein (CRP);
fibrinogen; coronary artery calcification — ↑ total serum cholesterol level
Emerging risk factors
(CAC); homocysteine; lipoprotein(a); small, — ↑ non- HDL-C
dense LDL

Risk algorithms include lipid levels with some combination of the Risk Algorithms
following other traditional risk factors:
The most commonly used risk algorithms developed with United States
— Age population cohorts include the following:
— Gender — Framingham Risk Score (FRS; multiple adaptations)
— Family history of premature coronary heart disease (CHD); i.e. — Reynolds Risk Score (RRS)
in a first-degree male relative < 55 y or female relative < 65 y — American College of Cardiology/American Heart Association
— arteriosclerotic cardiovascular disease risk estimator (AC/AHA-
— Smoking ASCVD)
— Hypertension
— Diabetes mellitus Commonly used risk algorithms developed with European population
— Obesity
cohorts include the following:
— Systematic Coronary Risk Evaluation (SCORE)
— Sedentary lifestyle
— QRisk2
 Framingham Risk Score Using Framingham Risk Score Assessment
— The Framingham Risk Score (FRS) was developed in 1998 to assess
the 10-year risk of coronary heart disease (CHD) for individuals with
different combinations of risk factors.
— Since 1998, many adaptions and revisions of the score have been
published.
— Risk factors in FRS include:
ØGender
ØAge
ØHDL-C
Ø total cholesterol
Øsystolic blood pressure
Øcigarette smoking
Ødiabetes.

Dyslipidemia Clinical Practice Guidelines

(2019)
European Society of Cardiology (ESC), European
Atherosclerosis Society (EAS)
— In August 2019, the European Society of Cardiology (ESC)
and European Atherosclerosis Society (EAS) released updates
to their 2016 guidelines for the management of
dyslipidemia.Among the changes are new and more
aggressive proposed goals for low-density lipoprotein
cholesterol (LDL-C) levels and revised cardiovascular (CV) risk
stratification.
New LDL Targets Across CV Risk Categories
— For very-high-risk patients (10-year risk of CV death ≥10%): Use an
LDL-C reduction of at least 50% from baseline and an LDL-C goal of
below 1.4 mmol/L (<55 mg/dL).
— For very high-risk patients who experience a second vascular event
within 2 years (not necessarily of the same type as the first event)
while taking maximally tolerated statin therapy: An LDL-C goal of
below 1.0 mmol/L (<40 mg/dL) may be considered.
— For patients at high risk (10-year risk for CV death of 5% to <10%):
Use an LDL-C reduction of at least 50% from baseline and an LDL-C
goal of below 1.8 mmol/L (<70 mg/dL).
— For individuals at moderate risk (10-year risk for CV death of 1% to
<5%): Consider an LDL-C goal of below 2.6 mmol/L (<100 mg/dL).
— For individuals at low risk (10-year risk for CV death <1%): Consider
an LDL-C goal of below 3.0 mmol/L (<116 mg/dL).
 Available treatments for dyslipidemia
Treatment categories for dyslipidemia:
◦ Lifestyle changes
– Physical activity
– Medical nutrition therapy
– Smoking cessation
— A comprehensive strategy
to control lipid levels is
Management…
– Weight reduction
◦ Pharmacologic therapy
recommended primarily
1. Statins
using lifestyle changes and
2. Fibrates
patient education with
3. Omega-3 fish oil
pharmacotherapy as needed
4. Niacin
to achieve targets (Grade
5. Bile acid sequestrants
A evidence)
6. Cholesterol absorption inhibitors
7. New agents (PCSK9 inhibitors, MTP inhibitor,
Antisense apo B oligonucleotide )
– Combination therapies

The rationale of lowering TC and LDL-C: Lifestyle management

— A 2020 meta-analysis evaluated outcomes in 11,750 statin-
treated patients and 9742 patients treated with non-statin
therapy . Patients were from primary and secondary prevention
trials.
— LDL-C-lowering therapy significantly reduced the risk of major
vascular events (a composite of cardiovascular death, MI, or
other acute coronary syndrome and stroke) by 26 % per 1
mmol/L reduction in LDL-C, or 10% fall in TC.
(1) healthy diet
— reduce intake of saturated fat and trans fatty acids. The AHA
recommends limiting saturated fat to less than 6% of daily calories
and minimizing the amount of trans fatty acids (limiting intake of red
meat and dairy products made with whole milk. Choose skim milk,
low-fat or fat-free dairy products instead. limiting fried food and
cooking with vegetable oil).
— A heart-healthy diet emphasizes fruits, vegetables, whole grains,
poultry, fish, nuts and vegetable oils, while limiting red and processed
meats, sodium and sugar-sweetened foods and beverages.
— LDL-C-lowering macronutrient intake should include plant
stanols/sterols (2-3 g/ day) and soluble fiber (10-25 g/day).
 (2) Physical activity (↑HDL, ↓ TG) :
— At least 150 minutes of moderate-intensity aerobic
exercise a week is enough to lower both cholesterol and
high blood pressure.
— brisk walking, swimming, bicycling or even gardening.
(3) Smoking cessation (↑HDL) : can lower LDL
cholesterol and increase HDL cholesterol levels.
(4) Weight reduction (↓LDL) : weight loss of as little as 5%
to 10% can help improve cholesterol

Lipid lowering therapy

— Statins: — According to ATP IV guidelines, the actual statin used is not
◦ Statin therapy is recommended as the primary pharmacologic agent to achieve
target LDL-C goals (Grade A).
important. Rather, the intensity of therapy is the focus.
— Fibrates Ølow-intensity statin therapy intends to reduce the LDL-C
◦ Fibrates should be used to treat severe hypertriglyceridemia (TG >500 mg/dL) by less than 30%
(Grade A).
Ømoderate-intensity statin therapy intends to reduce the
— Combination Therapy LDL-C by 30-50%
◦ Combination therapy of lipid-lowering agents should be considered when the LDL- Øhigh intensity statin therapy intends to reduce the LDL-C
C/ non-HDL-C level is markedly increased and monotherapy (usually with a statin)
does not achieve the therapeutic goal. by 50% or more.
 Pharmacotherapy in details:
1) HMG-COA reductase inhibitors (Statins):

• They are the agent of choice to treat primary hypercholesterolemia

because they are most potent LDL-C lowering drugs.

• All have been shown to both slow the progression of coronary

atherosclerosis & prevent primary and secondary heart disease.

• If the diabetes status of the patient is unknown, a hemoglobin A1C

should be checked before starting statin.
• New-onset diabetes is increased in individuals treated with statins;
however, it is dose-related, occurs primarily in individuals with Metabolic
Synd., and occurs overall to a lesser extent than the associated decrease
in ASCVD. (benefits outweigh the risk)

•Mechanism of action: •Effect:

1. Inhibit enzyme, HMG-COA reductase , that is responsible to vItreduce: LDL-C 18-55%

convert HMG-COA to mevalonate. (rate limiting step in cholesterol TG 7-30%
synthesis) vIncrease : HDL-C 5-15%

2. Increase clearance of LDL-C by upregulation of hepatic LDL

receptors.
üBecause relatively short half-lives, statins should be taken at bed
time , so peak concentration occur in early morning hours, when
3. Increase degradation of apolipoprotein B, so decrease hepatic cholesterol production at its greatest.
production & secretion of VLDL.
 Cont…
•Statinscause liver transaminase elevations (>3 times the upper limit)
in up to 2-3% of patients. This elevation usually occur in first 12 wks
of therapy or after dose titration & are reversible with dose
reduction or discontinuation.
•pre-treatment ALT should be checked to screen for liver disease,
and if normal, no further monitoring for hepatotoxicity is indicated
unless symptoms are suggestive.
Cont…
Ø Enhanced susceptibility to statin-associated myopathy occurs in patients
with acute or chronic renal failure, obstructive liver disease, and
hypothyroidism.
Ø increased risk with co-administration of statin with some drugs (e.g:
ciclosporin and gemfibrozil)
ØIfa patient requires a statin and experiences muscle toxicity (other than
rhabdomyolysis) with a statin, once symptoms have resolved off statin
therapy, it is reasonable to consider a trial of pravastatin or fluvastatin with
careful monitoring. Or a trial of decreasing the dose of the same agent with
monitoring.
ØPatientcan experience statin-induced myalgia without elevation in CK so
we must monitor patient in this condition and STOP it if there is increase in
CK more than 7-10 times of normal.
Myopathies:
Ø Development of muscle toxicity remains a concern with the use of the
statins. Myopathic syndromes associated with statins span a spectrum of
complaints ranging from myalgias to myositis to overt rhabdomyolysis,
which may be associated with acute renal failure from myoglobinuria.
ØMuscle injury is uncommon with statin therapy alone, with a frequency of
2 to 11 % for myalgias, 0.5 % for myositis, and less than 0.1 %for
rhabdomyolysis.
Ø If the patient is at risk for myositis from statins (e.g., positive family
history; muscle symptoms), a pre-treatment creatine kinase (CK) should
be checked.
Drug interactions:
ØThe risk is substantially increased for most statins that extensively
metabolized by cytochrome P-450 3A4, with concurrent therapy with
drugs that interfere with CYP3A4.
ØPravastatin, fluvastatin, and
rosuvastatin are preferred when concurrent
therapy with a strong inhibitor of CYP3A4 cannot be avoided.
ØGrapefruit juice inhibits CYP3A4, however daily consumption of eight
ounces or less of grapefruit juice, or one half of a grapefruit or less, is
unlikely to increase the risk of an adverse interaction or muscle injury.
 Inhibitors of CYP3A4
Strong inhibitors Moderate inhibitors

Atazanavir Amiodarone
Clarithromycin Amprenavir
Conivaptan Aprepitant
Imatinib Cyclosporine
Indinavir Darunavir
Isoniazid Delviridine
Itraconazole Diltiazem
Ketoconazole Erythromycin
Nefazodone Fluconazole
Posaconazole Fosamprenavir
Ritonavir Grapefruit juice
Saquinavir Verapamil
Telithromycin Amlodipine
Voriconazole

2) Bile acid sequestrans :

•Mechanism of action:
•Recent meta-analysis found benefit from BAS in cardiac mortality,
Bind bile acids in intestines, reducing its absorption.
reduce risk of CHD , but not overall mortality.
•Effect:
•It remains unabsorbed in GI tract, so no systemic toxicity.
It reduce LDL-C 5-25%
increase HDL 3-5%
increase TG so should be used with caution when TG level > 400 mg/dl. •Side effects:
Gastrointestinal: constipation, abdominal pain, bloating, flatulence.
•Itis second line agents as monotherapy for patients with moderately
elevated LDL-C and it may be added to statin for further LDL-C reduction
when LDL-C goal is not met.

•Cholestipol, Colesevelam, and Cholestyramine

 3) Nicotinic acid (niacin):
•Mosteffective agent to increase HDL-C (15-35%) with moderate
LDL-C (5-25%) and TG (20-30%) lowering.
•These drugs (BAS) may reduce absorption of folic acid ,fat-
soluble vitamins such as vitamins A, D, E, and K, and potential •Can be added to statin for more improving in lipoprotein level.
drugs.
Mechanism of action:
•Decrease absorption of certain drugs that administered ØDecrease hepatic uptake of free fatty acids.
concomitantly as:
ØDecrease synthesis of VLDL.
Levothyroxin, propranolol, warfarin, amiodarone, digoxin. ØIncrease clearance of plasma chylomicrons & VLDL.
This interaction can be avoided by administer these drugs 1 hr
before or 4 hrs after administration of BAS.

4) Fibric acid derivatives (Fibrates ):

•Adverse effects:
1. Cutaneous flushing & itching: can be reduced by pre-treating with aspirin 325 mg half •Primarily used to decrease TG (25-50%), moderate HDL-C elevation
to one hour before drug and by taking drug during or after meal. (10-20%) & slight LDL-C lowering (5-20%).
3. Headache & GI distress ,including activation of peptic ulcer.
•First choice in treating hypertriglyceridemia.
4. Hepatotoxicity. (rare but may be severe).
5. Hyperurecemia: can precipitate acute attack of gout. •Can improve diabetic retinopathy.
6. Hyperglycemia: this drug decrease insulin sensitivity. So, blood glucose level should be
monitored carefully in diabetics taking nicotinic acid. (DM is not contraindication to use
it, but less than ideal choice for diabetic patients). • Gemfibrozil, Clofibrate, and Fenofibrate.
7. atrial fibrillation
• All S.E occur more frequently in doses of 2g or higher , regardless of formulation.
•Mechanism of action: alter gene transcription causing
Contraindications: active liver disease , peptic ulcer disease. decrease secretion of VLDL by liver & increase VLDL clearance
(stimulate the uptake and metabolism of VLDL from the plasma,
Liver transaminase levels should be measured before and 3 months after niacin
treatment initiation. they should be measured annually thereafter, and which can lead to increased LDL levels in patients who have very
medication should be discontinued if liver enzymes reach 3-times the upper high baseline triglyceride levels).
limit of normal.
 5) Cholesterol Absorption Inhibitors (Ezetimibe):
•Side effects: Mechanism of action:
Ø GI symptoms ( nausea, anorexia or diarrhea), fatigue, headache. Inhibit intestinal absorption of cholesterol & phytoesterols at brush border.
Ø Myopathy ( rare, risk increases if used with statins).
Ø Increase Biliary cholesterol excretion and increase risk of cholesterol Effect:
gallstones (not used in active GB disease)
Decrease LDL-C 19% as monotherapy & when combined with statin cause
more reduction in LDL-C than statin alone (additional 22%).
ØShould not be used in patients with severe liver disease ( ALT ≥ 2-3 upper
limit of normal) and renal dysfunction.
Main Considerations
üMyopathy/rhabdomyolysis (rare)
ØFibric acid derivatives should not be prescribed if a patient is receiving a üWhen coadministered with statins or fenofibrate, risks associated with
statin ( some allow the use of combination but with caution ; when those drugs remain (e.g., myopathy/ rhabdomyolysis, cholelithiasis)
combination therapy is used, clinicians should be sure that patient has normal
üMonitor transaminase level periodically, especially when combined with
renal function & low doses should be initiated).
statin.
üPatients taking cyclosporine may have increase level of ezetimibe & should
be monitored carefully

6)Omega-3 fatty acids:

•The only available sources of omega-3 fatty acids were OTC fish oil supplements or in diet rich in
fatty fish. (Dietary supplements are not FDA-approved for treatment of hypertriglyceridemia)

•Effect:
ü Used primarily to decrease TG by 45% when administered as 3-4 g/d.
ü ↓VLDL-C up to 42%, in individuals with severe hypertriglyceridemia (TG>500mg/dl) by reducing hepatic VLDL-
TG synthesis and/or secretion.

•Itwill decrease all causes of death, non fatal MI, non fatal stroke, however after 3.5 yrs , 50% of study
participants also receive statins.

•Side effects:
ü Bleeding disease (May prolong bleeding time. Monitor coagulation status periodically) & thrombocytopenia
in higher dose.
ü Most common adverse events include arthralgia, dyspepsia, and taste disturbance. May also
experience constipation, vomiting, rash, or pruritus.

•It is used in patients who need reduction in TG levels & can not tolerate fibric acid or nicotinic acid.
•Monitor ALT and AST levels periodically during treatment in patients with hepatic impairment.
 The metabolic syndrome: Other associations:
— Obesity, particularly abdominal obesity, is associated with resistance to insulin on Metabolic syndrome has also been associated with several obesity-related disorders
peripheral glucose and fatty acid utilization, often leading to type 2 DM. Insulin resistance, including:
the associated hyperinsulinemia and hyperglycemia, may also lead to vascular endothelial
● Fatty liver disease with fibrosis, and cirrhosis
dysfunction, an abnormal lipid profile, and hypertension, all of which promote the
development of atherosclerotic cardiovascular disease (CVD) ● Hepatocellular carcinoma and intrahepatic cholangiocarcinoma.
— It is known as the insulin resistance syndrome, or the obesity dyslipidemia syndrome ● Chronic kidney disease and microalbuminuria
— The prevalence was about 35% in 2016 according to ATP III criteria ● Polycystic ovary syndrome
— studies demonstrate a strong association between metabolic syndrome and the risk for ● Sleep-disordered breathing, including obstructive sleep apnea
subsequent development of type 2 diabetes. the relative risk (RR) of developing diabetes ● Hyperuricemia and gout
ranges from 3.5 to 5. ● Several components of metabolic syndrome, including hyperlipidemia, hypertension,
— Many meta-analyses, found that metabolic syndrome increases the risk for incident CVD and diabetes, have been associated with an increased risk of cognitive decline and
(RRs ranging from 1.5 to 2.2) and all-cause mortality. dementia.
 Metabolic syndrome diagnosis
According to ATP III criteria Diagnose Metabolic Syndrome if 3 of the following
are present:

— Abdominal obesity (men > 94 cm, women> 80 cm)

— Elevated triglycerides (³ 150 mg/dl) or drug treatment for elevated triglycerides
— Low HDL cholesterol (men < 40, women < 50 mg/dl)
— Raised blood pressure(³ 130/ ³ 85mmHg),or on antihypertensive
— Fasting plasma glucose (FPG) ≥100 mg/dL or drug treatment for elevated blood
glucose

Management: Aggressive lifestyle modification focused on weight reduction and

increased physical activity is the primary management of metabolic syndrome

Thank you