Management of dyslipidemia 2019 update

Management of Dyslipidemia for primary prevention
2019 update
By
Moustafa Mokarrab,MD
Al-Azhar faculty of medicine.

• Perhaps the most important role of cholesterol is that of an essential
structural element of the membranes of all animal cells and subcellular
particles.
• The typical animal membrane consists basically of a mixed double layer
of cholesterol and phospholipid molecules, arranged at right angles to
the plane of the membrane so that the polar groups face outwards from
both surfaces, with various other constituents embedded in the
membrane. Esterified cholesterol cannot readily participate in
membrane formation.
• Hence, since the bulk of tissue cholesterol is present in membranes,
the cholesterol in most tissues is predominantly in free or unesterified
form.

• As well as forming cell membranes, cholesterol is a constituent of
plasma lipoproteins.
• The free cholesterol of plasma lipoproteins is probably associated
with protein and phospholipid to form a membranelike structure
covering the surface of the lipoprotein molecule and thus enabling
much of the non-polar lipid of the plasma to be transported in soluble
form.

• In addition to its structural role, cholesterol is an obligatory precursor
of bile acids and of all the steroid hormones, including the sex
hormones and the hormones made in the adrenal cortex.

EXCHANGEABLE CHOLESTEROL
• The normal human body contains about 2 g of cholesterol per kg total
weight. Much of this is exchangeable with the plasma cholesterol.
• Equilibration between plasma and tissue cholesterol is complex. In
some tissues, such as liver and intestine, equilibration approaches
completion within hours; in others, such as skin and artery,
equilibration may not be achieved for days or weeks. Moreover, the
proportion of the total cholesterol that is exchangeable varies from
one tissue to another.
• For these reasons it is difficult, if not impossible, to measure the total
amount of exchangeable cholesterol in the whole body.

HMG CoA Reductase
(More Than Cholesterol Synthesis)
Acetyl CoA
HMG CoA
Mevalonate
Farnesyl Pyrophosphate
Cholesterol
HMG CoA Reductase
Isopentenyl
adenine
(transfer RNA)
Prenylation of
signalling peptides
(ras, rho, etc.)
Ubiquinones
(CoQ-10, etc.)Dolichols
Inhibition of other key products of mevalonate may relate to
nonlipid effects & rare side effects of statins.

NORMAL CHOLESTEROL METABOLISM
Tissue
pools
70G
0.8 G
SYN CHOL*
*SYN CHOL = CHOLESTEROL SYNTHESIS
0.4 G CHOL

NORMAL CHOLESTEROL METABOLISM
Tissue
pools
70G
.65 G
.20 G
.20 G CHOL 0.65 G CHOL
0.85 G
ABS CHOL
50%
0.4 G CHOL
0.8 G
SYN CHOL*
*SYN CHOL = CHOLESTEROL SYNTHESIS
1.3 G
CHOL

400 mg/day
1,300 mg/day
NORMAL CHOLESTEROL ABSORPTION
Oil phase

400 mg/day
1,300 mg/day
17,400 mg/day
Plant sterols compete
For cholesterol here
Oil phase

400 mg/day
1,300 mg/day
17,400 mg/day
850 mg/day
Ezetimibe competes
For cholesterol here
Oil phase

Magnitude of the problem
• In 1970, cardiovascular disease were responsible for only
12.4% of deaths, infections and gastrointestinal for 32.8%.
• Two decades later, cardiovascular diseases caused 42.5% of
deaths, while infections and gastrointestinal diseases were
responsible for 14.1% It is expected that this trend will
increase and possibly, we will be facing an epidemic of
cardiovascular diseases .
• Adoption of western life style, increased rates of obesity,
cigarette smoking and other cardiovascular risk factors are definitely contributing
factors.

World Health Organization - Noncommunicable Diseases (NCD) Country Profiles, 2014.

https://www.heartfoundation.org.au/news/many-aussies-have-poor-understanding-of-heart-disease-risk-factors
Heart Disease risk factors

LDL cholesterol
Strongly associated with atherosclerosis and CVD events.
10% increase results in an approximate 20% increase in CHD risk.
Most of the cholesterol in plasma is found in LDL particles.
Smaller denser LDL are more atherogenic than larger, less dense particles.
Risk associated with LDL-C is increased by other risk factors:
low HDL-C
smoking
hypertension
diabetes and the metabolic syndrome
References
1. Wood D et al, for the Joint European Committee, Second Task Force of European and other Societies. Atherosclerosis 1998;140:199–270.
2. In: Fast Facts - Hyperlipidaemia. Eds Durrington P, Sniderman A. Health Press Ltd, Oxford, Second Edition, 2002. 7–12.
Chain reaction

- Trials of LDL-lowering indicate RELATIVE RISK reduction is
proportional to the ABSOLUTE REDUCTION in LDL-C
- Lower is better: lowering LDL-C with statins, ezetimibe, or
PCSK9-inhibitors safe and effective to <1.4 mmol/L (55 mg/dL)
- Intensity of LDL-lowering therapy should be based on (A) risk,
irrespective of cause(s) of the risk (e.g., primary or secondary
prevention, diabetes, or chronic kidney disease); and (B)
baseline LDL cholesterol (which determines how much
reduction in risk can be achieved)
7
Fundamental principles for LDL-lowering therapy

HDL-C has a protective effect for risk of atherosclerosis and CHD
Epidemiological studies show the lower the HDL-C level, the higher the
risk for atherosclerosis and CHD
low level (<40 mg/dL, 1 mmol/L) increases risk
HDL-C tends to be low when triglycerides are high
HDL-C is lowered by smoking, obesity and physical inactivity
ApoA-I is the major apolipoprotein in HDL and an elevated ApoA-I is
linked to reduced CVD risk
HDL cholesterol
References
1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001:285;2486–2497.
2. Wood D et al, for the Joint European Committee, Second Task Force of European and other Societies. Atherosclerosis 1998;140:199–270.
3. In: Fast Facts - Hyperlipidaemia. Eds Durrington P, Sniderman A. Health Press Ltd, Oxford, Second Edition, 2002. 7–12.

• May be associated with increased risk of CHD events
• Link with increased CHD risk is complex may be direct
effect of smaller TG-rich lipoproteins and/or may be
related to:
• low HDL levels
• highly atherogenic forms of LDL-C
• hyperinsulinaemia/insulin resistance
• procoagulation state
• hypertension
• abdominal obesity
Triglycerides
1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001:285;2486–2497.

J.R.NelsonaO.WanibH.T.MaycM.Budoffd Potential benefits of eicosapentaenoic acid on atherosclerotic plaques
Vascular Pharmacology
Volume 91, April 2017, https://doi.org/10.1016/j.vph.2017.02.004
Atherosclerosis

Lipid Profile: When, Who & How to read

Screening of secondary dyslipidemia
• Autoimmune chronic inflammatory conditions such as rheumatoid
arthritis, systemic lupus erythematosus (SLE)
• diabetes or hypertension during pregnancy are risk indicators
• Erectile dysfunction in men
• Patients with CKD are also at increased risk for CVD events and should
be screened for dyslipidaemias
• Patients with thyroid disorders
• Patients with liver disease
Adapted from Alberico L. Catapano et al. Eur Heart J 2016;eurheartj.ehw272

Monitoring patients with high risk of
atherosclerosis
• Hypertension
• Smoking
• Diabetes
• Metabolic syndrome
• Sedentary life style
• All adult men ≥40 years of age and in women ≥50 years of age or
postmenopausal
• Peripheral arterial disease (PAD)
• the presence of increased carotid intima-media thickness (CIMT) or carotid
plaques

Management of
Dyslipidemia in High risk
patient

Case Presentation
• Mr. WM is a 50 year old male.
• He is a smoker, HTN for 6 years.
• He is coming for a regular check up.
• BP: 160/90 mmHg.

When should we screen our Egyptian
population for risk factors of CV disease?
A) All ages should be screened regardless of their family history.
B) Men above 40 years and women above 50 years.
C) Men and women above 50 years.
D) Men above 50 years and women above 40 years.

Men >40 years old and women >50 years should be
considered for CVD risk factors screening and risk
estimation of future cardiovascular fatal and nonfatal
events using (SCORE) charts of the ESC/EAS Guidelines.
The Egyptian consensus of dyslipidemia management.December 2017

Frequently Asked Questions
• Q. Which lipid parameter should be used as a primary target for
treatment?
• A: LDL-C IS THE PRIMARY TARGET for treatment LDL-C target depends on
the risk of the patient and the base line LDL-C level.
• Q. Should I stop or decrease statin dosage after reaching the target?
• A: No. Once statin type and dose is indicated it should be continued
indefinitely (Statins for life).
• Q: If my patient is a high risk despite low baseline LDL-C, what should I do?
• A: Any high risk patient should have a moderate or high intensity statin
regardless of the base line LDL-C.

Treatment targets
Recommendations for lipid analyses as treatment targets in the prevention of cardiovascular
disease
Recommendations Class Level
LDL-C is recommended as the primary target for treatment. I A
TC should be considered as a treatment target if other analyses are not
available.
IIa A
Non-HDL-C should be considered as a secondary treatment target. IIa B
ApoB should be considered as a secondary treatment target, when
available.
IIa B
HDL-C is not recommended as a target for treatment. III A
The ratios apoB/apoA1 and non-HDL-C/HDL-C are not recommended as
targets for treatment.
III B

The results of the lipid profile were:
TC 210
TG 180
LDL 119
HDL 30

What is the CV risk of this patient?
A. Low.
B. Moderate.
C. High.
D. Very high.

Egypt is a very high risk country
Adapted from Alberico L. Catapano et al. Eur
Heart J 2016;eurheartj.ehw272

Total cardiovascular risk
Risk categories
Very high-risk Subjects with any of the following:
• Documented cardiovascular disease (CVD), clinical or unequivocal on imaging.
Documented CVD includes previous MI, ACS, coronary revascularisation (PCI, CABG) and other arterial
revascularization procedures, stroke and TIA, and PAD. Unequivocally documented CVD on imaging is
what has been shown to be strongly predisposed to clinical events, such as significant plaque on coronary
angiography or carotid ultrasound.
• DM with target organ damage such as proteinuria or with a major risk factor such as smoking,
hypertension or dyslipidaemia.
• Severe CKD (GFR <30 mL/min/1.73 m2).
• A calculated SCORE ≥10% for 10-year risk of fatal CVD.
High-risk Subjects with:
• Markedly elevated single risk factors, in particular cholesterol >8 mmol/L (>310 mg/dL) (e.g. in familial
hypercholesterolaemia) or BP ≥180/110 mmHg.
• Most other people with DM (some young people with type 1 diabetes may be at low or moderate risk).
• Moderate CKD (GFR 30–59 mL/min/1.73 m2).
• A calculated SCORE ≥5% and <10% for 10-year risk of fatal CVD.
Moderate-
risk
SCORE is ≥1% and <5% for 10-year risk of fatal CVD.
Low-risk SCORE <1% for 10-year risk of fatal CVD.

2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce
cardiovascular risk (European Heart Journal 2019 -doi: 10.1093/eurheartj/ehz455)www.escardio.org/guidelines
Cardiovascular risk categories (1)
©ESC
Very-high-risk People with any of the following:
Documented ASCVD, either clinical or unequivocal on imaging.
Documented ASCVD includes previous ACS (MI or unstable angina), stable angina,
coronary revascularisation (PCI, CABG and other arterial revascularization procedures),
stroke and TIA, and peripheral arterial disease. Unequivocally documented ASCVD on
imaging includes those findings that are known to be predictive of clinical events, such as
significant plaque on coronary angiography or CT scan (multivessel coronary disease with
two major epicardial arteries having >50% stenosis) or on carotid ultrasound.
DM with target organ damage, ≥3 major risk factors or early onset of
T1DM of long duration (>20 years).
Severe CKD (eGFR <30 mL/min/1.73 m ).
A calculated SCORE ≥10% for 10-year risk of fatal CVD.
FH with ASCVD or with another major risk factor.
2

Cardiovascular risk categories (2)
©ESC
High-risk People with:
Markedly elevated single risk factors, in particular TC >8 mmol/L (>310
mg/dL), LDL-C >4.9 mmol/L (>190 mg/dL), or BP ≥180/110 mmHg.
Patients with FH without other major risk factors.
Patients with DM without target organ damage*, with DM duration ≥10 years
or another additional risk factors.
Moderate CKD (eGFR 30–59 mL/min/1.73 m ).
A calculated SCORE ≥5% and <10% for 10-year risk of fatal CVD.2
Moderate-risk Young patients (T1DM <35 years; T2DM <50 years) with DM duration <10 years, without
other risk factors. Calculated SCORE ≥1% and <5% for 10-year risk of fatal CVD.
Low-risk Calculated SCORE <1% for 10-year risk of fatal CVD.
*Target organdamage is defined as microalbuminuria, retinopathy or neuropathy

How serious is the problem of CV disease and
dyslipidemia in Egypt?
• It is not a burden at all.
• CV disease is the third highest in number of mortality.
• Premature atherosclerosis and dyslipidemia are very rare in Egypt.
• None of the above are true.

The Egyptian perspective
• CVDs are the number one cause of death globally: more people die annually from
CVDs than from any other cause.
• Cardiovascular diseases represent 46% of the total mortality in Egypt
• The Egyptian Cardiovascular Risk Factors project in ACS patients showed that 47%
of males and 69% of female had premature atherosclerosis.
• One of the major causes and risk factors of CV disease is Dyslipidemia
• 37% of the Egyptian population has high cholesterol level with an overall
achievement goal of ONLY 34.4% as per CEPHEUS trial.

What are the appropriate measures to
implement in our patient?
A) Lifestyle modifications alone for 3 months.
B) Immediate hypo-lipidemic therapy with lifestyle modifications.

Risk-based intervention strategies as a
function of total CV risk and LDL-C level

Intervention strategies as a function of total
cardiovascular risk and untreated low-density
lipoprotein cholesterol levels
©ESC

What lifestyle modifications would you
recommend for our patient?
A) Low amount of trans saturated fats and carbohydrates.
B) 2.5 to 5 hours moderate physical activity per week.
C) Body weight reduction.
D) All of the above.

Recommended
Lifestyle
modifications
The Egyptian consensus of dyslipidemia
management.December 2017

Which of the following is not a recommended
treatment goal?
A) LDL reduction.
B) HDL elevation.
C) Total Cholesterol reduction.
D) Non HDL reduction.

What is the LDL target in our patient?
A) < 130.
B) < 115.
C) < 100.
D) < 70.

Recommendations for treatment goals for
low-density lipoprotein cholesterol (1)
©ESC
In secondary prevention patients at very-high risk , an LDL-C reduction ofc
at least 50% from baseline
are recommended.
d and an LDL-C goal of <1.4 mmol/L (<55 mg/dL) I A
In primary prevention, for individuals at very-high risk but without FH , anc
LDL-C reduction of at least 50% from baseline
mmol/L (<55 mg/dL) are recommended.
d and an LDL-C goal of <1.4 I C
In primary prevention, for individuals with FH at very-high risk, an LDL-C
reduction of at least 50% from baseline and an LDL-C goal of <1.4 mmol/L
(<55 mg/dL) should be considered.
IIa C
c
For definitions see Table 1.
d
The term ‘baseline’ refers to the LDL-C level in a person not taking any LDL-C lowering medication. In people who
are taking LDL-C-lowering medication(s), the projected baseline (untreated) LDL-C levels should be estimated, based
on the average LDL-C-lowering efficacy of the given medication or combination of medications.

©ESC
For patients with ASCVD 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 <1.0 mmol/L (<40
mg/dL) may be considered.
IIb B
In patients at high-risk , an LDL-C reduction of at least 50% fromc
baselined and an LDL-C goal of <1.8 mmol/L (<70 mg/dL) are
recommended.
I A
c
d
The term ‘baseline’ refers to the LDL-C level in a person not taking any LDL-C lowering medication. In people who
are taking LDL-C-lowering medication(s), the projected baseline (untreated) LDL-C levels should be estimated, based
on the average LDL-C-lowering efficacy of the given medication or combination of medications.

©ESC
In individuals at moderate risk , an LDL-C goal of <2.6 mmol/L (<100 mg/dL)
should be considered.
c
IIa A
In individuals at low risk an LDL-C goal <3.0 mmol/L (<116 mg/dL) may be
considered.
c
IIb A
C

Treatment goals for low-density lipoprotein
cholesterol (LDL-C) across categories of total cardiovascular
disease risk
©ESC
Low
Moderate
High
Very-High
3.0 mmol/L
(116 mg/dL)
Treatment goal
for LDL-C
2.6 mmol/L
(100 mg/dL)
1.8 mmol/L
(70 mg/dL)
1.4 mmol/L
(55 mg/dL)
& ≥50%
reduction
from baseline
Low Moderate High very-High CV Risk
•SCORE <1%
•SCORE ≥1% and <5%
•Young patients (T1DM <35 years; T2DM <50 years) with DM
duration <10 years without other risk factors
•SCORE ≥5% and <10%
•Markedly elevated single risk factors, in particular TC >8 mmol/L (310
mg/dL) or LDL-C >4.9 mmol/L (190 mg/dL) or BP ≥180/110 mmHg
•FH without other major risk factors
•Moderate CKD (eGFR 30–59 mL/min)
•DM w/o target organ damage, with DM
duration ≥10 years or other additional risk factor
•ASCVD (clinical/imaging)
•SCORE ≥10%
•FH with ASCVD or with another major risk factor
•Severe CKD (eGFR <30 mL/min)
•DM & target organ damage: ≥3 major risk factors; or
early onset of T1DM of long duration (>20 years)

Recommendations for pharmacological
low-density lipoprotein cholesterol lowering (1)
©ESC
It is recommended to prescribe a high-intensity statin up to the highest
tolerated dose to reach the goals set for the specific level of risk.c I A
If the goals are not achieved with the maximum tolerated dose of statin,
combination with ezetimibe is recommended.
c
I B
For primary prevention patients at very-high risk, but without FH, if
the LDL-C goal is not achieved on a maximum tolerated dose of statin
and ezetimibe, a combination with a PCSK9 inhibitor may be
considered.
IIb C
c
For definitions see Full Text.

©ESC
For secondary prevention, patients at very-high risk not achieving their
goal on a maximum tolerated dose of statin and ezetimibe, a combination
with a PCSK9 inhibitor is recommended.
c I A
For very-high-risk FH patients (that is, with ASCVD or with another major
risk factor) who do not achieve their goal on a maximum tolerated dose of
statin and ezetimibe, a combination with a PCSK9 inhibitor is
recommended.
I C
If a statin-based regimen is not tolerated at any dosage (even after re-
challenge), ezetimibe should be considered. IIa C

©ESC
If a statin-based regimen is not tolerated at any dosage (even after re-challenge), a
PCSK9 inhibitor added to ezetimibe may also be considered. IIb C
If the goal is not achieved, statin combination with a bile acid sequestrant may be
considered.
c
IIb C
c
For definitions see Full Text.

Recommendations for drug treatments of
patients with hypertriglyceridaemia (1)
©ESC
Statin treatment is recommended as the first drug of choice for reducing
CVD risk in high-risk individuals with hypertriglyceridaemia (TG >2.3
mmol/L (>200 mg/dL)).
I B
In high-risk (or above) patients with TG between 1.5 and 5.6 mmol/L (135–
499 mg/dL) despite statin treatment, n-3 PUFAs (icosapent ethyl 2 x 2 g/day)
should be considered in combination with statin.
IIa B

Intensity of Statins

What medications should be given to achieve
the LDL goal?
A) Statins.
B) Fibrates.
C) Ezetimibe.
D) Bile acid sequestrants.

Drugs for treatment of hypercholesterolaemia
Recommendations for the pharmacological treatment of hypercholesterolaemia
Prescribe statin up to the highest recommended doseor highest
tolerable dose to reach the goal.
I A
In the case of statin intolerance, ezetimibe or bile acid sequestrants, or these combined,
should be considered. IIa C
If the goal is not reached, statin combination with a cholesterol absorption inhibitor should be
considered. IIa B
If the goal is not reached, statin combination with a bile acid sequestrant may be considered.
IIb C
In patients at very high-risk, with persistent high LDL-C despite treatment with maximal
tolerated statin dose, in combination with ezetimibe or in patients with statin intolerance, a
PCSK9 inhibitor may be considered.
IIb
C

What have statins to provide in primary
prevention?
A) LDL reduction.
B) Mortality benefit.
C) Reduction of strokes.
D) All of the above.

Even among patients without
cardiovascular disease, statins reduced
the following end points in primary
prevention trials:
• All-cause mortality by 14% .
• Combined fatal and non-fatal CVD by 25% .
• Combined fatal and non-fatal CHD events by 27% .
• Combined fatal and non-fatal stroke by 22% .
• Revascularization rates by 38% .

Should I stop or decrease statin dosage after
reaching the target?
A)Yes.
B) No.

NO!!!
Once statin type and dose is indicated it should be
continued indefinitely (Statins for life).

Recommendations for lipid-lowering therapy
in very-high-risk patients with acute coronary syndromes (1)
©ESC
In all ACS patients without any contra-indication or definite history of
intolerance, it is recommended to initiate or continue high dose statin as
early as possible, regardless of initial LDL-C values.
I A
Lipid levels should be re-evaluated 4–6 weeks after ACS to determine
whether a reduction of at least 50% from baseline and goal levels of LDL-
C <1.4 mmol/L (<55 mg/dL) have been achieved. Safety issues need to be
assessed at this time and statin treatment doses adapted accordingly.
IIa C
If the LDL-C goal is not achieved after 4–6 weeks with the maximally
tolerated statin dose, combination with ezetimibe is recommended.
I B

Recommendations for lipid-lowering therapy in
very-high-risk patients with acute coronary syndromes (2)
©ESC
If the LDL-C goal is not achieved after 4–6 weeks despite maximal
tolerated statin therapy and ezetimibe, adding a PCSK9 inhibitor is
recommended.
I B
In patients with confirmed statin intolerance or in patients in whom a
statin is contra-indicated, ezetimibe should be considered.
IIa C
For patients who present with an ACS and whose LDL-C levels are not
at goal despite already taking a maximally tolerated statin dose and
ezetimibe, adding a PCSK9 inhibitor early after the event (if possible,
during hospitalization for the ACS event) should be considered.
IIa C

Recommendations for the treatment of
dyslipidaemias in older people (aged >65 years)
©ESC
Treatment with statins is recommended for older people with ASCVD in
the same way as for younger patients.
I A
Treatment with statins is recommended for primary prevention, according to
level of risk, in older people aged ≤ 75.
I A
Initiation of statin treatment for primary prevention in older people aged
> 75 may be considered, if at high risk or above.
IIb B
It is recommended that the statin is started at a low dose if there is
significant renal impairment and/or the potential for drug interactions,
and then titrated upwards to achieve LDL-C treatment goals.
I C

Take Home Messages
• We are in the era of evidence based medicine.
• We need to screen for lipid parameters in those that are at risk.
• Risk profiling is of utmost importance as we are not only
improving lab numbers, but we are reducing mortality as well.
• Lifestyle changes should always be implemented.
• Statins, when indicated should be for life.
• Not only lower is better , the Lowest is the best .

Management of dyslipidemia 2019 update

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