REFERAT

Dislipidemia dan
Tatalaksana
Oleh :

1. Ryan Kusumawardani I4061191011

2. April Lusi Triningsih I4061191014
3. Rikianto I4061191043
4. Arifna Fitriyanti I4061191015
5. Pamela Rita Sari I4061172080
6. Lia Pramita I4061191023
7. Kevin Chikrista I4061172039
8. Wahyu farhurrachman I4061172041

Pembimbing : dr. Arinta Setyasari, Sp.JP

Stase Kardiologi
Universitas Tanjungpura
2019
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 Definisi
Dislipidemia
Dislipidemia adalah terganggunya metabolisme lipid akibat
interaksi faktor genetik dan faktor lingkungan.

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 Recommendation for Measurement of LDL-C and HDL-C

Class II a Level C-LD

Adult (≥ 20 years)
Class I Level B-NR
LDL-C : < 70 mg/dL (1,8 mmol)
Adult (≥ 20 years)
that Measurement using direct
Not on lipid-lowering therapy
or modified LDL-C
Either Fasting or Non-Fasting
LDL-C measurement using
Friedewald formula should be
performed
Class I Level B-NR
Class II a Level C-LD
Adult (≥ 20 years) Adult (≥ 20 years)
Not on lipid-lowering therapy With Family of ASCVD,
Non-Fasting TGC ≥ 400mg/dL Hypaerlipidemia
(≥ 4,5 mmol) Fasting Plasma Lipid should
Fasting TGC and LDL-C be performed
should be performed
Cardiovascular risk categories
 SCORE Cardiovascular Risk Chart

Note:
 Cholesterol: 1 mmol/L=38.67 mg/dL
 Used for Moderate-Low Risk
Intervention Strategies as a Function of Total Cardiovascular Risk and
Untreated Low-density Lipoprotein Cholesterol Levels
 Treatment targets and goals for cardiovascular disease prevention

SMOKING Diet Physical Activity Body Weight

No Exposure to  Healthy Diet  Moderate to vigorous BMI 2025 kg/m2,
Tobacco in any form ≥210-420 min/week Waist circumference <94 cm
 Aerobic and (men) and <80 cm (women)
resistance training.

Blood Pressure ApoB HbA1C LDL-C

 Very High Risk : <65  <7% (53 mmol/mol) Very-high risk
< 140/90 mmHg mg/dL  Achieves ≥ 50% LDL-C reduction from
 High : <80 mg/dL baseline
 Moderatte : 100 mg  LDL-C goal of <1.4 mmol/L (<55 mg/dL).
TGC mg/dL
Non-HDL-C High risk:
 Achieves regimen that achieves ≥50%
 Very High Risk : <2,2 mmol/L or85 LDL-C reduction from baseline
< 1,7 mmol or 1,5 mg/dL  LDL-C goal of <1.8 mmol/L (<70 mg/dL)
mg/dL
 High Risk: <2,6 mmol/L or 100 mg/dL Moderate risk:
 Moderatte Risk : <3,4 mmol/L or 130  A goal of <2.6 mmol/L (<100 mg/dL).
Low risk:
mg/dL
 A goal of <3.0 mmol/L (<116 mg/dL)
Dyslipidemia Management Algorithm
 Multifactorial Approaches of patients with DM (II a B)
Decrease CV
events by
75%.

Aspirin
Very high/ high
CV risk
LDL- C

 Very high CV risk,  <1.4

HbA1c mmol/L (<55 mg/dL)
 <7.0%(53  High CV risk  <1.8
mmol/mol) mmol/L (<70 mg/dL)
Blood (adults)  Moderate CV risk  <2.5
Pressure  <6.5% (48 mmol/L (<100 mg/d
mmol/mol) if
Smoking Physical Weight Diet  SBP 130 mmHg tolerated
Activity <130-120 mmHg  <8% (64
 Moderate to vigorous ≥150 if tolerated mmol/mol) or
min/week  SBP 130 - 139 in <_9% (75
 Aerobic and resistance older patients mmol/mol for
training. (aged >65 years) older patient
Terapi Farmakologi Dislipidemia
 Statin
Mekanisme Obat

Statins reduce the synthesis of cholesterol in the liver by

competitively inhibiting the enzyme HMG-CoA reductase,

the rate-limiting step in cholesterol biosynthesis.

The reduction in intracellular cholesterol promotes

increased LDL receptor (LDLR) expression at the surface of

the hepatocytes, which in turn results in increased uptake of

LDL from the blood, and decreased plasma concentrations

of LDL- and other ApoB-containing lipoproteins, including

TG-rich particles.
 Efek Terhadap Lipid
LDL-C Triglycerides HDL-C Lipoprotein(a)

 Statins usually Given the marked statin- Previous studies

A highintensity reduce TG levels by mediated decrement in
regimen is defined as 1020% from baseline
have reported either
atherogenic ApoB-containing
the dose of a statin that, values. lipoproteins, the extent to
no effect on or an
on average, reduces  The mechanism of which the very modest effect increase of Lp(a)
LDL-C by >_50%; the TG-lowering on HDL-C levels might levels after statin
moderate-intensity effect has not been contribute to the overall treatment
therapy is defined as fully elucidated, but it observed reductions in CV
risk consistently observed in
the dose expected to seems to be partly
statin intervention trials
reduce LDL-C by independent of the
cannot reliably be
3050%. LDLR pathway disentangled.
Cholesterol absorption inhibitor

Mekanisme Obat

 Ezetimibe inhibits intestinal uptake of dietary and biliary cholesterol

at the level of the brush border of the intestine [by interacting with

the Niemann-Pick C1-like protein 1 (NPC1L1)] without affecting the

absorption of fat-soluble nutrients.

 By inhibiting cholesterol absorption, ezetimibe reduces the amount of

cholesterol delivered to the liver. In response to reduced cholesterol

delivery, the liver reacts by upregulating LDLR expression, which in

turn leads to increased clearance of LDL from the blood.

Effect on Lipids
 Clinical Study : monotherapy at 10 mg/day reduces LDL-C in
hypercholesterolaemic patients by 1522% with relatively high
interindividual variation.
 A meta-analysis of RCTs that included over 2700 people showed an
18.5% reduction in LDL-C as compared with placebo.

Effect on CV morbidity & mortality

 In the Improved Reduction of Outcomes: Vytorin Efficacy International
Trial (IMPROVE-IT), ezetimibe was added to simvastatin (40 mg) in
patients after acute coronary syndrome (ACS).
 A total of 18 144 patients were randomized to statin or statin plus
ezetimibe, and 5314 patients over 7 years experienced a CV event;
170 fewer events (32.7 vs. 34.7%) were recorded in the group taking
simvastatin plus ezetimibe (P=0.016). The average LDL-C during the
study was 1.8 mmol/L (70 mg/dL) in the simvastatin group and 1.4
mmol/L (55 mg/dL) in patients taking ezetimibe plus simvastatin. Also,
ischaemic stroke was reduced by 21% in this trial.

Adverse effect and Interaction

The recommended dose of ezetimibe of 10mg/day can be
administered in the morning or evening irrespective of food
intake.
B i l e a c i d s e q u e s t r a n t s

Mekanisme Obat

Bile acids are synthesized in the liver from cholesterol

and are released into the intestinal lumen, but most of

the bile acid is returned to the liver from the terminal

ileum via active absorption.

The two older bile acid sequestrants, cholestyramine

and colestipol, are both bile acid-binding exchange

resins.
 B A
Effect on Lipids
 At the top daily dose of 24 g of cholestyramine,
20 g of colestipol, or 4.5 g of colesevelam, a
reduction in LDL-C of 1825% has been
observed.
 No major effect on HDL-C has been reported,
while TGs may increase in some predisposed
patients.274 Colesevelam can also reduce
glucose levels in hyperglycaemic patients
Effect on CV morbidity and mortality
 In clinical trials, bile acid sequestrants have contributed greatly to
the demonstration of the efficacy of LDL-C lowering in reducing
CV events in hypercholesterolaemic people, with a benefit
proportional to the degree of LDL-C lowering.
 Of note, these studies were performed before many of the
modern treatment options were available
S
Adverse effect and interactions
 Gastrointestinal (GI) adverse effects (most
commonly flatulence, constipation,
dyspepsia, and nausea) are often present with
these drugs, even at low doses, which limits their
practical use.
 Bile acid sequestrants have major drug
interactions with several commonly prescribed
drugs, and must therefore be administered
either 4 h before or 1 h after other drugs.
 Colesevelam is better tolerated and has fewer
interactions with other drugs, and can be taken
together with statins and several other drugs.
 Protein convertase subtilisin/kexin type 9 inhibitors
Mechanism of action
Elevated concentration or function of this protein
in plasma reduces LDLR expression by promoting,
upon binding, LDLR lysosomal catabolism and a
subsequent increase in plasma LDL concentrations,
while lower concentration or function of PCSK9 is
related to lower plasma LDL-C levels.
Effect on Lipids
 Cinical trials : alirocumab and evolocumab—
either alone or in combination with statins, and/or
other lipid-lowering therapies—have been shown
to significantly reduce LDL-C levels on average
by 60%, depending on dose
 In phase II trials : evolocumab lowered TG levels
by 26%, and raised HDL-C and ApoA-I by 9 and
4%, respectively; similar findings have been
reported for alirocumab.
Effect on CV morbidity and mortality
 In the FOURIER trial, allocation to evolocumab did not
reduce the risk of CV mortality (HR 1.05, 95% CI 0.881.25)
or all-cause mortality.
 The ODYSSEY Outcomes trial : There was a 15% relative
reduction in the primary outcome (composite of CHD death,
nonfatal MI, ischaemic stroke, or unstable angina requiring
hospitalization) (HR 0.85, 95% CI 0.780.93) after a median
follow-up of 2.8 years.
Adverse effect and Interactions
Mendelian randomization studies have also
suggested that PCSK9 inhibition may increase the
risk of DM with an LDL-C-related effect, as
apparently occurs for statins.
 Lomitapide

• Lomitapide  MTP inhibitor designed for o.d. oral treatment

of HoFH
• LDL-C  reduced by 50% from baseline at 26 weeks and by
44% at 56 weeks.
• lomitapide  increased aminotransferase levels, which most
likely reflects the increased fat in the liver, as well as poor GI
tolerability.
• prescription of lomitapide requires careful patient education
and liver function monitoring during therapy.
 Mipomersen

• Mipomersen is an antisense oligonucleotide able to bind the

(mRNA) of ApoB-100, which triggers the selective
degradation of mRNA molecules.
• oligonucleotide transported to the liver, where it binds to a
specific mRNA preventing the translation of ApoB protein
and, reducing the production of LDL and Lp(a).
• adverse effect  are related to liver toxicity. Mipomersen
may lead to the development of steatosis.
 Fibrat

• Fibrates  agonists of (PPAR-a), acting via transcription factors

regulating, among other things, various steps in lipid and
lipoprotein metabolism.
• good efficacy in lowering fasting TG levels
• 50% ↓ TG level, <20% ↓ LDL-C , and ↑HDL-C level of <20%.
• adverse effect  myopathy, liver enzyme ↑, and cholelithiasis, ↑ e
both serum creatinine and ↑ homocysteine levels
• ↑ homocysteine  blunt elevation of both HDL-C and ApoA1
levels,  may contribute to the smaller than estimated benefits of
fenofibrate in CV outcome parameters.
 N3 fatty acids/ omega 3

• Reduce TG reduce cardiovascular morbidity and mortality

• The administration of n-3 fatty acids  safe and devoid of
clinically significant interactions.
• side effect  GI disturbance. The antithrombotic effects may
increase the propensity for bleeding
• Recently, data from one study have associated a risk of
prostate cancer with high dietary intake of n-3 PUFA
 Nicotinic acid

• In the liver, nicotinic acid inhibits diacylglycerol

acyltransferase-2 resulting in decreased secretion of VLDL
particles, which is also
• raises HDL-C and ApoA1 by stimulating ApoA1 production in
the liver.
 Cholesteryl ester transfer protein
inhibitors

• Anacetrapib which raises HDL-C and ApoA-I levels, and

lowers LDL-C and ApoB (by 17 and 18%, respectively),
• Anacetrapib reduced major coronary events by 9%
 Future perspectives

• to reduce LDL cholesterol PCSK9 inhibitor, Bempedoic

acid
• to reduce triglyceride-rich lipoproteins ANGPTL3 antibody
• increase high-density lipoprotein cholesterol focused on
ApoA1 mimetic peptides and recombinant forms of HDL
possessing potential for in vivo
Recommendations for pharmacological low-
density lipoprotein cholesterol lowering
 Expected
clinical
benefits of
low-
density
lipoprotein
cholesterol
-lowering
therapies
 Treatment
algorithm for
pharmacologic
al low-density
lipoprotein
cholesterol
lowering
 Treatment goals
for low-density
lipoprotein
cholesterol across
categories of total
cardiovascular
disease risk
Recommendations for drug treatment of
patients with hypertriglyceridaemia
Terapi Non Medikamentosa
Treatment targets and goals for cardiovascular
disease prevention
Food choices to lower low-density lipoprotein cholesterol and
improve the overall lipoprotein profile
Pengaruh perubahan
gaya hidup pada
konsentrasi lipid
Pengaruh perubahan gaya hidup pada konsentrasi
lipid
 Aktivitas fisik

Aktivitas fisik yang dianjurkan adalah aktivitas yang terukur

seperti jalan cepat 30 menit per hari selama 5 hari per minggu
atau aktivitas lain setara dengan 4-7 kkal/menit atau 3-6
METs.
• Berjalan cepat (4,8-6,4 km per jam) selama 30-40 menit
• Berenang selama 20 menit
• Bersepeda baik untuk kesenangan atau transportasi, jarak 8
km dalam 30 menit
 Diet suplemen

• Fitosterol  ↓ kolesterol total

• Protein kedelai  ↓3-5% LDL
• Makanan serat  ↓LDL 5%. Anjuran diet serat yang larut
dalam air untuk menurunkan kolesterol LDL adalah 5-15
gram/hari.
• Pufa omega 3 ↓ TG 25-30%, ↓ LDL 5-10%, dan ↑ HDL
sebesar 1-3%
Follow Up Terapi
Manajemen Dislipidemia pada
Kondisi Tertentu
 Pada WANITA

1. Statin treatment is recommended for

primary prevention of ASCVD in high-
risk women.
2. Statins are recommended for
secondary prevention in women with
the same indications and goals as in
men.
3. Lipid-lowering drugs should not be
given when pregnancy is planned,
during pregnancy, or during
breastfeeding period. However, for
severe FH patients, bile acid
sequestrants (which are not absorbed)
and/or LDL apheresis may be
considered
 Pada LANSIA Usia > 65
tahun
Usia 65 – 75 tahun || Usia > 75 tahun

 >80% individuals who die from CVD

are >65 years.

1. Statins treatment is recommended for

older people with ASCVD in the same
way as for younger patients.
2. Statins treatment is recommended for
primary prevention, according to the
level of risk, in older people aged ≤ 75
years.
3. Initiation of statin treatment for primary
prevention in older people aged > 75
years may be considered, if at high-risk Statin-associated adverse effects:
or above.
 Myalgia
4. Statin is started in low dose if there is
 Myopathy with CK elevation
significant renal impairment and/or the
potential for drug interactions, and then  Rhabdomyolysis
titrated upwards to achieve LDL-C
treatment goals.
 Pada DIABETES

1. In patients with T2DM at very-high risk,

an LDL-C reduction of ≥50% from
baseline and LDL-C goal of <55 mg/dL is
recommended!
2. In patient with T2DM at high risk, an
LDL-C reduction of 50% from baseline
and an LDL-C goal of <70 mg/dL is
recommended!
3. Statins are recommended in patient with
T1DM who are at high or very-high risk. 6. Statin therapy is not recommended in
4. Intensification of statin therapy should be premenopausal patients with diabetes
considered before the introduction of who are considering pregnancy or are
combination therapy! not using adequate contraception.
5. If the goal is not reached, statin 7. Statin therapy may be considered in
combination with ezetimibe should be both T1DM and T2DM patients aged ≤30
considered! years with evidence of end organ
damage and/or an LDL-C
level>2.5mmol/L as long as pregnancy is
not being planned.
 Pada Heart Failure
&Valvular Disease

1. Statins in patients WITH CAD (stable

or history of ACS) REDUCES the
incidence of HF!
2. Initiation of lipid-lowering therapy IS
NOT RECOMMENDED in patients with
HF in the absence of other indications
for their use.
3. Initiation of lipid-lowering treatment in
patients with aortic valvular stenosis
without CAD to slow progression of
aortic valve stenosis in the absence of
other indications for their use is not
recommended!
Stroke

 Pasien dengan riwayat stroke dan TIA dikategorikan ke

dalam kelompok dengan risiko kardiovaskular sangat tinggi.
 Terapi penurun lipid pada pasien dengan risiko
kardiovaskular tinggi bertujuan untuk menurunkan angka
kejadian stroke dan TIA sehingga terapi statin ditujukan
untuk pencegahan primer stroke dan menurunkan risiko
kejadian kardiovaskular lainnya.
Stroke iskemik

Terapi Statin + Ezetimibe menurunkan kejadian stroke iskemik

Pada pasien SKA secara bermakna

Penurunan risiko terjadinya stroke

Terapi Statin + Inhibitor iskemik pada pasien dengan penyakit
PCSK9 kardiovaskular (25%)

Terapi statin pada pasien dengan riwayat stroke iskemik (non-

kardioembolik) atau TIA bertujuan untuk menurunkan risiko kejadian
stroke berulang (tindakan pencegahan sekunder Stroke)
Stroke hemoragik

• Hubungan antara konsentrasi lipid rendah dengan

peningkatan insiden stroke perdarahan hanya dibuktikan
oleh studi observasional dan tidak konsisten.

Terapi Statin + Inhibitor Menurunkan kolesterol LDL

PCSK9 hingga 30 mg/dL tanpa
Pada pasien dengan meningkatkan kejadian stroke
penyakit kardiovaskular hemoragik secara bermakna
Terapi statin pada pasien dengan
riwayat stroke atau TIA
• Terapi statin  bertujuan untuk menurunkan risiko terjadinya
stroke berulang, infark miokard, dan kematian vaskular.

Terapi statin
Ditujukan untuk terapi
tunggal atau
pencegahan primer
terapi kombinasi
terjadinya kejadian stroke
dengan Ezetimibe
pada pasien dengan
atau Inhibitor
penyakit kardiovaskular
PCSK9
Sindrom Koroner Akut

• Terapi statin dosis tinggi direkomendasikan diberikan pada

hari 1 - 4 perawatan sindrom koroner akut tanpa
memandang konsentrasi kolesterol LDL awal.

Terapi Statin Menurunkan

Pasien dengan LDL
konsentrasi LDL
awal ≥70 mg/dL
menjadi <70 mg/dL
• Jika terapi tunggal statin gagal:

Jika Terapi Statin +

Gagal Etezimibe

Target Terapi
LDL < 70 mg/dL

Ganti Terapi Statin + Inhibitor

Dengan PCSK9 Profil Lipif perlu diperiksa ulang
4 - 6 minggu kemudian untuk
evakuasi pencapaian target
kolesterol LDL
Thank you