Understanding the Needs of

The High Productive

Dyslipidemia Patients

(Nama Dokter)

1
Doc No: ID-ATO-00044 Exp.Date: 21 Feb 2022
Current gaps in dyslipidemia
in relation with ASCVD
management 2
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
On average 1.5% of Indonesian
population has been diagnosed
coronary disease

Kementerian Kesehatan. 2018. RISKESDAS

3
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Atherosclerosis is the Underlying Cause of ASCVD and
May Progress Silently for Many Years

 Stroke
Foam Fatty Intermediate
Atheroma
Fibrous Complicated  TIA
Cells Streak Lesion Plaque Lesion/Rupture

 MI
 Angina

 High BP
 Renal
failure
Endothelial Dysfunction
 PAD

From First Decade From Third Decade From Fourth Decade

Smooth
Thrombosis
Growth Mainly by Lipid Accumulation Muscle and
Hematoma
Collagen

Pepine CJ. The effects of angiotensin-converting enzyme inhibition on endothelial dysfunction: potential role in myocardial ischemia. Am J Cardiol. 1998;82:23S-
27S.
4
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
LDL-C and
Atherogenesis

5
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 LIPOPROTEIN CLASSIFICATION

LDL Cholesterol
(mg/dL)
<100 Optimal
100-129 Near optimal / above
optimal
130-159 Borderline high
160-189 High
≥190 Very high
6
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 LDL Particles Promote Atherogenesis
LDL Particles Promote Atherogenesis

 Particle
Particle Movement
Movement into
into Intima
Intima
–– Gradient
Gradient driven
driven
“The
“The rate
rate of
of passive
passive diffusion
diffusion is
is 
 Enhanced
Enhanced
increased
increased when
when the
the circulating
circulating Endothelial
Endothelial
levels
levels of
of LDL
LDL are
are elevated.”
elevated.” 11 Dysfunction
Dysfunction
Monocyte
Colony-
Adhesion Tissue
stimulating
molecules PAI-1 MCP-1 factor
factors
Lumen

Endothelial cells
Mildly modified LDL Intima

Extensively modified LDL

 Particle
Particle Uptake
Uptake by
by

 Particle
Particle Retention
Retention 
 Particle
Particle Oxidation
Oxidation  Macrophage
Macrophage
–– Lipoprotein
Lipoprotein particle
particle
binding
binding to
to proteoglycans
proteoglycans
 Cholesterol
Cholesterol Deposition;
Deposition;
 Increased
Increased Plaque
Plaque Burden
Burden
1 Weissberg PL, Rudd JH. Textbook of Cardiovascular Medicine. 2002. p. 6.
7
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Case
1
Patient : M.K. Medical History:
Profile : 41 years old Type 2 Diabetes Mellitus since 4 years
male, employee ago, A1c 7.1 MI with PCI 3 years ago
BMI : 29.7 kg/m2
Hypertension with
BP : 180/110 mm Hg
“They said life HR : 65 bpm LVH
Microalbuminuria
begin at 40, Medication: Smoker
but chronic Aspirin 81 mg
Bisoprolol 5 mg po Labs:
disease also daily TC 300 mg/dl
Telmisartan 80 mg po
noticed at 40” daily Janumet
LDL 171 mg/dl
100/1000 XR HDL 30 mg/dl
Empagliflozin 10 mg Triglycerides 550 mg/dl
po daily Atorvastatin
40 mg po od

Doc No: ID-ATO-00044 Exp.Date: 21 Feb 2022

“They said life begin
at 40, but chronic
disease also noticed
at 40” Doc No: ID-ATO-00044 Exp.Date: 21 Feb 2022
Case
1

Majority Indonesian Population with Chronic Heart Disease are

having an active and productive lifestyle

They are, civil employee, entrepreneur and others who

need to continue giving impacts to the Society

Riskedas, 2018 Doc No: ID-ATO-00044 Exp.Date: 21 Feb 2022

Case
1 Question

? 1 is the risk level of this man base

What
on Coronary Risk Estimation chart?

A.Very High Risk

B.High Risk
C.Moderate Risk
D.Low Risk

Doc No: ID-ATO-00044 Exp.Date: 21 Feb

2022
Heart SCORE (Systematic Coronary Risk Estimation)
based on ESC 2019

Very High
Risk
High Risk 1 mmol/L = 38.67 mg/dL
Moderate
Risk
Doc No: ID-ATO-00044 Exp.Date: 21 Feb2022
 LDL Particles Cause Atherosclerosis

Consistent evidence from numerous and multiple different types

of clinical and genetic studies unequivocally establishes
that LDL causes ASCVD.1

The more LDL particles a person has, the higher the risk for plaque
buildup that causes heart attacks, regardless of how much cholesterol
those particles carry.

1.Ference.2017. European Heart Journal (2017) 38, 2459–2472

13
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Individuals who will greatly benefit from LDL
Reduction

Clinical 10-year
ASCVD ASCVD
risk of
≥7.5%

LDL–C Diabetes
≥190 mg/dL
Stone NJ, et al. Circulation. Published online November 12, 2013 14
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
Case
1 Question

?
2 patient, what is your LDL goal?
In this

A.Less than 115 mg/dl

B. Less than 100 mg/dl
C. Less than 70 mg/dl
D. Less than 55 mg/dl

Doc No: ID-ATO-00044 Exp.Date: 21 Feb

2022
 Current Challenges in LDL-C Management and
Unmet Need of Statin Treatment:

LDL-C level: how low should we go?

16
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Based on ESC/EAS 2019
guideline:
LDL is still the main target of lipid
management and reduction of LDL
cholesterol must be of prime concern in
the prevention of CVD

ESC Guidelines on Diabetes, pre-diabetes and cardiovascular diseases in collaboration with EASD. Eur Heart J. Epub ahead of print August 31, 2019. doi: 10.1093/eurheartj/ehz486.

17
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Based on ESC 2019:
Very high risk patients should achieve >50% and
<55 mg/dl

LDL-C target (mg/dl)

Risk level
ESC 2016 ESC 2019

Very high ↓50% and <70 ↓50% and <55*

High ↓50% and <100 ↓50% and <70

Moderate <100
<115
Low <116
* <40 mg/dl may be considered for patients with ASCVD who
experience a second vascular event within 2 years
ESC Guidelines on Diabetes, pre-diabetes and cardiovascular diseases in collaboration with EASD. Eur Heart J. Epub ahead of print August 31, 2019. doi: 10.1093/eurheartj/ehz486.
18
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Based on ESC 2019:
Very high risk patients should achieve >50% and
<55 mg/dl
Risk group LDL-C goal Class/Level

Very high risk (secondary prevention) Reduction ≥50% from baseline IA

and <1.4 mmol (<55 mg/dL)
Very high risk (primary prevention, without Reduction ≥50% from baseline IC
FH) and <1.4 mmol (<55 mg/dL)
Very high risk (primary prevention, with FH) Reduction ≥50 from baseline IIa/C
and <1.4 mmol (<55 mg/dL)
ASCVD + second event within 2 years <1.0 mmol (<40 mg/dL) IIb/B

High risk Reduction ≥50% from baseline IA

and <1.8 mmol (<70 mg/dL)
Moderate risk <2.6 mmol (<100 mg/dL) IIa/A

Low risk <3.0 mmol (<116 mg/dL) IIb/A

ESC Guidelines on Diabetes, pre-diabetes and cardiovascular diseases in collaboration with EASD. Eur Heart J. Epub ahead of print August 31, 2019. doi: 10.1093/eurheartj/ehz486.
19
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 CV risk stratification also determine LDL-C level goal
High to very high CV risk patients should achieve ≥50% LDL-C
reduction

ESC Guidelines on Diabetes, pre-diabetes and cardiovascular diseases in collaboration with EASD. Eur Heart J. Epub ahead of print August 31, 2019. doi: 10.1093/eurheartj/ehz486.
20
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 CV events will be reduced with
even lowest LDL-C level achieved
4S-PI
30 Series 1
20
25 Prevention
CV events (%)

4S-Rx

20
LIPID-PI
LIPID-Rx
15
CARE-Rx CARE-PI
WOSCOPS-PI
10 TNT-Rx TNT-PI WOSCOPS-Rx
AFCAPS-TexCAPS-Rx
ASCOT-Rx
5JUPITER-Rx AFCAPS-TexCAPS-PI 10
JUPITER-PI ASCOT-PI Prevention
0
50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200

LDL-C achieved (mg/dl)

1. Ballantyne CM. Am J Cardiol. 1998;82:3Q–12Q.,
2. Halcox JPJ, Deanfield JE. Circulation. 2004;109[supplII]:II-42–II-48. 21
3. LaRossa JC, et al. N Engk J Med 2005;352
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Based on ESC 2019:
CV risk categories and recommendations
for management of dyslipidemia
Patients with DM and established CVD

Very or other target organ damage (proteinuria, renal impairment [eGFR≥30 mL/min/1.73 m 2])

high-risk or 3 or more major risk factors (age, hypertension, dyslipidemia, smoking, obesity)

or early onset T1DM of long duration (>20 years)

Patients with DM duration ≥10 years without target organ damage plus
High-risk any other additional risk factor

Young patients (T1DM <35 years; T2DM <50 years) with DM duration <10 years,
Moderate-risk without other risk factors

Recommendations Class Level

Targets
In patients with T2DM at moderate CV risk, an LDL-C target of <2.6 mmol/L (<100 I A
mg/dL) is recommended.
In patients with T2DM at high CV risk, an LDL-C target of <1.8 mmol/L (<70 mg/dL) I A
and an LDL-C reduction of at least 50% is recommended.
In patients with T2DM at very high CV risk, an LDL-C target of <1.4 mmol/L I B
(<55 mg/dL) and an LDL-C reduction of at least 50% is recommended.
In patients with T2DM, a secondary goal of a non–HDL-C target of <2.2 mmol/L (<85 I B
mg/dL) in very high CV risk patients, and <2.6 mmol/L (<100 mg/dL) in high CV risk
eGFR, estimated glomerular filtration rate
patients,
ESC Guidelines is
on recommended. 22
Diabetes, pre-diabetes and cardiovascular diseases in collaboration with EASD. Eur Heart J. Epub ahead of print August 31, 2019. doi: 10.1093/eurheartj/ehz486.
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ APhA/ASPC/NLA/PCNA
Guideline on the Management of Blood Cholesterol

Recommendations for Primary Severe Hypercholesterolemia (LDL-C >190 mg/dL

[>4.9 mmol/L])
COR LOE RECCOMENDATIONS
I B-R In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL or higher (≥4.9 mmol/L) maximally
tolerated statin therapy is recommended
IIa B-R In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL or higher (≥4.9 mmol/L) who achieve
less than a 50% reduction in LDL-C while receiving maximally tolerated statin therapy and/or have an
LDL-C level of 100 mg/dL or higher (≥2.6 mmol/L) ezetimibe therapy is reasonable
IIb B-R In patients 20 to 75 years of age with a baseline LDL-C level 190 mg/dL or higher (≥4.9 mmol/L), who
achieve less than a 50% reduction in LDL-C levels and have fasting triglycerides 300 mg/dL or lower
(≤3.4 mmol/L). while taking maximally tolerated statin and ezetimibe therapy, the addition of a bile acid
sequestrant may be considered
IIb B-R In patients 30 to 75 years of age with heterozygous FH and with an LDL-C level of 100 mg/dL or higher
(≥2.6 mmol/L) while taking maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9
inhibitor may be considered
IIb C-LD In patients 40 to 75 years of age with a baseline LDL-C level of 220 mg/dL or higher (≥5.7 mmol/L) and
who achieve an on-treatment LDL-C level of 130 mg/dL or higher (≥3.4 mmol/L) while receiving
maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered

2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/ APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the
American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018;Nov 10:
[Epub ahead of print].
23
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
Achieving optimal LDL level in lipid management
Are we there yet?
LDL Cholesterol Goal Attainment in Hypercholesterolemia: CEPHEUS Indonesian Survey,
2013
Only 12% hyperlipidemia patients in Indonesia achieving LDL
level <70 mg/dl
Proportion of patients attaining their LDL-C goals according the updated 2004 NCEP ATP III
(per protocol population).
70.00%

60.00%

50.00%

40.00%

30.00%

20.00%

10.00%

0.00%
< 70 mg/dL < 100 mg/dL < 130 mg/dL < 160 mg/dL
24
Munawar.2013.Acta Cardiol Sin ;29:7181
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
Case
Question
1
3

?
What should you do now?

A.Keep the patient on the current

treatment
B. Doubling the dose of
Atorvastatin to 80 mg
C. Switch to rosuvastatin 40 mg
D.To proceed for combination
therapy (Atorvastatin +
Ezetimibe
Doc No: ID-ATO-00044 Exp.Date: 21 Feb
2022
The Cardiologist prescribed

Doubling the dose of Atorvastatin to 80 mg od and advised

about stopping smoking and lifestyle modifications.

but ,
unfortunately after 6 month of routine consumption,
SAMS (Statin Associated Muscle Symptoms) developed

Doc No: ID-ATO-00044 Exp.Date: 21 Feb

2022
Case
Question
1
4

?
Doubling the dose of a statin will result in how many
additional
% decrease in LDL?

A. 6%
B. 12%
C. 18%
D. >25%

Doc No: ID-ATO-00044 Exp.Date: 21 Feb

2022
Doubling a Statin Dose Yields Only
6% Incremental Drop in LDL-C

Statin Rule of 6
Reduction of LDL-C, %

6% drop
6% drop
6% drop

0 10 20 30 40 60 70 80

50

Statin, mg

Adapted from Knopp RH. N Engl J Med. 1999;341:498–511; Stein EA. Am J Cardiol.
2002;89(suppl):50C–57C.
Doc No: ID-ATO-00044 Exp.Date: 21 Feb 2022
 Risk-Benefit Ratio of Statin
Titration
Atorvastatin Lovastatin Simvastatin
10 mg 20 mg 40 mg 80 mg 20 mg 40 mg 40 mg 80 mg
0 80 mg

% Decrease in LDL-C
-10

-20

-30

-40

-50

-60
2.5
Elevated Transaminases
(% of Patients)

2.0

1.5

1.0

0.5

0.0 10 mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg 40 mg 80 mg

Data from prescribing information for atorvastatin, lovastatin,

simvastatin. This does not represent data from comparative study
Counter regulation of cholesterol
absorption and synthesis

~50% ~50%

According to Sheperd J et al.

SheperdJ. EurHeart J 2001; 3(suppl E):E2-E512 Assmann G, et al. Curr Med Res Opin. 2008;24(1):249–259. Bays H et al. ClinTher2004; 26(11):1758-
1773
SantosaS et al. Life Sci2007; 80:505-51414
Bays H. Expert Opin Investig Drugs 2002; 11:1587-1604

Doc No: ID-ATO-00044 Exp.Date: 21

Feb 2022
Statin limitation: dose titration raises
counterregulatory effect and cholesterol
absorption
Atorvastatin 20mg Atorvastatin 80mg
+71%
% Change
80
+48%
60
P<0.05
40
P<0.05
20

0
-20

-40
Cholesterol
-60 P<0.05
P<0.05 production
(lathosterol)
-80

-100
-69% Cholesterol
-76% Absorption
Lamon Fava et al J Lipid Res 2007; 48: 1746-53 (campesterol)

Doc No: ID-ATO-00044 Exp.Date: 21

Feb 2022
Case
Question
1
5

?
What should you do now?

A. Keep the patient on the current

treatment
B. Reduce the dose of Atorvastatin
back to 40 mg
C. Switch to rosuvastatin 40 mg
D. Adding Ezetimibe 10 mg to
Atorvastation 40 mg (in different
pills)
E. Doc
ToNo: proceed for fixed dose
ID-ATO-00044 Exp.Date: 21 Feb
combination 2022 therapy (40
 A significant proportion of
patients at high-risk or with very
high LDL-C levels
Didn’t achieve optimal LDL level
with statin monotherapy

33
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
Recommendations for management of dyslipidemia with lipid lowering drugs ( ESC ,
2019 ):
The needs of adding non-statin therapy to achieve
LDL-C goal
Recommendations Class Level
Targets
Statins are recommended as the first-choice I A
lipid-lowering treatment in patients with DM and high LDL-C
levels: administration of statins is defined based on the CV risk profile
of the patient and the recommended LDL-C (or non–HDL-C) target
levels.
combination therapy
If the target LDL-C is not reached, I B
with ezetimibe is recommended.
In patients at very high CV risk, with persistent high LDL-C despite I A
treatment with maximum tolerated statin dose, in
combination with ezetimibe or in patients with statin
intolerance, a PCSK9 inhibitor is recommended.

ESC Guidelines on Diabetes, pre-diabetes and cardiovascular diseases in collaboration with EASD. Eur Heart J. Epub ahead of print August 31, 2019. doi: 10.1093/eurheartj/ehz486.

34
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Strategies to further lower LDL-C
Statin has been classified based on the intensity level1,2:

High intensity Moderate Low intensity

statin therapy intensity statin statin therapy
(mg) therapy (mg) (mg)
Daily dose lowers Daily dose lowers Daily dose lowers
LDL-C on average, by LDL-C on average, LDL-C on average, by
approx. ≥50% by approx. 30% to approx. ˂30%
˂50%
Atorvastatin 40-80 Atorvastatin 10-20 Simvastatin 10
Rosuvastatin 20-40 Rosuvastatin 5-10 Pravastatin 10-20
Simvastatin 20-40 Lovastatin 20
Pravastatin 40-80 Fluvastatin 20-40
Lovastatin 40 Pitavastatin 1
Fluvastatin Xl 80
Fluvastatin 40 bid
Pitavastatin 2-4
1.Donald M. Lloyd-Jones DM, Morris PB, et al. JACC 2016;68:92-125
2. American College of Cardiology.2018 (Updated 2019).guideline of blood cholesterol 35
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Strategies to further lower LDL-C
Cholesterol lowering therapy has been classified based on the intensity
level:

36
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Strategy to achieve optimal LDL level with combination of
High Intensity Statin with non-statin agent to high-very high risk patients

High risk Very high risk

Baseline Baseline
LDL-C LDL-C
(mg/dl) (mg/dl)
High intensity High intensity
statin statin
+ +
Non-statin Non-statin
135
High intensity
105
statin
High intensity
(50% reduction
statin (50%
from baseline) 70 reduction from

55 baseline)

37
ESC Guidelines on Diabetes, pre-diabetes and cardiovascular diseases in collaboration with EASD. Eur Heart J. Epub ahead of print August 31, 2019. doi: 10.1093/eurheartj/ehz486.
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Strategy to achieve optimal LDL level with combination of
High Intensity Statin with non-statin agent to high-very high risk patients
Target <50% reduction from baseline

Statin
Target not achieved

Increase statin dose or

change to high intensity

Target not achieved

High intensity statin

plus
Non-statin
38
ESC Guidelines on Diabetes, pre-diabetes and cardiovascular diseases in collaboration with EASD. Eur Heart J. Epub ahead of print August 31, 2019. doi: 10.1093/eurheartj/ehz486.
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Ezetimib
e Ezetimibe

PCSK9
inhibitoinhibitor
PCSK9

Non-statin r

LDL-C- Bile acid

sequestr
Bile acid
sequestrant
lowering
ant

drugs LomitapideLomitapi
de

Mipomer
sen Mipomersen
39
ESC Guidelines on Diabetes, pre-diabetes and cardiovascular diseases in collaboration with EASD. Eur Heart J. Epub ahead of print August 31, 2019. doi: 10.1093/eurheartj/ehz486.
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Average LDL-C Reduction from Lipid Lowering
Treatment
(statin and non statin)
Treatment Average LDL-
C reduction
(Approximate
ly)
Moderate intensity statin 30 %
High intensity statin 50 %
High intensity statin plus Ezetimibe 65 %
PCSK9 inhibitor* 60 %
PCSK9 inhibitor* plus High intensity statin 75 %
PCSK9 inhibitor* plus High intensity statin plus Ezetimibe 85 %

*not available in Indonesia

Mach F, et al. Eur Heart J 2019. doi:10.1093/eurheartj/ehz455

40
ESC Guidelines on Diabetes, pre-diabetes and cardiovascular diseases in collaboration with EASD. Eur Heart J. Epub ahead of print August 31, 2019. doi: 10.1093/eurheartj/ehz486.
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
Unlock the Gaps with
Potential Effects of
Atorvastation in combination
with Ezetimibe
to Achieve Optimal LDL level 41
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Atorvastatin+Ezetimbe
Mechanism of Action
“The synergy mechanism of action from HMG-CoA reductase inhibitors and
cholesterol-lowering medications”

42
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
Rationale for Coadministration of Ezetimibe
and Statins Cholesterol homeostatis depends on
the balance cholesterol biosynthesis and cholesterol absorption

• Statins primarily affect hepatic production of cholesterol by

blocking HMG CoA reductase
• Reduces hepatic stores
• Leads to up-regulation of LDL receptors and removal of cholesterol
from circulation
• Enterohepatic recirculation of cholesterol into the bile with transport
to the intestine
• Ezetimibe inhibits intestinal absorption of cholesterol
• Reduces amount of cholesterol delivered to the liver
• Leads to up-regulation of LDL receptors, facilitating removal of
cholesterol from circulation
• Dual inhibition of cholesterol absorption and synthesis by
coadministration of ezetimibe and statins provides greater LDL-C
lowering efficacy than inhibition of either pathway alone
Grigore L et al. Vas Health Risk Manag. 2008;4:267–278. 43
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
Statins Inhibit Synthesis of Cholesterol in the Liver
1 2 3 4
Inhibition of HMG-CoA Reduction of hepatic Increased LDL Increased
reductase activity cholesterol HMG- receptor expression clearance of LDL-C
CoA
Statin X
Cholester
1
Cholestero s Live
l Pool ol r
(Micelles)
3
2 Cholester
ol LDL
Pool Receptor
NPC1L Remnan Expression
1 t
Recepto
rs
4
CM
R

LDL-
C
M
C
Bloo
Athero d
ma

HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; NPC1L1 = Niemann-Pick C1-like 1; CMR = chylomicron

remnant
Grigore L et al. Vas Health Risk Manag. 2008;4:267–278.
44
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
Ezetimbe Inhibits Absorption of Cholesterol in the
Small Intestine

Liver
HMG-CoA

Cholesterol Cholesterol
Pool (Micelles)
4
3 Cholesterol
Pool LDL Receptor
1. Inhibition of NPC1L1 activity Ezetimibe Expression
NPC1L1 Remnant
2. Reduction of cholesterol X Receptors

transported to the liver 1

5
3. Reduction of hepatic cholesterol CMR

2 2
LDL-C
4. Increased LDL receptor CM
expression Blood
Atheroma
5. Increased clearance of LDL-C

NPC1L1 = Niemann-Pick C1-like 1; HMG-CoA = 3-hydroxy-3-methylglutaryl acetyl coenzyme A; CMR = chylomicron

remnant.

Grigore L et al. Vas Health Risk Manag. 2008;4:267–278.

45
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
Ezetimbe & Statins have complementary MoA
1 Reduction of hepatic 2 3 Increased clearance
Increased LDL receptor
cholesterol of plasma LDL-C
expression
HMG-
CoA Liver
HMG-CoA

Cholesterol
Statins X
Cholesterol
Pool (Micelles)
2
1 Cholesterol
Pool LDL Receptor
Ezetimibe Expression
NPC1L1 Remnant

X Receptors

3
CMR

LDL-C
CM
Blood
Atheroma

NPC1L1 = Niemann-Pick C1-like 1; HMG-CoA = 3-hydroxy-3-methylglutaryl acetyl coenzyme A; CMR = chylomicron

Grigore L et al. Vas Health Risk Manag. 2008;4:267–278. remnant. 46
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
WHY FIXED DOSE COMBINATION IS THE RIGHT CHOISE
FOR THE PRODUCTIVE DYSLIPIDEMIA PATIENTS?

47
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Can get more patients to achieve LDL goal

With lower statin doses (statin sparing

effect)

Less side effects

The convenient and
effective of Fixed Dose Lesser pill burden (fixed dose
Combination Therapy combination)
(Statin + Ezetimibe) for
Better adherence
the prodictive patients

Overcome clinical inertia

Address mixed dyslipidemia

(↑LDL,↓HDL,↑TG)
48
Grigore L et al. Vas Health Risk Manag. 2008;4:267–278.
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Conclusion to Case 1

Current Gaps
• Hyperlipidemia is a risk factor for CHD.1
• The need for adding non-statin treatment since many patients, including those on
statins, have elevated LDL-C or non–HDL-C levels.2,3
How do we close the gap?

• FDC Ezetimibe/atorvastatin, as an adjunct to diet and exercise, is a therapeutic option to

help manage hyperlipidemia in statin-treated patients.5
• FDC Ezetimibe/atorvastatin may be an effective therapeutic option to help reduce the risk
of cardiovascular events in patients with CHD.5
• Compared with standard statin monotherapy, the FDC ezetimibe/atorvastatin showed
greater coronary plaque regression6
CHD = coronary heart disease.
1. NCEP ATP III Expert Panel. Circulation. 2002;106:3143–3421. 2. Gitt AK et al. Eur J Prev Cardiol. 2011;19:221–230. 3. Santos RD et al. Atherosclerosis.
Doc No: ID-ATO-00044 Exp.Date: 21 Feb
2012;224:150–153. 4. Grigore L et al. Vas Health Risk Manag. 2008;4:267–278. 5. Data on file, MSD..6Tsujita K, et al. 2015 J Am Coll Cardiol 2015;66: 495– 49
507. 2022
.
THANK YOU
50
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 You’ve Got the Power

References

1. Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka LJ, Suresh R, Sun S, LeBeaut AP, Sager PT, Veltri EP. Effect of ezetimibe coadministered
with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation. 2003 May 20;107(19):2409-15. doi: 10.1161/01.CIR.0000068312.21969.C8. Epub 2003 Apr
28. PubMed PMID: 12719279.
2. Bays HE, Averna M, Majul C, Muller-Wieland D, De Pellegrin A, Giezek H, Lee R, Lowe RS, Brudi P, Triscari J, Farnier M. Efficacy and safety of ezetimibe added to atorvastatin versus atorvastatin uptitration
or switching to rosuvastatin in patients with primary hypercholesterolemia. Am J Cardiol. 2013 Dec 15;112(12):1885-95. doi: 10.1016/j.amjcard.2013.08.031. Epub 2013 Sep 21. PubMed PMID: 24063830.
3. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA,
Braunwald E, Califf RM. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015 Jun 18;372(25):2387-97. doi: 10.1056/NEJMoa1410489. Epub 2015 Jun 3. PubMed PMID: 26039521.
4. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, Reiner Ž, Riccardi G, Taskinen MR, Tokgozoglu L, Verschuren WMM, Vlachopoulos C, Wood DA,
Zamorano JL, Cooney MT. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J. 2016 Oct 14;37(39):2999-3058. doi: 10.1093/eurheartj/ehw272. Epub 2016 Aug 27. PubMed PMID: 27567407.
5. Conard SE, Bays HE, Leiter LA, Bird SR, Rubino J, Lowe RS, Tomassini JE, Tershakovec AM. Efficacy and safety of ezetimibe added on to atorvastatin (20 mg) versus uptitration
of atorvastatin (to 40 mg) in hypercholesterolemic patients at moderately high risk for coronary heart disease. Am J Cardiol. 2008 Dec 1;102(11):1489-94. doi: 10.1016/j.amjcard.2008.09.075. Epub 2008 Oct 23. PubMed
PMID: 19026302.
6. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, Federici M, Filippatos G, Grobbee DE, Hansen TB, Huikuri HV, Johansson I, Jüni P, Lettino M, Marx N, Mellbin LG, Östgren CJ, Rocca B, Roffi M, Sattar N,
Seferović PM, Sousa-Uva M, Valensi P, Wheeler DC. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020 Jan 7;41(2):255-323. doi:
10.1093/eurheartj/ehz486. PubMed PMID: 31497854.
7. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, Hegele RA, Krauss RM, Raal FJ, Schunkert H, Watts GF, Borén J, Fazio S, Horton JD, Masana L, Nicholls SJ, Nordestgaard BG, van de Sluis B, Taskinen MR,
Tokgözoglu L, Landmesser U, Laufs U, Wiklund O, Stock JK, Chapman MJ, Catapano AL. 
Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.  Eur
Heart J. 2017 Aug 21;38(32):2459-2472. doi: 10.1093/eurheartj/ehx144. Review. PubMed PMID: 28444290; PubMed Central PMCID: PMC5837225.
8. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE,
Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J. 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 Jun 25;73(24):3168-3209. doi: 10.1016/j.jacc.2018.11.002. Epub 2018 Nov 10. PubMed PMID: 30423391.
9. Kementerian Kesehatan. Hasil RISKESDAS.2018. available online at: https://www.kemkes.go.id/resources/download/info-terkini/hasil-riskesdas-2018.pdf
10. Leiter LA, Bays H, Conard S, Bird S, Rubino J, Hanson ME, Tomassini JE, Tershakovec AM. Efficacy and safety of ezetimibe added on to atorvastatin (40 mg) compared with uptitration
of atorvastatin (to 80 mg) in hypercholesterolemic patients at high risk of coronary heart disease. Am J Cardiol. 2008 Dec 1;102(11):1495-501. doi: 10.1016/j.amjcard.2008.09.076. Epub 2008 Oct 23. PubMed PMID:
19026303.
11. Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD Jr, DePalma SM, Minissian MB, Orringer CE, Smith SC Jr. 
2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardio
logy Task Force on Clinical Expert Consensus Documents. 
J Am Coll Cardiol. 2016 Jul 5;68(1):92-125. doi: 10.1016/j.jacc.2016.03.519. Epub 2016 Apr 1. Review. PubMed PMID: 27046161.
12. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine
MS, Taskinen MR, Tokgozoglu L, Wiklund O. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020 Jan 1;41(1):111-188. doi:
10.1093/eurheartj/ehz455. PubMed PMID: 31504418.
13. Munawar M, Hartono B, Rifqi S. LDL Cholesterol Goal Attainment in Hypercholesterolemia: CEPHEUS Indonesian Survey. Acta Cardiol Sin. 2013 Jan;29(1):71-81. PubMed PMID: 27122687; PubMed Central PMCID:
PMC4804963.
14. Pepine CJ. The effects of angiotensin-converting enzyme inhibition on endothelial dysfunction: potential role in myocardial ischemia. Am J Cardiol. 1998 Nov 19;82(10A):23S-27S. doi: 10.1016/s0002-9149(98)00805-
4. Review. PubMed PMID: 9860352.
15. Steven E. Nissen and Paul Yock. Novel Pathophysiological Insights and Current Clinical Applications. Circulation. 2001;103:604–616. Originally published 30 Jan 2001. https://doi.org/10.1161/01.CIR.103.4.604
16. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW, Eddleman KM, Jarrett NM,
LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ, Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF. 
2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guideli
nes. 
ATOZET Selected Safety Information

Indications: ATOZET contains ezetimibe and atorvastatin. ATOZET is indicated as adjunctive therapy to diet for use in adults with primary
hypercholesterolaemia or mixed hyperlipidaemia where use of a combination product is appropriate in patients not appropriately controlled with a statin alone
or already treated with a statin and ezetimibe.

Dosing: Patients with Hypercholesterolemia: The dosage range is 10/10 to 10/80 mg once daily. The recommended starting dose is 10/10 mg or 10/20 mg
once daily. Patient who require a larger reduction in LDL-C (more than 55%) may be started at 10/40 mg once daily. After initiation and/or up titration of
ATOZET, lipid levels should be analyzed within 2 or more weeks and dosage adjusted accordingly. Patients with Homozygous Familial Hypercholesterolemia:
The dosage is 10/40 or 10/80 mg daily. ATOZET should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such
treatments are unavailable.

Contraindications: Hypersensitivity to ezetimibe, atorvastatin, or any of its inactive ingredients. Active liver disease or unexplained persistent elevations of
serum transaminases exceeding three times the upper limit of normal (ULN). Pregnancy and nursing.

Precautions

Myopathy/Rhabdomyolysis: Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin and
with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring
for skeletal muscle effects. Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with
increases in CPK values >10 times ULN. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked
elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or
fever or if muscle signs and symptoms persists after discontinuing ATOZET. ATOZET therapy should be discontinued if markedly elevated CPK levels occur or
myopathy is diagnosed or suspected. ATOZET therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition
suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (eg, severe acute infection,
hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).

Liver Enzymes: In controlled coadministration trials in patients receiving ezetimibe with atorvastatin, consecutive transaminase elevations (≥3 X the upper
limit of normal [ULN]) have been observed. It is recommended that liver enzyme tests be obtained prior to initiating therapy with ATOZET and repeated as
clinically indicated. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with ATOZET, promptly interrupt
therapy.

Endocrine function: Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have
shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. Caution should be exercised if ATOZET is administered
concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.

Increases in hemoglobin A1c (HbA1c) and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin. Periodic
monitoring of these patients is recommended.

52 is
Hepatic impairment: Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe hepatic impairment, ATOZET
not recommended in these patients.
ATOZET Selected Safety Information

Drug Interactions

CYP3A4 Interactions: Concomitant administration of atorvastatin with inhibitors of cytochrome P450 3A4 can lead to increases in plasma concentrations of
atorvastatin, thus increasing the risk of myopathy.

(eg clarithromycin, combination of protease inhibitor, cyclosporine, itraconazole, grapefruit juice)

Other Interactions: Fibrates: Concomitant administration of ATOZET with gemfibrozil should be avoided due to an increased risk of
myopathy/rhabdomyolysis. ATOZET should be administered with caution when used concomitantly with fenofibrate as the risk of myopathy is increased.
Coadministration of ATOZET and other fibrates is not recommended as it has not been established. Fusidic acid: Patients on fusidic acid treated concomitantly
with ATOZET may have an increased risk of myopathy/ rhabdomyolysis. Coadministration with fusidic acid is not recommended. Anticoagulants: if ATOZET is
added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalized Ratio (INR) should be appropriately monitored. Inhibitors of
Breast Cancer Resistant Protein (BCRP): Dose of ATOZET should not exceed 10/20mg daily when concomitant administration of products containing elbasvir
and grazoprevir. Digoxin: When multiple dose of atorvastatin and digoxin were coadministered, steady-state plasma digoxin concentrations increased by
approximately 20%. Patients taking digoxin should be monitored appropriately. Niacin: The risk of skeletal muscle effects may be enhanced when ATOZET is
used in combination with niacin; a reduction in ATOZET dosage should be considered. Colchicine: Cases of myopathy, including rhabdomyolysis, have been
reported with atorvastatin coadministered with colchicine, and caution should be exercised when prescribing ATOZET with colchicine.

Side Effects

ATOZET (or coadministration of ezetimibe and atorvastatin equivalent to ATOZET) has been evaluated for safety in more than 2400 patients in 7 clinical trials.
ATOZET was generally well tolerated. Common side effects (≥1/100, <1/10) include: diarrhea and myalgia. In controlled clinical trials, the incidence of clinically
important elevations in serum transaminases (ALT and/or AST ≥3X ULN, consecutive) was 0.6% for patients treated with ATOZET. These elevations in
transaminases were generally asymptomatic, not associated with cholestasis, and returned to baseline spontaneously or after discontinuation of therapy.

Further information is available upon request. Before initiating therapy, please consult the full Prescribing Information.

53