Understanding the Needs of

The High Productive

Dyslipidemia Patients

MAKBUL AMAN MANSYUR

D I V I S I O N O F E N D O C R I N E A N D M E TA B O L I S M , D E PA RT M E N T O F
I N T E R N A L M E D I C I N E FA C U LT Y O F M E D I C I N E H A S A N U D D I N
U N I V E R S I T Y / R S U P D R . WA H I D I N S U D I R O H U S O D O M A K A S S A R

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Doc No: ID-ATO-00044 Exp.Date: 21 Feb 2022
Atherosclerosis Cardiovascular Disease
(ASCVD) Is A Major Cause Of Death

2
 Major ACVD Risk Factors
Major risk factors Additional risk factors Nontraditional risk
factor
Advancing agea-d Obesity, abdominal ⇧ Lipoprotein (a)
⇧ Total serum obesity c,d ⇧ Clotting factors
cholesterol levela,b,d Family history of ⇧ Inflammation markers
⇧ Non–HDL-C d hyperlipidemia d (hsCRP; Lp-PLA2)
⇧ LDL-Ca,d
a,d,e
STRONG ⇧ASSOCIATION
Small, dense LDL-Cd OF⇧LIPID
d
Homocysteine levels
Low HDL-C ⇧ Apo B Apo E4 isoform
Diabetes mellitusa-d STATUS AND
⇧ LDL particle ACVD ⇧ Uric acid
concentration
Hypertensiona-d
(ATHEROSCLEROSIS)
Fasting/post-prandial
Chronic kidney disease 3,4h hypertriglyceridemiad
⇧ TG-rich remnants

Cigarette smokinga-d PCOSd

Family history of ASCVDa,d,g Dyslipidemic triadf

a Risk factors identified in the Framingham Heart study.

b Risk factors identified in the MRFIT study
(Multiple Risk Factor Intervention Trial).
c Risk factors identified in the INTERHEART study.
d Risk factors identified in guidelines and position statements
e Elevated HDL-C is a negative risk factor.
f Hypertriglyceridemia; low HDL-C; and an excess of small,
dense LDL-C.
g Definite myocardial infarction or sudden death before age 55
years in father or other male first-degree relative or before age 65
years in mother or other female first-degree relative.
h Based on a pooled analysis of community-based studies (N =
22,634).
4
LIPOPROTEIN CLASSIFICATION

5
 Reduction of LDL-C has been one of the
cornerstones of CVD prevention therapy over
the past 2 decades.

 LDL-C lowering with standard statin regimens

reduces the risk of CV events in a wide range
of individuals.

 Further reduction in LDL-C with more intensive

regimens produce further reductions in the
incidence of CV events.
7
9/21/2020 For Healthcare Professional Only 8
 Pharmacologic Therapy
Drug Class LDL-C TG Apo B Total Chol HDL-C

HMG-CoA reductase
inhibitors
↓ 21-55% ↓ 6-30% ↑ 2-10%
(Statins)

Cholesterol Absorption ↓ 10-18% ↓ 11-16

Inhibitors (Ezetimibe)
In combination with Statins ↓34-61 ↓25-26%
In combination with ↓20-22%
Fenofibrate

PCSK9 inhibitors ↓ 48-71% ↓42- 55% ↓36-42%

(alirocumab, evolocumab)

Fibric acid derivatives

Fenofibrate ↓ 20-25 ↓ 20-55 ↓ 20-25 ↑ 6-18

Niacin (Nicotinic Acid) ↓ 10-25 ↓ 20-30 ↑10-35

Bile Acid Sequestrants
Cholestyramine ↑15-25

MTP Inhibitor
Lomitapide ↓ 40 ↓ 45 ↓ 39 ↓ 36 9
Current Challenges in LDL-C Management and
Unmet Need of Statin Treatment:

LDL-C level: how low

should we go?
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Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
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2013
Focus on ASCVD Risk Reduction: 4 statin benefit groups

Use Statins to Treat Risk, Not Cholesterol.

Stone NJ, Robinson J, Lichtenstein AH, et al. 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 Guidelines. Circulation 2014;129(25 Suppl 2):S1-45
 Intensity of Statin Therapy

High-Intensity Statin Moderate-Intensity Low-Intensity Statin

Therapy Stain Therapy Therapy

LDL–C ↓ ≥50% LDL–C ↓ 30% to <50% LDL–C ↓ <30%

Atorvastatin (40†)–80 mg Atorvastatin 10 (20) mg Simvastatin 10 mg

Rosuvastatin 20 (40) mg Rosuvastatin (5) 10 mg Pravastatin 10–20 mg
Simvastatin 20–40 mg‡ Lovastatin 20 mg
Pravastatin 40 (80) mg Fluvastatin 20–40 mg
Lovastatin 40 mg Pitavastatin 1 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg bid
Pitavastatin 2–4 mg

Stone NJ, et al. Circulation 2014;129(25 Suppl 2):S1-45

Lifestyle modification remains a critical component of ASCVD risk reduction, both prior to and in concert with the use
of cholesterol lowering drug therapies.

Statins/doses that were not tested in randomized controlled trials (RCTs) reviewed are listed in italics
†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL
‡Initiation of or titration to simvastatin 80 mg not recommended by the FDA due to the increased risk of myopathy, including
rhabdomyolysis.
2016 ESC/EAS Guidelines

European
Heart Journal
2016 –
TARGET VS INTENSITY
doi:10.1093/eu
rheartj/ehv272
17
 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 18
August 31, 2019. doi: 10.1093/eurheartj/ehz486. 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
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. 19
Epub ahead of print August 31, 2019. doi: 10.1093/eurheartj/ehz486. Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Reality in life

“They said life begin at 40, but chronic

disease also noticed at 40”

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

Case
Patient : M.K. Medical History:
Profile : 41 years old Type 2 DM since 4 years ago, A1c 7.1
male, employee MI with PCI 3 years ago
BMI : 29.7 kg/m2
Hypertension with
BP : 180/110 mm Hg
HR : 65 bpm LVH
Microalbuminuria
Smoker

Medication: Labs:
Aspirin 81 mg Bisoprolol TC 300 mg/dl
5 mg po daily
LDL 171 mg/dl
Telmisartan 80 mg po daily
Janumet 100/1000 XR HDL 30 mg/dl
Empagliflozin 10 mg po daily Triglycerides 350 mg/dl
Atorvastatin 40 mg po od

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

Case Question 1
What is the risk level of
this man On ASCVD ?

A.Extrem Risk
B. Very High Risk
C.High Risk
D.Moderate Risk
E. Low Risk

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

2022
Case
Question 2
In this patient, what is your

?
LDL goal?
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
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%

A significant
40.00% proportion of patients at high-risk or with
very
30.00%
high LDL-C levels Didn’t achieve optimal LDL
level with statin monotherapy
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 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
 Treatment options for a high-risk patient
not at LDL-C goal on statin therapy
1. Doubling the statin dose

The Doctor 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
Case Question 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
Treatment options for a high-risk patient
not at LDL-C goal on statin therapy
Using a combined Non Statin - statin therapy
 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
31
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
(Approxima
tely)
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 85 %
Ezetimibe

*not available in Indonesia

Mach F, et al. Eur Heart J 2019. doi:10.1093/eurheartj/ehz455 32
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
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Recommendations for management of dyslipidemia with lipid
lowering drugs ( ESC ,2019 ):
The needs of adding non-statin therapy to
achieve LDL-C goal
Recommendations Clas Lev
s el
Targets

Statins are recommended as the first- I A

choice 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.
If the target LDL-C is not reached, combination I B
therapy with ezetimibe is recommended.
In patients at very high CV risk, with persistent high LDL- I A
C despite 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, 35
2019. doi: 10.1093/eurheartj/ehz486.
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Lipid-Lowering Therapy
Accounted for >70% of CV
Risk Reduction in Diabetes
Risk Reduction in CVD Events

80 Steno-2 study
Percent of Total Calculated

60
Multifactorial therapy in type 2 DM ,
to achieve :
40
BP <130/80, HbA1c < 6.5%, total
cholest < 175 mg/dL
20

0
Lipids HbA1c Blood Pressure

The most of the CV benefit in Diabetes was

attributable to the use of lipid-lowering therapy 36
 Sequence of therapies for
LDL-C lowering
1. High-intensity statin to highest tolerated dose to
reach goals
2. Goals not achieved: add ezetimibe
3. Consider/add PCSK9 inhibitor if:
• Primary prevention, very high risk, without FH, goal not achieved on
max. statin + ezetimibe
• Secondary prevention, goal not achieved on max. statin + ezetimibe
• Very high-risk FH, goal not achieved on max. statin + ezetimibe
4. If statin not tolerated at any dose, consider
ezetimibe or ezetimibe + PCSK9 inhibitor
5. Goal not reached: consider statin + bile acid
sequestrant

PCSK9= Proprotein convertase subtilisin/kexin type 9, FH= Familial hypercholesterolemia

Mach F, et al. Eur Heart Journal 2019, 00,1-78

 Unlock the Gaps with
Potential Effects of Atorvastation
in combination with Ezetimibe
to Achieve Optimal LDL level

“The synergy mechanism of action from HMG-

CoA reductase inhibitors and cholesterol-
lowering medications” 38
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. 39
Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
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41
 Strategies to further lower LDL-C
Cholesterol lowering therapy has been classified based on the intensity
level:

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Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
9/21/2020 For Healthcare Professional Only 43
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 Conclusion to Case
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.
Doc No: ID-ATO-00044 Exp.Date: 21 Feb
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. 2012;224:150–153. 45
2022 2015;66: 495–507.
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
.
THANK YOU
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Doc. No: ID-ATO-00043 Exp. Date: 3rd Feb 2022
 Heart SCORE (Systematic Coronary Risk
Estimation)
based on ESC 2019
Very High Risk
High Risk
Moderate Risk
Low Risk

1 mmol/L = 38.67 mg/dL

Doc No: ID-ATO-00044 Exp.Date: 21 Feb2022