The Un-meet Need in LDL-C Lowering

when Regular Statin Won’t Do

Dr. Ade Meidian Ambari, SpJP(K)

National Cardiovascular Center Harapan Kita
Department of Cardiology and Vascular Medicine, Faculty of Medicine,
Universitas Indonesia
 Dyslipidemia

• Described as lipid abnormalities containing any combination of

elevated total cholesterol (TC), elevated low-density lipoprotein
cholesterol (LDL-C), elevated triglycerides (TG), or low high-
density lipoprotein cholesterol (HDL-C)

• One of CVD risk factors associated with elevated LDL-C, low

HDL-C

Mohamed-Yassin M-S, et al. BMJ Open 2021;11:e049662.

doi:10.1136/bmjopen-2021-049662
 LDL-C Plays an Important Role in Initiation,
Progression, Complications of Atherosclerosis
Initiation Progression Complications

• LDL entering into the artery wall • Sustained LDL entry, oxidation and endothelial • Aggravation of inflammation and enlargement of lipid core

• LDL oxidization dysfunction • Reduction of smooth muscle cells and fibrous tissues

• Monocytes involvement, • Formation of foam cells • Formation and rupture of unstable plaques

triggering inflammation • Proliferation of smooth muscle cells and fibrosis • Erosion of substances in unstable plaques into lumen, causing

• Endothelial function decline • Vascular inflammations and formation of lipid core acute thrombosis

Cholesterol AS plaques ASCVD event

Normal Artery Endothelial Intimal

Dysfunction Thickening Atheroma formation Unstable Ruptured
Plaques Plaques

1. Daniel J, et al. Nature. 2008; 451: 904-913

2.Pepine CJ, et al. Am J Cardiol. 1998; 82(10A): 23S-27S.
 Cardiovascular Diseases (CVDs)
in Indonesia
ASCVD remains the leading cause of death in Indonesia (2005 CVDs account for 37% of total deaths2
– 2015)1

1. Institute for Health Metrics and Evaluation (IHME) 2015

2. Noncommunicable diseases Country Profile 2014. WHO 2014
The Burden of Dyslipidemia
Skrining dislipidemia
How Important is Reducing
LDL-C Level ?
LDL-C: The Lower The Better

1.0 mmol/L
Reduction LDL-C

20%
reduction in the risk of CVD
 The Relationship Between Achieved LDL-C Level and Change in
Percent Atheroma Volume
(Stronger LDL-C Reduction is Directly Related To Plaque Regression)

1.0

Change in Percent Atheroma Volume, %

0.5

-0.5

-1.0

-1.5
10 20 30 40 50 60 70 80 90 100 110

On- Treatment LDL-C, mg/dL

Nicholls SJ, et al. JAMA. doi:10.1001/jama.2016.16951

TREATMENT RECOMMENDATION
 2019 ESC/EAS Guidelines for the
management of dyslipidemias: lipid
modification to reduce cardiovascular 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 revascularization
(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,a or at least three major risk factors, or early onset of T1DM
of long duration (>20 years).
Severe CKD (eGFR <30 mL/min/1.73 m2).
A calculated SCORE >_10% for 10-year risk of fatal CVD.
FH with ASCVD or with another major risk factor.

Adapted from: Mach F, et al. European Heart Journal (2019) 00, 1-78
ESC = European Society of Cardiology; EAS = European Atherosclerosis Society; ASCVD = atherosclerotic cardiovascular disease; ACS = acute
coronary syndrome; MI = myocardial infarction; PCI = percutaneous coronary intervention; CABG = coronary artery bypass graft surgery; TIA =
transient ischaemic attack; CT = computed tomography; DM = diabetes mellitus; T1DM = type 1 DM; CKD = chronic kidney disease; eGFR =
estimated glomerular filtration rate; SCORE = Systematic Coronary Risk Estimation; CVD = cardiovascular disease; FH = familial
hypercholesterolaemia;
 2019 ESC/EAS Guidelines for the management of
dyslipidemias: lipid modification to reduce cardiovascular 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 damagea,with DM duration >_10 years
or another additional risk factor.
Moderate CKD (eGFR 3059 mL/min/1.73 m2).
A calculated SCORE ≥ 5% and <10% for 10-year risk of fatal CVD.

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.

Calculated SCORE <1% for 10-year risk of fatal CVD.

a
Target organ damage is defined as microalbuminuria, retinopathy, or neuropathy.

ESC = European Society of Cardiology; EAS = European Atherosclerosis Society; TC = total cholesterol; LDL-C=Low Density Lipoprotein Cholesterol; BP
= blood pressure; FH = familial hypercholesterolaemia; DM = diabetes mellitus; CKD = chronic kidney disease; eGFR = estimated glomerular filtration
rate; SCORE = Systematic Coronary Risk Estimation; CVD = cardiovascular disease; T1DM = type 1 DM; T2DM = type 2 DM
Adapted from: Mach F, et al. European Heart Journal (2019) 00, 1-78
 2019 ESC/EAS Guidelines
for the management of
dyslipidemias: lipid
modification to reduce
cardiovascular risk

ESC = European Society of Cardiology; EAS = European Atherosclerosis Society; LDL-C=Low Density Lipoprotein Cholesterol; SCORE = Systematic Coronary Risk Estimation; T1DM = type 1 DM; T2DM = type 2 DM; DM =
diabetes mellitus; TC = total cholesterol; BP = blood pressure; FH = familial hypercholesterolaemia; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; ASCVD = atherosclerotic cardiovascular
disease; TIA = transient ischaemic attack. CV = Cardiovascular

Adapted from: Mach F, et al. European Heart Journal (2019) 00, 1-78
 2019 ESC/EAS Guidelines for the management of dyslipidemias:
lipid modification to reduce cardiovascular risk
Recommendations for pharmacological low-density lipoprotein cholesterol lowering

ESC = European Society of Cardiology; EAS = European Atherosclerosis Society; FH = familial

hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol; PCSK9 = Proprotein
Adapted from: Mach F, et al. European Heart Journal (2019) 00, 1-78 convertase subtilisin/kexin type 9; ASCVD = atherosclerotic cardiovascular disease;
Flow chart of cardiovascular disease
risk and risk factor treatment in
apparently healthy persons.

European Heart Journal (2021) 42, 3227-3337

 Flow chart of cardiovascular risk
and risk factor treatment in patients
with established atherosclerotic
cardiovascular disease.

European Heart Journal (2021) 42, 3227-3337

 Class 1 Dyslipidemia Recommendations
• In patients with established ASCVD, lipid-lowering treatment with an ultimate LDL-C goal of <1.4
mmol/L (55 mg/dL) and a >50% reduction of LDL-C vs. baseline is recommended.
• For secondary prevention patients not achieving their goals on a maximum tolerated dose of a
statin and ezetimibe, combination therapy including a PCSK9 inhibitor is recommended.
• In patients with type 2 DM at very high risk (e.g. with established ASCVD and/or severe TOD),
intensive lipid-lowering therapy, ultimately aiming at > 50% LDL-C reduction and an LDL-C of <1.4
mmol/L (<55 mg/dL) is recommended.
• In patients with type 2 DM >40 years of age at high risk, lipid-lowering treatment with an
ultimate LDL-C goal of >50% LDL-C reduction and an LDL-C of <1.8 mmol/L (70 mg/dL) is
recommended.

European Heart Journal (2021) 42, 3227-3337

 Treatment algorithm for
1ST pharmacological LDL-C
lowering

EZETIMIBE as an add-on therapy to

2
ND
achieve expected target of LDL-c
Target dan Tujuan Terapi Dislipidemia
Target dan Tujuan Terapi Dislipidemia
 *Percent reductions are estimates from data across large populations. Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical
practice.
†LDL-C lowering that should occur with the dosage listed below each intensity.
‡Evidence from 1 RCT only: down titration if unable to tolerate atorvastatin 80 mg in the IDEAL (Incremental Decrease through Aggressive Lipid Lowering) study.
§Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA because of the increased risk of
myopathy, including rhabdomyolysis.
BID = twice daily; FDA = US Food and Drug Administration; LDL-C = low-density lipoprotein cholesterol; RCT = randomized controlled trial
Adapted from Grundy SM, et al. Circulation. 2019;139:e1082–e1143
Lipid lowering treatment

European Heart Journal (2021) 42, 3227-3337

 In the Guideline: LDL-C level is Considered to Be "Lower
is Better” Lowering LDL-C in Patients at Very High Risk of
ASCVD should Be "as Low as Possible"

The lower the achieved LDL-C values, the lower the risk of The greater the absolute LDL-C reduction, the greater the
future cardiovascular (CV) events, with no lower limit for LDL- CV risk reduction
C values

Lowering of LDL-C beyond the goals that were set in set in

the previous EAS/ESC Guidelines is associated with fewer
ASCVD events. Therefore, it seems appropriate to reduce
LDL-C to as low a level as possible, at least in patients at
very high CV risk, and for this reason a minimum 50%
reduction is suggested for LDL reduction, together with
reaching the tailored goal.
Throughout the range of LDL-C levels, "lower is better"
with no lower threshold, at least down to 1mmol/L.
Lowering LDL-C may yield worthwhile benefits in patients
with average or below average LDL-C who are already
receiving LDL-C-lowering treatment.

European Heart Journal. 2019; 00: 1-78.

 One of Two Safety, High-intensity Statin up to the Highest Tolerated
Dose: Statins are Well Tolerated, True Statin Intolerance is Rare
Haemorrhagic stroke?
No increased in risk, although
SPARCL suggested a possible
increase in risk with prior
stroke
• Patients taking statin therapy Effects on cognition?
Cataract? No evidence that statins
frequently report muscle symptoms No evidence for increased adversely affect cognitive
so-called ‘statin-associated muscle risk function
symptoms (SAMS)’
• However, in double-blind RCTs, this Statin
Muscle symptoms Effects on liver
Therapy
#
case is absent or slight, which may Double-blind RCTs: 0.1%-
Clinically relevant effects
0.2%
be caused by nocebo effects * Non-blind observational are very rare (~ 1 per
studies: 7%-29% 100,000)

Dysglycaemia,
Proteinuria
New onset diabetes
Low frequency of mild
RCTs: ~ 0.1 per year
proteinuria
Individuals with metabolic
No evidence of clinically
syndrome or prediabetes are at
significant deterioration of renal
greater risks
function

• The absolute reduction in the risk of

CVD in high-risk patients clearly
outweighs the possible adverse effects
of a small increase in the incidence of # DILI, Drug-induced liver injury: increased transaminases ＞ 5×ULN and/or ALP ＞ 2×ULN
(ULN: upper limited of normal; ALP: alkaline phosphatase)
diabetes

1.Mach F, et al. Eur Heart J. 2018; 39: 2526-2539. * Doubt and distrust of treatment in patients with nocebo effects make them see worse
2.European Heart Journal. 2019; 00: 1-78. treatment outcomes.
Third Generation Statin
Highest-Potency Generation of Statins

Kapur Navin K,et al. Vascular Health and Risk Management 2008:4(2) 341–353
Superiority of Rosuvastatin vs Other Statins
Powerful efficacy in all lipid parameters
Among PCI Treated Patients:
Switching Atorvastatin to non CYP3A4-metabolized statin (Rosuvastatin)
Significantly decrease platelet reactivity and the prevalence of HPR*

*HPR = High Platelet Reactivity

Park Y, et al. European Heart Journal 2012
 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%

A significant proportion of patients at high-risk or with very high

50.00%

40.00%LDL-C levels Didn’t achieve optimal LDL level with statin

monotherapy
30.00%

20.00%

10.00%

0.00%
< 70 mg/dL < 100 mg/dL < 130 mg/dL < 160 mg/dL

Munawar.2013.Acta Cardiol Sin ;29:7181

 What are the treatment options for a patient
not at goal on statin therapy ?

1. Doubling the statin dose

2. Switching to a more effective statin
3. Using a combined statin and non-statin therapy
 Average LDL-C Reduction from Lipid Lowering
Treatment
(statin and non statin)
Treatment Average LDL-
C reduction
(Approximatel
y)

Moderate intensity statin 30 %

High intensity statin 50 %

High intensity statin plus Ezetimibe 65 %

PCSK9 inhibitor* 60 %

PCSK9 inhibitor* plus High intensity 75 %

statin
PCSK9 inhibitor* plus High intensity 85 %
statin plus Ezetimibe

*not available in Indonesia

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

For patients with ASCVD,
ezetimibe added to statin
therapy provided an additional
reduction of

22 mg/dL in LDL-C compared

with statin monotherapy.
GRAVITY: Gauging the lipid effects of Rosuvastatin plus
Ezetimibe Versus Simvastatin plus Ezetimibe Therapy

Co-administration of
rosuvastatin 10 or 20 mg
plus ezetimibe achieved
significant improvements

in lipid profiles in high-risk

patients vs. simvastatin 40 or
80 mg plus ezetimibe

Ballantyne CM, et al. Atherosclerosis 232 (2014) 86e93

 I-ROSETTE (Ildong Rosuvastatin & Ezetimibe for
Hypercholesterolemia) RCT

Combinations of ezetimibe and

rosuvastatin significantly improved
lipid profiles in patients with
hypercholesterolemia compared with
rosuvastatin monotherapy.

The safety and tolerability of

ezetimibe/rosuvastatin therapy were
comparable with those of rosuvastatin
monotherapy
*P o 0.001 versus rosuvastatin group

Least squares mean percent change in LDL-C after 8 weeks of treatment with
ezetimibe/ rosuvastatin and rosuvastatin.

Hong SJ, et al. Clinical Therapeutics 2018;40(2):227-41

 Effect of Combination Therapy of Ezetimibe and
Rosuvastatin on Regression of Coronary Atherosclerosis
in patients With Coronary Artery Disease

PV: Plaque volume

The combination therapy with ezetimibe and a usual-dose statin provided

significant incremental reduction in coronary plaques compared with usual-
dose statin monotherapy in patients with stable CAD

Masuda J, et al. Int Heart J 2015; 56: 278-285

 Take Home Messages
• Dual inhibition of both cholesterol absorption and cholesterol production will lower
plasma cholesterol levels more than either agent alone
• ESC/EAS/IHA Guidelines, in very high risk and high risk patient, the goal of LDL-C
reduction is 50 % and use high intensity statin is recommended or using combination
therapy such as High intensity Statin+Ezetimibe.
• Today, Rosuvastatin is the strongest statin (High Intensity ). Rosuvastatin 10 mg is equal
to 20 mg atorvastatin in reducing LDL-C and more tolerable (lower incidence of myalgia)
• Ezetimibe and statins have complimentary mechanisms of action.
• Combination therapy with ezetimibe has a greater efficacy in lower
doses of statin
Thank You