[Organon] Proprietary

Best Practice in Dyslipidemia Management

[Organon] Proprietary

CTT Meta-analysis: the relationship between the reduction in

LDL-C and reduction in vascular events is Linear

CTT = Cholesterol Treatment Trialists; CI = Confidence Interval

Lancet .2010;376:1670-1681
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There remain unmet clinical

needs in achieving LDL-C
reduction goals.

Z. Reiner et al. / Atherosclerosis 246 (2016) 243e250

[Organon] Proprietary

Challenges with statin-monotherapy

Dose Dependent
Side Effects

Recommended
LDL-C Levels
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Non-Statin therapy with proven

outcomes Trials:
FOURIER:
Evolocumab “PCSK 9 Inhibitor”
IMPROVE-IT:
Ezetimibe “Cholesterol Absorption Inhibitor”
REVEAL:
Anacetrapib “CETP Inhibitor”

21% risk reduction per 1 mmol/L

(39mg/dL) is virtually the same as the
22% reduction seen in the overall
CTTC analysis in which the starting
LDL-C was nearly twice as high.
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It’s time to….

[Organon] Proprietary

Ezetimibe / Statin

A Powerful New Partner

for Co-Administration with A Statin
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Ezetimibe Co-administered with Statins:

Efficient Control of LDL-C
+6% +6% +6%

20 40 80
Statin 10 mg mg mg mg The “rule of 6”
+18%

+ Ezetimibe
Statin 10 mg 10 mg One-step coadministration

0 10 20 30 40 50 60

% Reduction in LDL-C
• Most of the LDL-C reduction with statins occurs at the starting dose and subsequent doubling of the statin dose lowers

• LDL-C an average about an additional 6%.

• One-step coadministration of ezetimibe is the same as doubling the statin dose 3 times.
Stein E Eur Heart J Suppl 2001;3(suppl E):E11-E16.
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Evidence for Efficacy of LDL-Lowering Therapies Lower Than 1.4
mmol/L (55 mg/dL)
[Organon] Proprietary

What are the other benefits of

adding ezetimibe to statin?
[Organon] Proprietary

IMPROVE-IT
Even Lower is Even Better
IMPROVE-IT: a landmark trial of ∼18,000 patients
presenting with ACS at LDL-C baseline was 95 mg/dL

Efficacy Outcomes

69.9

53.2

N Engl J Med 2015; 372:2387-97.

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The benefit of adding

ezetimibe to statin was
enhanced in patients with DM

2017;CIRCULATIONAHA.117.030950
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Outcomes by TIMI Risk Score
for Secondary Prevention
High-risk patients (≥ 3 risk indicators) for recurrent CV
events had 19% RRR in “CV death/ MI/ Stroke” with
ezetimibe/statin, thus translating to
a number-needed-to-treat of 16.
[Organon] Proprietary

It’s safe to go to low levels of LDL-C

N Engl J Med 2015; 372:2387-97.

[Organon] Proprietary

Changes in LDL-C Goals From 2016 to 2019 Guidelines

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American Association of Clinical Endocrinologists and American College of Endocrinology

Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease

2017
Writing Committee 
Chair: Paul S. Jellinger, MD, MACE George Grunberger, MD, FACP, FACE
Co-Chair: Yehuda Handelsman, MD, FACP, FACE Chris K. Guerin, MD, FNLA, FACE
Members: Jeffrey I. Mechanick, MD, FACP, FACE, FACN, ECNU
David S. H. Bell, MD, FACP, FACE Rachel Pessah-Pollack, MD, FACE
Zachary T. Bloomgarden, MD, MACE Paul D. Rosenblit, MD, PhD, FNLA, FACE
Eliot A. Brinton, MD, FAHA, FNLA Donald A. Smith, MD, MPH, FACE
Michael H. Davidson, MD, FACC, FACP, FNLA Kathleen Wyne, MD, PhD, FNLA, FACE
Sergio Fazio, MD, PhD Reviewers:
Vivian A. Fonseca, MD, FACE Michael Bush, MD
Alan J. Garber, MD, PhD, FACE Farhad Zangeneh, MD

AACE/ACE CPG. 2017;epub ahead of print; Cannon, CP, et al. N Engl J Med. 2015;372(25):2387-239; Jellinger P, Handelsman Y,
Rosenblit P, et al. Endocr Practice. 2017;23(4):479-497.
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ASCVD Risk Categories and LDL-C Treatment Goals

Treatment goals
Risk category Risk factors/10-year risk LDL-C Non-HDL-C Apo B
(mg/dL) (mg/dL) (mg/dL)
– Progressive ASCVD including unstable angina in
individuals after achieving an LDL-C <70 mg/dL
 
Extreme risk – Established clinical cardiovascular disease in individuals <55 <80 <70
with DM, stage 3 or 4 CKD, or HeFH  

– History of premature ASCVD (<55 male, <65 female)

– Established or recent hospitalization for ACS, coronary,
carotid or peripheral vascular disease, 10-year risk >20%
Very high risk – DM or stage 3 or 4 CKD with 1 or more risk factor(s) <70 <100 <80

– HeFH
– ≥2 risk factors and 10-year risk 10%-20%
High risk – DM or stage 3 or 4 CKD with no other risk factors <100 <130 <90

Moderate ≤2 risk factors and 10-year risk <10%

<100 <130 <90
risk
Low risk 0 risk factors <130 <160 NR
Abbreviations: ACS, acute coronary syndrome; apo, apolipoprotein; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; DM, diabetes mellitus; HeFH, heterozygous
familial hypercholesterolemia; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; NR, not recommended.

Barter PJ, et al. J Intern Med. 2006;259:247-258; Boekholdt SM, et al. J Am Coll Cardiol. 2014;64(5):485-494; Brunzell JD, et al. Diabetes Care. 2008;31:811-822; Cannon CP, et al.
N Engl J Med. 2015;372(25):2387-2397; Grundy SM, et al. Circulation. 2004;110:227-239; Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22; Jellinger P,
Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4):479-497; Lloyd-Jones DM, et al. Am J Cardiol. 2004;94:20-24; McClelland RL, et al. J Am Coll Cardiol.
2015;66(15):1643-1653; NHLBI. NIH Publication No. 02-5215. 2002; Ridker PM, J Am Coll Cardiol. 2005;45:1644-1648; Ridker PM, et al. JAMA. 2007;297(6):611-619; Sever PS, et
al. Lancet. 2003;361:1149-1158; Shepherd J, et al. Lancet. 2002;360:1623-1630; Smith SC Jr, et al. Circulation. 2006;113:2363-2372; Stevens RJ, et al. Clin Sci. 2001;101(6):671-
679; Stone NJ. Am J Med. 1996;101:4A40S-48S; Weiner DE, et al. J Am Soc Nephrol. 2004;15(5):1307-1315.
[Organon] Proprietary

Question: How are different drugs used to treat dyslipidemia?

Recommendations associated with this

Statins
question:

• R56. Statin therapy is recommended as the primary pharmacologic agent to achieve target LDL-C goals on the basis of
morbidity and mortality outcome trials (Grade A; BEL 1).
• R57. For clinical decision making, mild elevations in blood glucose levels and/or an increased risk of new-onset T2DM
associated with intensive statin therapy do not outweigh the benefits of statin therapy for ASCVD risk reduction (Grade
A, BEL 1).
• R58. In individuals within high-risk and very high-risk categories, further lowering of LDL-C beyond established
targets with statins results in additional ASCVD event reduction and may be considered (Grade A, BEL 1).
• R59. Very high-risk individuals with established coronary, carotid, and peripheral vascular disease, or diabetes, who
also have at least 1 additional risk factor, should be treated with statins to target a reduced LDL-C treatment goal of <70
mg/dL (Grade A, BEL 1).
• R60. Extreme risk individuals should be treated with statins or
with combination therapy to target an even lower LDL-C treatment
goal of <55 mg/dL (Grade A, BEL 1).
Abbreviations: ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein
cholesterol;
TG, triglycerides.
Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4):479-497. 
[Organon] Proprietary
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[Organon] Proprietary
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Tailoring Lipid-Lowering Therapy Based on Patient and Disease
Characteristics
[Organon] Proprietary
2019 ESC/EAS Guidelines
New Lipid Goals
(Very High Risk)
[Organon] Proprietary

Main Principles for LDL-Lowering Therapy

[Organon] Proprietary

26
[Organon] Proprietary

Should the
High Intensity Cholesterol Lowering Therapy

Replace the
High Intensity Statin Therapy???
[Organon] Proprietary

Intensity of Statin Therapy

*Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a biologic basis for a less-than-average response.
†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al).
‡Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy,
including rhabdomyolysis.
[Organon] Proprietary
[Organon] Proprietary
[Organon] Proprietary

ADA / Diabetes Care 2021

Diabetes Care Volume 44, Supplement 1, January 2021

[Organon] Proprietary

Changes in ezetimibe recommendation

I
IIa
[Organon] Proprietary
Intensifying Lipid-Lowering Treatment
to Reach LDL-C Goals
[Organon] Proprietary

Getting Patients to LDL-C Goal

MTD: Maximal Tolerated Dose

[Organon] Proprietary
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Efficacy and Safety of Ezetimibe Added on to

Atorvastatin (40 mg) Compared With Up titration of Atorvastatin
(to 80 mg) in Hypercholesterolemic Patients at High Risk of
Coronary Heart Disease

(EZ-PATH Study)

EZ-PATH = EZetimibe Plus Atorvastatin Versus Atorvastatin Titration in Achieving Lower LDL-C Targets in
Hypercholesterolemic Patients

Leiter LA et al. Am J Cardiol. 2008;102:1495–1501

[Organon] Proprietary

EZ-PATH: (Study Design)¹

Patients With Hypercholesterolemia at High Risk of Coronary Heart Disease

(Based on NCEP ATP III Criteria)

Ezetimibe + Atorvastatin 40 mg (n=288)

Atorvastatin 40 mg

Atorvastatin 80 mg (n=291)

Week -5 to -4 Week 0 Week 6

Run-In Double-Blind Period

Randomization
(LDL-C 70–160 mg/dL [≈1.8–4.1 mmol/L]
and triglycerides ≤350 mg/dL [≈4.0 mmol/L])
EZ-PATH = Ezetimibe Plus Atorvastatin Versus Atorvastatin Titration in Achieving Lower LDL-C Targets in Hypercholesterolemic Patients

NCEP ATP III = National Cholesterol Education Program Adult Treatment Panel III
High risk of CHD: Without CVD, T2DM, > 2 risk factors,10-yr risk > 20% or with known CVD
1 Leiter LA et al. Am J Cardiol. 2008;102:1495–1501
[Organon] Proprietary

EZ-PATH: Ezetimibe/Atorvastatin 10/40 mg Provided Greater Additional

LDL-C Reduction vs Doubling Atorvastatin Dose to 80 mg¹
Primary Endpoint: Percentage change in LDL-C
Ezetimibe as an adjunct to diet when diet and exercise alone are not enough
10

Statin-Treated Baseline, %
LDL-C

Mean Change From

0
Series1

–10
–11

–20

–30 –27
P<0.001

Ezetimibe added to atorvastatin 40 mg (n=277) Atorvastatin 40 mg titrated to 80 mg (n=279)

Mean on-statin baseline LDL-C = 89 mg/dL Mean on-statin baseline LDL-C = 90 mg/dL
(≈2.3 mmol/L) (≈2.3 mmol/L)

Adapted with permission from Leiter LA et al.

EZ-PATH = Ezetimibe Plus Atorvastatin Versus Atorvastatin Titration in Achieving Lower LDL-C Targets in Hypercholesterolemic Patients

Leiter LA et al. Am J Cardiol. 2008;102:1495–1501

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EZ-PATH: More Than Twice as Many Patients Reached LDL-C <70 mg/dL With
Ezetimibe/Atorvastatin 10/40 mg Additional LDL-C vs Doubling Atorvastatin Dose to 80 mg¹
Secondary Endpoint: Patients Reaching LDL-C <70 mg/dL (≈1.8 mmol/L) at 6 Weeks
as a Result of Greater LDL-C Reduction

Ezetimibe Added to Atorvastatin 80 mg

Atorvastatin 40 mg (n=279)
(n=277)

32%
74%

P<0.001

Mean Statin-Treated Mean Statin-Treated

Baseline LDL-C: 89 mg/dL (≈2.3 mmol/L) Baseline LDL-C: 90 mg/dL (≈2.3 mmol/L)

The mean decrease in LDL-C from statin-treated baseline was 27% with ezetimibe added to atorvastatin
40 mg compared with 11% with atorvastatin 80 mg; P<0.001.

1.Leiter LA et al. Am J Cardiol. 2008;102:1495–1501.

[Organon] Proprietary
Sub-analysis of IMPROVE-IT

Addition of Ezetimibe to statin in

High-risk patients (≥ 3 risk indicators) for
recurrent CV events had 19% RRR in
“CV death/ MI/ Stroke” thus translating to
a NNT of 16
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EWTOPIA 75 = Ezetimibe lipid loWering Trial On PreventIon of

Atherosclerosis in 75 or older

https://www.tctmd.com/news/ewtopia-75-ezetimibe-bests-dietary-counseling-alone-lowering-cardiovascular risk-elderly
[Organon] Proprietary

EWTOPIA75 Trial (continued)

Background:
• Trial evaluated ezetimibe in primary prevention of cardiovascular events in elderly
patients with elevated LDL-C levels.
• A multicenter, prospective open-label randomized controlled trial conducted in
Japan.
Patients ≥ 75 years with
LDL ≥ 140 md/dL
No history of CAD
(n = 3,796)

Dietary Counseling Dietary Counseling + Ezetimibe 10 mg

(n = 1,695) ( n = 1,716)

Follow-up: 5 years
Primary Endpoint: Cardiac death, MI, PCI or CABG and Stroke

https://www.tctmd.com/news/ewtopia-75-ezetimibe-bests-dietary-counseling-alone-lowering cardiovascular-risk-elderly
[Organon] Proprietary

EWTOPIA75 Trial: Ezetimibe prevents CV events in

elderly patients

Results:
 Ezetimibe + diet compared to diet alone significantly reduced the primary
endpoint by 34% (HR 0.66, p = 0.002).

 LDL-C at baseline was 161 mg/dL reduced to 120 mg/dL and 131 mg/dL
in the ezetimibe and control group, respectively.

 There were no safety concerns seen in the study, despite the age of the
population.

https://www.tctmd.com/news/ewtopia-75-ezetimibe-bests-dietary-counseling-alone-lowering-cardiovascular-risk elderly
[Organon] Proprietary

PRECISE-IVUS: Plaque REgression with Cholesterol Absorption Inhibitor or Synthesis Inhibitor Evaluated by IntraVascular
UltraSound
[Organon] Proprietary

PRECISE-IVUS Trial
Aggressive lipid-lowering with ezetimibe/ atorvastatin demonstrated stronger
coronary plaque regression compared to atorvastatin in patients with ACS

PAV: Percent Atheroma Volume

SAP: Stable Angina Pectoris
ACS: Acute Coronary Syndrome
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Summary and Conclusion

 LDL-C remains the primary target of therapy in most strategies of dyslipidemia management.

 Even Lower (LDL-C) is Even Better (CV benefits). The higher the risk, the more the benefit.

 No distinction between primary and secondary prevention management (the recommendations are similar for
a similar level of risk regardless of whether a patient has had a previous event).

 Addition of ezetimibe to atorvastatin (ATOZET™) provided a well-tolerated, effective lipid lowering therapy for
patients at high risk of CVD.

 In terms of C.V outcomes, Ezetimibe to reduce LDL-C have proven CV benefit up to 19% RRR in “CV death, MI,
or ischemic stroke”.

 In EZ-PATH study, ATOZET™ (ezetimibe/atorvastatin) resulted in superior LDL-C–lowering and goal attainment
vs doubling the dose of atorvastatin.1
[Organon] Proprietary

Summary & Conclusions

• The world’s biggest killer is ischaemic heart disease, responsible for 16% of the world’s total deaths.
• Consistent reduction of LDL-C levels is associated with CV benefits even at very low levels (Even
Lower is Even Better).
• Recent dyslipidemia guidelines recommend very low LDL-C levels specially for high- & very high-
risk patients.
• No distinction between primary and secondary prevention management (the recommendations are
similar for a similar level of risk regardless of whether a patient has had a previous event).
• Alarming LDL-C goal attainment levels in Egypt whether for very-high risk or ACS patients.
• High intensity statin plus Ezetimibe achieve an average LDL-C reduction ≈65%.
• Addition of Ezetimibe to Atorvastatin provided a greater reduction in LDL-C levels and enabled more
patients to reach their LDL-C targets rather than doubling the dose of statins or switching to other
statin.
[Organon] Proprietary

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