dyslipidemia

Managing Dyslipidemia,
HOW LOW SHOULD WE GO?
Prof. Mahmoud Yousof
Head of Cardiology Department-
Mansoura University

3
Prof. Mahmoud Youssof
Professor of Cardiology,
Head of Cardiovascular Dep,
Mansoura University
You can contact me at:
myousif200@gmail.com

CV Mortality is the killer #1 in the world
• Every 40 seconds, someone dies from
Cardiovascular Disease
• Every 4 minutes, someone dies from
Stroke
• 18 million people across the globe died from
heart disease in 2015
• Over 400 million men and women have a
kind of cardiovascular illness

Slide Source
LipidsOnline
www.lipidsonline.org
Atherosclerosis
Many risk
factors some of
them are
modifiable and
others are non
modifiable But
still
dyslipidemia is the
most important risk
factor because it
touches the core
of pathology BUT

Relative
Risk
for CHD (Log
Scale)
3.7
2.9
2.2
1.7
1.3
1.0
LDL-C (mg/dL)
40 70 100 130 160 190
0
1
Grundy SM et al. Circulation 2004;110:227–239.
A log-linear relationship exists between LDL levels and relative risk
for CHD suggesting that for every 30 mg/dl change in LDL-C, the
relative risk for CHD is changed in proportion by about 30%.

Slide Source
LipidsOnline
Benefits of Hypolipidemic Treatment
% Reduction in
Risk of
Cardiac End Points
0%
20%
40%
70%
10 13 26 35 60
LRC-CPPT
WOSCOPS
4S
?
% LDL-C Reduction

Relationship Between Changes in
LDL-C and HDL-C Levels and CHD Risk
a
l
.
N
E
n
g
l
J
M
e
d
1
9
9
9
;
3
4
1
:
4
1
0
–
4
1
8
1% decrease
in LDL-C reduces CHD
risk by
1%1
1% change
in HDL-C associated with 1–
3% reduction in CHD risk2–5

More versus Less Intensive Statin Treatment is
Associated with Further Reductions in Major
Vascular Events
0.51 mmol/L
further reduction
in LDL-C with more
intensive statin
therapy
15%
additional reduction
in major vascular
events (p<0.0001)
CTT Collaborators. Lancet 2010; 376: 1670–1681

<50mg/dl (National Health and Nutritional Survey
(NHANES)
< 20 mg/dl is considered extremely low
Low LDL does not appear to be unsafe, as long as some
LDLC is still present .

The COURAGE study demonstrated that if LDL >80
mg/dL, decreas need for angioplasty. (stable angina)
•The IMPROVE-IT trial demonstrated a significant
improvement in outcomes when the LDL cholesterol was
reduced to a mean of 53.7 mg/dL on a combination of
statin and ezetimibe vs 69.5 mg/dL on statin alone
•IMPROVE-IT trial proved the cholesterol hypothesis:
the lower, the better

10% RRR with lower LDL-C
achieved after 1 month mainly
with Simvastatin/Ezetimibe

ASTEROID Study
•
LDL cholesterol dropped to an average of 60.8 mg/dl
atheroma volume shrank by 6.8%.

N Engl J Med 2015; 372:2387-97.
It’s safe to go to low level of LDL-C

Non Statin therapy with proven
outcomes Trials:
FOURIER:
Evolocumab “PCSK 9 Inhibitor”
IMPROVE-IT:
Ezetimibe “Cholesterol Absorption Inhibitor”
REVEAL:
Anacetrapib “CETP Inhibitor”

European Heart Journal (2016) 37, 2999–3058
Very High Risk patient:
LDL-C goal ˂ 70 mg/dL or a reduction of at least 50% if
baseline ( 70 – 135 mg/dL)

American Endocrinology Guidelines
- Management of Dyslipidemia -
Jellinger P.S. et al., ENDOCRINE PRACTICE Vol 23 (Suppl 2) April 2017

Slide Source
LipidsOnline
Dyslipidaemia Remains
Under-treated

Slide Source
LipidsOnline
Dyslipidaemia Remains Undertreated and
Many Patients do not Reach Treatment Goal
The EURIKA Study
74.4%
25.6%
43.3%
56.7%
Treated patients
who reached target
Banegas J et al. Eur J Heart
2011; 32: 2143–2152
Untreated
Treated
• Of 4407 patients with dyslipidaemia included in the
EURIKA study, 74% received lipid-lowering agents
Reached
target
Did not
reach target
• Only 43% of treated patients reached
total cholesterol goal of <5 mmol/L

Z. Reiner et al. / Atherosclerosis 246 (2016) 243e250
There remains unmet clinical
needs in achieving LDL-C
reduction goals.
EUROASPIRE IV

Recommended
LDL-C Levels
Dose Dependent
Side Effects
Distance from Target
Challenges with statin-
monotherapy

(1)-Despite use of statins, cardiovascular diseases
and strokes are responsible for 25% of deaths worldwide
(2)-Most of the statin trials
31% of relative risk reduction
69% of relative risk is still present.
.

-(3)South Asian paradox which denotes
that South Asian people are more prone
to develop CAD despite having within-
target LDL level. So, we have to consider
whether further lowering of LDL below
the existing target level would help in
reduction of CV events in those cases

(4)Intensive lipid lowering treatment has been found to halt
progression of atherosclerosis as compared to moderate lipid lowering
treatment.
It also regresses the atheroma plaque volume as reported by
REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering)
trial and
ASTEROID (A Study to Evaluate the Efect of Rosuvastatin on
Intravascular Ultrasound-Derived Coronary Atheroma Burden) trial.
SATURN (Study of Coronary Atheroma by Intravascular Ultrasound:
Efect of Rosuvastatin Versus Atorvastatin) trial also .
GLAGOV trial -- evolocumab with statins demonstrated plaque
regression in a larger number of patients as compared to placebo afer
76 weeks of therapy.

Death is inevitable but
premature death is not.

Ezetimibe Coadministered with
Statins: Efficient Control of LDL-C
Stein E Eur Heart J Suppl 2001;3(suppl E):E11-E16.
0 60
The “rule of 6”
One-step coadministration
Statin 10 mg
Statin 10 mg
+ Ezetimibe
10 mg
50
+6%
30
20
10
20
mg
40
mg
80
mg
% Reduction in LDL-C
+6% +6%
+18%
40
• Most of the LDL-C reduction with statins occurs at the starting dose and subsequent doubling of the statin dose lowers LDL
an average about an additional 6%.
• One-step co-administration of ezetimibe is the same as doubling the statin dose 3 times.

A Powerful New Partner
for Co-Administration with A Statin
Ezetimibe / Statin

Ezetimibe and Statins Have Complementary
Mechanisms of Action1
Together, ezetimibe in combination
with a statin provides:
Reduction of hepatic cholesterol
Increased LDL receptor expression
Increased clearance of plasma LDL-C
1
2
3
Atheroma
Blood
Remnant
Receptors
LDL Receptor
Expression
HMG-CoA
CMR
CM
Statins
Ezetimibe
X
2
LDL-C
1
Cholesterol
Pool
NPC1L1 = Niemann-Pick C1-like 1; HMG-CoA = 3-hydroxy-3-methylglutaryl acetyl coenzyme A; CMR = chylomicron remnant.
1. Grigore L et al. Vas Health Risk Manag. 2008;4:267–278.
Cholesterol
Pool (Micelles)
X
3
NPC1L1

It’s time to….
Think Byond Statin Monotherapy

Question: How are different drugs used to treat dyslipidemia?
Statins
•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).
Recommendations
associated
with
this
question:
Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23(4):479-497.
Abbreviations: ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol;
TG, triglycerides.

Diabetes Care Volume 44, Supplement 1,
January 2021
ADA / Diabetes Care 2021

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

EZ-PATH: (Study Design)¹
Patients With Hypercholesterolemia at High Risk of Coronary Heart Disease
(Based on NCEP ATP III Criteria)
Atorvastatin 40 mg
Run-In
Week -5 to -4 Week 0 Week 6
Randomization
(LDL-C 70–160 mg/dL [≈1.8–4.1 mmol/L]
and triglycerides ≤350 mg/dL [≈4.0 mmol/L])
Double-Blind Period
Ezetimibe + Atorvastatin 40 mg (n=288)
Atorvastatin 80 mg (n=291)
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
1.Leiter LA et al. Am J Cardiol. 2008;102:1495–1501
High risk of CHD: Without CVD, T2DM, > 2 risk factors,10-yr risk > 20% or with known CVD

Mean
Change
From
Statin-Treated
Baseline,
%
Atorvastatin 40 mg titrated to 80 mg (n=279)
Mean on-statin baseline LDL-C = 90 mg/dL
(≈2.3 mmol/L)
Ezetimibe added to atorvastatin 40 mg (n=277)
Mean on-statin baseline LDL-C = 89 mg/dL
(≈2.3 mmol/L)
Ezetimibe as an adjunct to diet when diet and exercise alone are not enough
–10
–20
–30
0
10
LDL-C
–27
–11
P<0.001
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
1. Leiter LA et al. Am J Cardiol. 2008;102:1495–1501
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 Added to
Atorvastatin 40 mg
(n=277)
Atorvastatin 80 mg
(n=279)
74%
32%
Mean Statin-Treated
Baseline LDL-C: 89 mg/dL (≈2.3 mmol/L)
Mean Statin-Treated
Baseline LDL-C: 90 mg/dL (≈2.3 mmol/L)
P<0.001
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.
Patients Reaching LDL-C <70 mg/dL (≈1.8 mmol/L) at 6 Weeks
as a Result of Greater LDL-C Reduction
1.Leiter LA et al. Am J Cardiol. 2008;102:1495–1501.
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:

Efficacy and Safety of Ezetimibe Added to Atorvastatin
Versus Atorvastatin Uptitration or Switching to Rosuvastatin
in Patients With Primary Hypercholesterolemia
(PACE Study)
PACE: Patients with Primary Hypercholesterolemia and High Cardiovascular Risk Who Are Not Adequately Controlled with Atorvastatin 10 mg: a
Comparison of the Efficacy and Safety of Switching to Coadministration Ezetimibe And Atorvastatain Versus Doubling the Dose of Atorvastatin or
Switching to Rosuvastatin

High-Risk Patientsa With Hypercholesterolemia Not at LDL-C <100 mg/dL (≈2.6 mmol/L) on Atorvastatin 10 mg
PACE: Efficacy of Ezetimibe Added to Atorvastatin vs
Atorvastatin Uptitration or Switching to Rosuvastatin¹
Atorva 20 mg
EZ 10 mg + Atorva 10 mg
Atorva 20 mg
Rosuva 10 mg
Rosuva 20 mg
Atorva 10 mg
(N=2,646)
(n=30)
(n=240
)
(n=476
)
Week: -
6
-
5
Day
1
Screening Run-In
Double-Blind
Treatment
Phase 1
Atorva 40 mg
(n=28)
(n=124
)
(n=126
)
(n=234)
(n=206
)
6 1
2
Double-Blind
Treatment
Phase 2
(n=90)
Rosuva 10 mg
(n=468
)
(n=243
)
Randomizatio
n
(n=1,547)
aHigh risk of CHD was defined as 1) subjects without CVD who had type 2 diabetes mellitus, or ≥2 CVD risk factors and a 10-year risk for CHD
>20% as determined by the Framingham risk calculation, or 2) subjects with CVD, including established coronary or other atherosclerotic
vascular disease.
1. Bays HE et al. Am J Cardiol. 2013;112(12):1885–1895.

IRLS
Mean
Change
From
Treated
Baseline
at
Week
6,
%
Doubling atorvastatin
to 20 mg
(n=480)
Mean on-statin baseline
LDL-C = 120 mg/dL (≈3.1 mmol/L)
Adding ezetimibe
to atorvastatin 10 mg
(n=120)
–10
–20
–30
0
10
LDL-C
–22
–10
P<0.001
PACE Phase 1: Adding Ezetimibe to Atorvastatin 10 mg Provided Greater
Additional LDL-C Reduction vs Doubling Atorvastatin to 20 mg or Switching to
Rosuvastatin 10 mg¹
–13
Switching to
rosuvastatin 10 mg
(n=939)
P<0.001
IRLS = iteratively reweighted least squares

PACE Phase 1: Adding Ezetimibe to Atorvastatin 10 mg Resulted in Greater
Attainment of LDL-C <100 mg/dL vs Doubling Atorvastatin to 20 mg or
Switching to Rosuvastatin 10 mg¹
The IRLS mean decrease in LDL-C from statin-treated baseline was 22% with ezetimibe + atorvastatin 10 mg
compared with 10% with atorvastatin 20 mg and 13% with rosuvastatin 10 mg; P<0.001 for each comparison
vs ezetimibe + atorvastatin 10 mg.
High-Risk Patients Reaching LDL-C <100 mg/dL (≈2.6 mmol/L) at 6 Weeks
56% 37% 44%
Ezetimibe Added to
Atorvastatin 10 mg
(n=119)
Mean treated baseline LDL-C:
121 mg/dL (≈3.1 mmol/L)
Rosuvastatin 10 mg
(n=915)
121 mg/dL (≈3.1 mmol/L)
Atorvastatin 20 mg
(n=471)
120 mg/dL (≈3.1 mmol/L)
P<0.01
P<0.001

PACE: Efficacy of Ezetimibe Added to Atorvastatin vs Atorvastatin
Uptitration or Switching to Rosuvastatin¹
High-Risk Patientsa With Hypercholesterolemia Not at LDL-C <100 mg/dL (≈2.6 mmol/L) on Atorvastatin 10 mg
Atorva 20 mg
Atorva 20 mg
Rosuva 10 mg
Rosuva 20 mg
Atorva 10 mg
(N=2,646)
(n=30)
(n=240
)
(n=476
)
Week: -
6
-
5
Day
1
Screening Run-In
Double-Blind
Treatment
Phase 1
Atorva 40 mg
(n=28)
(n=124
)
(n=126
)
(n=234
)
(n=206
)
6 1
2
Double-Blind
Treatment
Phase 2
(n=90)
Rosuva 10 mg
(n=468
)
(n=243
)
Randomizatio
n
(n=1,547)
aHigh risk of CHD was defined as 1) subjects without CVD who had type 2 diabetes mellitus, or ≥2 CVD risk factors and a 10-year risk for CHD
>20% as determined by the Framingham risk calculation, or 2) subjects with CVD, including established coronary or other atherosclerotic
vascular disease.

IRLS
Mean
Change
From
Treated
Baseline
at
Week
6,
%
Doubling atorvastatin
to 40 mg
(n=124)
LDL-C = 121 mg/dL
(≈3.1 mmol/L)
Adding ezetimibe 10 mg
(n=124)
Mean on-statinbaseline
LDL-C = 119 mg/dL
(≈3.1 mmol/L)
–10
–20
–30
0
10
LDL-C
–17
–7
–17
Doubling rosuvastatin
to 20 mg
(n=205)
LDL-C = 120 mg/dL
(≈3.1 mmol/L)
P<0.001
–8
P<0.001
Switching from
rosuvastatin 10 mg to
ezetimibe 10 mg + atorvastatin 20 mg
(n=231)
LDL-C = 119 mg/dL
(≈3.1 mmol/L)
PACE Phase 2: Greater Additional LDL-C Reduction With
Ezetimibe Plus Atorvastatin 20 mg¹

P<0.001
High-Risk Patients Reaching LDL-C <100 mg/dL (≈2.6 mmol/L)
P<0.001
Doubling
atorvastatin to 40 mg
(n=123)
LDL-C = 121 mg/dL
(≈3.1 mmol/L)
Ezetimibe 10 mg added
(n=120)
LDL-C = 119 mg/dL
(≈3.1 mmol/L)
Doubling
rosuvastatin to 20 mg
(n=201)
LDL-C = 120 mg/dL
(≈3.1 mmol/L)
Switching from rosuvastatin 10 mg
to ezetimibe 10 mg + atorvastatin 20 mg
(n=228)
LDL-C = 119 mg/dL
(≈3.1 mmol/L)
The IRLS mean decrease in LDL-C from statin-treated baseline was 17% with ezetimibe plus
atorvastatin 20 mg compared with 7% with doubling atorvastatin to 40 mg and 17% with ezetimibe plus
atorvastatin 20 mg compared with 8% with doubling rosuvastatin to 20 mg; P<0.001 for each comparison.
PACE Phase 2: Greater Attainment of LDL-C <100 mg/dL
With Ezetimibe Plus Atorvastatin 20 mg¹
56% 34% 36%
54%

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

risk-elderly
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

EWTOPIA75 Trial: Ezetimibe prevents CV
events in elderly patients
risk-elderly
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.

What are the benefits of adding
ezetimibe to statin?

N Engl J Med 2015; 372:2387-97.
Efficacy Outcomes
IMPROVE-IT
Even Lower is Even Better

2017;CIRCULATIONAHA.117.030950
The benefit of adding ezetimibe
to statin was enhanced in
patients with DM

Aggressive lipid-lowering with ezetimibe/ atorvastatin demonstrated stronger
coronary plaque regression compared to atorvastatin in patients with PCI
PAV: Percent Atheroma Volume SAP: Stable Angina Pectoris ACS: Acute Coronary Syndrome
PRECISE-IVUS Trial

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.

Should the
High Intensity Cholesterol Lowering
Therapy
Replace the
High Intensity Statin Therapy???

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.

Summary and Conclusion
Achieving even lower LDL-C in high risk populations further
reduces risk & appears safe.
Addition of ezetimibe to atorvastatin (ATOZET™)provided a
well-tolerated, effective lipid lowering therapy for patients at
high risk of CVD.
In EZ-PATH study of high-risk patients, ATOZET™
(ezetimibe/atorvastatin) resulted in superior LDL-C–lowering
and goal attainment vs doubling the dose of atorvastatin.

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