Statin/Ezetimbe Combination Therapy: Emerging Evidence

Statin/Ezetimbe Combination
Therapy: Emerging Evidence
Ihab Attia, MD
Prof. of Cardiology
Ain Shams University

Nonfatal MI and CHD Death
Relative Risk Reduction, %
Correlation Between LDL-C Lowering and
Decreased CHD Risk According to Treatment
Modality in a Meta-Regression Analysis 1,a
100
80
60
40
20
0
–20
15 20 25 30 35 40
LDL-C Reduction, %
London
Oslo
MRC
Los Angeles
Upjohn
LRC
NHLBI
POSCH
4S b
WOSCOPS b
CARE b
LIPID b
AF/TexCaps b
HPS b
ALERT b
PROSPER b
ASCOT-LLA b
CARDS b
Reprinted from Journal of the American College of Cardiology, 46(10), Robinson JG, Smith B, Maheshwari N, et al, Pleiotropic effects of statins: benefits beyond cholesterol
reduction? A meta-regression analysis, 1855–1862, Copyright © (2005), with permission from Elsevier.
CHD=coronary heart disease; MI=myocardial infarction; MRC=Medical Research Council; LRC=Lipid Research Clinics; NHLBI=National Heart, Lung, and Blood Institute;
POSCH=Program on the Surgical Control of the Hyperlipidemias; 4S=Scandinavian Simvastatin Survival Study; WOSCOPS=West of Scotland Coronary Prevention Study;
CARE=Cholesterol And Recurrent Events Trial; LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease; AF/TexCAPS=Air Force/Texas Coronary Atherosclerosis
Prevention Study; HPS=Heart Protection Study; ALERT=Assessment of LEscol in Renal Transplantation; PROSPER=PROspective Study of Pravastatin in the Elderly at Risk;
ASCOT-LLA=Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm; CARDS=Collaborative Atorvastatin Diabetes Study.
Estimated change in the 5-year relative risk of nonfatal MI or CHD death associated with mean LDL-C reduction for the diet, bile-acid sequestrant, surgery, and statin trials (dashed
line) along with the 95% probability interval (shaded area). The solid line has a slope=1. The crude risk estimates from the individual studies are plotted along with their associated
95% confidence intervals. The Sydney trial is not shown but was included in the analysis.
a
Analysis included 19 trials of high-risk primary prevention and secondary prevention (CHD, cardiovascular disease, renal transplant, diabetes) patients; b Statin trials.
1. Robinson JG et al. J Am Coll Cardiol. 2005;46(10):1855–1862.

Recommendations for Lipid Analyses as
Treatment Target
LDL-C remains
the primary target
of therapy in most
strategies of
dyslipidemia
management
ESC/EAS GUIDELINES. Zˇ eljko Reiner et al. European
Heart Journal (2011) 32, 1769–1818

LDL-C Treatment Goals
ESC/EAS
2011
Guidelines
Very high CV risk
LDL-C goal is

Cholesterol Goal Attainment
in Egypt Real World (Labs)
Slide 5

% of patients
Cholesterol Goal Attainment in Egyptian Real World
Majority of Patients on a Statin monotherapy
100%
90%
80%
87%
Base = 3036
Patients
70%
60%
50%
40%
30%
20%
11%
10%
0%
(n=2645)
(n=339)
2%
(n=52)
Statins Fibrates Others
Slide 6

Cholesterol Goal Attainment in Egyptian Real World
Vast Majority of Patients on Statins monotherapy failed to
achieve the recommended LDL goal (by risk/goal)
% of pts reaching at goal
20%
17.1%
16%
12%
8%
7.6%
5.50%
8.1%
4%
0%
0.80%
(n=2183) (n= 434) (n= 419)
DM alone CHD alone DM + CHD
0.70%
< 100 mg/dl < 70 mg/dl
*LDL-C goal of

Cholesterol Goal Attainment in Egyptian Real World
Results Summary
• Most patients received statins as
initial therapy
• Approximately 91% did not achieve their
cholesterol target goal
• Egyptian goal attainment data seem to be less than the worldwide
data
Slide 8

Why do statins alone don’t
get our patients to where we
want ?
Slide 9

Reduction of LDL-C, %
Doubling a Statin Dose Yields Only
a 6% Incremental Drop in LDL-C
Statin Rule of 6
6% drop
6% drop
6% drop
0 10 20 30 40 50 60 70 80
Statin, mg
Adapted from Knopp RH. N Engl J Med. 1999;341:498–511; Stein EA. Am J Cardiol. 2002;89(suppl):50C–57C.
10

Statins Adverse Events
• Hepatotoxicity (0.1% - 2.7%)
• Myopathy/Myaligia (1% - 7%)
• Rhabdomyolysis (1% - 2%)
They occur when :
1. Larger Statin doses
2. Pre existing liver disease
3. Use of associated hepatotoxic substances
4. Concurrent use of cytochrome 450 inhibitors
5. Lipophilic
11

Elevated Transaminases
(% of Patients)
% Decrease in LDL-C
Risk:Benefit Ratio of
StatinTitration
Atorvastatin
Lovastatin
Simvastatin
0
10 mg 20 mg 40 mg 80 mg
20 mg 40 mg 80 mg
40 mg 80 mg
-10
-20
-30
-40
-50
-60
2.5
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 a comparative study.

Severe Adverse Event Rates for Each Trial:
Meta-Analysis of Intensive vs Moderate Statin
Therapy
Cannon CP et al. JACC 2006;48:438–45

Inter-individual variability in
response to statins
Extrinsic factors
(extraneous influences)
Intrinsic factors
(genetically-determined)
poor compliance
background diet
dose and uptitration of drug
concomitant drug therapy
LDL-receptor gene mutations
apo-B-100 gene mutations
rate of cholesterol biosynthesis
rate of cholesterol absorption
CYP/Transporter polymorphism
CETP polymorphism
apoE polymorphism

INHIBITION OF CHOLESTEROL SYNTHESIS RESULTS IN A HIGHER
ABSORPTION RATE OF CHOLESTEROL FROM THE INTESTINE*
HEPATIC
BIOSYNTHESIS
INTESTINAL
ABSORPTION
Inhibition of
cholesterol synthesis
(simvastatin 10-80 mg)
Food
STATINS
30-50% absorption
synthesis
absorption
Cholesterol
excreted in the
faeces
LDL-C
31-46%
* Measured as the ratio of serum levels of cholesterol absorption marker (sitosterol) and total cholesterol.
Assmann G, et al. J Am Coll Cardiol 2004;43(5, Suppl. 2):A445-A446; Goldberg AC, et al. Mayo Clin Proc. 2004 May;79(5):620-9.

Atorvastatin 20mg and 80mg Reduced Cholesterol
Production and Increased Cholesterol Absorption
% Change
80
60
40
20
Atorvastatin 20mg
+48%
P

Exogenous
Endogenous
Cholesterol Absorption Inhibition for Broader Lipid Control
VLDL
IDL
LDL
Statins
synthesis
BILIARY SECRETION
Absorption
DIETARY
CHOLESTEROL
INTESTINE
ABC
SGLT2
Excretion
Cholesterol
Absorption
Inhibition

Cholesterol Management:
Absorption as a Target
• Cholesterol absorption inhibitors
– Target the exogenous pathway
– Have a mechanism of action complementary to that
of statins
– Have lipid-lowering efficacy additive to that of statins
– Help achieve broader lipid control
– Provide an important new approach to decrease
the risk of CHD
Adapted from Miettinen TA Int J Clin Pract 2001;55:710-716; Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2-E5.

CAI
THE INHIBITION OF CHOLESTEROL ABSORPTION
RESULTS IN INCREASED CHOLESTEROL BIOSYNTHESIS
HEPATIC
BIOSYNTHESIS
INTESTINAL
ABSORPTION
Inhibition of cholesterol
absorption
(ezetimibe)
Food
absorption
synthesis
30-50% absorption
Cholesterol
excreted in the
faeces
LDL-C
20%
CAI = cholesterol absorption inhibitor
Assmann G, et al. J Am Coll Cardiol 2004;43(5, Suppl. 2):A445-A446; Goldberg AC, et al. Mayo Clin Proc. 2004 May;79(5):620-9.

MEAN LDL-C LOWERING 2,3
CHANGE OF SYNTHESIS
Inhibition of
absorption
Ezetimibe alone
Inhibition of
synthesis
Statin alone
Dual Inhibition
Ezetimibe/Statin
AND ABSORPTION MARKERS 1
synthesis
absorption
synthesis
absorption
synthesis absorption
10%
20%
30%
40%
50%
LDL-C LDL-C LDL-C
20%
30-45%
STATIN
+
EZETIMIBE
As high as
60%
1. Assmann G, et al. J Am Coll Cardiol 2004;43(5, Suppl. 2):A445-A446; 2. Goldberg AC, et al. Mayo Clin Proc. 2004 May;79(5):620-9.;
3. Davidson M et al. J Am Coll Cardiol 2002; 40:2125-34.

Switching to Combination vs. Statin Titration
5–6% 5–6% 5–6%
Statin at starting dose 1st 2nd 3rd
3-STEP
TITRATION
Doubling
15–18%
Statin at starting dose
+ GI-acting
drug
1-STEP
COADMINISTRATION
% Reduction in LDL-C
Bays HE et al. Expert Opin Pharmacother 2003;4:779-790.

Am J Cardiol 2011;108:523–530
August 2011

EfficACy and SafeTy of Ezetimibe Added on to Rosuvastatin
Vs. Up-Titration of Rosuvastatin (ACTE Study)
• 440 hypercholesterolemic
men & women
• 18-79 years
Stratum I
Rosuva 5mg
N= 197
R
Rosuva 5mg + EZ 10mg
N= 99
Rosuva 10mg
N= 98
• Moderately high risk*/
High risk with** or
without*** AVD
• LDL-C above NCEP ATP
III recommended targets
AVD= Atherosclerotic vascular Disease
NCEP= National Cholesterol Education
Program
R
Stratum II
Rosuva 10mg
N= 243
R
Rosuva 10mg + EZ 10mg
N= 122
Rosuva 20mg
N= 121
ATP III = Adult Treatment Panel III
4-5 wks run-in period 6 wks
* Subjects with ≥2 risk factors conferring a 10-year risk of CHD of 10% to 20%, as estimated from the Framingham risk scores.
** Subjects with established CHD or patients with CHD risk equivalents and other AVD [peripheral arterial disease, atherosclerotic aortic disease, or carotid artery disease]
*** subjects with CHD risk equivalents such as diabetes mellitus or ≥2 risk factors conferring a 10-year risk of CHD > 20%, as estimated from the Framingham risk scores
Adapted from Harold E. Bays et al. Am J Cardiol 2011;108:523–530

EfficACy and SafeTy of Ezetimibe Added on to Rosuvastatin
Vs. Up-Titration of Rosuvastatin (ACTE Study)
Adapted from Harold E. Bays et al. Am J Cardiol 2011;108:523–530

EfficACy and SafeTy of Ezetimibe Added on to Rosuvastatin
Vs. Up-Titration of Rosuvastatin (ACTE Study)
Adapted from Harold E. Bays et al. Am J Cardiol 2011;108:523–530

J Clin Pharmacol 2009;49:838-847

The Vytorin on CIMT and Overall
Arterial Rigidity (VYCTOR) Study
90 high-risk
coronary
patients
Adapted from Alejandra Meaney et al. J Clin Pharmacol 2009;49:838-847

The Vytorin on CIMT and Overall
Arterial Rigidity (VYCTOR) Study
• Simvastatin + Ezetimibe resulted in 25% reduction in IMT
• This study is one of the first providing evidence that dual therapy has a
beneficial effect on a surrogate marker of atherosclerosis.
Adapted from Alejandra Meaney et al. J Clin Pharmacol 2009;49:838-847

A Recent Meta-analysis
May
2011
27 Trials
21,794
Patients
First &
Second
Line
4-24
Weeks

LDL-C Lowering
0
-10
-20
First Line
(n= 12,157)
Second Line
(n= 9,105)
With DM Without DM With DM Without DM
-9 -8
-30
-40
-50
-60
-38 -37
-48
-52
-31
-27
-70
Eze/ Statin
Statin
Adapted from Guyton et al. Diabetes and Vascular Disease Research 2011; 8(2): 160–172

LDL-C Goal Achievement
100
90
80
70
60
50
40
30
20
10
0
Eze/ Statin Statin
80
70
60
39
39
19
27
9

What is New about
Simvastatin/
Ezetimibe
Combination ?

SHARP: Rationale
• Risk of vascular events is high among
patients with chronic kidney disease
• Lack of clear association between
cholesterol level and vascular disease risk in
CKD
• Pattern of vascular disease is atypical, with a
large proportion being non-atherosclerotic
• Previous trials of LDL-lowering therapy in
chronic kidney disease are inconclusive

SHARP: 9,438 Patients
18 Countries
380 Centers
Canada
USA
11
Countries*
Thailand
Malaysia
China
Newzeland
Australia
* Austria, Finland, Sweden, Norway,
Denmark, Netherlands, Poland, France,
UK, Germany & Czech Republic.

Study of Heart And Renal Protection (SHARP)
• Enrolled approximately 9000 patients with chronic kidney
disease
– 6000 predialysis patients
– 3000 patients undergoing dialysis
• Patients with chronic kidney disease [creatinine 130 mol/l
(1.5 mg/dl) in women or 150 mol/l (1.7 mg/dl) in men, or
receiving dialysis]
– Age 40 yr
– No history of MI or coronary revascularization
– Statin not considered to be indicated
Adapted from SHARP Collaborative Group, Am Heart J 2010;160:785-794.

SHARP: Randomization Structure
Arm 1
Placebo
(4000 patients)
Placebo
500 patients
Placebo
Placebo
Arm 3
Simva 20mg
(1000 patients)
1 year
500 patients
EZE/Simva 10/20
Arm 2
EZE/Simva 10/20
(4000 patients)
EZE/Simva 10/20
6 weeks run-in
3+ years
Screening
Randomization
1 year
Study end
9,478 Subjects
Randomized
Adapted from SHARP Collaborative Group, Am Heart J 2010;160:785-794.

Proportion suffering event (%)
SHARP: Major Atherosclerotic Events
25
20
15
Risk ratio 0.83 (0.74 – 0.94)
Logrank 2P=0.0022
Placebo
Eze/simv
10
5
0
0 1 2 3 4 5
Years of follow-up

SHARP: Safety
Myopathy
Eze/simv
(n=4650)
Placebo
(n=4620)
CK >10 x but ≤40 x ULN 17 (0.4%) 16 (0.3%)
CK >40 x ULN 4 (0.1%) 5 (0.1%)
Hepatitis 21 (0.5%) 18 (0.4%)
Persistently elevated ALT/AST >3x ULN 30 (0.6%) 26 (0.6%)
Complications of gallstones 85 (1.8%) 76 (1.6%)
Other hospitalization for gallstones 21 (0.5%) 30 (0.6%)
Pancreatitis without gallstones 12 (0.3%) 17 (0.4%)

Proportion suffering event (%)
SHARP: Cancer incidence
25
20
15
10
Risk ratio 0.99 (0.87 – 1.13)
Logrank 2P=0.89
Eze/simv
Placebo
5
0
0 1 2 3 4 5
Years of follow-up

SHARP: Conclusions
• No increase in risk of myopathy, liver and biliary disorders,
cancer, or nonvascular mortality
• No substantial effect on kidney disease progression
• Two-thirds compliance with eze/simv reduced the risk of
major atherosclerotic events by 17% (consistent with metaanalysis
of previous statin trials)
• Full compliance would reduce the risk of major
atherosclerotic events by one quarter, avoiding 30–40 events
per 1000 treated for 5 years

First ESC/EAS guidelines for dyslipidemia
- EAS 2011 Gothenburg, Sweden
ESC/EAS
2011
Guidelines
Bile acid sequestrants or nicotinic acid, or a cholesterol absorportion inhibitor,
either alone or in combination with bile acid sequestrants or nicotinic acid,
can be considered in patients who do not tolerate statins.
Statin combination therapy with either a cholesterol absorption
inhibitor, bile acid sequestrant or nicotinic acid may be considered if
the target level is not reached.
Chronic kidney disease (CKD) is regarded as a coronary artery
disease equivalent with LDL cholesterol as the primary target for
treatment. Statins are the first line treatment and also have protective effects
on the rate of kidney function loss and on proteinuria. Patients with
moderate to severe CKD should be considered as very high risk and
clinicians should therefore aim to achieve a LDL cholesterol target of

Conclusion
• Recent major clinical trials have shown the benefits of lower LDL-C
goals for high-risk patients
• Recent ESC/ EAS guidelines recommend LDL-C goal of 70 mg/dl for
very high risk patients (documented CVD, diabetes with organ
damage and CKD)
• To reach LDL-C goals, mentioned by guidelines, intensive therapy
should be considered
• Statin therapy is an integral part in management of high risk patients
“Lower is better”
• High dose statin therapy is not practical and has its limitations.

Overall Conclusion
• A beneficial approach by selectively blocking cholesterol absorption, provides
Dual Inhibition of the two sources of cholesterol
• Statin/ Ezetimibe combination is a unique tool in the management of
dyslipidemia that offers the advantage of intensive lowering and the safety of
low dose statin monotherapy.
• Therefore Statin/ Ezetimibe combination is recommended for;
Dyslipidemic patients uncontrolled on regular dose of statin monotherapy
Dyslipidemic patients very high risk patients for whom goal of 70 mg/dl is
recommended
Dyslipidemic patients with high baseline LDL-C (need more than 50% LDL-
C reduction)