Statin/Ezetimbe Combination Therapy: Emerging Evidence

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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)

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