The importance of lipid lowering through liver and intestine:

An overview of all relevant data for atherosclerosis

Prof. Alberto CorsiniUniversity of Milan

Italy

Factors affecting the response to statins

poor compliancebackground diet

dose and uptitration of drugconcomitant drug therapy

Extrinsic factors(extraneous influences)

Intrinsic factors(genetically-determined)

LDL-receptor gene mutationsapo-B-100 gene mutations

CYP/transporter polymorphism apoE polymorphism

rate of cholesterol biosynthesisrate of cholesterol absorption

Data from prescribing information for atorvastatin, lovastatin, simvastatin. This does not represent data from a comparative study.

Risk:Benefit Ratio of Statin TitrationRisk:Benefit Ratio of Statin Titration

Atorvastatin Lovastatin20 mg 40 mg 80 mg

20 mg 40 mg 80 mg

Simvastatin

40 mg 80 mg

40 mg 80 mg

1.7

x

2.3

x

% D

ecre

ase

in L

DL-

C

10 mg 20 mg 40 mg 80 mg

-60

-50

-40

-30

-20

-10

0

10 mg 20 mg 40 mg 80 mg0.0

0.5

1.0

1.5

2.0

2.5

Ele

vate

d T

rans

amin

ases

(% o

f P

atie

nts) 4

x

Muscular symptoms were reported in 10% of statin treated patients and led to discontinuation in 30% of the symptomatic patients

Nutrition, Metabolism & Cardiovascular Diseases 1-5, 2012 in press

Preiss D et al

Individual responses of lipids and the plasma sterols among the statin treatment groups

Van Himbergen TM et al. J Lip Res 54:730-9; 2009

Lathosterol and campesterol changes in relation to changes in total cholesterol and LDL cholesterol during statin treatment

Van Himbergen TM et al. J Lip Res 54:730-9; 2009

Correlation of the synthesis and absorption markers with reductions in cholesterol and LDL-C

Descamps OS et al. Atherosclerosis 217 (2011) 308– 321

Dietary cholesterol

Cholesterol

DARM

Excretion

Dual Inhibition: Ezetimibe and Statin

Synthesis of Cholesterol

Bile

Intestine

StatinStatin

LDL-CLDL-C

absorption

EzetimibeEzetimibe

LDL-C LDL-C LDL-C

20%

30-45%

STATIN

+As high as

60%

10%

20%

30%

40%

50%

ME

AN

LD

L-C

LO

WE

RIN

G2,

3

synthesis absorptionsynthesis

absorptionsynthesis

absorption

As high as 60% LDL-C lowering via dual inhibition

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.

CH

AN

GE

OF

SY

NT

HE

SIS

A

ND

AB

SO

RP

TIO

N M

AR

KE

RS

1

Inhibition of absorption

Dual inhibition Statin + EZETIMIBE

Inhibition of synthesis

EZETIMIBE

0

20

40

60

80

100

120

140

LovaCo-admin

PravaCo-admin

SimvaCo-admin

AtorvaCo-admin

Add-OnStudy

Statin alone

Statin + EZE

LD

L-C

(m

g/d

L)

at s

tud

y e

ndConsistency of Co-Administration Studies

21% 19%

23% 23%

21%

Lipka L, et al. J Am Coll Cardiol (Suppl). 2002.Melani L, et al. J Am Coll Cardiol (Suppl). 2002.

Davidson M, et al. J Am Coll Cardiol (Suppl). 2002. Ballantyne C, et al. J Am Coll Cardiol (Suppl). 2002.

Bays H, et al. J Am Coll Cardiol (Suppl). 2002.

Ezetimibe lowers LDL-C an added 19%-23% compared with statin alone

Eze + Rosuva vs Rosuva Uptitration (the ACTE Study)

Study Design

- 6 - 5 - 1 0 6 Week

Rosuva 5 mg + Eze 10 mg

Rosuvastatin 10 mg

Ran

dom

izat

ion

Rosuvastatin 5 mg

(n=99)

(n=122)

LDL-C not at goal *

Screening

Run-in

Rosuva 10 mg + Eze 10 mgRosuvastatin 10 mg

Rosuvastatin 20 mg

(n=98)

(n=121)

* LDL-C target < 100 mg/dL for moderately high or high risk subjects without atherosclerotic vascular disease (AVD), < 70 mg/dl for high risk subjects with AVD

Stratum I

Stratum II

Bays et al. Am J Cardiol 2011; 108: 523-30

Rosuva 5 mg and 10 mg + Ezetimibe vsRosuva 10 mg and 20 mg (Pooled data)

% change from baseline

*

*

* p < 0.001

% c

hang

e fr

om b

asel

ine

*

Bays et al. Am J Cardiol 2011; 108: 523-30

Attainement of pre-specified LDL-C targets after 6 weeks of therapy

LDL-C < 100 mg/dL – Patients w/o AVD

**

* p < 0.001

% p

atie

nts

atta

inin

g sp

ecifi

ed L

DL-

C ta

rget

*

Across Strata Stratum I Stratum II

LDL-C < 70 mg/dL – Patients w/ AVD

n=219 n=217 n=98 n=96 n=121 n=121

Bays et al. Am J Cardiol 2011; 108: 523-30

-23,7-22,3 -21,7

-20,3

-16,3 -15,9

-41,1

-37,2 -36,7-33,9

-29,4-27,8

-45

-30

-15

0

Statin alone Eze/Statin

Pooled-analysis of 27 clinical trials comparing the efficacy of Eze/Statin vs Statin therapies in patients with and without diabetes

LDL-C Non-HDL-C ApoB/ApoA1with

diabeteswithout diabetes

with diabetes

without diabetes

with diabetes

without diabetes

% c

hang

e fr

om b

asel

ine

Leiter et al. Diab Obes Metab 2011; 13: 615-28Leiter et al. Diab Obes Metab 2011; 13: 615-28

-17.4%

-14.9% -15.0% -13.6%

-13.0% -11.9%

p < 0.0001

p = 0.0015

p = 0.0297

= difference vs statin alone = difference vs statin alone

n 3043 3394 7012 7831 3044 3397 7013 7832 2342 2467 4461 5238n 3043 3394 7012 7831 3044 3397 7013 7832 2342 2467 4461 5238

Ezetimibe alone and in combination lowersthe concentration of small, dense low-density lipoproteins in type 2 diabetes mellitus

% C

hang

e

p=0.043

p=0.029 p=0.02

p=0.007

p=0.003

p=0.002

p value versus baseline

Winkler et al. Atherosclerosis 2012; 220: 189-93 Winkler et al. Atherosclerosis 2012; 220: 189-93

6-week treatment effect of Eze 10 mg, Simva 20 mg and Combination on concentrations of sd LDL (41 patients)

6-week treatment effect of Eze 10 mg, Simva 20 mg and Combination on concentrations of sd LDL (41 patients)

Effect of Atorvastatin 20 mg and Atorvastatin/Ezetimibe 5/5 mg on Fasting and PP Triglycerides in Combined Hyperlipidemia

Randomized, open-label study, 8 weeks of treatment; 60 patients with LDL-C > 130 mg/dL and TG 150-499 mg/dL

* PP TG=post-prandial TG (2h after an oral fat load test)

% c

hang

e fr

om b

asel

ine

Lee et al. J Cardiol Pharmacol Ther 2012; 17: 65-71

p=0.07

p=0.03

p=0.12

p=0.04

p=0.09

The non alcoholic fatty liver disease (NAFLD)

• After an initial phase characterized by liver fat deposition, it may

evolve to steatohepatitis, cyrrhosis and hepatocarcinoma, without

abuse of alcohol.

• In the world the incidence is 25-30% in adults but it is rapidly

growing also in children.

• Possible causes: obesity, metabolic syndrome, type II diabetes,

nutritional imbalance, drug abuse and toxic exposure.

The sine qua non of fatty liver disease: hepatic triglyceride accumulation due to imbalance between TG acquisition and removal

J C Cohen et al. Science 2011;332:1519-1523

Proposed mechanisms for NPC1L1 deficiency or ezetimibe treatment to prevent NAFLD

Jia et al. Annu Rev Physiol 2011; 73: 239-59

Ezetimibe

Effects of low-dose simvastatin and ezetimibe compared to high-dose simvastatin on endothelial function

Effects of low-dose simvastatin and ezetimibe compared to high-dose simvastatin on endothelial function

39 patients with type 2 diabetes or IGT and stable CAD

Randomized to Simva 80 mg or Eze/Simva 10/10 mg for 6 weeks

Key results

Same increases in FMD and decreases in CRP in both groups

ConclusionCholesterol lowering is more important than pleiotropic effects of statins for improvement in endothelial function and inflammatory markers.

Settergren et al. Eur Heart J 2008; 29: 1753-60 Settergren et al. Eur Heart J 2008; 29: 1753-60

After Oral Fat Load

Baseline values

Randomized double-blind crossover trial in 19 male obese patients with MS treated with high-dose simva 80 mg vs low-dose simva 10 mg + eze 10 mg

Olijhoek JK et al. J Cardiovasc Pharmacol 2008; 52: 145-50 Olijhoek JK et al. J Cardiovasc Pharmacol 2008; 52: 145-50

0

2

4

6

8

10

% F

MD

Simva 80mg Simva 10 + Eze 10mg

NSp = 0.001 Baseline Simva 80

Simva 10 + EZ 10

LDL-C 143±27 81±19 81±19

TG 143±26 111±49 127±49

HDL-C 44±10 44±12 43±10

(mg/dL)

Low dose Simvastatin and Eze preserved post-fat load endothelial function in male MS patients

231 patients attending a Stroke Prevention Clinic (Ontario, Canada),(mainly patients unable to take high doses of statins)

Effect of Ezetimibe on carotid plaque burden

Bogiatzi et al. Stroke 2012; 43: 1153-5 Bogiatzi et al. Stroke 2012; 43: 1153-5

Carotid total plaque area measured for 2 years before and 2 years after initiation of therapy.

Effect of Ezetimibe on carotid plaque burden

Bogiatzi et al. Stroke 2012; 43: 1153-5 Bogiatzi et al. Stroke 2012; 43: 1153-5

p < 0.01

Journal of Cardiology 158 (2012) 400–404

CAD patients (n=83, 63±9 years, 57% men) receiving S20, were randomly allocated to receive E10/S20 or S80, for 6 weeks Lipids, inflammatory markers (C-reactive protein, interleukin-6, monocyte chemoattractant protein-1, soluble CD40 ligand and oxidized LDL), and platelet aggregation (platelet functionanalyzer [PFA]-100) changes were determined

Percentual changes of LDL-C and inflammatory markers between randomized treatment groups

Journal of Cardiology 158 (2012) 400–404

Take home messages

Optimal LDL-C lowering and therapeutical targets can be achieved by inhibiting cholesterol absorption and production with ezetimibe/simvastatin The SHARP trial establish the clinical benefits of

eze/simv consistently with meta-analysis of statin trials

Beyond its LDL-lowering effects, other potential benefits of ezetimibe have been recently described:

improvement of post-prandial hyperlipidemia improvement of liver steatosis positive effect on endothelial dysfunction antiatherosclerotic benefits