PACE Corsini (PPTX 7MB)

Report
The importance of lipid lowering
through liver and intestine:
An overview of all relevant data for
atherosclerosis
Prof. Alberto Corsini
University of Milan
Italy
Factors affecting the
response to statins
Extrinsic factors
(extraneous influences)
poor compliance
background diet
dose and uptitration of drug
concomitant drug therapy
Intrinsic factors
(genetically-determined)
LDL-receptor gene mutations
apo-B-100 gene mutations
rate of cholesterol biosynthesis
rate of cholesterol absorption
CYP/transporter polymorphism
apoE polymorphism
Risk:Benefit Ratio of Statin Titration
% Decrease in LDL-C
Atorvastatin
Lovastatin
10 mg
20 mg
40 mg
80 mg
10 mg
20 mg
40 mg
80 mg
20 mg
40 mg
Simvastatin
80 mg
40 mg
80 mg
0
-10
-20
-30
-40
-50
Elevated Transaminases
(% of Patients)
-60
2.5
2.0
1.5
1.0
0.5
0.0
Data from prescribing information for atorvastatin, lovastatin, simvastatin.
This does not represent data from a comparative study.
20 mg
40 mg
80 mg
40 mg
80 mg
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
Dual Inhibition:
Ezetimibe and Statin
Statin
Synthesis of Cholesterol
LDL-C
Bile
absorption
Cholesterol
Ezetimibe
Intestine
DARM
Dietary
cholesterol
Excretion
As high as 60% LDL-C lowering
via dual inhibition
MEAN LDL-C LOWERING2,3
CHANGE OF SYNTHESIS
AND ABSORPTION MARKERS1
Inhibition of
absorption
absorption
synthesis
10%
LDL-C
Inhibition of synthesis
synthesis
synthesis absorption
absorption
LDL-C
20%
30%
40%
50%
Dual inhibition
Statin + EZETIMIBE
LDL-C
STATIN
20%
30-45%
+
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.
Consistency of
Co-Administration Studies
Ezetimibe lowers LDL-C an added 19%-23% compared with statin alone
LDL-C (mg/dL) at study end
Lova
Co-admin
Prava
Co-admin
Simva
Co-admin
Atorva
Co-admin
Add-On
Study
0
Statin alone
20
Statin + EZE
40
60
80
23%
23%
100
120
140
21%
19%
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.
Eze + Rosuva vs Rosuva Uptitration
(the ACTE Study)
Study Design
LDL-C not at goal *
Stratum I
Rosuva 5 mg + Eze 10 mg
(n=99)
Rosuvastatin 10 mg
(n=98)
Stratum II
Rosuvastatin 10 mg
Randomization
Rosuvastatin 5 mg
-5
(n=121)
Rosuvastatin 20 mg
Run-in
Screening
-6
Rosuva 10 mg + Eze 10 mg (n=122)
-1
0
6
Week
* 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
Bays et al. Am J Cardiol 2011; 108: 523-30
Rosuva 5 mg and 10 mg + Ezetimibe vs
Rosuva 10 mg and 20 mg (Pooled data)
% change from baseline
% change from baseline
*
*
*
* p < 0.001
Bays et al. Am J Cardiol 2011; 108: 523-30
Attainement of pre-specified LDL-C
targets after 6 weeks of therapy
% patients attaining specified LDL-C target
LDL-C < 100 mg/dL – Patients w/o AVD
LDL-C < 70 mg/dL – Patients w/ AVD
* p < 0.001
*
*
*
n=219
n=217
Across Strata
n=98
n=96
Stratum I
n=121
n=121
Stratum II
Bays et al. Am J Cardiol 2011; 108: 523-30
Pooled-analysis of 27 clinical trials
comparing the efficacy of Eze/Statin vs
Statin therapies in patients with and
without diabetes
LDL-C
with
diabetes
% change from baseline
0
n 3043 3394
Non-HDL-C
ApoB/ApoA1
without
diabetes
with
diabetes
without
diabetes
with
diabetes
without
diabetes
7012 7831
3044 3397
7013 7832
2342 2467
4461 5238
-16,3
-15,9
-15
-23,7
-20,3
-21,7
-22,3
-30
-33,9
-37,2
-45
-27,8
-29,4
-41,1
-36,7
 -13.6%
 -14.9%
 -13.0%
 -11.9%
p = 0.0297
 -15.0%
p = 0.0015
 -17.4%
p < 0.0001
 = difference vs statin alone
Statin alone
Eze/Statin
Leiter et al. Diab Obes Metab 2011; 13: 615-28
Ezetimibe alone and in combination lowers
the concentration of small, dense low-density
lipoproteins in type 2 diabetes mellitus
% Change
6-week treatment effect of Eze 10 mg, Simva 20 mg and Combination on
concentrations of sd LDL (41 patients)
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
Effect of Atorvastatin 20 mg and
Atorvastatin/Ezetimibe 5/5 mg on Fasting and
PP Triglycerides in Combined Hyperlipidemia
% change from baseline
Randomized, open-label study, 8 weeks of treatment; 60 patients with
LDL-C > 130 mg/dL and TG 150-499 mg/dL
p=0.09
p=0.07
p=0.03
p=0.04
p=0.12
* PP TG=post-prandial TG (2h after an oral fat load test)
Lee et al. J Cardiol Pharmacol Ther 2012; 17: 65-71
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
Ezetimibe
Jia et al. Annu Rev Physiol 2011; 73: 239-59
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
Conclusion
Cholesterol 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
Low dose Simvastatin and Eze preserved
post-fat load endothelial function in male
MS patients
10
p = 0.001
NS
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
% FMD
8
6
(mg/dL)
4
Baseline values
2
After Oral Fat Load
0
Simva 80mg
Simva 10 + Eze 10mg
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
Effect of Ezetimibe on carotid
plaque burden
 231 patients attending a Stroke Prevention Clinic (Ontario,
Canada),(mainly patients unable to take high doses of
statins)
 Carotid total plaque area measured for 2 years before and
2 years after initiation of therapy.
Bogiatzi et al. Stroke 2012; 43: 1153-5
Effect of Ezetimibe on carotid
plaque burden
p < 0.01
Bogiatzi et al. Stroke 2012; 43: 1153-5
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 function
analyzer [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

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