prof. alberto corsini university of milan italy
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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. Intrinsic factors (genetically-determined). LDL-receptor gene mutations - PowerPoint PPT PresentationTRANSCRIPT
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