Transcript In patients with type 2 diabetes, are the clinical effects

Master Class Lipid Innovations
Prague, Czech Republic
May 27-28, 2011
Presentation topic
The importance of lipid lowering through
liver and intestine: An overview of all
relevant data for atherosclerosis
Slide lecture prepared and held by:
Dr. Kees Hovingh, MD
Academic Medical Centre,
Amsterdam , The Netherlands
Cholesterol: target?
Br Med J 1992;305:15
LDL lowering
Primary prevention
POSCH-PL
4S-PL
Secondary prevention
% Patients with CHD Event
25
POSCH-Rx
4S-Rx
20
15
CARE-PL
LIPID-PL
TNT-10A
CARE-Rx
WOSCOPS-PL
LIPID-Rx
TNT-80A
WOSCOPS-Rx
HPS-Rx
LRC-PL
ASCOT-PL
LRC-Rx
ASCOT-Rx
AFCAPS-PL
AFCAPS-Rx
10
5
0
50
1.3
70
1.8
90
2.3
110
2.8
130
3.4
150
3.9
4.4
170
4.9
190
5.4
LDL cholesterol
210
(mg/dL)
(mmol/L)
Statins : Corner Stone
 CHD - stable
 High cholesterol
 CHD - stable
4S

Low vs High
TNT, IDEAL, SEARCH

Normal cholesterol
ALLIANCE

Real World
GREACE
 Normal cholesterol MIRACL

Heart Failure
CORONA / GISSI-HF
 PTCA
 CHD – ACS
 Normal cholesterol CARE/LIPID
 CHD – ACS
AVERT
 CHD - CABG
 Normal cholesterol
Post CABG

Low vs High dose

pre PTCA
 High cholesterol
WOSCOPS

 Normal cholesterol
AFCAPS/TEXCAPS
 No CHD
 No CHD + risk factor
 Diabetes
ASCOT/ ALLHAT
CARDS
 SPECIAL GROUPS
 high risk, low chol
 Elderly
ARMYDA- Recapture NAPLES II
 STROKE
 No CHD
 Hypertension
PROVE-IT; A-Z
HPS
PROSPER
 Renal Disease
4D, AURORA
 Asian population
J-LIT, MEGA
Normal cholesterol SPARCL

High CRP
JUPITER

Asian population
J-LIT, MEGA
 IMAGING

FH
ASAP/ ENHANCE

no CHD
METEOR

Stable CHD
REVERSAL, ASTEROID, SANDS

Children
LIPIDS
Statins: Effect on CAD Risk
0
Percent change
-20
HPS1
-27
WOSCOPS2
-31
4S3
-34
ASCOTLLA4
CARDS5*
-36
-37
Reduction
in major coronary
events vs placebo
(%)
-40
Potential for
further risk
reduction
-60
-80
-100
• 1. Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22
• 2. Shepherd J et al. N Engl J Med. 1995;333:1301-1307
• 3. Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389
• 4. Sever PS et al. Lancet. 2003;361:1149-1158
• 5. Colhoun HM et al. Lancet. 2004;364:685-696.
However......
Reduction of LDL-C, %
Statin: “Rule of 6”
6% drop
6% drop
6% drop
Guideline
0
10
20
30
40
50
60
70
80
Statin, mg
In addition:
compliance, adverse effects, misconception (no control of
efficacy)
Knopp RH. N Engl J Med. 1999;341:498–511; Stein EA. Am J Cardiol. 2002;89(suppl):50C–57C.
Cholesterol balance
(µmol/day.100 g body wt) in mice
Liver
VLDL
LDL
Peripheral cells
Forward pathway
LDL
Bile
HDL
4
2
Reverse pathway
5
5
Feces
Diet
10
7
Duodenum
Jejunum
Ileum
Ezetimibe strongly increases TICE
Control
Ezetimibe
bile
TICE
Control
Ezetimibe
Control
Ezetimibe
(re)absorption
Diet
Control
Ezetimibe
Feces
Control
Ezetimibe
Cholesterol fluxes
(mg/day.70 kg body wt) in man
Liver
VLDL
Peripheral cells
LDL
Forward pathway
LDL
Reverse pathway HDL
Bile
700
1000
300
700
Feces
Diet
1000
400
Duodenum
Jejunum
Ileum
Statin
Effect on Cholesterol Absorption and
Production
Statin 10–80 mg
(n=232)
Placebo
(n=62)
Mean change in ratio*
at 12 weeks
30
21
20
10
0.4
3
0
–4
–10
–20
–30
–27
–40
–38
–50
Total cholesterol
Cholesterol production
Cholesterol absorption
*Ratio (sterol:TC)=mean (102 mmol/mol). Sterol=sitosterol (absorption) and lathosterol (production)
Adapted from Assman G et al. Poster presented at the American College of Cardiology, New Orleans, Louisiana, USA,
March 7–10, 2004.
Ezetimibe
Effect on Cholesterol Absorption and
Production
% change
Cholesterol Production
Cholesterol Absorption
113
75
+89%
p < 0.001
38
0
-38
-54%
p < 0.001
-75
Sudhop T et al. Circulation. 2002;106:1943-1948
Ezetimibe/Simvastatin
Dual Action
Peripheral Tissues
Cholesterol
2/3
Bile
Liver
1/3
Food
Inhibition of
cholesterol
absorption
and
production
Blood Vessel
Small Intestine
Lower LDL-C
Adapted from van Heek M, et al. Br J Pharmacol. 2000;129:1748–1754; Shepherd J. Eur Heart J Suppl. 2001;3(suppl E):E2–E5; Bays H.
Expert Opin Investig Drugs. 2002;11:1587–1604.
Ezetimibe + Statin =
Mean change at 12 weeks
Reduced Cholesterol Absorption and
Production
Placebo
(n=62)
30
20
10
0
–10
–20
–30
–40
–50
Statin 10–80 mg
(n=232)
Ezetimibe 10 mg +
statin 10–80 mg
(n=229)
21
0.4
3
–4
–22 –25
–27
–38
Total cholesterol
Cholesterol production
–38
Cholesterol absorption
Sitosterol (absorption) and lathosterol (production)
Assmann G et al. Poster American College of Cardiology
LDL-C–Lowering
Study 2
0
–5
–4%
–10
–15
–20
–25
–30
–27%
Ezetimibe + simvastatin 10–20 mg (n=204)
Placebo + simvastatin 10–20 mg (n=207)
Mean Change From Baseline,a %
Mean Change From Baseline,a %
Study 1
0
–1%
–5
–10
–15
–20
–25
–25%
–30
Ezetimibe + simvastatin 10–20 mg (n=179)
Placebo + simvastatin 10–20 mg (n=186)
Brohet C, et al. Curr Med Res Opin. 2005;21(4):571–578; Farnier M, Volpe M, Massaad R, et al. Int J Cardiol.
2005;102:327–332.
Ezetimibe + Simvastatin
Superior Goal Attainment
Study 1
Study 2
100
Patients at LDL-C Goal %
Patients at LDL-C Goal %
100
80%
80
60
40
20
17%
0
80
74%
60
40
20
17%
0
Ezetimibe + simvastatin 10–20 mg (n=204)
Placebo + simvastatin 10–20 mg (n=207)
Ezetimibe + simvastatin 10–20 mg (n=179
Placebo + simvastatin 10–20 mg (n=186)
Brohet C,. Curr Med Res Opin. 2005;21(4):571–578;
Farnier M, Volpe M, Massaad R, et al. Int J Cardiol. 2005;102:327–332.
Different statin, ... similar result
LS Mean % Change
From Baselinea to Week 6
0
–5
–4%
–10
–15
–20
–25
–30
–35
–31%b
Ezetimibe 10 mg + atorvastatin 10 mg to 20 mg (n=219)
Placebo + atorvastatin 10 mg to 20 mg (n=225)
Adapted from Cruz-Fernández JM, et al. Int J Clin Pract. 2005;59:619–627.
Effects of Rosuvastatin +
Ezetimibe
P=NS
Change From Baseline, %
20
11
Ezetimibe 10 mg +
rosuvastatin 40 mg
Rosuvastatin 40
mg
9
0
–20
25
–40
35
42
P<0.001
51
–60
–80
57
52
P<0.001
65
70
P<0.001
P<0.001
LDL-C
Total
Cholesterol
HDL-C
Non–HDL-C
Triglycerides
CM Ballantyne. Am J Cardiol 2007;99:673– 680
Laboratory Values:
Muscle and Liver
Eze/ Simva
(n=1226)
Ezetimibe
(n=298)
Simva
10 mg to 80
mg
(n=1217)
CK > 10xULN
0.2
0.0
0.3
0.7
ALT >3ULN
1.6
0.0
0.7
0.3
AST >3xULN
0.8
0.3
0.4
0.3
Placebo
(n=307)
ENHANCE
ENHANCE
LDL lowering
IMT No change
Kastelein et al, ENHANCE NEJM 2008;358 ;1431-43
ASAP vs ENHANCE
ASAP
cIMT mm
progression
regressio
n
0.9
5
0.9
0
0.8
5
0.8
0
0.7
5
0.7
0
0.6
5
P <0.05
Simva LDLc 40%
Atorva
LDLc 52%
ENHANCE
Simva LDLc -40%
Simva/Eze LDLc 57%
0
1
years
2
Conclusions
•
Statins: first step
•
Need for additional therapy
•
Cholesterol absorption inhibition + Statin = two hits on
cholesterol metabolism
•
CVD outcome:
SEAS (post-hoc, sec endpoint), SHARP (no
Ezetimibe-only arm); IMPROVE-IT: answer