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New Approaches to LDL Reduction Cholesterol Absorption Inhibitors.
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Transcript of New Approaches to LDL Reduction Cholesterol Absorption Inhibitors.
2
Inhibition of Cholesterol Absorption and Production With Ezetimibe/Simvastatin
Simvastatin
Extrahepatictissues
Dietarycholesterol
Liversynthesis
Excretion
1000 mg/day
Absorption
~300 mg/day–700 mg/day
Intestine
Ezetimibe
Biliary cholesterol~1000 mg/day
3
Peripheral cellsLiver
Diet Feces
Duodenum Jejunum Ileum
Bile
LDL
Forward pathway
VLDL LDL
HDL
Reverse pathway
Cholesterol Balance in Mice (µmol/day.100 g body wt)
7
24
5
10
5
4
Ezetimibe strongly increases TICE
TICE(re)absorption
bile
Diet Feces
Control
+ Ezetimibe
0
2
4
6
8
Ch
ol
inta
ke(µ
mo
l/10
0gr/
day
)
Control Ezetimibe
0
10
20
30
40
50
60
Ab
sorp
tio
n (
%)
Control Ezetimibe
0
20
40
60
80
TIC
E (
µmo
l/10
0g
r/d
ay)
Control Ezetimibe
Control Ezetimibe
0
20
40
60
80
Neu
tral
ste
rols
(µ
mo
l/10
0gr/
day
)
5
Peripheral cellsLiver
Diet Feces
Duodenum Jejunum Ileum
Bile
VLDL LDL
HDL
LDL
Forward pathway
Reverse pathway
400
1000700
700
1000
300
Cholesterol Fluxes in Humans(mg/day.70 kg body wt)
6
Next Steps
• Assessment of direct intestinal cholesterol excretion in vivo in humans.
• Determine the contribution of TICE in low and high absorbers
• Test the effect of pharmacological manipulation in humans.
9
ENHANCE - Logical Next Step After ASAP -
LIPID (pediatric)
Atorvastatin 80 mgVersus
Simvastatin 40 mg
ASAPSimvastatin 80 mg+ Ezetimibe 10 mg
VersusSimvastatin 80 mg
ENHANCE
Timeline
2000 20101995 2005
Pravastatin 20-40 mgVersus
Placebo
Wiegman et al, Efficacy and Safety of Statin Therapy in Children With FH. JAMA 2004; 292(3):331-7 Smilde et al, Atorvastatin versus Simvastatin on Atherosclerotic Progression study. Lancet 2001;357:577-81
10
ENHANCE Study Population
Major inclusion criteria
HeFH:• Genotyping• Diagnostic criteria WHO
Age 30-75 years
Untreated LDL-C levels > 210 mg/dL(5.43 mmol/l)
Patients on lipid-lowering treatment LDL-c after wash –out > 210 mg/dL (5.43 mmol/l)
Major exclusion criteria
High-grade carotid stenosis
History carotid endarterectomy
Carotid stenting
Congestive heart failure III/IV
NO MINIMAL CAROTID IMT ENTRY CRITERIA
Kastelein et al, ENHANCE NEJM 2008;358 ;1431-43
11
ENHANCE Study Design
Simvastatin 80 mg
RANDOMIZATION
0 24
Months
3 6 9 12 15 18 21
Pre-randomization Phase
FH:LDL-c ≥ 210 mg/dL
Screening and Fibrate
Washout
Placebo Lead-In/ Drug Washout
Weeks
-6-10 to -7
Ezetimibe 10 mg-Simvastatin 80 mg
IMT assessment
12
Baseline CharacteristicsSimvastatin Monotherapy Simvastatin plus
Ezetimibe
All randomized patients n=363 n=357 P-value
Age (yr) 45.710.0 46.19.0 0.69
Male sex no. (%) 179(49%) 191 (54%) 0.26
Body-mass index 26.74.4 27.44.6 0.047
History of diabetes 5(1%) 8 (2%) 0.38
Hypertension 51 (14%) 67 (19%) 0.09
Current smoking 104 (29%) 102 (29%) 0.98
History of MI 26 (7%) 14 (4%) 0.06
Prior use of statins 297 (82%) 286 (80%) 0.56
Systolic mm Hg 12415 12515 0.31
Diastolic mm Hg 7810 789 0.41
Kastelein et al, ENHANCE NEJM 2008;358 ;1431-43
13Months
LDL-Cholesterol
SimvaEze-Simva
-40
0 6 12 18 24
-50-60-70
0
-10-20-30
10
Perc
enta
ge c
hang
e fr
om b
asel
ine
P<0.01
-16.5 % incremental reduction
Kastelein et al, ENHANCE NEJM 2008;358 ;1431-43
Baseline (mg/dL)
24 months (mg/dL)
Simva 318 ± 66 193 ± 60
Eze-Simva 319 ± 65 141 ± 53-40%
-56%
Decrease (%)
14
ENHANCEhsCRP
SimvaEze-Simva
Med
ian
perc
ent c
hang
e fr
om B
asel
ine p < 0.01
3 6 12 18 24
Months
10
-10
-20
-30
-40
-50
-60
-70
-80
0
-26 % incremental reduction
Baseline (mg/L)
24 months (mg/L)
Simva 1.7 (0.8-4.1) 1.7(0.8-3.9)
Eze-Simva 1.2(0.6-2.4) 0.9(0.5-1.9)
15
Mean cIMT During 24 Months of TherapyLongitudinal, Repeated Measures Analysis
Mea
n IM
T (m
m)
SimvaEze-Simva
6 12 18 240.60
0.70
0.75
0.80
0.65
Months
P=0.88
Kastelein et al, ENHANCE NEJM 2008;358 ;1431-43
16
Possible Explanations for the Absence of an Incremental Reduction in cIMT
Measurement TechniqueTechnique not accurate enough to reflect changes
in atherosclerotic burden?
The Population At too low a risk to detect changes, which would limit the ability to detect a differential response
The CompoundEzetimibe lacks vascular benefit despite the
observed LDL-c and hsCRP reduction
17
The Trial Design and Population
To have any chance of success using cIMT to demonstrate that one treatment is better than another one of two critical factors must be present – preferably both:
• The ‘control’ group must show significant progression – if not then only significant regression in the ‘test’ group can result in a positive trial
• The population studied must have significant and quantifiable lipid rich intima – if minimal or no significant atherosclerosis is present then only possible change to be assessed is progression
18
Critical Factors for Successful cIMT Trial
regression
progression
regression
progressioncI
MT
mm
years0 1 2
0.80
0.85
0.75
0.90
0.95
0.70
0.65
ASAP - 1997
ASAP
Simva LDLc -40%
Atorva LDLc -52%
Simva/Control progressed; atorva/Test stable/regressed SUCCESS!!
P <0.05
19
Critical Factors for Successful cIMT Trial
regression
progression
regression
progressioncI
MT
mm
years0 1 2
0.80
0.85
0.75
0.90
0.95
0.70
0.65
ASAP - 1997
ENHANCE - 2003ENHANCE
Simva LDLc -40%
Simva/Eze LDLc -57%
ASAP
Simva LDLc -40%
Atorva LDLc -52%
P= ns
20
ASAP and ENHANCEBaseline cIMT in LIPID (Pediatric)
LIPID (pediatric)
0.4 0.8 1.2 1.6 2.0
ENHANCEASAP
Freq
uenc
y
Mean CIMT (mm)
2.4
Baseline mean cIMT
LIPID (pediatric) 0.495±0.050
ASAP 0.92±0.20
ENHANCE 0.70±0.13
21
What About the Trial Indicating Potential Harm from Increased CVD Events?
• Although ENHANCE was a relatively small trial in low risk FH patients was there any evidence from the CVD events that addition of ezetimibe caused harm?
• Can one even pick up such a signal from such small trials as ENHANCE in this FH population?
22
CVD Events – Recent FH cIMT Trials:RADIANCE I (CETPi) and CAPTIVATE (ACATi)
Incidence of CVD events (%) Atorva Atorva + Torcet Statin Statin+ ACATi
(n=454) (n=450) (n=438) (n=443)
CVD death/MI/
Revasc/Stroke 11 (2.4%) 23 (5.1%)` 15 (3.4%) 28 (6.3%)`
RADIANCE I
*Kastelein et al NEJM 2007; 356:1620-30 **Meuwese MC et al JAMA in press
CAPTIVATE
`p<0.05
Thus even small studies (700-900 patients) in FH appear to be able to detect potential CVD harm
`p<0.02
23
Conclusion from ENHANCE
While the results of ENHANCE have been less than optimal for the sponsors of the trial they actually carry very good news for those with FH, and all patients on long term lipid lowering therapy, in that the data would seem to strongly indicate that even moderate, long term LDLc lowering dramatically reduces the atherosclerotic burden, at least in carotid arteries, and virtually halts progression of the underlying disease.