New Approaches to LDL Reduction Cholesterol Absorption Inhibitors.

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New Approaches to LDL Reduction Cholesterol Absorption Inhibitors

Transcript of New Approaches to LDL Reduction Cholesterol Absorption Inhibitors.

New Approaches to LDL Reduction

Cholesterol Absorption Inhibitors

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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

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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)

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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

mo

l/10

0gr/

day

)

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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)

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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.

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Cholesterol Absorption Inhibitors Lower LDL-C and that is Enough in Itself

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ENHANCE

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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

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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

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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

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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 (%)

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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)

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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

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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

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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

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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

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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

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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

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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?

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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

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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.