Effect of Cilostazol on Primary and Secondary Prevention ...
Transcript of Effect of Cilostazol on Primary and Secondary Prevention ...
Effect of Cilostazol on Primary and Secondary Prevention of Atherosclerotic Cardiovascular Disease
in Korean Patients with type 2 DM
Department of Endocrinology and Metabolism,
Kyung Hee University School of Medicine
Sang Youl Rhee M.D., Ph.D.
Introduction
Type 2 diabetes is associated with Serious Complications
Diabetic Retinopathy
Leading cause of blindness in adults1,2
Diabetic Nephropathy
Leading cause of end-stage renal disease3,4
Cardiovascular
Disease
Stroke 2- to 4-fold increase in cardiovascular mortality and stroke5
Diabetic Neuropathy
Leading cause of non-traumatic lower extremity amputations7,8
8/10 individuals with diabetes die from CV events6
1UK Prospective Diabetes Study Group. Diabetes Res 1990; 13:1–11. 2Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S102. 3The Hypertension in Diabetes Study Group. J Hypertens 1993; 11:309–317. 4Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–S98. 5Kannel WB, et al. Am Heart J 1990; 120:672–676. 6Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences. 7King’s Fund. Counting the cost. The real impact of non-insulin dependent diabetes. London: British Diabetic Association, 1996. 8Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79.
Significant overlap in “traditional risk factors” among those with or without CHD
Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9.
Framingham Heart Study: 26-year follow-up
LDL cholesterol distribution
320 240 160
LDL-C( mg/dl)
20
0
15
10
5 Fre
qu
en
cy p
er
hu
nd
red
CHD cases
Controls
80
25
120 200 280
Genest J, et al. JACC 19: 792-802, 1992.
Screening for novel CV risk factors & subclinical atherosclerosis
Carotid intima-media thickness (CIMT) as Surrogate markers for CVDs
IVUS IMT
Kim CS et al. Diabetes Res Clin Pract. 2006;72:183-9
An increased IMT was defined as an IMT greater than the mean healthy subject value, +1S.D (≈ 0.82~0.84mm)
Carotid IMT, Plaque & Event
Wuxiang Xie et al.,Heart 2011;97:1326-1331
Behavioral change
• Lausanne, Switzerland
• Randomized trial in smokers
• N=153
• Counseling ± imaging
• Absolute 22.2% quit rate
• NNT 6
Bovet P, et al. Preventive Medicine 34: 215-220, 2002.
Smokers with plaque were 6-fold more likely to quit smoking
Changes in physician management after CIMT screening
J Am Soc Echocardiogr 24: 738-747, 2011. 12
Cilostazol: Clinical evidences
Cilostazol
Antiplatelet, vasodilator properties
Phosphodiesterase-3 inhibitor
Indication
Intermittent claudication: 100 mg bid
PCI: 100 mg bid (+ aspirin or clopidogrel)
Secondary prevention of stroke or TIA
Modified from Okuda Y et al. Cardiovascular Drug Review. 1993;11(4):451-465
Mechanism of Cilostazol : Elevation of cAMP
cAMP AMP ATP
PDE III Adenylate Cyclase
Arachidonic Acid
PGG2
PGH2
Thromboxane A2
Cyclooxygenase
Release Reaction
Ca2+ Ca Ca2+
Thromboxane Synthetase
Receptor
Platelet
ADP Serotonin
Cilostazol
Phospholipids
Phospholipase A2
PGI2 PGE1
Degranulation
TXA2
GP IIb
GP IIIa
: Inhibition
: Activation
: Enzyme
× ×
×
Decrease in carotid intima media thickness after 1 year of
Cilostazol treatment in patients with type 2 diabetes mellitus
【Methods】
【Results】
【Conclusion】
-0.1
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-0.06
-0.04
-0.02
0
0.02
0.04
0.06
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1 2 3 4
placebo
pletaal
* *
*
*** Changes of intima media thickness in common
carotid arteries after 1year of treatment
Avg. IMT Avg. IMT Max. IMT Max. IMT
(*,+ : p < 0.05)
Left CCA Right CCA
Cilostazol can be used effectively and safely
for the control of atherosclerosis as
assessed by IMT in diabetic patients.
Cilostazol Gr.(n=60) : Cilostazol 100 or 200mg/d during 1 year
Placebo Gr. (n=60) : Placebo
Measurement of CCA IMT using ultrasound after 6 and 12 months of treatment
<C.W. Ahn Diabetes Res Clin Pract, 2001 >
Placebo cilostazol
Left Avg. IMT 0.02 -0.02
Max IMT 0.03 -0.01
Right Avg. IMT 0.03 -0.02
Max IMT 0.09 -0.08
* CCA : Common Carotid Artery
Retrospective Evidence for CVD Prevention in T2DM pts
Patient disposition
Rhee SY, et al, DRCP 2012.
Total Macrovascular Disease Events in the Subjects
Rhee SY, et al, DRCP 2012.
Total Macrovascular Disease Events in the Subjects
Rhee SY, et al, DRCP 2012.
Katakami N., Kim YS et al., Circulation 2010.
DAPC, Study of Diabetic Atherosclerosis Prevention by Cilostazol
Patients with type 2 diabetes and arteriosclerosis obliterans
from the Eastern Asian countries were registered online and
randomly assigned either to the aspirin group (81–100
mg/day) or the cilostazol group (100–200 mg/day) in this
international, 2-year, prospective follow-up interventional
study.
Katakami N., Kim YS et al., Circulation 2010.
Study Disposition: DAPC study
Katakami N., Kim YS et al., Circulation 2010.
Results (1): Change in max IMT
Katakami N., Kim YS et al., Circulation 2010.
Results (2): Change in mean IMT
Katakami N., Kim YS et al., Circulation 2010.
Results (3): Changes of Lipid Profiles
Katakami N., Kim YS et al., Circulation 2010.
Result (4): Clinical Outcomes
Katakami N., Kim YS et al., Circulation 2010.
DAPC: Conclusion
Cilostazol potently inhibited progression of carotid IMT, an established surrogate marker of cardiovascular events, in patients with T2DM suspected of having PAD compared with aspirin.
Katakami N., Kim YS et al., Circulation 2010.
Effect of cilostazol on carotid IMT in
diabetic patients without cardiovascular event
Huh JH et al. Endocrine 47: 138-145, 2014.
Result
Changes IMT from baseline to 2 years. Data presented as mean(+SD)
*P values were calculated as interactions of treatment and time by linear mixed model adjusted for age, gender, DM duration, and statin use
Mean IMT Maximum IMT
Huh JH et al. Endocrine 47: 138-145, 2014.
Result
First prospective, multicenter, patient registration in Korean Subjects with type 2 Diabetes Mellitus
Comsist of 12 University Hospitals
CAPPA (Cilostazol versus Aspirin for primary
Prevention of Atherosclerotic Events)
Clinicaltrial.gov, NCT00886574
Cilostazol: Laboratory Evidences
Mechanism by which cilostazol treatment potently inhibited the progression of CIMT
due in part to improvement of lipid profiles
Cilostazol cAMP
LPL activity
5′AMP 5'AMP
LPL activity, LPL release
cAMP PDE III X
TG ↓
HDL-C ↑
Apo A/ Apo B ↑
RLP ↓
LPL activity ↑
LPL release↑
RCT(Reverse
cholesterol transport )↑
A. Control
B. Balloon Injured
C. Cilostazol 10 mg/kg
D. Cilostazol 30 mg/kg
E. Cilostazol 100 mg/kg
Lee IK et al. Hypertension. 2005 Apr;45(4):552-6
Cilostazol inhibited high
glucose-induced VSMC
proliferation.
250
200
150
100
50
0
- + + + +
- - 10 30 100
Intim
al A
rea (
m2)
Balloon Injured
*
## ##
#
Cilostazol (mg/kg)
*p < 0.01 vs control #p < 0.05, ##p < 0.01 vs balloon injured.
Cilostazol inhibits vascular smooth muscle cell growth by downregulation of the transcription factor E2F
A B C D E
- Rat Carotid Artery
Summary and Conclusions
Summary
Surrogate marker for sub-clinical
atherosclerosis
Clinical usefulness of IMT in T2DM subjects
IMT as a behavioral modifier?
Clinical Evidences of cilostazol
Effective in IMT regression
Comparable outcome with aspirin for Korean T2DM subjects
Even in the primary prevention?
Summary
Laboratory based evidences
Improvement of lipid profiles
diminish neo-intimal formation in animal model
ROS↓
cellular senescence↓ - possible age resister?
Conclusion
We can consider cilostazol as a useful
treatment option for treatment and
prevention of cardiovascular complications
in Korean patients with T2DM