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

-0.08

-0.06

-0.04

-0.02

0

0.02

0.04

0.06

0.08

0.1

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.

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.


Study Disposition: DAPC study


Results (1): Change in max IMT


Results (2): Change in mean IMT


Results (3): Changes of Lipid Profiles


Result (4): Clinical Outcomes


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.


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

effect of cilostazol on primary and secondary prevention

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