1. 8th Platelet Colloquium dddd8th Platelet Colloquium
The Diabetic Patient and
the Optimal Antiplatelet Therapy
Dominick J. Angiolillo, MD, PhD
Director of Cardiovascular Research
Associate Professor of Medicine

2. Dominick J. Angiolillo, MD, PhD
Honoraria/Lectures: Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc.,
Advisory Board: Bristol Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Novartis, Arena Pharmaceuticals, Accumetrics, Medicure, Merck, Evolva
Research Grants: GlaxoSmithKline, Otsuka, Accumetrics, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Schering-Plough, Astra Zeneca, Johnson&Johnson, Bristol Myers Squibb, Sanofi-Aventis

3. Cumulative Incidence of All-Cause Mortality Through 1 Year After ACS
Diabetes Subgroup Analysis
11 TIMI Trials, >62,000 pts
10,613 diabetics (17.1%)
STEMI
UA/STEMI
Diabetes
Diabetes
No Diabetes
No Diabetes 14 12 10
P< STEMI 8
P<0.0001
Mortality, % 6
P< UA/NSTEMI 4 2
P<0.0001
No. at Risk
STEMI
Diabetes
No diabetes
UA/NSTEMI
Diabetes
No diabetes
Days after ACS
Donahoe SM et al. JAMA. 2007;298:

4. Mechanisms Involved in Platelet Dysfunction in Diabetes Mellitus
Hyperglycemia
Deficient Insulin Action
Associated Metabolic Conditions
Other Cellular Abnormalities
Increased P-selectin expression
Impaired response to NO and PGI2
Platelet
Endothelial Dysfunction
Osmotic effect
Obesity
IRS-dependent factors:
Increased intracellular Ca++
Degranulation
Activation of PKC
Dyslipidemia
Decreased membrane fluidity by glycation
of surface proteins
Inflammation
Increased platelet turnover
Increased intracellular Ca++
Upregulation of P2Y12
signaling
Oxidative stress
H2O
Increased P-selectin and GP expression
Increased production of TF
Decreased NO and PGI2 production
Endothelial Cells
ACP=adenosine disphosphate; GP=glycoprotein; IRS-1=insulin receptor substrate-1; NO=nitric oxide; PGI2=prostacyclin; PKC= protein kinase C; TF=tissue factor.
Reprinted with permission from Ferreiro JL, Angiolillo DJ. Circulation :

5. Influence of Diabetes Mellitus on
Clopidogrel-induced Antiplatelet Effects
Acute Phase of Treatment
Long-term Phase of Treatment 80
P=0.002 DM
No-DM
P<0.0001
P=0.04 60 8%
38%
14%
Platelet aggregation (%)
56% 40
78% 6%
24 hrs post 300 mg LD 20
Non-responders (Platelet inhibition <10%)
Low responders (Platelet inhibition 10-29%) DM
No DM DM
No DM
ADP 20M
ADP 6M
Responders (Platelet inhibition >30%)
Angiolillo DJ et al. Diabetes. 2005;54:
Angiolillo DJ et al. J Am Coll Cardiol. 2006;48:

6. Overcoming suboptimal antiplatelet drug response in diabetic patients
Play smarter with what we have
Adding other agents with antiplatelet properties
Use new drugs

7. Overcoming suboptimal antiplatelet drug response in diabetic patients
Play smarter with what we have
Adding other agents with antiplatelet properties
Use new drugs

8. Pathways of oxidative stress associated with diabetes mellitus
Increased Turnover
Tackling the DM platelet:
1) oxidative stress
2) Give aspirin bid
Ferroni P et al. J Thromb Haemost 2004

9. Influence of intensive insulin treatment
Urinary
11-dehydro-TXB2
nmol/day NS
P < 0.01
Before
Tight
Unsuccessful
Metabolic Control
Davì G et al, NEJM 1990; 322:

10. Schematic of circadian release of platelets into bloodstream from bone marrow and impact of a single daily dose of aspirin on newly generated platelets in type 2 DM
Capodanno D et al. Circ Cardiovasc Interv. 2011;4:180-7.

11. Impact of once vs twice daily aspirin dosing on platelet reactivity
LTA –collagen (2mg/mL)
VerifyNow ASA
P = 0.02
P = 0.02
P = 0.006
P = NS
P = 0.046
P = NS
Capodanno D et al. Circ Cardiovasc Interv. 2011;4:180-7.

12. OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus)
Impact of high clopidogrel maintenance dosing on platelet function
in DM patients with suboptimal clopidogrel response
VerifyNow P2Y12 substudy
%IPA
PRU 20 40 60 80
75 mg
150 mg
Platelet inhibition (%)
p=0.009
P2Y12 Reactivity Units 50
100
150
200
250
300
p=0.007
Only ~40% of patients reach therapeutic target!
Angiolillo DJ et al. Circulation. 2007;115:
Angiolillo DJ et al. Am J Cardiol. 2008;101:440-5.

13. Overcoming suboptimal antiplatelet drug response in diabetic patients
Play smarter with what we have
Adding other agents with antiplatelet properties
Use new drugs

14. Upregulation of P2Y12 receptor signaling in type 2 diabetes mellitus
Clopidogrel
ATP
ADP
15% active metabolite
HOOC
* HS N O Cl
OCH3 N S O Cl
CH3 C
P2X1
P2Y1
Gastro-intestinal absorption Gq
G12
“Rho”
Ca2+ flux
PIP2
Shape change
P2Y12
Shape change
PLCβ + Gi
IP3
DAG
Hepatic CYP Biotransformation
PKC αi βγ
Ca2+
mobilization
MLCK-P AC
PI3K
85% inactive metabolites
(Esterases in blood)
GP IIb/IIIa
receptor activation
Granule secretion
PKB/Akt
Rap1b
Cilostazol
GP IIb/IIIa receptor activation
PDE-III
Initiation of Platelet Aggregation
cAMP
Stabilization of Platelet Aggregation
VASP
VASP-P AC Gs
PGE1
cAMP
GP IIb/IIIa receptor activation
Angiolillo DJ et al JACC 2007

15. OPTIMUS-2: p=0.002 p=0.0001 PRU P2Y12 inhibtion
Impact of adjunctive treatment with cilostazol in Diabetes Mellitus patients on aspirin and clopidogrel
VerifyNow P2Y12 assay
PRU
P2Y12 inhibtion
p=0.002
p=0.0001
CILOSTAZOL
PLACEBO
CILOSTAZOL
PLACEBO
Angiolillo DJ et al. Eur Heart Journal 2008; 29:

16. P2Y12 Reactivity Index (PRI)
Impact of adjunctive treatment with cilostazol according to
Diabetes Mellitus status in patients on aspirin and clopidogrel
P2Y12 Reactivity Index (PRI)
* p between  = 0.039
p<0.0001
p<0.0001
 = 23.1*
 = 15.0*
Angiolillo DJ et al. Thromb Haemost May 26;106(2). [Epub ahead of print]

17. Triple versus Dual Antiplatelet Therapy Role for cilostazol in addition to aspirin and clopidogrel?
Stent 30 days (Lee SW et al JACC 2006)
Triple therapy vs dual therapy
9/1597 (0.5%) vs 1/1415 (0.1%) p=0.024
DECLARE-DIABETES: Triple therapy significantly reduced late loss at 6 months after DES implantation and the occurrence of TLR and MACE at 9 months in patients with Diabetes (Lee SW et al JACC 2008)

18. Overcoming suboptimal antiplatelet drug response in diabetic patients
Play smarter with what we have
Adding other agents with antiplatelet properties
Use new drugs

19. Efficacy of New Drugs/Approaches in Reducing Adverse Outcomes in Diabetes Mellitus From Large-Scale Clinical Trials
Study % of Events Hazard Ratio (95% confidence interval)
Standard New Drug/Approach
TRITON-TIMI (0.58 – 0.85)
PLATO (0.76 – 1.03)
CURRENT OASIS (0.66 – 1.15) (PCI Cohort)
0.5 1
1.5
New Drug/Approach Better
Standard Clopidogrel Better
CURRENT-OASIS= Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events Optimal Antiplatelet Strategy for Interventions; PCI=percutaneous intervention; PLATO= A Study of Platelet Inhibition and Patient Outcomes; TRITON-TIMI= Trial To Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction.
Reprinted with permission from Ferreiro JL, Angiolillo DJ. Circulation :

20. Diabetic Subgroup N=3146 Clopidogrel CV Death / MI / Stroke18
Clopidogrel
17.0 16
CV Death / MI / Stroke 14
12.2 12
HR 0.70 P<0.001
Endpoint (%)
Prasugrel 10
NNT = 21 8
Patients with diabetes are of particular interest since they are known to have increased rates of events and more aggregable platelets.
PRASUGREL REDUCED THE RATE OF THE PRIMARY ENDPOINT IN DIABETIC PATIENST FROM
17% with clopidogrel to 12.2% of prasugrel patients.
68 events were prevented.
There was a 30% reduction in the HR with P < 0.001
As shown at the bottom of the slide these striking benefits in a high risk subgroup were achieved with prasugrel with a virtually identical rate of major non CABG bleeding compared with clopidogrel. 6
TIMI Major NonCABG Bleeds 4
Clopidogrel
2.6
2.5 2
Prasugrel 30 60 90
180
270
360
450
Days
Wiviott, Braunwald, Angiolillo et al Circulation 2008 21

21. Wiviott, Braunwald, Angiolillo et al Circulation 2008
CV death/MI/stroke
by diabetic status
Pras
Clop
Reduction in Risk
No DM
9.2%
10.6%
14%
DM No Insluin
11.5%
15.3%
26%
DM on Insulin
14.3%
22.2%
37%
0.3 1 2
Prasugrel Better
Clopidogrel Better
Wiviott, Braunwald, Angiolillo et al Circulation 2008 22

22. Verify Now®-P2Y12 % Inhibition
OPTIMUS-3: Optimizing Antiplatelet Therapy in Diabetes Mellitus
Prasugrel (standard dose) vs Clopidogrel (high dose) in DM patients
Verify Now®-P2Y12 % Inhibition
***p<0.0001
Mean±SE
Similar findings obtained with MPA to 5 and 20 µM ADP, VASP PRI, and Verify Now® PRU
Angiolillo DJ et al. European Heart Journal 2011; 32:

23. Diabetes N=4662 Primary endpoint
16.2%
14.1%
CV death, MI or stroke (%)
10.2%
8.4%
No diabetes
Number at risk
Diabetes Ticagrelor Clopidogrel
No diabetes Ticagrelor Clopidogrel
Days after randomization
James, Angiolillo, Cornel, et al Eur Heart J. 2010;31:

24. HbA1c N=15,050 Primary endpoint
Diabetes
14.2%
HbA1c >6
11.4%
9.0%
HbA1c <6
8.2%
Primary endpoint
Number at risk
HbA1c >6 Ticagrelor Clopidogrel
HbA1c <6 Ticagrelor Clopidogrel
Days after randomization
James, Angiolillo, Cornel, et al Eur Heart J. 2010;31:

25. Need for tailored antithrombotic drug regimens in diabetics?
Platelet Stimuli
Need for tailored antithrombotic drug regimens in diabetics?
Collagen
Shear rate
P2Y12 ADP
Thrombin
Anti-II (gatrans)
Anti X (xabans)
Serotonin
Thrombin
Epinephrine
PAR-1 antagonists
Atopaxar
Vorapaxar AA
COX-1
TxA2
TxA2
TX inhibitors
Ridogrel
NCX-4016
S18886
EV-077
GP IIb/IIIa integrin
Platelet Aggregation

26. ABCs of Treatment of Diabetic Patients and Impact on Thrombosis
A1C (blood glucose): <7% B
Blood pressure: <130/80 mm Hg
Platelet Reactivity C
Cholesterol-LDL: <70 mg/dl

27. Conclusions
Platelets from patients with diabetes mellitus are dysfunctional:
increased platelet reactivity
reduced responsiveness to antiplatelet agents
Increased platelet reactivity and reduced responsiveness to standard dual antiplatelet treatment regimens (aspirin plus clopidogrel) are associated with atherothrombotic risk.
Control of “ABC” ameliorates platelet function profiles.
Abnormalities intrinsic to the diabetic platelet suggest the need for specific (“tailored”) drug regimens.
The introduction of novel and more potent antiplatelet agents will enable more efficient blockade of the diabetic platelet.