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Is There a DES That Works Better for Diabetics?
by Aloke Finn, MD
DISCLOSURES
Aloke Finn, MD
Sponsored Research Grant From Boston
Scientific
Diabetes Mellitus: A Growing Epidemic
 Diabetes Mellitus affects over 100 million people
worldwide
 Over the next 20 years there will be a 42% increase in the
number of people with diabetes
 By 2050 almost 10% of the US population will have diabetes
with the largest percentage increase among those 75 years
or older
 Vascular disease remains by far the leading cause of
mortality in patients with diabetes accounting 80% of deaths
in type 2 diabetics
 Ischemic heart disease accounts for the majority of these deaths
JAMA. 2001; 286: 1195-2000.
Diabetes and Drug Eluting Stents
• Given the increased risk of restenosis seen in
this population, DES have become the standard
of care for patients with symptomatic CAD and
DM
• Little is know about the vascular responses to
DES in this population
• It remains unknown which DES is superior in
terms of intimal suppression and
endothelialization in patients with diabetes
Clinical Decision Making:
• Choosing sirolimus or paclitaxel DES is currently
based upon clinical restenosis rates yet these
agents are very different in terms of their effects
on the arterial wall and on intracellular signaling
cascades
• Both devices cause a delay in endothelialization
and this is the major pathologic substrate
underlying late stent thrombosis
• A better understanding of the mechanisms of
action by which each agent prevents restenosis
is necessary to fully realize the benefits of this
technology
– Appropriate patient selection
– Design of future anti-restenotic therapies
Mechanism of Action Sirolimus
Endothelial Cell
PI3K
PI3K
Growth factors (VEGF, Insulin)
mTOR
migration
proliferation
Sirolimus
mTORC1
mTORC2
S6K
Akt
Migration, proliferation, survival
Angiogenesis and Endothelial Regrowth
Sirolimus (SRL) inhibits the mTOR (mammalian target of rapamycin), which plays an
important role in connecting extracellular signals with intracellular pathways critical for
arterial repair. As a result the potential exists for interaction between diabetic agents
which share convergent molecular signaling with mTOR pathways and sirolimus. This
may have adverse effects on endothelial regrowth given both Akt and S6K are involved
in endothelial cell recovery
Mechanism of Action of Paclitaxel
Paclitaxel binds to
microtubles to
prevent mitosis
Prophase
Anaphase
Metaphase
X
Telophase
Inhibits smooth muscle cell proliferation
Inhibits neointimal hyperplasia
G2
M
Prevents restenosis
Cell
Cycle
S
G2
Endothelial regrowth is also inhibited
M
G1
The mechanism of action of paclitaxel (Ptx) involves binding to the β subunit of the tubulin
heterodimer, promoting tubulin polymerization, cell cycle arrest, and, eventually, inhibition
of cell migration and proliferation. Although tubulin cycling is critical for cell division, it is
independent of transmission of extra-/intracellular signaling. Thus, in contrast to the effects
of SRL on the diverse actions of the mTOR pathway, the action of Ptx may make it
independent of these signaling mechanisms
Limus versus Ptx: Differential Effects Do
Occur in Patients with DM:
Data From SPIRIT IV
7
P<0.001
P=ns
6
TLF (%)
5
P interaction=0.02
The effects of PES
and SES are
significantly different
in DM versus no DM
4
3
2
1
0
EES
PES
No DM
Stone GW TCT 2009.
EES
PES
DM
•
•
•
•
•
PPAR
Is a ligand-inducible nuclear transcription factor expressed in SMCs and
endothelial cells
PPAR agonists are commonly prescribed to type 2 diabetics—
Rosiglitazone (Avandia) and Pioglitazone (Actos)--have remarkable effects
on insulin sensitivity, and some studies suggest they enhance
endothelialization after arterial injury. Moreover, these agents are well
known to have effects on the coronary vascular wall in doses normally
given to humans
These agents have been reported to have effects on regulators of
translational control (S6K)—thus the possibility for convergent signaling
with mTOR exists
mTOR itself has also been reported to be involved in control of PPAR
mediated gene transcription though this has not been well explored
The potential for drug interaction between PPAR agonists and sirolimus
exists and its effect of endothelial regrowth remains unknown
Hypothesis
• To test our hypothesis that convergence of molecular
signaling between oral anti-diabetic medications such as the
TZD PPAR agonists and locally eluted SRL can result in
significant effects on vascular healing, we examined the effect
of the oral PPAR agent rosiglitazone (RSG) in combination with
sirolimus-eluting (SES), Ptx-eluting (PES), or bare-metal (BMS)
stents on endothelialization in the rabbit iliac model and
explored the molecular mechanisms underlying the results
Study Protocol
SRL stent (3.0 x 18)
Placebo
Paclitaxel stent(3.0 x 16)
Bare Metal stent (3.0 x 18) 28 day stent
SRL (3.0 x 18)
Rosiglitazone
(3mg/kg/day)
Paclitaxel stent (3.0 x 16)
Bare Metal stent (3.0 x 18)
endothelialization
or 14 day organ
culture/western
blot
Bare Metal Stent
Placebo
*p=0.01 vs. CypherPlacebo
+RSG
Sirolimus-Eluting
Stent
Placebo
+RSG
Paclitaxel-Eluting
Stent
Placebo
+RSG
Group
Endothelial Strut
Coverage (%)
Uncovered Strut Area
(mm2)
Cypher-Placebo
42.50±16.33
4.43±0.80
Cypher-Rosiglitazone
18.57±5.89*
5.69±0.27*
Bare Metal-Placebo
87.70±19.29
1.25±1.91
Bare Metal-Rosiglitazone
90.85±15.40
1.03±1.76
Taxus-Placebo
87.37±8.16
1.64±1.13
Taxus-Rosiglitazone
80.53±24.5
2.42±3.11
Finn AV et al.
Circ Research.
2009.
14 Day Organ Culture for VEGF
A.
B.
2
P=0.05
Relative VEGF levels (% of control ( placebo))
Relative VEGF levels (% of control ( placebo))
1.2
1
0.8
0.6
0.4
0.2
0
SES-Placebo
SES-RSG
P=0.007
1.5
1
0.5
0
BMS-Placebo
Group
Group
2.5
Relative VEGF levels (% of control ( placebo))
C.
2
BMS-RSG
D.
P=0.05
1.5
1
0.5
0
PES-Placebo
PES-RSG
Group
Group Ratio
Comparisons
Abs.
dif.
95% CI
P value
BMS vs. SES
0.84
0.41,1.58
0.003
PES vs. SES
0.99
0.43,1.55
0.008
BMS vs. PES
0.15
-0.40,0.71
0.55
8
Fold increase in VEGF Transcript
Fold increase in VEGF Transcript
A.
P=0.002
P=0.0002
B.
6
P=0.0001
4
P=0.01
2
0
0 0.001 0.01 0.1
1
10
25
50
75 100
3
2
1
DMSO
(N= 4 experiments/group)
D.
P=0.002
7
Fold increase in VEGF Transcript
Fold increase in VEGF Transcript
C.
6
5
4
3
2
1
0
DMSO
Ptx
RSG
(N= 4 experiments/group)
SRL
RSG
SRL/RSG
(N= 4 experiments/group)
P=0.001
8
P=0.0007
4
0
Rosiglitazone Concentration (uM)
p<0.0001
5
Ptx/RSG
8
7
P=0.02
P=0.02
6
5
4
3
2
1
0
Scr siRNA
DMSO
Scr siRNA PPAR siRNA
RSG
DMSO
(N= 4 experiments/group)
PPAR siRNA
RSG
P=0.001
1.5
P=0.001
1
0.5
0
DMSO
SRL
RSG
4
3
P=0.006
2.5
2
P<0.0001
1.5
1
0.5
Scr shRNA
RSG
DMSO
(N= 4 experiments/group)
D
Input (negative primer)
Input (positive primer)
IP-PPARγ (negative primer)
Relative gene transcript
DMSO RSG SRL SRL+RSG
14
10
*
VEGF
HO-1
8
6
4
2
10
*
*,#
!
8
*
VEGF
HO-1
6
*,!
4
2
*.#
** *,#
0
0
(N= 3 experiments/group)
mTORshRNA mTOR shRNA
DMSO
RSG
(N= 4 experiments/group)
12
IP-PPARγ (positive primer)
P=0.02
0 Scr shRNA
SRL+RSG
C
P=0.0
4
3.5
Relative gene transcript
2
B
P=0.002
P=0.01
Relative HO-1 gene transcript
Relative HO-1 gene transcript
A
Scr siRNA p70 siRNA Scr siRNA p70 siRNA
DMSO
DMSO
RSG
RSG
N= 4 experiments/ group
*p<0.05 versus Scr siRNA DMSO
and siRNA p70s6k DMSO
#p<0.05 versus p70 siRNA RSG
!p=0.09 versus Scr siRNA DMSO
Scr siRNA Akt2 siRNA Scr siRNA Akt2 siRNA
DMSO
DMSO
RSG
RSG
N= 4 experiments/ group
*p<0.05 versus Scr siRNA DMSO
and siRNA p70s6k DMSO
#p<0.05 versus Scr siRNA RSG
!p<0.05 versus Akt2 siRNA DMSO
And Akt2 siRNA RSG
**p<0.05 versus Scr siRNA DMSO
VEGF Receptor
PI 3 kinase
Endothelial Cell
mTORC2
Sirolimus
PDK-1
Akt
mTORC1
Rosiglitazone
4EPB1
p70S6K
? Downstream
mediator
eIF4E
Translation
S6
DNA
Cell
Growth
HIF-1α
VEGF transcription
PPAR-mediated
transcription
Nucleus
VEGF/HO-1
Conclusions
• mTOR signaling is best known for its role in translational
regulation via two downstream effectors, S6K1 and 4E-BP1
• In this study we reveal that mTOR also interacts with PPARγ
likely through control of transcriptional regulation
• This interaction has important consequences for patients
receiving sirolimus (and its analogues?) DES who are also
taking oral PPAR agents (rosiglitazone and pioglitazone) in
that it results in further delay of vascular healing of the
vessel wall
• Do other commonly used diabetic agents also share
convergence with sirolimus/mTOR (i.e. insulin,
metformin)and how does this affect healing?
Clinical Data
 Numerous studies have shown diabetes to be an independent predictor of





late stent thrombosis after DES (Iacovou JAMA 2005, Daemen J Lancet 2007)
Meta-analysis of 4 pivotal randomized trials with sirolimus stent (SES) has
shown significantly increased cardiac death, Q wave MI, and late stent
thrombosis in patients w/ DM treated with SES versus BMS but with
significantly reduced TLR (Caixeta A et al. JACC 2009.)
Meta-analysis of 5 randomized trials of paclitaxel eluting stents (PES)
demonstrated significantly reduced TLR with no differences in death, MI or
stent thrombosis in DM patients treated with PES versus BMS (Kirtane AJ et
al. JACC 2008)
Paucity of data exists on the vascular responses to stents in diabetic models
despite the routine use of these devices in patients with DM
Long term data from diabetic only randomized trials are lacking
Indeed use of DES in patients with DM is considered “off-label”
Conclusion
• Mechanisms of action of different DES may have
important clinical consequences in patients with
DM
• Considerable overlap exists between mTOR
signaling and many meds used to treat DM but
the effect of these interacts remains unknown
• Diabetic patients talking TZD in combination with
SES may be at risk for delayed stent healing
• Further work needs to be done in both clinical
and basic realms to improve outcomes in patients
with diabetes after PCI
Sirolimus (500 nM)
Rosiglitazone (100 uM)
-
+
-
+
p-Akt
B
+
+
p-Akt
Akt
p-p70s6k
p70s6k
1.5
+
+
+
+
-
+
+
D
p-p70s6k
p70s6k
p-Akt
0
-
HIF-1α
p-p70s6k
p-Akt
β-Actin
(N= 4 arteries/group)
SRL/RSG
+
F
DMSO SRL
2
0.8
1.5
0.6
1
0.4
0.5
0.2
0
2
SRL/RSG
P=0.04
P=0.03
1
RSG
p-p70s6k
1.2
2.5
Relative Phosphorylation
+
RSG
0 DMSO
DMSO
RSG
RSG
Scr siRNA PPAR siRNA Scr siRNA PPAR siRNA
Bare Metal Stent Sirolimus Stent
-
SRL
p-Akt
3
(N=4 experiments/group)
RSG
P=0.002
0.5
Akt
E
P=0.002
DMSO
Relative Phosphorylation
C
+
+
-
P=0.0002
1.2
P<0.0001
P=0.004
1
P=0.04
0.8
0.6
0.4
0.2
0
1
(N=4 experiments/group)
Scr siRNA
PPARγ siRNA
DMSO
RSG
p-p70s6k
P=0.001
Relative Phosphorylation
A
.
P=0.02
P=0.01
P=0.01
DMSO
RSG
RSG
DMSO
Scr siRNA PPAR siRNA Scr siRNA PPAR siRNA
p-p70s6k
p-Akt
HIF-1
*
1.5
1
*
*
*
* **
0.5
0
*, #
*,#
*P<0.05 versus BMS
#P<0.05 versus BMS-RSG and SES
BMS
BMS-RSG SES
Group
SES-RSG