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CV
disease
17.3
Cancer
7.6
Respiratory4.2 Diabetes
1.3
0
50
100
150
200
250
MI Stroke Heart
failure
97
151
243
per 10,000 person-years
Framingham
5 X increase
In diabetes
Ra
tes
of C
V e
ve
nts
in
Dia
be
tes
pa
tie
nts
Causes of death in Diabetes
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IVUS vh
1 year later
Angina
Onset of CV event can be sudden
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Management
of type 2DM:
2016 state of
the art
Remaining
clinical
challenges
CV endpoints / death
Atrial fibrillation
Diastolic dysfunction
Hypoglycemia/syncope
Microvascular endpoints
Prevention
Eye disease prevention
Diabetes vasculopathy /PVDx
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HYPERTENSION
Macrovascular eventsACS
Heart failure
Stroke
PVDx
Microvascular events
#1 Blindness
Kidney
Neuropathy
All
important
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0
5
10
15
20
Healthy CAD MI CHF Stroke
20
12.610.8
4
7.8
Years of life remaining
Years
Framingham 40 year follow up
N=5070
Eur Heart J 2002; 23: 458–466
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1.
2.
3.
4.
LAD
FFR 0.85
Metformin for diabetes HbA1c 8.9 in lab
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• Fractional Flow Reserve, calculated from
coronary pressure measurement, is an accurate,
invasive, and lesion-specific index to demonstrate
or exclude whether a particular coronary stenosis
can cause reversible ischemia.
• FFR can be determined easily, in the cath-lab,
immediately prior to a planned intervention
DEFER study: background
FFR based strategy for PCI in equivocal stenosis
( DEFER – Study)
Patients scheduled for PCI without Proof
of Ischemia (n=325)
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DEFER
GroupREFERENCE Group PERFORM
Group
Patients scheduled for PCI
without Proof of Ischemia
(n=325)
performance of PTCA (158)
deferral of PTCA
(167)
FFR 0.75
(91)
No PTCA
FFR 0.75
(90)
PTCA
FFR < 0.75
(76)
PTCA
FFR < 0.75
(68)
PTCA
Randomization
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78.8
72.7
64.4
0 1 2 3 4 50
25
50
75
100
Defer
Perform
Reference(FFR < 0.75)
p=0.52
p=0.17
p=0.03
Years of Follow-up
Ev
en
t –
fre
e s
urv
iva
l (%
)
Less CV events in patients deferred with FFR >0.75 (.80)
J Am Coll Cardiol. 2007;49(21):2105-2111
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Just returned to ER with chest pain….cath 6 months ago
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1.
2.
3.
4.
DAPT
trial
DOI: 10.1161/CIRCULATIONAHA.115.016783
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MAYBE
ASA
AntiP
DOI: 10.1161/CIRCULATIONAHA.115.016783
Diabetes
N=Diabetes 8257/11648
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DOI: 10.1161/CIRCULATIONAHA.115.016783
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Conclusions—In patients with DM, continued
thienopyridine beyond 1-year after coronary
stenting is associated with reduced risk of MI, although
this benefit is attenuated when compared
with patients without DM.
Diabetes patient after MI and receives DES………..
DOI: 10.1161/CIRCULATIONAHA.115.016783
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Short look at incretins
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Introduction
SAVOR
EXAMINE
TECOS
Reduction in CV death
Reduction in heart failure
Reduction in all cause mortality
EMPA-REGDPP 4 inhibitors
SGLT2 inhibitors
2-5% per yr
7-8% per yr
4.5% per yr
4.5% per yr
CV event rate
per year
HbA1c
Safe & well tolerated
SDF1
Diastolic stiffness
Platelets
P=NS
?
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0
10
20
30
40
50
60
70
80
90
100
Age Yearly
events
HbA1c HT Hx CVDx
65
2.58
81 78
61
7.58
83
100
65
4.5 7.2
86
63
4.5
8
95
75
SAVOR EXAMINE TECOS EMPA-REG
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Cardiovascular endpoint trials in diabetes
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What is the estimated CV event rate in 1
year for type 2 diabetes patients with ACS
Acute coronary syndrome within 15-90
days, age ≥ 18 post
treatment..EXAMINE
1. <1%
2. 2-3%
3. 7-8%
4. 20% Percent
Months
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Time to first occurrence of:
Cardiovascular-related death
Nonfatal myocardial infarction
Nonfatal stroke
Hospitalization for unstable angina
Primary Composite
Cardiovascular Outcome
Green JB et al. NEJM 2015; DOI: 10.1056/NEJMoa1501352
Type 2 diabetes (A1c ≥6.5% and ≤8.0%)
≥50 years old
Preexisting vascular disease
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Overview-DPPIV inhibitor trials
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SAVOR-16492 EXAMINE-5380 TECOS-14671
Patient type CAD-stable ACS CAD stable
Yearly CV
events2-3% 7-8% 4-5%
Age 65 61 61
HT 81% 83% 75-80%
Statins Large % 90% 80%
ACE blockers 82% 79%
HbA1c 8.0 8.0 7.2
Hx of HF 12.7% 27.8% 18%
Hx of CAD 78% 100% 100%
GFR 30-50cc 13.6 30-60 9.3%
Insulin 40% 30% 23%
Chilton 2015
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0
1
2
3
4
Drug
Placebo
3.5
2.8
3.9
3.33.13.1
3.4
3
% Hospitalization for Heart Failure
SAVOR EXAMINE TECOS ALL 3
Percentage1.14 (0.97-1.34)
NS
NS NSNS
P=NS
All 3
Significant++ Not significant
3-4 years
Chilton 2015
++ (3.5% vs. 2.8%; hazard ratio, 1.27;
95% CI, 1.07 to 1.51; P = 0.007)
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Drugs reducing CV events in diabetes
Aspirin
Statins
? PPAR
Beta blockers & CCB
Thiazide “like” diuretics
RAAS blockers
? Metformin
EMPA-REGHypoglycemic drugs
All have off target side effects
Others drugs in
small studies
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Cardiovascular endpoint trials in diabetes
CV death
Heart failure
All cause
mortality
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0246
8
10
UKPDS 38ADVANCE
EMPA-REG
Blo
od
pre
ssu
re
UKPDS 38 ADVANCE EMPA-REG
SBP reduction 10 5.6 4
CV Benefits of BP Reduction in Type 2 Diabetes
mmHg
32% reduction in diabetes related death
18% reduction in risk of CV death
38% reduction in risk of CV death
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Necrotic core
Thin fibrous cap
Wall stress (BP)Endothelial
cells
(dysfunction
al)
↑ ROS
↑ MCP1
Vascular wall
Stress concentrations form
within the fibrotic cap due to
stiffness of the cap with respect to the normal
vessel wall
Biomechanics of vulnerable vascular wall
↑ Macrophages↑ MMPs
Lipid/necrotic coreYellow
Thin cap
NIRS- lipidsIntravascular Ultrasound
Blood vessel wall
Atherosclerosis
Lumen
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•
•
•
• SODIUM LOSS
•
•
•
•
•
•
31
Diabetes Care 2009; 32: 650–657
Diabetes 2011; 60 (Suppl 1): A582–A643
Kidney Int Suppl 2011: S20–S27
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Results-EMPA REG
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Patients with event/analysed
Empagliflozin Placebo HR (95% CI) p-value
3-point MACE 490/4687 282/2333 0.86(0.74,
0.99)*0.0382
CV death 172/4687 137/2333 0.62(0.49,
0.77)<0.0001
Non-fatal MI 213/4687 121/2333 0.87(0.70,
1.09)0.2189
Non-fatal stroke 150/4687 60/2333 1.24(0.92,
1.67)0.1638
0.25 0.50 1.00 2.00
33
Favours empagliflozin Favours placebo
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101
102
103
104
105
106
107
Ad
just
ed
me
an
(SE)
wa
ist
cir
cu
mfe
ren
ce
(c
m)
Week2259
2272
2273
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
1869
1836
1857
2183
2219
2209
2110
2155
2157
1562
1644
1648
1220
1285
1329
418
475
486
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
28 52 1080 164 22012
34
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0
1
2
3
4
5
6
CV deaths Non fatal
MI
Non fatal
CVA
Hosp HF
5.95.2
2.6
4.13.7
4.5
3.22.7
Placebo Empa
DOI: 10.1056/NEJMoa1504720
EASD 2015
0.62 (0.49–0.77) <0.001
0.87 (0.70–1.09) 0.22
Pe
rce
nta
ge
CV mortality (MI, CVA)drives the primary endpoint
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0
1
2
3
4
5
65.9
1.6
0.5 0.50.1
0.8
2.4
3.7
1.10.3 0.3 0.1 0.2
1.6
DOI: 10.1056/NEJMoa1504720
EASD 2015
0.62 (0.49–0.77) <0.001
Percentage
No significant effect on MI or stroke..
Benefit not atherosclerotic related?
Placebo
Empa
All deaths not attributed to the categories of CV death and not attributed to a non-CV cause were presumed CV deaths
ARR=2.2%
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Immediate benefit
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0
1
2
3
4
5
6
7
8
9
Hosp for HF Hosp for HF/death
4.1
8.5
2.7
5.7
Excluded stroke
0.65 (0.50–0.85)
P<0.002
0.66 (0.55–0.79)
P<0.001
Pe
rce
nta
ge
BP difference 4/2 mm Hg
EmpaControl
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DOI: 10.1056/NEJMoa1504720
EASD 2015
BP difference 4/2 mm Hg
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Measure of arterial stiffness
ADA 2015 Chilton et al
SGLT2 inhibitor significantly improves arterial stiffness in diabetes
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Possible hemodynamic mechanisms
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•
•
•
•
•
Increased stiffness: increased atherosclerosis the
reflected wave arrives at the heart closer to systole,
placing a greater load on the heart-increased work
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CHD and nonfatal MI
ASCOT: Differing effect of statin added to -blocker-based or CCB-based therapy
Sever PS et al. Circulation. 2005;
112(suppl II):II-134. Abstract 730.
Sever PS et al. AHA Scientific Sessions. Nov 2005.
*Atenolol (50–100 mg) ± bendroflumethiazide (1.25–2.5 mg)†Amlodipine (5–10 mg) ± perindopril (4–8 mg)
Events/1000
patient-years
P (interaction between
lipid lowering and BP
lowering) = 0.025
+ Atorvastatin (10 mg)
- Atorvastatin (+ placebo)
01
2
3
4
5
6
7
8
9
10
Atenolol*Amlodipine
7.5
4.6
9 9.8
NS
NS
P < 0.0001
†
P = 0.015
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Examples of peripheral (A) and
corresponding derived central aortic (B) waveforms from patients of equal age treated with atenolol (solid line) or amlodipine (broken line) as monotherapy, achieving equivalent brachial blood pressures.
Peripheral BP
Derived central aortic pressure
Circ March7, 2006;113:000
CAFÉ in ASCOTAffects of Reduced Central Aortic
Pressure
Primary objective: a comparison of the effects of the
2 treatment regimens on central aortic pressures
derived from applanation tonometry
• Conduit Artery Function
Evaluation (CAFÉ) trial
• Sphygmocor
• Substudy of ASCOT BPLA
(n=2199)
• Compared central aortic
pressure
– Amlodipine group
– Atenolol group
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“This is about as normal as an adult
aorta in America get”
Abdominal aorta
↑ CV risk factors + diabetes
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Precath patient with diabetes
40% of individuals with PAD have no leg
pain
Heart Disease and Stroke Statistics 2015
Update AHA
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Closing comments
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J Am Coll Cardiol 2010; 55:1318–1327
Cardiovascular Diabetology 2014, 13:28
↑↑ 1 m/s PWV-- risk increase of 15% for
cardiovascular events and all-cause mortality
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↑↑↑ pulse wave velocity
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Wall stress
Sympathetic
nervous system
Arterial wall stiffness
Circadian rhythm
Metabolic changes
Waist circumference / adipocytes
Glucose
Lipids
Insulin
Leptin
Microvascular
Reactive
oxygen
species /
inflammation
Other
Endothelium
Possible mechanisms involved in CV benefits of SGLT2
Chilton 2015 pending publication
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Global risk reduction best choice
Heart needs a diet
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Cardiovascular treatment of diabetes: REDUCE CV deaths!!
SAVOR
EXAMINE
TECOS
Safe, no hypoglycemia or HF
EMPAgliflozin
Safe and no significant hypoglycemia
Reduces significantly CV death
No CV benefit
CV reduction ?
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DEATH
1. 4S investigator. Lancet 1994; 344: 1383-89,;
2. HOPE investigator N Engl J Med 2000;342:145-53,
Simvastatin1
for 5.4 years
High CV risk 5% diabetes, 26% hypertension
1994 2000 2015
Pre-statin era
High CV risk38% diabetes, 46% hypertension
Ramipril2
for 5 years
Pre-ACEi/ARB era
<29% statin
Empagliflozin for 3 years
T2DM with high CV risk 92% hypertension
>80% ACEi/ARB
>75% statin