CVOT in Diabetes: Implications for SGLT2 Inhibitors?•Fractional Flow Reserve, calculated from...

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

IVUS vh

1 year later

Angina

Onset of CV event can be sudden

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

HYPERTENSION

Macrovascular eventsACS

Heart failure

Stroke

PVDx

Microvascular events

#1 Blindness

Kidney

Neuropathy

All

important

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

1.

2.

3.

4.

LAD

FFR 0.85

Metformin for diabetes HbA1c 8.9 in lab

• 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)

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

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

Just returned to ER with chest pain….cath 6 months ago

1.

2.

3.

4.

DAPT

trial

DOI: 10.1161/CIRCULATIONAHA.115.016783

MAYBE

ASA

AntiP

DOI: 10.1161/CIRCULATIONAHA.115.016783

Diabetes

N=Diabetes 8257/11648

DOI: 10.1161/CIRCULATIONAHA.115.016783

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

Short look at incretins

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

?

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

Cardiovascular endpoint trials in diabetes

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

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

Overview-DPPIV inhibitor trials

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

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)

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

Cardiovascular endpoint trials in diabetes

CV death

Heart failure

All cause

mortality

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

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

•

•

•

• SODIUM LOSS

•

•

•

•

•

•

31

Diabetes Care 2009; 32: 650–657

Diabetes 2011; 60 (Suppl 1): A582–A643

Kidney Int Suppl 2011: S20–S27

Results-EMPA REG

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

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

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

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%

Immediate benefit

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

DOI: 10.1056/NEJMoa1504720

EASD 2015

BP difference 4/2 mm Hg

Measure of arterial stiffness

ADA 2015 Chilton et al

SGLT2 inhibitor significantly improves arterial stiffness in diabetes

Possible hemodynamic mechanisms

•

•

•

•

•

Increased stiffness: increased atherosclerosis the

reflected wave arrives at the heart closer to systole,

placing a greater load on the heart-increased work

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

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

“This is about as normal as an adult

aorta in America get”

Abdominal aorta

↑ CV risk factors + diabetes

Precath patient with diabetes

40% of individuals with PAD have no leg

pain

Heart Disease and Stroke Statistics 2015

Update AHA

Closing comments

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

↑↑↑ pulse wave velocity

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

Global risk reduction best choice

Heart needs a diet

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 ?

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