Why could patients with HF and T2DM benefit from SGLT2i?€¦ · *p

Why could patients with

HF and T2DM benefit from

SGLT2i?

Subodh Verma, MD

Ontario, Canada

May 25, 2019 - Athens, Greece

Verma 2019

AHA 2019

Verma S and McMurray JJV. Circulation 2019

DE/EMP/01531

Rationale for exploring SGLT2i in the Rx of HF

There is mechanistic rationale to investigate the

CV outcomes of SGLT2 inhibitors beyond T2D

Patients with HF

have similar

pathophysiological features

as patients with diabetes1,2

Glucosuria, natriuresis and

metabolic effects of SGLT2

inhibitors are seen in

patients with and without

diabetes3−5

The CV benefits observed

in SGLT2i trials were

largely independent of

glucose levels6

CV, cardiovascular; HF, heart failure; SGLT2, sodium-glucose co-transporter-2; T2D, type 2 diabetes

1. Sena CM et al. BBA Mol Basis Dis 2013;1832:2216; 2. Aroor AR et al. Heart Fail Clin 2012;8:609; 3. Seman L et al. Clin Pharmacol Drug Dev 2013;2:152;

4. Heise T et al. Diabetes Obes Metab 2013;15:613; 5. Al-Jobori H et al. Diabetes 2017;66:199; 6. Fitchett D. ESC-HF 2017; oral presentation

Empagliflozin is not indicated for the treatment of heart failure

EMPA-REG OUTCOMERenal Impairment Did Not Affect CV Benefits

Adapted from Zinman B et al. N Engl J Med. 2015 Nov 26;373(22):2117-28 and Fitchett D et al. Eur Heart J. 2016 May 14;37(19):1526-34.

HHF or CV deathHR (95% CI)

CV death HR (95% CI)

HHFHR (95% CI)

eGFR (MDRD), mL/min/1.73 m2

≥90 (normal)

60 to <90 (mild RI)

30 to <60 (moderate RI)

0,25 0,5 1 2

Favours empagliflozin

Favours placebo

0,25 0,5 1 2 0,25 0,5 1 2


Favours placebo


Favours placebo

100%Secondary Prevention

SGLT2 inhibition and cardiorenal protection

Verma S, McMurray JJV, Cherney D. JAMA Cardiol 2017;2:939

Direct effects

on NHE

Adipokines

EAT

Fibrosis

Potential mechanisms

• Improve ventricular loading conditions– Diuresis

– Natriuresis

– Afterload reduction

• Myocardial energetics and metabolomics

• Direct effects on myocardium

• TGF and reduction in IGH

Natriuresis is seen with SGLT2 inhibitors even in

non-diabetic patients

*p<0.01 versus baseline; †Baseline defined as mean of four 24-hour urine collections. SGLT2, sodium-glucose co-transporter-2

Adapted from: Al-Jobori H et al. Diabetes 2017;66:1999

DiabetesNon-diabetes

Uri

ne

so

diu

m

(me

q/2

4 h

ou

rs)

300

200

100

Day

*

Start of empagliflozin

Baseline† 0 1 12 130

Day

0 1 12 13

*

Start of empagliflozin

Baseline†

47,9

64.4

56.5

78.4

0

10

20

30

40

50

60

70

80

Non-diabetes T2D

Uri

na

ry g

luc

os

e e

xc

reti

on

(g

)

1 2

Glycosuria is also seen in non-diabetic patients

CV, cardiovascular

1. Seman L et al. Clin Pharmacol Drug Dev 2013;2:152; 2. Heise T et al. Diabetes Obes Metab 2013;15:613; 3. Zinman B et al. N Engl J Med 2015;373:2117

Empagliflozin 10 mg

Empagliflozin 25 mg

Glucose excreted within 24 hours after single dose

• In EMPA-REG OUTCOME, the reduction in CV outcomes was consistent between 10 mg and 25 mg doses

of empagliflozin3

• A difference in the magnitude of glucosuria seen between 10 mg and 25 mg doses (and diabetes vs

non-diabetes) may be unlikely to impact the risk of CV outcomes with empagliflozin

Verma S, McMurray J. Diabetologia 2018

SGLT2i reduces IF>BV relative to loop diuretics

14 Verma S, McMurray J. Diabetologia 2018

DE/EMP/01531

What about energetics and ketones?

Verma S et al. JACC BTS 2018DE/EMP/01531

DE/EMP/01531

Can an

increase in

ketones reduce

fibrosis?

Lopaschuk and Verma Cell Metabolism 2016

DE/EMP/01531

SGLT2i and Vascular Function?

19

DE/EMP/01531

What about cardiac remodeling?

Short-term SGLT2 TreatmentLowers LV Mass and Improves Diastolic Function

Cluing in on the EMPA-REG OUTCOME Trial?

Verma S et al. Diabetes Care. 2016.

Pre-EMPA Post-EMPA

LV

ma

ss

in

de

x (

g/m

2)

0

25

50

75

100

125

150

Mean 88.2 g/m2

74.5 g/m2

P=0.01

(SD) (22.0 g/m2) (19.1g/m

2)

Pre-EMPA Post-EMPA

La

tera

l e

' (c

m/s

)

0

2

4

6

8

10

12

Mean 8.5 cm/s 9.7 cm/s

P=0.002

(SD) (1.6 cm/s) (1.2 cm/s)

N = 10 with T2DM and established CVDBaseline Age = 67.6 years Baseline A1C = 7.3%

EMPA-HEART CardioLink-6 TrialA randomized trial of empagliflozin on

left ventricular structure, function and biomarkers in people with type 2 diabetes and coronary heart disease

Subodh Verma, C David Mazer, Andrew T Yan, David H Fitchett, Peter Jüni

Lawrence A Leiter, Deepak L Bhatt, Adrian Quan, Bernard Zinman & Kim A Connelly

University of Toronto, Toronto, ON, Canada

-15,0

-10,0

-5,0

0,0

5,0

10,0

Placebo Empagliflozin

Me

an

ch

an

ge

in

DB

P

fro

m b

ase

line

(m

mH

g)

-25,0

-20,0

-15,0

-10,0

-5,0

0,0

5,0

10,0

15,0


Me

an

ch

an

ge

in

SB

P

fro

m b

ase

line

(m

mH

g)

Empagliflozin TreatmentLowers Ambulatory Blood Pressure (ABPM)

Data are presented as mean (SD) for the intention-to-treat population.

Baseline SBP

(mmHg)138.4 139.3

Systolic Blood Pressure

-0.7

-7.9

Baseline DBP

(mmHg)78.5 79.7

Diastolic Blood Pressure

-0.8-3.1

Adjusted difference (95% CI)

between groups

-6.8 (-11.2, -2.3)

P = 0.003


between groups

-3.2 (-5.8, -0.6)

P = 0.02

Primary OutcomeEmpagliflozin Reduces LVMIa

Data are presented as mean (95% CI) for the intention-to-treat population.a, LV mass with papillary muscle mass indexed to body surface area.

-8,0

-4,0

0,0


Me

an

ch

an

ge

in

LVM

Iafr

om

ba

selin

e

(g/m

2)

Baseline LVMIa

(g/m2)62.2 59.5

-0.01

-2.6

Adjusted difference (95% CI) between groups

-3.35 (-5.9, -0.81)

P = 0.01

LVM regression (g) -0.39 (10.83) -4.71 (15.43)

Sensitivity Analysis (LVM Regression)

LVM indexed to height P=0.03

LVM indexed to height1.7 P=0.02

LVM indexed to height2.7 P=0.01LVM indexed to weight P=0.005

Pre-specified Subgroup Analysis by Baseline LVMI

a, LV mass with papillary muscle mass indexed to body surface area.

Baseline

LVMIaAdjusted Difference Between Groups

(95% CI) PInteraction

≤60 g/m2 -0.46 (-3.44, 2.52)0.007

>60 g/m2 -7.26(-11.4, -3.12)

-12 -8 -4 0 4

Secondary cMRI Outcomes

Data are presented as mean (95% CI) for the per-protocol population.a, indexed to body surface area.

-4,0

-2,0

0,0

2,0


Me

an

ch

an

ge

in L

VESV

Ia

fro

m b

ase

line

(m

L/m

2)

Baseline

LVESVIa

(mL/m2)

32.3 27.1

LVESVIa

-8,0

-6,0

-4,0

-2,0

0,0


Me

an

ch

an

ge

in L

VED

VIa

fro

m b

ase

line

(m

L/m

2)

Baseline

LVEDVIa

(mL/m2)

71.4 63.3

LVEDVIa

-4,0

-2,0

0,0

2,0


Me

an

ch

an

ge

in L

VEF

fro

m b

ase

line

(%

)

Baseline

LVEF

(%)

55.5 58.0

LVEF

0.04

-1.0

-2.1-1.6

-0.1

2.2


between groups

-1.20 (-3.77, 1.37)

P = 0.36


between groups

-1.16 (-4.99, 2.66)

P = 0.55


between groups

2.21 (-0.23, 4.66)

P = 0.07

DE/EMP/01531

Empagliflozin prevents worsening of cardiac function in

experimental models of heart failure without diabetes

EMPA, empagliflozin; LVEF, left ventricular ejection fraction; TAC, transverse aortic constriction

Jason Dyck and Subodh Verma et al. JACC Basic Trans Sci 2017;2:347

Yurista et al. Eur J Heart Fail. 2019 Apr 29. doi: 10.1002/ejhf.1473

Effect of EMPA on cardiac function in non-diabetic rats with LV dysfunction after MI

RESULTS - RT-PCR – Pro-fibrotic markers

Empagliflozin suppresses expression of pro-fibrotic markers

A C T A 2 F N 1 C T G F

0

5 0

1 0 0

1 5 0

%m

RN

A E

xp

re

ss

ion

Re

lati

ve

to

EM

PA

0

M* * *

*p<0.05

n = 5

72 hours

α-SMA FibronectinConnective Tissue

Growth Factor

RESULTS - RT-PCR – Collagen and MMP

Empagliflozin reduces the capacity of ECM turnover

C o l1 A 1 M M P 1 M M P 2

0

5 0

1 0 0

1 5 0

%m

RN

A E

xp

re

ss

ion

Re

lati

ve

to

EM

PA

0

M* * *

*p<0.05

n = 5

72 hoursCollagen

Matrix

Metalloproteinase-1

Matrix

Metalloproteinase-2

Empagliflozin improves diastolic function in experimental HFpEF

Dyck and Verma (unpublished)

-20

-10

0

10

20

30

40

50

0 26 52 78 104

Me

dia

n%

ch

an

ge

fro

mb

ase

line

Time point (weeks)

N-terminal pro-B type natriuretic peptide

Placebo

(n=145)

Canagliflozin

(n=328)

* †

*

-20

-10

0

10

20

30

40

50

0 26 52 78 104

Me

dia

n%

ch

an

ge

fro

mb

ase

line

Time point (weeks)

High-sensitivity troponin I

Placebo

(n=117)

Canagliflozin

(n=247)†

*

†

SGLT2 Inhibition and Cardiac Biomarkers

Adapted from Januzzi JL Jr et al. J Am Coll Cardiol. 2017 Jun 9. pii: S0735-1097(17)37754-9. doi: 10.1016/j.jacc.2017.06.016.

Effects on Adipokines

Garvey et al. Metabolism 2018

Canagliflozin on inflammatory markers

Garvey et al. Metabolism 2018

DE/EMP/01531

SGLT2i counters renal hypoxia as a mechanism of

increased EPO secretion

37 Sano and Goto Circulation 2019

DE/EMP/01531

SGLT2i modulate SNS activity through cardiorenal

signaling

38

Renal Stress/Hypoxia + Afferent renal sympathetic nerves

Central SNS Activation

Heart Failure

DE/EMP/01531

What about cardiorespiratory fitness?

Kumar N, Garg A, Bhatt DL, Verma S. CJPP 2018

40VERMA and McMURRAY, DIABETOLOGIA 2018

DE/EMP/01531

Key take-home messages

SGLT2i exhibit multiple effects on systemic and renal

hemodynamics and cardiac metabolism which may be

beneficial in heart failure.

The mechanistic benefits appear to be independent of A1C

lowering, and in preliminary experimental studies observed in

non-diabetic models of heart failure

In T2D SGLT2i treatment demonstrates cardiac reverse

remodeling (LVMI regression) within 6 months

HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; QOL, quality of life; SGLT2, sodium-glucose co-transporter-2; SOC, standard of care; T2D, type 2 diabetes

Why could patients with HF and T2DM benefit from SGLT2i?€¦ · *p

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