why could patients with hf and t2dm benefit from sglt2i?€¦ · *p
TRANSCRIPT
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 empagliflozin
Favours placebo
Favours empagliflozin
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
15
-
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
Placebo Empagliflozin
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
Adjusted difference (95% CI)
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
Placebo Empagliflozin
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
Placebo Empagliflozin
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
Placebo Empagliflozin
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
Placebo Empagliflozin
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
Adjusted difference (95% CI)
between groups
-1.20 (-3.77, 1.37)
P = 0.36
Adjusted difference (95% CI)
between groups
-1.16 (-4.99, 2.66)
P = 0.55
Adjusted difference (95% CI)
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