Why could patients with HF and T2DM benefit from SGLT2i? Subodh - - PowerPoint PPT Presentation

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 OUTCOME

Renal 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 death HR (95% CI) CV death HR (95% CI) HHF HR (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

• n 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

Diabetes Non-diabetes

Urine sodium (meq/24 hours)

300 200 100 Day

*

Start of empagliflozin Baseline† 1 12 13 Day 1 12 13

*

Start of empagliflozin Baseline†

47,9 64.4 56.5 78.4

10 20 30 40 50 60 70 80 Non-diabetes T2D Urinary glucose excretion (g)

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
• f 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

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What about energetics and ketones?

Verma S et al. JACC BTS 2018

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Can an increase in ketones reduce fibrosis?

Lopaschuk and Verma Cell Metabolism 2016

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SGLT2i and Vascular Function?

19

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What about cardiac remodeling?

Short-term SGLT2 Treatment Lowers 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 mass index (g/m2)

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/m2) Pre-EMPA Post-EMPA Lateral e' (cm/s)

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 CVD Baseline Age = 67.6 years Baseline A1C = 7.3%

EMPA-HEART CardioLink-6 Trial

A 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

Mean change in DBP from baseline (mmHg)

• 25,0
• 20,0
• 15,0
• 10,0
• 5,0

0,0 5,0 10,0 15,0

Placebo Empagliflozin

Mean change in SBP from baseline (mmHg)

Empagliflozin Treatment Lowers 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 Outcome

Empagliflozin 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

Mean change in LVMIa from baseline (g/m2)

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=0.01 LVM 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 LVMIa Adjusted 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

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 Mean change in LVESVIa from baseline (mL/m2) Baseline LVESVIa (mL/m2) 32.3 27.1

LVESVIa

• 8,0
• 6,0
• 4,0
• 2,0

0,0

Placebo Empagliflozin Mean change in LVEDVIa from baseline (mL/m2) Baseline LVEDVIa (mL/m2) 71.4 63.3

LVEDVIa

• 4,0
• 2,0

0,0 2,0

Placebo Empagliflozin Mean change in LVEF from baseline (%) 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

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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 5 0 1 0 0 1 5 0

% m R N A E x p re s sio n R e la tiv e to E M P A 0 M

* * *

*p<0.05 n = 5 72 hours α-SMA Fibronectin

Connective 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

5 0 1 0 0 1 5 0

% m R N A E x p re s sio n R e la tiv e to E M P A 0 M

* * *

*p<0.05 n = 5 72 hours Collagen

Matrix Metalloproteinase-1 Matrix Metalloproteinase-2

Empagliflozin improves diastolic function in experimental HFpEF Dyck and Verma (unpublished)

• 20
• 10

10 20 30 40 50 26 52 78 104 Median % change from baseline Time point (weeks)

N-terminal pro-B type natriuretic peptide

Placebo (n=145) Canagliflozin (n=328)

*

†

*

• 20
• 10

10 20 30 40 50 26 52 78 104 Median % change from baseline 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

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SGLT2i counters renal hypoxia as a mechanism of increased EPO secretion

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Sano and Goto Circulation 2019

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SGLT2i modulate SNS activity through cardiorenal signaling

38

Renal Stress/Hypoxia + Afferent renal sympathetic nerves Central SNS Activation Heart Failure

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What about cardiorespiratory fitness?

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

40

VERMA and McMURRAY, DIABETOLOGIA 2018

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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