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

Rationale for exploring SGLT2i in the Rx of HF Glucosuria, natriuresis and Patients with HF The CV benefits observed metabolic effects of SGLT2 have similar in SGLT2i trials were inhibitors are seen in pathophysiological features largely independent of patients with and without as patients with diabetes 1,2 glucose levels 6 diabetes 3 − 5 There is mechanistic rationale to investigate the CV outcomes of SGLT2 inhibitors beyond T2D Empagliflozin is not indicated for the treatment of heart failure 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; DE/EMP/01531 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

100% EMPA-REG OUTCOME Secondary Prevention Renal Impairment Did Not Affect CV Benefits HHF or CV death CV death HHF HR (95% CI) HR (95% CI) HR (95% CI) eGFR (MDRD), mL/min/1.73 m 2 ≥90 (normal) 60 to <90 (mild RI) 30 to <60 (moderate RI) 0,25 0,5 1 2 0,25 0,5 1 2 0,25 0,5 1 2 Favours Favours Favours Favours Favours Favours empagliflozin placebo empagliflozin placebo empagliflozin placebo 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.

SGLT2 inhibition and cardiorenal protection Potential mechanisms • Improve ventricular loading conditions – Diuresis Direct effects – Natriuresis on NHE – Afterload reduction Adipokines • Myocardial energetics and metabolomics EAT • Fibrosis Direct effects on myocardium • TGF and reduction in IGH Verma S, McMurray JJV, Cherney D . JAMA Cardiol 2017;2:939

Natriuresis is seen with SGLT2 inhibitors even in non-diabetic patients Non-diabetes Diabetes * 300 * (meq/24 hours) Urine sodium 200 100 0 Baseline † Baseline † 0 1 12 13 0 1 12 13 Day Day Start of empagliflozin Start of empagliflozin * 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

Glycosuria is also seen in non-diabetic patients Glucose excreted within 24 hours after single dose 80 Urinary glucose excretion (g) 78.4 70 60 56.5 50 Empagliflozin 25 mg 40 Empagliflozin 10 mg 64.4 30 47,9 20 10 0 1 2 Non-diabetes T2D • In EMPA-REG OUTCOME, the reduction in CV outcomes was consistent between 10 mg and 25 mg doses of empagliflozin 3 • 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 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

SGLT2i reduces IF>BV relative to loop diuretics Verma S, McMurray J. Diabetologia 2018

Verma S, McMurray J. Diabetologia 2018 14

- 15

What about energetics and ketones? DE/EMP/01531

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

Short-term SGLT2 Treatment Lowers LV Mass and Improves Diastolic Function Cluing in on the EMPA-REG OUTCOME Trial? N = 10 with T2DM and established CVD Baseline Age = 67.6 years Baseline A1C = 7.3% 150 12 125 10 LV mass index (g/m 2 ) 100 8 Lateral e' (cm/s) 6 75 4 50 88.2 g/m 2 74.5 g/m 2 Mean Mean 8.5 cm/s 9.7 cm/s (22.0 g/m 2 ) (19.1g/m 2 ) 2 25 (SD) (SD) (1.6 cm/s) (1.2 cm/s) P=0.002 P=0.01 0 0 Pre-EMPA Post-EMPA Pre-EMPA Post-EMPA Verma S et al. Diabetes Care. 2016.

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

Empagliflozin Treatment Lowers Ambulatory Blood Pressure (ABPM) Systolic Blood Pressure Diastolic Blood Pressure Baseline SBP Baseline DBP 138.4 139.3 78.5 79.7 (mmHg) (mmHg) Placebo Empagliflozin Placebo Empagliflozin 15,0 10,0 from baseline (mmHg) from baseline (mmHg) Mean change in DBP Mean change in SBP 10,0 5,0 5,0 0,0 0,0 -0.7 -0.8 -5,0 -3.1 -5,0 -10,0 -7.9 Adjusted difference (95 % CI) Adjusted difference (95 % CI) -15,0 between groups between groups -10,0 -20,0 -6.8 (-11.2, -2.3) -3.2 (-5.8, -0.6) P = 0.003 P = 0.02 -15,0 -25,0 Data are presented as mean (SD) for the intention-to-treat population.

Primary Outcome Empagliflozin Reduces LVMI a Adjusted difference (95 % CI) between groups Baseline LVMI a 62.2 59.5 -3.35 (-5.9, -0.81) (g/m 2 ) P = 0.01 Placebo Empagliflozin 0,0 LVMI a from baseline -0.01 Mean change in -2.6 (g/m 2 ) -4,0 -8,0 LVM regression (g) -0.39 (10.83) -4.71 (15.43) 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.

Sensitivity Analysis (LVM Regression) LVM indexed to height P=0.03 LVM indexed to height 1.7 P=0.02 LVM indexed to height 2.7 P=0.01 LVM indexed to weight P=0.005

Pre-specified Subgroup Analysis by Baseline LVMI Baseline Adjusted Difference Between Groups P Interaction (95% CI) LVMI a ≤60 g/m 2 -0.46 (-3.44, 2.52) 0.007 >60 g/m 2 -7.26(-11.4, -3.12) -12 -8 -4 0 4 a , LV mass with papillary muscle mass indexed to body surface area.

Secondary cMRI Outcomes LVEF LVESVI a LVEDVI a Baseline Baseline Baseline Adjusted difference (95 % CI) Adjusted difference (95 % CI) Adjusted difference (95 % CI) LVESVI a 32.3 27.1 LVEDVI a 71.4 63.3 LVEF 55.5 58.0 between groups between groups between groups (mL/m 2 ) (mL/m 2 ) (%) 2.21 (-0.23, 4.66) -1.20 (-3.77, 1.37) -1.16 (-4.99, 2.66) P = 0.07 P = 0.55 P = 0.36 Placebo Empagliflozin Placebo Empagliflozin Placebo Empagliflozin 0,0 2,0 2,0 2.2 Mean change in LVEDVI a Mean change in LVESVI a from baseline (mL/m 2 ) from baseline (mL/m 2 ) Mean change in LVEF 0.04 -1.6 -2,0 from baseline (%) -2.1 0,0 0,0 -0.1 -4,0 -1.0 -2,0 -2,0 -6,0 -4,0 -8,0 -4,0 Data are presented as mean (95% CI) for the per-protocol population. a , indexed to body surface area.

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 DE/EMP/01531

Effect of EMPA on cardiac function in non-diabetic rats with LV dysfunction after MI Yurista et al. Eur J Heart Fail. 2019 Apr 29. doi: 10.1002/ejhf.1473

RESULTS - RT-PCR – Pro-fibrotic markers Empagliflozin suppresses expression of pro-fibrotic markers R e la tiv e to E M P A 0  M 1 5 0 % m R N A E x p re s sio n * * * 1 0 0 5 0 0 A C T A 2 F N 1 C T G F *p<0.05 Connective Tissue α -SMA Fibronectin n = 5 Growth Factor 72 hours

RESULTS - RT-PCR – Collagen and MMP Empagliflozin reduces the capacity of ECM turnover R e la tiv e to E M P A 0  M 1 5 0 % m R N A E x p re s sio n * * * 1 0 0 5 0 0 C o l1 A 1 M M P 1 M M P 2 *p<0.05 Matrix Matrix n = 5 Collagen Metalloproteinase-1 Metalloproteinase-2 72 hours

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

SGLT2 Inhibition and Cardiac Biomarkers N-terminal pro-B type natriuretic peptide High-sensitivity troponin I 50 50 Median % change from baseline Median % change from baseline 40 40 Placebo (n=145) 30 30 20 20 * Canagliflozin Placebo (n=328) (n=117) 10 10 0 0 0 26 52 78 104 0 26 52 78 104 † † * Canagliflozin -10 -10 † (n=247) * -20 -20 Time point (weeks) Time point (weeks) 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

SGLT2i counters renal hypoxia as a mechanism of increased EPO secretion Sano and Goto Circulation 2019 37 DE/EMP/01531

SGLT2i modulate SNS activity through cardiorenal signaling Renal Stress/Hypoxia + Afferent renal sympathetic nerves Central SNS Activation Heart Failure 38 DE/EMP/01531

What about cardiorespiratory fitness? Kumar N, Garg A, Bhatt DL, Verma S. CJPP 2018 DE/EMP/01531

40 VERMA and McMURRAY, DIABETOLOGIA 2018