Role of SGLT2i in cardio-renal protection

1. Glucose-lowering Therapies
Cardio-Renal-Metabolic Approach
Clinical Place of SGLT2-i Agents
Dr. Awadhesh Sharma , DM,FACC,FSCAI
LPS Institute of Cardiology
G.S.V.M. Medical College, Kanpur(UP)

2. A Prototype Indian Patient of T2DM
History Workup
52yr old male, nonsmoker,
K/c/o T2DM (3 yrs); HTN (9 yrs)
Moderately active lifestyle
Weight 76 Kg; BMI 26 Kg/m2
Blood Pressure 130 / 86 mmHg
ABPM: Nocturnal Non-dipping
pattern
Present Drug-Regimen:
O Metformin 1.5g per day
O Telmisartan 40 mg OD
O Amlodipine 10 mg OD
O Atorvastatin 20 mg OD
HbA1c: 8%
FPG: 154 mg/dL; PPG: 238 mg/dL
Serum creatinine: 1.0 mg/dL
eGFRCKD-EPI: 86 mL/min/1.73m2
UACR: 60 mg/gCr
Total-cholesterol: 191 mg/dL LDLc: 96
mg/dL; HDLc: 40 mg/dL; TG: 156
mg/dL
Recent Exercise TMT +veCoronary CT Angiography: (s/o CAD)
50% stenosis of Left-anterior descending artery

3. Clinical Priorities for This Patient
 Achievement of Metabolic Control
 Prevention of Complications
 Ensuring Sustainable Care and Good Quality of Life

4. Empagliflozin or Sitagliptin as Add-on to Metformin
Long-term (90 weeks) HbA1c Reduction
Ferrannini E et al. Diabetes Care. 2013 Dec;36(12):4015-21. Rosenstock J et al. Diabetes Obes Metab. 2013 Dec;15(12):1154-60.

5. For every 1% increase in baseline HbA1c, the corresponding increase in efficacy is:
• Empagliflozin 25mg: -0.49%
• Sitagliptin 100mg: -0.29%
Glycemia Control at Various Baseline HbA1c Levels
Patient-level Analysis of Evidence from RCT
Adapted: DeFronzo RA et al. Endocrinol Diabetes Metab. 2018 Apr 6;1(2):e00016.

6. Empagliflozin vs. Glimepiride as Add-on to Metformin
89% Lower Risk of Hypoglycemic Events Over 4 years
27.9
3.1
0
5
10
15
20
25
30
Percentageofpatientswithconfirmed
hypoglycemicadverseevents*
Glimepiride (n=780) Empagliflozin (n=765)
Cochran-Mantel-Haenszel test; treated set (patients who received ≥1 dose of study drug).
*Plasma glucose ≤70 mg/dL and/or requiring assistance. RR, risk ratio.
Adjusted RR 0.112
(95% CI 0.074, 0.169)
p<0.0001
Ridderstrale M et al. Diabetes Obes Metab. 2018 Dec;20(12):2768-77. Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA

7. Empagliflozin vs. Glimepiride as Add-on to Metformin
Weight-loss Maintained Over 4 years
MMRM analysis in the FAS using observed cases (excluding values observed after initiation of rescue therapy and
off-treatment values).
-5
-4
-3
-2
-1
0
1
2
3
0 208
Glimepiride 1–4 mg Empagliflozin 25 mg
743
737
610
642
524
590
458
551
331
443
301
420
269
395
248
368
745
739
15678 104 130 18212 28 52
703
706
Glimepiride
Empagliflozin
Difference: -4.9 kg
(95% CI -5.5 to -4.3)
p<0.0001
Week
Adjustedmean(SE)changefrom
baselineinweight(kg)
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA

8. Empagliflozin vs. Glimepiride as Add-on to Metformin
Systolic BP Reduction Maintained Over 4 years
MMRM analysis in the FAS using observed cases (excluding values observed after initiation of rescue therapy and/or after
changes in antihypertensive therapy and off-treatment values). *Number with data at visit; number of patients at 4 and 8
weeks, n=737 and n=705, respectively; †Number with data at visit; number of patients at 4 and 8 weeks, n=732 and n=696,
respectively. SBP, systolic blood pressure.
-6
-5
-4
-3
-2
-1
0
1
2
3
4
0 208
Glimepiride 1–4 mg Empagliflozin 25 mg
490
537
394
475
327
427
224
336
191
314
165
289
146
266
739
735
554
579
438
510
358
446
238
361
207
331
177
302
161
284
612
618
4 15665 78 104 130 18291 117 143 169 19512 4028 528 16
650
649
677
669
Glimepiride*
Empagliflozin†
Difference: -6.2 mmHg
(95% CI -8.5 to -4.0)
p<0.0001
Week
Adjustedmean(SE)changefrom
baselineinSBP(mmHg)
Salsali A et al. American Diabetes Association 76th Scientific Sessions; 10-14 June 2016, New Orleans, Louisiana, USA

9. -6.3
-11.7
-10
-2.5
-4.1
-3.5
-14
-12
-10
-8
-6
-4
-2
0
Nighttime BP Daytime BP 24-hour BP
ChangeinBPfromBaseline
(mmHg)
Systolic BP
129.8 143.0 138.871.0 78.3 75.9Baseline
All values significantly lower from baseline (p <0.05)
Kairo K et al. Circulation. 2019;139:2089-97.
Empagliflozin in Patients of T2DM with
Nocturnal Uncontrolled Hypertension (SACRA Study)

10. Clinical Priorities for This Patient
 Achievement of Metabolic Control
 Prevention of Complications
 Ensuring Sustainable Care and Good Quality of Life

11. Intensive vs Standard Glycemia Control in T2DM
Intensive Control Has Not Demonstrated Consistent Reduction in Mortality
15 *No change in primary microvascular composite but significant decreases in micro/macroalbuminuria2,3
**No change in major clinical microvascular events but significant reduction in ESRD (p = 0.007)5
1. Table adapted from Bergenstal et al. Am J Med 2010;123:374.e9–e18. 2. Genuth et al. Clin Endocrinol Metab 2012;97:41–8.
3. Ismail-Beigi et al. Lancet 2010;376:419–30. 4. Hayward et al. N Engl J Med 2015;372:2197-206 (VADT). 5. Zoungas et al. N Engl J Med 2014;371:1392-406.
Long-term follow-up1,4,5

12. CV Benefits with Known Cardioprotective Therapies
EMPA-REG OUTCOME: First Evidence of Mortality Benefit with Glucose-lowering Therapy
Included trials were undertaken with variety of background therapies and standard of care prevalent at the time of conduct of each trial
NNT: number needed to treat;
Adapted from Bajaj HS et al. Curr
Opin Cardiol. 2017 Sep;32(5):642-50.

13. SGLT2-i Related Mechanisms That May Influence LV Structure and Function
Lan NSR et al. ESC Heart Fail. 2019 Aug 10. doi: 10.1002/ehf2.12505.

14. Mechanisms of Favorable Cardio-Renal Effects with SGLT2-inhibitors
Zelniker TA, Braunwald E. J Am Coll Cardiol. 2020 Feb 4;75(4):422-34.

15. SGLT2 inhibitors Differentially Impact the
Interstitial and Intravascular Fluid Compartments
Image copyrights belong to Oomen G 2018
CHF, congestive heart failure; SGLT2, sodium-glucose co-transporter-2
1. Verma S & McMurray J. Diabetologia 2018:61;2108; 2. Hallow KM et al. Diabetes Obes Metab 2018:20;479
• Interstitial oedema is common in HF1
O SGLT2-i more selectively reduce interstitial volume
(classic diuretics reduce intravascular and
interstitial volumes)1
• Effects of larger reductions in interstitial volume:1,2
– Relieve signs / symptoms of interstitial congestion
– Relieve increased cardiac filling pressures
– Avoid rebound effects of blood volume depletion,
including neurohormonal activation
Interstitial Edema in CHF
SGLT2 inhibitors
Na+ Interstitial
volume
Intravascular
volume
Loop diuretics
Na+ Interstitial
volume
Intravascular
volume

16. Adapted: Uthman L et al. Front. Physiol. 9:1575. doi: 10.3389/fphys.2018.01575
Uthman L et al. Cardiovasc Res. 2019 Aug 1;115(10):1533-45.
Direct Myocardial Actions of SGLT2-i:
IHD and HF Pathogenesis in DM
Cardiac Effects of SGLT2-i agents
SGLT2-i agents directly bind to Sodium-
Hydrogen Exchanger-1 (NHE-1) on
myocardial cells
Inhibition of NHE-1 reduces intracellular
Na+ and Ca+ levels. This helps in:
 Correcting cytoplasmic Ca+ levels
during diastole and systole
 Improves mitochondrial function
These effects may plausibly facilitate:
 Improved cardiac functioning in HF
 Delay myocardial damage in stable
ischaemic conditions

17. Striepe K et al. Circulation. 2017 Sep 19;136(12):1167-1169.

18. Empagliflozin Improved
Central Aortic SBP,
and Arterial Stiffness
In Patients of T2DM
Striepe K et al. Circulation. 2017 Sep 19;136(12):1167-1169.

19. Verma S et al. Circulation. 2019 Aug 22. doi: 10.1161/CIRCULATIONAHA.119.042375.
EMPA HEART Study
The First Confirmatory Evidence of
Tangible, Mechanistic Cardiac Benefit
with an SGLT2-i agent,
in Patients of T2DM with Significant CAD

20. EMPA-HEART: Primary Outcome
Empagliflozin Reduced LVMi in Patients of T2DM with
CAD
Data are presented as mean (95% CI) for the intention-to-treat population. Adjusted difference: Adjusted for baseline LVMi values
-8.0
-4.0
0.0
Placebo Empagliflozin
MeanchangeinLVMIa
frombaseline(g/m2)
-0.01
-2.6
Adjusted Mean Reduction in LVMi with Empagliflozin:
-3.4 g/m2 (95% CI -5.9, -0.81; P = 0.01)
In Patients with Higher Baseline LVMi (>60g/m2):
Regression in LVMi was Greater (-7.3 g/m2; Pinteraction = 0.007)
Verma S et al. Circulation. 2019 Aug 22. doi: 10.1161/CIRCULATIONAHA.119.042375.

21. Clinical Implications of EMPA-HEART Study Findings
 First confirmatory evidence of LVMi regression with an SGLT2-i,
in Patients of T2DM with CAD, majorly without HF
 Most study participants (>90%) did not have HF, so the LV
salutary effects represent plausible cardiac benefit in CAD
without HF
 LVMi regression was observed early, within 6 months of therapy
 LVMi regression was not dependent on Preload (volume) or
Afterload (24-hour BP) Reduction, suggestive of effect at LV
myocardiumVerma S et al. Circulation. 2019 Aug 22. doi: 10.1161/CIRCULATIONAHA.119.042375.
Bami et al. P 1500. Presented at ESC Congress 2019 together with WCC; 31 August – 4 September 2019, Paris - France

22. Clinical Priorities for This Patient
 Achievement of Metabolic Control
 Prevention of Complications
 Ensuring Sustainable Care and Good Quality of Life

23. AACE
Algorithm
2020

24. Personalized Management in T2DM
Individualized Care for Patients
Adapted from: Peter PR et al. Curr Diab Rep. 2019 Nov 4;19(11):115.

25. Personalized Management in T2DM
Individualized Care for Patients
Adapted from: Peter PR et al. Curr Diab Rep. 2019 Nov 4;19(11):115.

26. Personalized Management in T2DM
Individualized Care for Patients
Adapted from: Peter PR et al. Curr Diab Rep. 2019 Nov 4;19(11):115.

27. Thank you.
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