management of ASCVD patients with SGLT-2 Inhibitors.

1. Holistic Approach to ASCVD and HF Risk in T2DM
SGLT2-inhibition in Clinical Practice
Dr Akhil Sharma MD,DM,FSCAI.
Professor (Jr)
Dept. of Cardiology
KGMU Lucknow.

2. 100%
People with T2DM
71%
+ Moderate CAD Risk
50%
+ High Risk for CAD
35%
+ Known CVD
18%
Prior CV Event
or Procedure
Prevalence of CVD Risk in Indian Outpatient Setting of T2DM
FACT India group. Presented at DiabetesIndia Conference. 2020 Feb. DI2020ABS0002.
Secondary analysis of I CaRe for Diabetes database, involving
1,202 people with T2DM across 304 Diabetes OPDs in India.
Risk-stratification for CAD is based on Age, Gender,
Duration of diabetes, Hypertension, Smoking, Total-
HDL cholesterol ratio, Family history of premature
CVD, Neuropathy, and correlated with significant
coronary artery stenosis on CT angiography, as well
as ECG and Albuminuria positivity.

3. Adapted: Mohan V et al. Heart Asia. 2012:69-76.
Type-2 Diabetes Mellitus and Cardiovascular Disease
Arise from the Common Soil

4. 13.1
21.9
29.5
38.1
41.1
3.1
5.4
7.9
11.8
16.0
0
10
20
30
40
50
≤ 5years >5 to 10 years >10 to 15 years >15 to 20 years >20 years
Median
QRISK3
Score
Duration of T2DM
Median QRISK3 Scores in Patients of T2DM and Healthy Adults
Patient of T2DM Healthy Adult
3.7-fold
3.6-fold
3.4-fold
2.7-fold
2.3-fold
 Presence of T2DM confers 2-4 fold increase in CVD risk, regardless of duration of T2DM
 Majority of patients with >5-years of T2DM, have High CVD risk
Ghosal S, et al. IHJ. 2020;72:119-22.
Measure of Asymptomatic
CVD Risk (MARK Survey)
Survey performed in 154
OPDs across India
1,538 patients with T2DM,
without known CVD, were
assessed for CVD risk
CVD risk was measured
using QRISK3 score
“High CVD risk” was defined
as median QRISK3 score >20,
representing >20% risk of
major event in 10-yrs

5. National Health Policy Goal
To Ensure 25% ↓ in Premature Deaths in India, by 20251
15%
28%
0%
10%
20%
30%
40%
50%
1990 2016
CV Deaths in Indian Population2
(as % of Overall Deaths)
1. MOHFW, GOI. National health policy 2017. https://mohfw.gov.in/sites/default/ files/9147562941489753121.pdf (accessed May 18, 2018).
2. India State-Level Disease Burden Initiative CVD Collaborators. Lancet Glob Health. 2018; 6: e1339-51.
CV Death is the leading cause of
premature deaths in Indian adults

6. Patel AP et al. Circulation. 2021;144:410-22.
South-Asian Ancestry Carries Higher Risk for ASCVD and HF
UK Biobank Prospective Cohort Study
5.12
2.95
2.31
1.65
0
2
4
6
8
Coronary Artery Disease Heart Failure
Incidence
Per
1000
Patient-years
Risk of CV Disease in South Asians vs. Europeans
South Asian European
HR 2.30
95% CI 2.10 to 2.53;
P-value <0.001 HR 1.83
95% CI 1.63 to 2.05;
P-value <0.001

7. Patients with T2DM and Atherosclerotic CVD (EMPA-REG OUTCOME)
Empagliflozin Confers Early and Sustained ↓ in Risk of CV Death
1. Zinman B et al. N Engl J Med 2015;373:2117 2. Fitchett D et al. J Am Coll Cardiol 2018;71:364. 3. Kaku K, et al. Circ J. 2017;81(2):227-34.
Overall Study Population
38% Risk-Reduction
Asian Patients
56% Risk-Reduction

8. Empagliflozin Consistently Reduces Risk of CV Death
In Patients with T2DM and CAD, Regardless of Prior MI (EMPA-REG OUTCOME)
5.5%
6.0%
5.7%
7.6%
4.0%
3.3%
3.0%
4.6%
0%
2%
4%
6%
8%
Single-vessel CAD Multi-vessel CAD History of CABG Prior MI
%
of
Patients
with
CV
Death
Category of Baseline CV Disease
Placebo Empagliflozin
All subgroups were consistent with overall effect of 38% risk-reduction for CV death. Zinman B et al. AHA 2016; abstract 16903; Fitchett D et al. J Am Coll Cardiol 2018;71:364
CV Death with Placebo vs. Empagliflozin, in Patients with CAD and T2DM

9. 7.5%
8.0%
11.1%
14.8%
4.5% 4.3%
8.2% 8.5%
0%
4%
8%
12%
16%
Peripheral Arterial
Disease
Prior Stroke Prior HF History of Atrial
Fibrillation
%
of
Patients
with
CV
Death
Type of CV Disease at Baseline
Placebo Empagliflozin
All subgroups were consistent with overall effect of 38% risk-reduction for CV death. Zinman B et al. AHA 2016; abstract 16903; Fitchett D et al. J Am Coll Cardiol 2018;71:364
Empagliflozin Consistently Reduces Risk of CV Death
In Patients with T2DM and PAD, Stroke, HF, or AF (EMPA-REG OUTCOME)

10. Empagliflozin Reduces Risk of First and Recurrent CV Events
In Patients with T2DM and Atherosclerotic CVD (EMPA-REG OUTCOME)
Favours
Empagliflozin
Favours
Placebo
Hazard
Ratio
1
Empagliflozin
(events per
1000 pt-yr)
Placebo
(events per
1000 pt-yr)
Rate
Ratio
Rate Ratio
(95% CI)
Clinical
Effect
P-value
Major Adverse
CV Events (3P-MACE)
44.9 57.6
0.78
(0.67, 0.91)
22%
↓sed risk
<0.05
Myocardial
Infarction
19.6 24.9
0.79
(0.62, 0.99)
21%
↓sed risk
<0.05
MI or Coronary
Revascularization
46.3 58.2
0.80
(0.67, 0.95)
20%
↓sed risk
<0.05
Adapted: McGuire DK et al. Lancet Diabetes Endocrinol 2020; 8: 949-59.
21% ↓ in Risk of Myocardial Infarction events, with Empagliflozin vs Placebo
*This secondary analysis of EMPA-REG OUTCOME study is
based on total events, including first and recurrent events.
Risk-reduction for MI events included consistent effects on
type-1 as well as type-2 MI events.

11. Empagliflozin may Reverse LV Remodeling in Patients with CAD and T2DM
↓ in LV Mass Index, and LV Extracellular Volume Fraction (EMPA-HEART Study)
Verma S et al. Circulation. 2019 Nov 19;140(21):1693-1702.
Mason T et al. JACC Cardiovasc Imaging. 2021 Jan 4;S1936-878X(20)30939-6.
EMPA-HEART Study
RCT in 97 Patients with Stable CAD
and T2DM (93% did not have HF)
Study Duration: 6 months
Assessment done by Cardiac MR
• ↓ in LVMi: -3.4 g/m2 (p <0.05)
• ↓ in LV-ECV: -1.4% (p <0.05)
Regression in LVMi Independent of:
• Systolic BP Reduction
• Volume Reduction

12. SGLT2-inhibition Results in ↑ in Erythropoiesis
and May Improve Anemia in Patients with HF and CKD
Mazer CD et al. Circulation. 2020 Feb 25;141(8):704-7.
Persisted
71% Persisted
50%
Resolved
29% Resolved
50%
0%
20%
40%
60%
80%
100%
Placebo (n = 259) Empagliflozin (n = 271)
Patients with HFrEF, CKD, and Prior Anemia
(% Resolution at Last Value On-Treatment)
2.5-fold ↑
Odds of
Resolution
of Anemia
EMPEROR-REDUCED: ↑ in Hb level at 52-wks (Empa vs Placebo)
• Patients with CKD: 0.67 g/dL (95% CI 0.55 to 0.80)
• Patients without CKD: 0.75 g/dL (95% CI 0.62 to 0.88)
P value for
Interaction: 0.42
EMPA-HEART
↑ in Erythropoiesis with Empagliflozin vs Placebo
Adapted: Zannad F et al. Circulation 2020. 10.1161/CIRCULATIONAHA.120.051685.

13. Proof-of-concept study, in patients admitted with ACS, with T2DM; hemodynamically stable at discharge
Empagliflozin (n = 22) vs No SGLT2-i (n = 22) initiation at discharge; TTE changes monitored at 3-6 months
Lan NSR et al. Int J Cardiovasc Imaging. 2020 Sep. doi: 10.1007/s10554-020-02034-w.

14. Empagliflozin mediated inhibition of Cardiac Na+ H+ Exchanger (NHE-1), as well as of SGLT-2 and NHE-3, had relevant effects for HFpEF
Bayes-Genis A et al. Sci Rep. 2021 Jun 8;11(1):12025.
Evaluation of action of empagliflozin, on pathophysiological alterations in HFpEF
Analysis based on deep-learning with artificial intelligence-based algorithm
Findings also further validated in patients with HFpEF, with empagliflozin use over 12 months
NHE-1 inhibition: Prominent role, by Modulation of Cardiomyocyte Oxidative Stress

15. Empagliflozin Lowers Risk of HF Hospitalizations and Mortality
In Real-World Setting of T2DM, Across CV Risk Subgroups (EMPRISE)
1,10,726 patients with T2DM, initiating Empagliflozin or DPP4-i. Patients with and without CVD (14,920 and 40,443 matched pairs respectively; 1:1 PS matching for >140 covariates)
All values are statistically significant (p<0.05). Patorno E et al. Diabetes 2021 Jun; 70 (Suppl 1): DOI: 10.2337/db21-320-OR.
3.5
1.2
6.3
2.7
0
2
4
6
8
10
Hospitalizations
for Heart Failure
All Cause
Mortality
Events
Per
1000
patient-years
Patients Without CVD
Empagliflozin DPP4-inhibitors
33.8
6.3
46.9
11.9
0
10
20
30
40
50
60
70
Hospitalizations
for Heart Failure
All Cause
Mortality
Events
Per
1000
patient-years
Patients With CVD
Empagliflozin DPP4-inhibitors
HR 0.55
(95% CI 0.42, 0.73)
HR 0.46
(95% CI 0.29, 0.74)
HR 0.71
(95% CI 0.60, 0.84)
HR 0.53
(95% CI 0.37, 0.76)

16. Empagliflozin Consistently Reduces Risk of CV Death In Patients with
ASCVD and T2DM, With / Without Heart-Failure (EMPA-REG OUTCOME)
15.3%
10.4%
0%
4%
8%
12%
16%
20%
CV Death
%
of
Patients
with
Events
Patients With HF Evidence
Placebo Empagliflozin
Hazard Ratio 0.67
(95% CI 0.47 to 0.97)
HF Evidence: Evidence of History of HF OR Reported During Study (as Hospitalization or Adverse event)
All values are statistically significant (p<0.05) Adapted: Fitchett D et al. Eur H J. 2019; 39: 363-70.
4.2%
2.7%
0%
4%
8%
12%
16%
20%
CV Death
%
of
Patients
with
Events
Patients Without HF Evidence
Placebo Empagliflozin
Hazard Ratio 0.63
(95% CI 0.48 to 0.84)
Patients with HF burden
ARR with Empagliflozin: 4.9%
NNT: 19 patients to prevent 1
additional CV death in 3.1 yrs

17. Hospitalisation n=5031 plus mortality n=463 is larger than total events (5399) due to events that required hospitalisation and led to death having been counted only once in the overall analysis.
ACH, all-cause hospitalisation; ACM, all-cause mortality; CI, confidence interval.
By Treating 6 Patients with ASCVD and T2DM Using Empagliflozin,
1 Additional Hospitalization or Death can be Prevented in 3 years (NNT = 5.4)
Inzucchi SE et al. Presented at 56th EASD Annual Meeting (Virtual Meeting AI), 21–25 Sep 2020.

18. In Patient Subgroups with Atherosclerotic CVD and T2DM
SGLT2-i CVOTs Have Demonstrated Improvements in CV Outcomes
43.9
41.3 41 40.3
37.4
34.1
36.8
40
0
10
20
30
40
50
EMPA-REG
OUTCOME
CANVAS
Program
DECLARE
TIMI 58
VERTIS CV
Major Adverse CV Events
Event-rates per 1000 pt-yrs
Placebo SGLT2-i
20.2
16.8
11.6
19
12.4
14.8
10.9
17.6
0
5
10
15
20
25
EMPA-REG
OUTCOME
CANVAS
Program
DECLARE
TIMI 58
VERTIS CV
Cardiovascular Death
Event-rates per 1000 pt-yrs
Placebo SGLT2-i
14.5
11.3
14.1
10.5
9.4
7.3
11.1
7.3
0
5
10
15
20
EMPA-REG
OUTCOME
CANVAS
Program
DECLARE
TIMI 58
VERTIS CV
Hospitalization for HF
Event-rates per 1000 pt-yrs
Placebo SGLT2-i
Comparison of studies should be interpreted with caution due to differences in study design, populations and methodology
Adapted: McGuire DK et al. JAMA Cardiol. doi:10.1001/jamacardio.2020.4511. Published Online, Oct 7 2020.
Represents significant reduction

19. 100
Patients
with CAD
and T2DM,
in 3-years
9.8
CV Events
Prevented
8.5
CKD Events
Prevents
3.4
AKI / ARF /
Hyperkalemia
Events
Prevented
12.9
Insulin
Requirements
Prevented
5.1
Additional
SBP Goals
Achieved in
Resistant
Hypertension
5.5
Oedema /
New OSA
Events
Prevented
3.4
Total
Additional
Life-years
Gained
100 Patients with T2DM and CAD, Treated with Empagliflozin in 3 years
Additional Non-Glycaemic Benefits on Top of Standard of Care (EMPA-REG OUTCOME)
Adapted:
1. Fitchett D et al. Circulation. 2020;142:A14960.
2. Wanner C et al. N Engl J Med 2016;375:323-34.
3. Vaduganathan M et al. Diabetes 2020 Jun; 69(Suppl 1). Doi:10.2337/db20-30-OR.
4. Ferreira JP et al. Am J Hypertens. 2020 Dec;33(12):1092-101.
5. Neeland IJ et al. Diabetes Care. 2020 Dec;43(12):3007-15.
6. Fitchett D et al. Eur Heart J. 2016;37:1526-34.
7. Mengozzi A et al. Trials. 2020 Jun 26;21(1):578.
EMPA-REG OUTCOME study was designed to evaluate CV Outcomes with empagliflozin
Additional effects in this figure, represent the additional statistically significant observations
Insulin requirements represent either new-initiation, or significant (>20%) increase in dose of insulin
Effect of SBP goal achievement in resistant HT, is based on assumption that all 100 participants have resistant uncontrolled hypertension.

20. EMPEROR-Preserved Study
*Randomized, double-blind, placebo-controlled trial. CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate.
Anker S et al. N Engl J Med. 2021 Aug 27. doi: 10.1056/NEJMoa2107038. Anker S. Presented at AHA Scientific Sessions, Nov 2021.
Phase III trial* in patients with HF and LVEF >40%
Aim: To investigate the safety and efficacy of empagliflozin versus placebo in patients with HF and LVEF
>40%, and compare and contrast the results in true HFpEF vs HFmrEF
Population: T2D and non-T2D, aged ≥18 years, chronic HF, and eGFR ≥20 mL/min/1.73m2
Median follow-up 26.2 months
EMPEROR-Preserved
LVEF >40%
5,988 patients
Placebo
Empagliflozin 10 mg OD
CONFIRMATORY KEY SECONDARY ENDPOINTS
• First and recurrent adjudicated HHF
• Slope of change in eGFR (CKD-EPI) from baseline
COMPOSITE PRIMARY ENDPOINT
• Time to first event of adjudicated CV death or
adjudicated HHF
Randomization stratified by
LVEF ≥50% versus 41-49%
Patients with structural heart disease
(LA enlargement or LV hypertrophy)
or HHF within 12 months of screening

21. EMPEROR-Preserved
Summary of Key Results for Confirmatory Outcomes
EMPEROR-Preserved
Primary endpoint:
Adjudicated CV death or
HHF
Confirmatory*
HR: 0.79
(95% CI: 0.69, 0.90)
p<0.001
Key secondary endpoint:
Adjudicated first and recurrent
HHF
Confirmatory†
HR: 0.73
(95% CI: 0.61, 0.88)
p<0.001
Key secondary endpoint:
eGFR slope
Confirmatory‡
+1.36
mL/min/1.73 m2 per year
p<0.001
*Cox regression with a=0.0497. †Joint frailty model that included CV death as source of information censoring. ‡Random coefficient model. See slide notes for more information.
Anker S et al. N Engl J Med. 2021 Aug 27. doi: 10.1056/NEJMoa2107038.

22. Empagliflozin Shows Consistent Efficacy in HFmrEF and HFpEF
EMPEROR-Preserved Study Results in Patients with LVEF 41-49% or LVEF ≥50%
10.0
8.0
7.2 6.7
0
2
4
6
8
10
12
14
HFmrEF HFpEF
Events
per
100
patient-years
CV Death or Hospitalization for HF
Placebo Empagliflozin
HR 0.83
95% CI 0.71, 0.98
P = 0.024
LVEF 41-49% LVEF ≥50%
RRR = Relative Risk-reduction; ARR = Absolute Risk-reduction; NNT = Number needed to treat to prevent 1 additional event over 26.2 months
Anker S. Presented at AHA Scientific Sessions, Nov 2021.
HR 0.71
95% CI 0.57, 0.88
P = 0.002
RRR 29%
ARR 4.9%
NNT 21
RRR 17%
ARR 2.4%
NNT 42

23. Empagliflozin Consistently Reduces Risk of CV Death or HHF
Regardless of T2D, Age, CKD, or AF, in Patients with HF and LVEF >40%
Adapted: Anker S et al. N Engl J Med. 2021 Aug 27. doi: 10.1056/NEJMoa2107038.

24. ADA Standards of Care - 2022 Guidance
ASCVD, HF, and CKD Benefits Recommended with Various SGLT2-i agents
American Diabetes Association. Diabetes Care. 2022 Jan;45(Suppl 1):S134.

25. Thank you
25