1. with type 2 diabetes without heart failure?
Does the risk for heart failure modulate the effectiveness of empagliflozin on heart failure hospitalization or cardiovascular death in patients
with type 2 diabetes without heart failure?
Insights from EMPA-REG OUTCOME Trial
Javed Butler, MD MPH, MBA on behalf of
David Fitchett, Philippe van de Borne, Bernard Zinman, Hans-Juergen Woerle, Michaela Mattheus, Jyothis George, Odd Erik Johansen, and Silvio E Inzucchi

3. Disclosures Javed Butler Consultant to:
Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, Janssen, Luitpold, Medtronic, Novartis, Relypsa, Roche, Vifor, and ZS Pharma
The EMPA-REG OUTCOME® trial was funded by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance.

4. hospTiitmaeltiozfairsttiohonspibtayliza3tio4n%for HF
Background
In EMPA-REG OUTCOME trial (7020 patients with T2DM and CV disease), empagliflozin reduced CV mortality by 38%, HF hospitalization by 35%, and the composite of CV mortality or HF
hospTiitmaeltiozfairsttiohonspibtayliza3tio4n%for HF
Time to first hospitalization for HF or CV death
Zinman et al. N Engl J Med. 2015;373:
Fitchett et al. Eur Heart J 2016;37:

5. Background II – Benefit stratified by baseline heart failure
These benefits were similar in those with (10.1%) and without (89.9%) HF at baseline
Fitchett et al. Eur Heart J 2016;37:
Prevention should be optimally targeted at individuals most likely to benefit
Aim: To understand whether the HF benefits varied by baseline HF risk in patients in the EMPA-REG OUTCOME trial

6. Methods – Heart Failure Risk Ascertainment
In 6314 patients without HF at baseline, we derived the 5-year risk for incident HF using the 9-variable Health ABC HF Risk score
The score has previously been validated internally (Health ABC study1) and externally (Cardiovascular Health Study2)
5-year HF risk was classified as low-to- average (<10%), high (10-20%) and very-high (≥ 20%)
1: Butler et al. Circ Heart Fail 2008;1: : Kalogeropoulos et al. Circ Heart Fail 2010;3:

7. Methods – Outcomes and Analyses
HF hospitalisation or CV death (excluding fatal stroke)
HF hospitalisation
CV death (including fatal stroke)
Analyses were performed on the pooled empagliflozin dose groups (10 and 25 mg) versus placebo utilizing a time-to-first-event approach
Cox proportional hazards model with factors for age, sex, baseline HbA1c, baseline eGFR, baseline BMI, region, baseline HF risk score, study treatment assignment, and the interaction of the baseline Health ABC HF Risk score and study treatment assignment
Cumulative incidence function estimates were corrected for non-CV mortality as a competing risk

8. Results – Baseline heart failure risk
Distribution across the HF risk spectrum of was balanced across treatment arms
Median Health ABC score was 4 (-8 to 16) in the placebo and 4 (-8 to 18) in the pooled empagliflozin group.
67.2% at low-to-average risk
24.2% at high risk
5.1% at very-high 5-year risk
*: 222 patients excluded due to missing variable

9. Results: Baseline characteristics
Low-Average Risk
< 10% 5 year HF risk
High Risk
10-20% 5 year HF risk
Very High Risk
≥ 20% 5 year HF risk
Treatment
Pbo
Empa N
1382
2864
515
1012
115
204
Median Health ABC HF risk score
2 (0,4)
7 (6,8)
11 (10, 12)
10.5 (10,
12)
Age, mean (SD), years
62.0 (8.2)
62.1 (8.2)
64.5 (9.4)
64.5 (8.7)
68.3 (9.9)
67.3 (9.7)
Coronary artery disease
921 (66.6)
1909 (66.7)
473 (91.8)
949 (93.8)
110 (95.7)
199 (97.5)
Atrial fibrillation
62 (4.5)
89 (3.1)
24 (4.7)
56 (5.5)
12 (10.4)
23 (11.3)
HbA1c, mean (SD), %
8.03 (0.83)
8.02 (0.84)
8.21 (0.85)
8.16 (0.84)
8.31 (0.91)
8.26 (0.86)
Systolic BP, mean (SD), mmHg
132.5
132.1
141.5
141.6
151.8
152.0
(15.4)
(15.5)
(16.5)
(21.2)
(21.1)
Diastolic BP, mean (SD), mmHg
76.0 (9.5)
76.0 (9.4)
78.1 (10.2)
77.7 (9.5)
81.0 (13.8)
80.6 (11.9)
eGFR, mean, mL/min/1.73m2
78.5 (20.0)
78.3 (21.0)
66.5 (20.2)
67.9 (20.6)
59.8 (20.7)
59.1 (20.1)
Beta-blockers
797 (57.7)
1747 (61.0)
383 (74.4)
722 (71.3)
77 (67.0)
137 (67.2)
Diuretics
496 (35.9)
1069 (37.3)
232 (45.0)
478 (47.2)
55 (47.8)
111 (54.4)
Loop diuretics
133 (9.6)
257 (9.0)
83 (16.1)
177 (17.5)
24 (20.9)
51 (25.0)

10. HF hospitalization or CV death in low-average risk group
Incidence per 100 pt- yrs Placebo group 1.68 (1.31, 2.10) Empagliflozin group 1.20 (0.98, 1.45)
HR: 0.71
(95% CI 0.52, 0.96)
*:excluding fatal stroke

11. HF hospitalization or CV death in high-risk group
Incidence per 100 pt-yrs
Placebo group 4.03 (3.06, 5.13)
Empagliflozin group: 2.07 (1.58, 2.62)
HR: 0.52
(95% CI 0.36, 0.75)

12. HF hospitalization or CV death in very high-risk grouprs
Incidence per 100 pt-y
Placebo group 7.0 (4.33, 10.29)
Empagliflozin group 3.8 (2.38, 5.54)
HR: 0.55
(95% CI 0.30, 1.00)

13. HF hospitalization or CV death in those with HF
Incidence per 100 pt-yrs
Placebo group 8.55 (6.33, 11.11)
Empagliflozin group 6.36 (5.01, 7.88)
HR: 0.73
(95% CI 0.51, 1.04)

14. Consistent effects on CV death and HHF by HF risk* **
*:excluding fatal stroke
**: including fatal stroke

15. Conclusions
Patients with T2DM and established CV disease are at risk for developing HF across the Health ABC score based risk spectrum
Empagliflozin reduced the risk for HF hospitalization and CV mortality in these patients with or without HF at baseline
In patients without HF at baseline, empagliflozin reduced HF hospitalization and CV mortality across a spectrum of HF risk

16. Further reading
511)
Effects of Empagliflozin on Risk for Cardiovascular Death and Heart Failure Hospitalisation Across the Spectrum of Heart Failure Risk in the
EMPA-REG OUTCOME® Trial
(Eur Heart J: doi /eurheartj/ehx