The Empa-Reg study evaluated the effects of empagliflozin, versus placebo, on cardiovascular morbidity and mortality in high-risk patients with type 2 diabetes. Results indicated that empagliflozin significantly reduced risks for cardiovascular death (38% reduction) and hospitalization for heart failure (35% reduction) while maintaining safety and tolerability. Additionally, empagliflozin reduced HbA1c levels without a corresponding increase in hypoglycemia, despite an increase in genital infections.

1. resultados del estudio
EMPA-REG: un punto de inflexión en el tratamiento de la diabetes
Domingo Marzal Martín
Casa del corazón. Madrid, noviembre 2015

2. Empagliflozin is a highly selective inhibitor of the
sodium glucose cotransporter 2 (SGLT2)
in the kidney

3. • Randomised, double-blind, placebo-controlled CV
outcomes trial
• Objective
To examine the long-term effects of empagliflozin versus
placebo, in addition to standard of care, on CV
morbidity and mortality in patients with type 2 diabetes
and high risk of CV events

4. Randomised
and treated
(n=7020)
Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342)
Placebo
(n=2333)
Screening
(n=11531)
Trial design

5. • Key inclusion criteria
–Adults with type 2 diabetes
–BMI ≤45 kg/m2
–HbA1c 7-10%
–Established cardiovascular disease
• Key exclusion criteria
–eGFR <30 mL/min/1.73m2 (MDRD)

6. • Primary outcome
3-point MACE: Time to first occurrence of CV
death, non-fatal MI or non-fatal stroke
• Further pre-specified outcomes
Hospitalization for heart failure
All-cause mortality

7. Baseline characteristics: type 2 diabetes
Glucose-lowering medication
Metformin 1734 (74.3) 1729 (73.7) 1730 (73.9)
Sulphonylurea 992 (42.5) 985 (42.0) 1029 (43.9)
Thiazolidinedione 101 (4.3) 96 (4.1) 102 (4.4)
Insulin 1135 (48.6) 1132 (48.3) 1120 (47.8)
Mean daily dose, U 65 (50.6) 65 (47.9) 66 (48.9)
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
HbA1c, % 8.08 (0.84) 8.07 (0.86) 8.06 (0.84)
Time since diagnosis of type 2 diabetes, years
≤5 423 (18.1) 406 (17.3) 434 (18.6)
>5 to 10 571 (24.5) 585 (24.9) 590 (25.2)
>10 1339 (57.4) 1354 (57.7) 1318 (56.3)

8. Baseline characteristics: CV complications
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
Any CV risk factor 2307 (98.9%) 2333 (99.5%) 2324 (99.2%)
Coronary artery disease 1763 (75.6%) 1782 (76.0%) 1763 (75.3%)
Multi-vessel coronary artery
disease
1100 (47.1%) 1078 (46.0%) 1101 (47.0%)
History of MI 1083 (46.4%) 1107 (47.2%) 1083 (46.2%)
Coronary artery bypass graft 563 (24.1%) 594 (25.3%) 581 (24.8%)
History of stroke 553 (23.7%) 535 (22.8%) 549 (23.4%)
Peripheral artery disease 479 (20.5%) 465 (19.8%) 517 (22.1%)
Single vessel coronary artery
disease
238 (10.2%) 258 (11.0%) 240 (10.2%)
Cardiac failure 244 (10.5%) 240 (10.2%) 222 (9.5%)

9. 6,0
6,5
7,0
7,5
8,0
8,5
9,0
Adjustedmean(SE)HbA1c(%)
Week
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
2294
2296
2296
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
2272
2272
2280
2188
2218
2212
2133
2150
2152
2113
2155
2150
2063
2108
2115
2008
2072
2080
1967
2058
2044
1741
1805
1842
1456
1520
1540
1241
1297
1327
1109
1164
1190
962
1006
1043
705
749
795
420
488
498
151
170
195
12 28 52 94 10880 12266 1360 150 164 178 192 20640
HbA1c

10. cardiovascular outcomes

11. HR 0.86
(95.02% CI 0.74-0.99)
p=0.0382
primary outcome: 3-point MACE

12. Empagliflozin 10 mg
HR 0.85
(95% CI 0.72, 1.01)
p=0.0668
Empagliflozin 25 mg
HR 0.86
(95% CI 0.73, 1.02)
p=0.0865
primary outcome: 3-point MACE

13. primary outcome: 3-point MACE
Patients with event/analysed
Empagliflozin Placebo HR (95% CI) p-value
3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382
CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001
Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189
Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638
Favours empagliflozin Favours placebo

14. CV death
HR 0.62
(95% CI 0.49, 0.77)
p<0.0001

15. Empagliflozin 10 mg
HR 0.65
(95% CI 0.50, 0.85)
p=0.0016
Empagliflozin 25 mg
HR 0.59
(95% CI 0.45, 0.77)
p=0.0001
CV death

16. Empagliflozin Placebo
All patients 4687 2333
Age, years 0.21
<65 2596 1297
≥65 2091 1036
Sex 0.32
Male 3336 1680
Female 1351 653
Race 0.43
White 3403 1678
Asian 1006 511
Black/African-American 237 120
HbA1c, % 0.51
<8.5 3212 1607
≥8.5 1475 726
Body mass index, kg/m2 0.05
<30 2279 1120
≥30 2408 1213
eGFR, mL/min/1.73m2 0.15
≥90 1050 488
60 to <90 2425 1238
<60 1212 607
CV death: subgroup analysis
HR (95% CI)
Favours empagliflozin Favours placebo
p-value
for interaction

17. heart failure

18. HR 0.65
(95% CI 0.50, 0.85)
p=0.0017
hospitalization for heart failure

19. Empagliflozin 10 mg
HR 0.62
(95% CI 0.45, 0.86)
p=0.0044
Empagliflozin 25 mg
HR 0.68
(95% CI 0.50, 0.93)
p=0.0166
hospitalization for heart failure

20. Heart failure hospitalization
in patients with vs without heart failure at baseline

21. all-cause mortality

22. all-cause mortality
HR 0.68
(95% CI 0.57, 0.82)
p<0.0001

23. HR 0.68
(95% CI 0.57, 0.82)
p<0.0001
Empagliflozin 10 mg
HR 0.70
(95% CI 0.56, 0.87)
p=0.0013
Empagliflozin 25 mg
HR 0.67
(95% CI 0.54, 0.83)
p=0.0003
all-cause mortality

24. Patients with event/analysed
Empagliflozin Placebo HR 95% CI p-value
All-cause mortality 269/4687 194/2333 0.68 (0.57, 0.82) <0.0001
CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001
Non-CV death 97/4687 57/2333 0.84 (0.60, 1.16) 0.2852
All-cause mortality: CV death and non-CV death
Favours empagliflozin Favours placebo

25. safety and tolerability

26. confirmed hypoglycaemic
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
n (%)
Confirmed hypoglycaemic
adverse events
650 (27.9%) 656 (28.0%) 647 (27.6%)
Events requiring
assistance
36 (1.5%) 33 (1.4%) 30 (1.3%)
Patients taking insulin at
baseline
Total 483 (42.6%) 494 (43.6%) 464 (41.4%)
Events requiring
assistance
28 (2.5%) 27 (2.4%) 25 (2.2%)

27. genital infection
Rate = per100 patient-years
Placebo
(n=2333)
Empagliflozin
10 mg
(n=2345)
Empagliflozin
25 mg
(n=2342)
n (%) Rate n (%) Rate n (%) Rate
Events consistent with
genital infection
42
(1.8%)
0.73 153
(6.5%)
2.66 148
(6.3%)
2.55
Serious events 3
(0.1%)
0.05 5
(0.2%)
0.08 4
(0.2%)
0.07
Events leading to
discontinuation
2
(0.1%)
0.03 19
(0.8%)
0.32 14
(0.6%)
0.23
By sex
Male 25
(1.5%)
0.60 89
(5.4%)
2.16 77
(4.6%)
1.78
Female 17
(2.6%)
1.09 64
(9.2%)
3.93 71
(10.8%)
4.81

28. conclusions

29. empagliflozin …
• Reduced HbA1c without increase in hypoglycaemia
• Increased genital infections but was well tolerated
• Reduced risk for 3-point MACE 14%
• Reduced hospitalization for heart failure 35%
• Reduced CV death 38%
• Improved survival by reducing all-cause mortality 32%

30. gracias por vuestra atención
@domingomarzal
domingo.marzal@secardiologia.es

31. NNT to prevent one death across landmark trials in
patients with high CV risk
1. 4S investigator. Lancet 1994;344:1383-9
2. HOPE investigator. N Engl J Med 2000;342:145-53
Simvastatin1
for 5.4 years
High CV risk
5% diabetes, 26% hypertension
1994 2000 2015
Pre-statin era
High CV risk
38% diabetes, 46% hypertension
Ramipril2
for 5 years
Pre-ACEi/ARB era
<29% statin
Empagliflozin
for 3 years
T2DM with high CV risk
92% hypertension
>80% ACEi/ARB
>75% statin