Empagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus

at High Cardiovascular RiskSilvio E Inzucchi, Christoph Wanner, John M Lachin, David Fitchett,

Stefan Hantel, Michaela Mattheus, Theresa Devins, Odd Erik Johansen, Hans J Woerle,

Uli C Broedl, Bernard Zinman

1

Disclosures: Silvio E Inzucchi• Professor of Medicine, Yale University School of

Medicine, New Haven, CT, USA

• Consultations and non-financial support – Boehringer Ingelheim, Merck, Janssen, Novo Nordisk,

Sanofi/Regeron, Intarcia, Lexicon, Poxel, Takeda, Eli Lilly

• CME funding to Yale University– Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Abbott, Merck and

Sanofi

2

Diabetes and heart failure• Heart failure is highly prevalent in patients with diabetes,1,2

occurring in >1 in 5 patients aged over 65 years.1

• Patients with both diabetes and heart failure have a poor prognosis, with a median survival ~4 years.3

• Glucose-lowering options for patients with type 2 diabetes and heart failure are limited. Meta-analysis of more vs. less intensive glucose control showed no benefit on heart failure hospitalization or death.4

• Specific glucose-lowering medications have not been shown to improve heart failure outcomes, and some may actually have deleterious effects.5-7

1. Bertoni AG et al. Diabetes Care 2004;27:699-7032. Shah AD et al. Lancet Diabetes Endocrinol 2015;3:105-113 3. Cubbon RM et al. Diab Vasc Dis Res 2013;10:330-3364. Turnbull FM et al. Diabetologia 2009;52:288-2298

5. Lago RM et al. Lancet 2007;370:1129-1133. 6. Scirica BM et al. Circulation 2014:130;1579-15887. Smooke S et al. Am Heart J 2005;149:168-174

3

Empagliflozin• Virtually all glucose filtered by the kidney is reclaimed in

the proximal tubule.1 Sodium glucose cotransporter 2 (SGLT2) is responsible for 90% of this reabsorption.

• Empagliflozin is a highly selective inhibitor of SGLT2.2

• By reducing renal glucose reabsorption, empagliflozin increases urinary glucose excretion.3

• In patients with type 2 diabetes, empagliflozin leads to:4

– Significant reductions in HbA1c– Weight loss– Reductions in BP without increases in heart rate

1. Abdul-Ghani et al. Curr Diab Rep. 2012;12:230-8.2. Grempler et al. Diabetes Obes Metab.2012 ;14:83-90.3. Heise T et al. Diabetes Obes Metab 2013;15:613-21.4. Liakos A et al. Diabetes Obes Metab 2014;16:984-93.

4

EMPA-REG OUTCOME®

Trial design

• Study medication was given in addition to standard of care.• The trial was to continue until ≥ 691 patients experienced an

adjudicated primary outcome event.• Key inclusion criteria:

– Adults with type 2 diabetes and established CVD– BMI ≤45 kg/m2; HbA1c 7–10%; eGFR ≥30 mL/min/1.73m2 (MDRD)

5

Randomized and treated

(n=7020)

Empagliflozin 10 mg(n=2345)

Empagliflozin 25 mg (n=2342)

Placebo (n=2333)

Screening(n=11531)

CV, cardiovascular;

Zinman B et al. N Engl J Med 2015 [Epub ahead of print].

BMI, body mass index; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease.

Planned outcomes and analyses• Primary outcome: 3-point MACE• Further outcomes included: heart failure hospitalization

or CV death, hospitalization for heart failure, all-cause mortality

• Analysis compared empagliflozin 10 mg and 25 mg (pooled) vs. placebo in patients treated with ≥1 dose of study drug (intent-to-treat population)

• Secondary analyses included comparisons of individual empagliflozin doses vs. placebo

• Subgroup analyses were based on baseline characteristics, including the presence/absence of investigator-reported heart failure

3-point MACE: Time to first occurrence of CV death, non-fatal MI or non-fatal stroke.MACE, Major Adverse Cardiovascular Event; CV, cardiovascular; MI, myocardial infarction.Zinman B et al. N Engl J Med 2015 [Epub ahead of print]. 6

Baseline characteristics: Demographics & DM Placebo (n=2333)

Empagliflozin10 mg

(n=2345)

Empagliflozin 25 mg

(n=2342)Age, years 63.2 (8.8) 63.0 (8.6) 63.2 (8.6)Body mass index, kg/m2 30.7 (5.2) 30.6 (5.2) 30.6 (5.3)

7

*Includes Australia and New Zealand

HbA1c, % 8.08 (0.84) 8.07 (0.86) 8.06 (0.84)>10 years of diabetes 1339 (57.4) 1354 (57.7) 1318 (56.3)

DM MedsMetformin 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)

Baseline characteristics: CV historyPlacebo (n=2333)

Empagliflozin10 mg

(n=2345)

Empagliflozin 25 mg

(n=2342)Any CV risk factor 2307 (98.9%) 2333 (99.5%) 2324 (99.2%)

- MI 1083 (46.4%) 1107 (47.2%) 1083 (46.2%)- CABG 563 (24.1%) 594 (25.3%) 581 (24.8%)- Stroke 553 (23.7%) 535 (22.8%) 549 (23.4%)

HF 244 (10.5%) 240 (10.2%) 222 (9.5%)

8

*Based on narrow standardised MedDRA query “cardiac failure”

LDL-C 84.9 (35.3) 86.3 (36.7) 85.5 (35.2)eGFR <60 607 (26.0%) 605 (25.8%) 607 (25.9%)

Statins 1773 (76.0%) 1827 (77.9%) 1803 (77.0%)ASA 1927 (82.6%) 1939 (82.7%) 1937 (82.7%)RAAS inhibitors 1868 (80.1%) 1896 (80.9%) 1902 (81.2%)

Patients withevent/analysed

Empagliflozin Placebo HR (95% CI) p-valuePrimary outcome:

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

0.25 0.50 1.00 2.00

Primary outcome

Cox regression analysis. 3-point MACE: Time to first occurrence of CV death, non-fatal MI or non-fatal stroke.

MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CI, confidence interval; CV, cardiovascular; MI, myocardial infarction.*95.02% CI

Zinman B et al. N Engl J Med 2015 [Epub ahead of print].

Favors empagliflozin Favors placebo

9

Heart failure hospitalization or CV death

Cumulative incidence function. CV, cardiovascular; HR, hazard ratio; CI, confidence interval.

10

Heart failure hospitalization or CV death

Cumulative incidence function. CV, cardiovascular; HR, hazard ratio; CI, confidence interval.

11

N analyzedEmpagliflozin Placebo

4687 2333All patientsAge (years) <65 2596 1297

≥65 2091 1036eGFR (mL/min/1.73m2) ≥90 1050 488

60–90 2425 1238<60 1212 607

Insulin No 2435 1198Yes 2252 1135

ACEIs/ARBs No 889 465Yes 3798 1868

Diuretics No 2640 1345Yes 2047 988

Beta-blockers No 1631 835Yes 3056 1498

Mineralocorticoid receptor antagonists

No 4382 2197Yes 305 136

0.25 0.50 1.00 2.00

Heart failure hospitalization or CV death: Subgroup analysis

Cox regression analysis.CV, cardiovascular; HR, hazard ratio; CI, confidence interval; ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate.

Favors empagliflozin Favors placebo

HR (95% CI)

Hospitalization for or death from heart failure

Cumulative incidence function. HR, hazard ratio; CI, confidence interval.

13

Patients with event/analyzedEmpagliflozin Placebo HR (95% CI) p-value

Investigator-reported heart failure*

204/4687 143/2333 0.70 (0.56, 0.87) 0.001

Investigator-reported serious heart failure*†

192/4687 136/2333 0.69 (0.55, 0.86) 0.001

0.25 0.50 1.00 2.00

Investigator-reported heart failure

Cox regression analysis. *Based on narrow standardized MedDRA query “cardiac failure”.†Reported as serious adverse events by investigator.HR, hazard ratio; CI, confidence interval.

Favors empagliflozin Favors placebo

14

All-cause hospitalization

Cumulative incidence function. HR, hazard ratio; CI, confidence interval.

Hospitalization Empa Placebo HR (95% CI)For HF 126/4687

(2.7%)95/2333 (4.1%)

0.65 (0.50, 0.85)

For non-HF cause 1695/4687(36.2%)

911/2333 (39.0%)

0.89(0.82, 0.96)

All-cause 1725/4687 (36.8%)

925/2333 (39.6%)

0.89(0.82, 0.96)

15

Patients hospitalized

for heart failure

(%)

Hospitalization for heart failurein patients with vs without heart failure at baseline

3.1

12.3

1.8

10.4

0

2

4

6

8

10

12

14

Patients withoutheart failureat baseline

Patients withheart failureat baseline

HR 0.75(95% CI 0.48, 1.19)

HR 0.59(95% CI 0.43, 0.82)

Cox regression analysis. HR, hazard ratio; CI, confidence interval.

Patients with

heart failure hospitalization

or CV death

(%)

Heart failure hospitalization or CV death in patients with vs without heart failure at baseline

7.1

20.1

4.5

16.2

0

5

10

15

20

25

Patients withoutheart failureat baseline

Patients withheart failureat baseline

HR 0.72(95% CI 0.50, 1.04)

HR 0.63(95% CI 0.51, 0.78)

Cox regression analysis. CV, cardiovascular; HR, hazard ratio; CI, confidence interval.

Patients with event/analyzedEmpagliflozin Placebo HR (95% CI)

HF hospitalization or CV deathAll patients 265/4687 198/2333 0.66 (0.55, 0.79)

Baseline HF: No 190/4225 149/2089 0.63 (0.51, 0.78)Baseline HF: Yes 75/462 49/244 0.72 (0.50, 1.04)

Hospitalization for HFAll patients 126/4687 95/2333 0.65 (0.50, 0.85)

Baseline HF: No 78/4225 65/2089 0.59 (0.43,0.82)Baseline HF: Yes 48/462 30/244 0.75 (0.48, 1.19)

CV deathAll patients 172/4687 137/2333 0.62 (0.49, 0.77)

Baseline HF: No 134/4225 110/2089 0.60 (0.47, 0.77)Baseline HF: Yes 38/462 27/244 0.71 (0.43, 1.16)

All-cause mortalityAll patients 269/4687 194/2333 0.68 (0.57, 0.82)

Baseline HF: No 213/4225 159/2089 0.66 (0.54, 0.81)Baseline HF: Yes 56/462 35/244 0.79 (0.52, 1.20)

0.25 0.50 1.00 2.00 4.00

Outcomes in patients with vs without heart failure at baseline

Cox regression analysis. HF, heart failure; CV, cardiovascular; HR, hazard ratio; CI, confidence interval.

Favorsempagliflozin

Favorsplacebo

Adverse events in patients with and without heart failure at baseline

AE, adverse event.AEs that occurred during treatment or ≤7 days after the last intake of study medication.

Data are n (%).

Patients withheart failure at baseline

Patients withoutheart failure at baseline

Placebo(N=244)

Empagliflozin(N=462)

Placebo(N=2089)

Empagliflozin(N=4225)

At least one AE 230 (94.3) 413 (89.4) 1909 (91.4) 3817 (90.3)

At least one severe AE 78 (32.0) 135 (29.2) 514 (24.6) 965 (22.8)

At least one serious AE 126 (51.6) 202 (43.7) 862 (41.3) 1587 (37.6)

Deaths 25 (10.2) 35 (7.6) 94 (4.5) 141 (3.3)

At least one AE leading to discontinuation

62 (25.4) 99 (21.4) 391 (18.7) 714 (16.9)

20

Conclusion• In patients with type 2 diabetes and high CV

risk, empagliflozin, given in addition to standard of care, reduced heart failure hospitalization or CV death, with a consistent benefit observed in both those with and without heart failure at baseline.

21

22

HbA1c

6.0

6.5

7.0

7.5

8.0

8.5

9.0

Ad

just

ed m

ean

(SE)

Hb

A1c

(%)

Week

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

229422962296

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

227222722280

218822182212

213321502152

211321552150

206321082115

200820722080

196720582044

174118051842

145615201540

124112971327

110911641190

96210061043

705749795

420488498

151170195

12 28 52 94 10880 12266 1360 150 164 178 192 20640

23X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements

All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat)

Weight

80

82

84

86

88

90

Ad

just

ed m

ean

(SE)

wei

ght (

kg)

Week228522902283

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

191518931891

221522382226

213821742178

159816731678

123912981335

425483489

Placebo

Empagliflozin 10 mg

Empagliflozin 25 mg

24

28 52 1080 164 22012

X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements

All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat)

Systolic blood pressure

25

125

127

129

131

133

135

137

139

141

143

145

Ad

just

ed m

ean

(SE)

syst

olic

b

lood

pre

ssur

e (m

mH

g)

Week232223222323

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

223522502247

220322352221

216121932197

213321742169

207321252129

202420952102

197420722066

177118531878

149215561571

127413271351

112611891212

98110341070

735790842

450518528

171199216

Placebo

Empagliflozin 10 mgEmpagliflozin 25 mg

16 28 52 94 10880 12266 1360 150 164 178 192 20640

X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements

All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat)

Diastolic blood pressure

26

70

71

72

73

74

75

76

77

78

79

80

Ad

just

ed m

ean

(SE)

dia

stol

ic

blo

od p

ress

ure

(mm

Hg)

Week232223222323

PlaceboEmpagliflozin 10 mgEmpagliflozin 25 mg

223522502247

220322352221

216121932197

213321742169

207321252129

202420952102

197420722066

177118531878

149215561571

127413271351

112611891212

98110341070

735790842

450518528

171199216

Placebo

Empagliflozin 10 mgEmpagliflozin 25 mg

X-axis: timepoints with reasonable amount of data available for pre-scheduled measurements

All patients (including those who discontinued study drug or initiated new therapies) were included in this mixed model repeated measures analysis (intent-to-treat)

16 28 52 94 10880 12266 1360 150 164 178 192 20640