DAPA-HF: Dapagliflozin And Prevention of Adverse-

outcomes in Heart Failure Trial

Log No: FOR0919001 Expiry Date: 09/2020

© AstraZeneca 2019
 Introduction
• In the DECLARE-TIMI 58 trial, DAPA was shown to reduce the risk of hHF compared with placebo in patients
with T2D, irrespective of the presence of HF history; only 10% of patients in DECLARE had a HF history. 1
• In the patients with HFrEF and T2D from a prespecified subgroup analysis, dapagliflozin not only reduced
hospitalization for HF but also CV death and all-cause mortality; these benefits with dapagliflozin appeared early in the
patients with HFrEF.2

• Based on current available data, the CV protective mechanisms of the SGLT2 inhibitors are believed to be
independent of glycemic control in patients with T2D3,4 and may be applicable to both patients with or without
T2D.
• In PK/PD studies in volunteers without T2D, dapagliflozin led to glucosuria and increased renal sodium excretion
suggesting biological activity in patients without T2D. 5,6

• The DAPA-HF trial is the first HF outcome study to report results with an SGLT2 inhibitor – dapagliflozin – in
addition to standard of care for the treatment of HFrEF in patients with or without T2D. 7,8
• The population enrolled in DAPA-HF is representative of patients in clinical practice, as evidenced by HF
CV registry data, and similar HF to =patients
heart failure;enrolled in other contemporary HFrEF randomized
reduced ejectioncontrolled
fraction; PD = trials.
8
= cardiovascular; DAPA = dapagliflozin; hHF = hospitalization for heart failure; HFrEF = heart failure with
pharmacodynamic; PK = pharmacokinetic; SGLT2 = sodium-glucose cotransporter 2; T2D = type 2 diabetes.
1. Wiviott SD et al. N Engl J Med. 2019:380:347-357; 2. Kato ET et al. Circulation. 2019;139:2528-2536; 3. Inzucchi SE et al. Circulation. 2018;138:1904-1907;
4. Inzucchi SE et al. Diabetes Care. 2018;41:356-363; 5. Komoroski B et al. Clin Pharmacol Ther. 2009;85:520-526; 6. Wilcox CS et al. J Am Heart Assoc. 2018;7.
pii:e007046; 7. McMurray JJV et al. Eur J Heart Fail. 2019;21:665-675; 8. McMurray JJV et al. Eur J Heart Fail. 2019;doi: 10.1002/ejhf.1548. Accessed August 20, 2019.

2 © AstraZeneca 2019
 Unmet Need in Patients with Heart Failure

patients worldwide are affected by heart failure and

~64 prevalence is expected to increase with the aging
million
population1,2

• Heart failure morbidity and mortality remain high, and are comparable to some of the most
common cancers, despite advances in therapy.5
• Patients with T2D have ~2.5-fold greater risk of developing HF than patients without
diabetes.8 Prevalence of T2D in patients with chronic HF is ~30%.9

Overall HF represents a substantial global burden with significant unmet needs in terms of morbidity and
mortality.3-7

1. Global Burden of Disease Study 2016. Lancet. 2017;390:1211-1259; 2.Benjamin EJ et al. Circulation. 2018;137:e67-e492 3.Lloyd-Jones D et al. Circulation. 2002;106:3068-
3072; 4. Vos T et al. Lancet. 2017;390:1211-1259; 5. Mamas MA et al. Eur J Heart Fail. 2017;19:1095-1104; 6. Cheng YJ et al. Diabetes Care. 2018;41:2306-2315; 7. Taylor CJ
3 et al. BMJ. 2019;364:l223; 8. Nichols GA et al. Diabetes Care. 2004;27:1879-1884; 9. Seferović PM et al. Eur J Heart Fail. 2018;20:853-872. © AstraZeneca 2019
DAPA-HF: Study Design

© AstraZeneca 2019
 Assessing Dapagliflozin in Patients with Chronic
HFrEF With or Without T2D1-4

4744 patients Dapagliflozin 10 mg

• ≥18 years of age
+ standard of care

Double-blind
• With or without T2D
• Diagnosis of symptomatic HFrEF

1:1
(NYHA class II-IV) for ≥ 2 months
• LVEF ≤40% within last 12 months
• Elevated NT-proBNP Placebo
• eGFR ≥30 ml/min/1.73 m2
• Stable SoC HFrEF treatment
+ standard of care

Visit 1 (enrollment) Visit 2 (randomization) Visit 3 Visit 4 Visit 5 Visit 6, etc. Target primary endpoint events: 8441
Day -14 Day 0 Day 14 Day 60 Day 120 Every 120 days Median follow-up: 18.2 months 2
Completion: July 20193

Primary Endpoint Secondary Endpoints

• Time to first occurrence of either of the components of the composite: CV
• Time to first occurrence of any of the death or hHF
components of the composite: CV • Total number of (first and recurrent) hHF and CV death
death or hHF or an urgent HF visit • Change from baseline measured at 8 months in the total symptom score of
the KCCQ
• Time to first occurrence of any of the components of the composite: ≥50%
sustained decline in eGFR or reaching ESRD or renal death
• Time to death from any cause

CV = cardiovascular; eGFR = estimated glomerular filtration rate; ESRD = end stage renal disease; HbA1c = glycated hemoglobin; HF = heart failure; HFrEF = heart failure with reduced ejection fraction;
hHF = hospitalization for heart failure; KCCQ = Kansas City Cardiomyopathy Questionnaire; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal pro B-type natriuretic peptide; NYHA = New York Heart
Association; SoC = standard of care; T2D = type 2 diabetes.
1. McMurray JJV et al. Article and supplementary appendix. Eur J Heart Fail. 2019;21:665-675; 2. McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France; 3. Study
5 NCT03036124. ClinicalTrials.gov website. Accessed August 19, 2019. 4. McMurray JJV et al. Eur J Heart Fail. 2019;doi: 10.1002/ejhf.1548. Accessed July 16, 2019. © AstraZeneca 2019
 Key Inclusion and Exclusion Criteria
Key Inclusion Criteria Key Exclusion Criteria
• Treatment within 8 weeks or intolerance to SGLT2
• Men and women ≥18 years of age, with or without
inhibitor
T2D
• T1D
• Documented diagnosis of symptomatic HFrEF for ≥2
months (NYHA class II-IV) • Symptomatic hypotension or SBP <95 mmHg
• LVEF ≤40% within the last 12 months • Current acute decompensated HF or
hospitalization within last 4 weeks due to
• Elevated NT-proBNP (≥600 pg/mL or ≥400 pg/mL if
decompensated HF
hHF within 12 months or ≥900 pg/mL if atrial
fibrillation/flutter irrespective of hHF history) • Coronary revascularization (PCI or CABG), valve
repair/replacement, or CRT device implantation
• Optimal pharmacological and device therapy for HF
within last 12 weeks or planned after
• Optimal and stablea (≥4 weeks) background standard randomization
of care for HFrEF as per local guidelines including • HF due to restrictive cardiomyopathy, active
(unless contraindicated or not tolerated): ACEI, ARB,
myocarditis, constrictive pericarditis, hypertrophic
or sacubitril/valsartan; beta-blocker; and if
cardiomyopathy, or uncorrected primary valvular
appropriate a MRA
disease
• eGFRb ≥30 mL/min/1.73 m2
• eGFR <30 mL/min/1.73 m2 or rapidly declining
renal function
a
This does not apply to diuretics; diuretic dosing may be titrated to symptoms, signs, weight and other information and may thus vary. Each patient should, however, be treated with a diuretic regimen aimed at
achieving optimal fluid/volume status for that individual; bCKD-EPI formula.
ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; CABG = coronary artery bypass grafting; CKD-EPI = Chronic Kidney Disease-Epidemiology Collaboration; eGFR =
estimated glomerular filtration rate; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; hHF = hospitalization for heart failure; LVEF = left ventricular ejection fraction; MRA = mineralocorticoid-
receptor antagonist; NT-proBNP = N-terminal pro B-type natriuretic peptide; NYHA = New York Heart Association; PCI = percutaneous coronary intervention; SBP = systolic blood pressure; T1D = type 1
diabetes;T2D = type 2 diabetes.
9 1. McMurray JJV et al. Article and supplementary appendix. Eur J Heart Fail. 2019;21:665-675. © AstraZeneca 2019
DAPA-HF
Baseline Characteristics

© AstraZeneca 2019
 Demographic Characteristics
All Patients
Demographic Characteristics (N=4744)
Yes 42
Diabetes history, %
No 58
Mean age, years 66
Female, % 23
Race, %
White 70
Black 5
Asian 24
Other 1
Region, %
Western Europe 11.6
Eastern Europe/Russia 33.8
North America 14.3
Latin America 17.2
Asia Pacific 23.1

11 1. McMurray JJV et al. Eur J Heart Fail. 2019;doi: 10.1002/ejhf.1548. Accessed July 16, 2019. © AstraZeneca 2019
 Key Baseline Characteristics
Characteristic Dapagliflozin Placebo
(n=2373) (n=2371)
Mean age (yr) 66 67
Male (%) 76 77
NYHA class II/III/IV (%) 68/31/1 67/32/1
Mean LVEF (%) 31 31
Median NT pro BNP (pg/mL) 1428 1446
Mean systolic BP (mmHg) 122 122
Ischaemic aetiology (%) 55 57
Mean eGFR (mL/min/1.73m2) 66 66
Prior diagnosis T2D (%) 42 42
Any baseline T2D (%)a 45 45
a
Includes 82 dapagliflozin and 74 placebo patients with previously undiagnosed diabetes i.e. two HbA1c ≥6.5% (≥48 mmol/mol).
BP = blood pressure; eGFR = estimated glomerular filtration rate; NT pro BNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; LVEF = left
ventricular ejection fraction; T2D = type 2 diabetes.

12 McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France. © AstraZeneca 2019
 Heart Failure Characteristics
All Patients
Heart Failure Characteristics (N=4744)
I 0
II 68
NYHA class, %
III 32
IV 1
Mean LVEF, % 31
History of HF hospitalization, % 47
Ischemic etiology, % 56
Mean systolic BP, mm Hg 122
Mean diastolic BP, mm Hg 74
Mean heart rate, bpm 72
Median NT-proBNP, pg/mL 1437
OSS 68
Mean KCCQ
CSS 71

Definitions of HF Measures

BP = blood pressure; bpm = beats per minute; CSS = clinical summary score; HF = heart failure; KCCQ = Kansas City Cardiomyopathy Questionnaire; LVEF = left
ventricular ejection fraction; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; OSS = overall summary score.
13 1. McMurray JJV et al. Article and Supplementary appendix. Eur J Heart Fail. 2019;doi: 10.1002/ejhf.1548. Accessed July 16, 2019. © AstraZeneca 2019
 Medical History/Comorbidity and Baseline Treatments
All Patients All Patients
Medical History/Comorbidity (N=4744) Baseline Treatments, % (N=4744)
Diabetes, % 42 Diuretic 93
Obese, % 35
ACEI 56
Median BMI, kg/m 2
27
ARB 28
Hypertension, % 74
Myocardial infarction, % 44 ACEI/ARB 94a

PCI, % 34 ARNI 11
CABG, % 17
Beta-blocker 96
Stroke, % 10
MRA 71
Atrial fibrillation flutter, %
History 40 Digitalis glycoside 19
ECG 24
Ivabradine 5
Mean eGFR, mL/min/1.73 m2 66
CRT 7
eGFR <60 mL/min/1.73 m2, % 41
Mean hemoglobin, g/L 136 ICD 26

a
Includes sacubitril/valsartan. ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; BMI = body mass index;
CABG = coronary artery bypass grafting; CRT = cardiac resynchronization therapy; ECG = electrocardiogram, eGFR = estimated glomerular filtration rate; ICD = implantable cardioverter-
defibrillator; MRA = mineralocorticoid receptor antagonist; PCI = percutaneous coronary intervention.
17 1. McMurray JJV et al. Eur J Heart Fail. 2019;doi: 10.1002/ejhf.1548. Accessed July 16, 2019. © AstraZeneca 2019
 Baseline Treatment

Dapagliflozin Placebo
Treatment (%) (n=2373) (n=2371)
Diuretic 93 94
ACE-inhibitor/ARB/ARNI 94 93
ACE inhibitor 56 56
ARB 28 27
Sacubitril/valsartan 11 11
Beta-blocker 96 96
MRA 71 71
ICD* 26 26
CRT** 8 7

*ICD or CRT-D
**CRT-P or CRT-D

ACE = angiotensin-converting enzyme; ARB = angiotensin-receptor blocker; ARNI = angiotensin receptor neprilysin inhibitor; MRA = mineralocorticoid receptor antagonist;
CRT = cardiac resynchronization therapy; ICD = implantable cardioverter-defibrillator.

18 McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France. © AstraZeneca 2019
DAPA-HF: Full Results

© AstraZeneca 2019
Primary Endpoint

© AstraZeneca 2019
 Primary Endpoint: CV Death or hHF or an Urgent HF Visit 1
36

32

28
Placebo 26% RRR
Cumulative Percentage (%)

24
HR 0.74 (0.65, 0.85)
DAPA p=0.00001
20

NNT = 21
16

12

0
0 3 6 9 12 15 18 21 24
No. at Risk Months from Randomization
DAPA 2373 2305 2221 2147 2002 1560 1146 612 210
Placebo 2371 2258 2163 2075 1917 1478 1096 593 210

DAPA = dapagliflozin; HF = heart failure; hHF = hospitalization for heart failure; HR = hazard ratio; NNT = number needed to treat.

25 1. McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France. © AstraZeneca 2019
 Component of Primary Endpoint:
Worsening HF Event
20

Placebo 30% RRR

15
Cumulative Percentage (%)
HR 0.70 (0.59,0.83)
DAPA p=0.00003

10

0
0 3 6 9 12 15 18 21 24
No. at Risk Months from Randomization
DAPA 2373 2305 2221 2147 2002 1560 1146 612 210
Placebo 2371 2258 2163 2075 1917 1478 1096 593 210

DAPA = Dapagliflozin; HF = Heart failure; HR = Hazard ratio.

26 McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France. © AstraZeneca 2019
 Component of Primary Endpoint:
Cardiovascular Death
20

15 Placebo 18% RRR

Cumulative Percentage (%)

HR 0.82 (0.69,0.98)
DAPA
p=0.029
10

0
0 3 6 9 12 15 18 21 24
No. at Risk Months from Randomization
DAPA 2373 2339 2293 2248 2127 1664 1242 671 232
Placebo 2371 2330 2279 2230 2091 1636 1219 664 234

DAPA = Dapagliflozin; HR = Hazard ratio.

27 McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France. © AstraZeneca 2019
 Primary Endpoint: Prespecified Subgroups

Characteristics HR (95% CI) HR (95% CI) Characteristics HR (95% CI) HR (95% CI)
Type 2 diabetes at baselinea NYHA Class

Yes 0.75 (0.63, 0.90) II 0.63 (0.52, 0.75)

No 0.73 (0.60, 0.88) III or IV 0.90 (0.74, 1.09)

Baseline eGFR (mL/min/1.73 m2) LVEF (%)

<60 0.72 (0.59, 0.86) ≤Median 0.70 (0.59, 0.84)

≥60 0.76 (0.63, 0.92) >Median 0.81 (0.65, 0.99)

MRA at baseline NT-proBNP (pg/mL)

Yes 0.74 (0.63, 0.87) ≤Median 0.63 (0.49, 0.80)
No 0.74 (0.57, 0.95) >Median 0.79 (0.68, 0.92)
Atrial Fibrilation or Flutter at Enrollment ECG
Yes 0.82 (0.63, 1.06)
No 0.72 (0.61, 0.84)

0.50 0.80 1.00 1.25 2.00 0.50 0.80 1.00 1.25 2.00
DAPA Better Placebo Better DAPA Better Placebo Better

A selection of subgroups is presented above.

a
Defined as history of T2DM or HbA1c ≥6.5% at both enrollment and randomization visits.

DAPA = dapagliflozin; ECG = electrocardiogram; eGFR = estimated glomerular filtration rate; HR = hazard ratio; MRA = mineralocorticoid receptor antagonist; NT pro BNP = N-
terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; LVEF = left ventricular ejection fraction.
28 © AstraZeneca 2019
McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France.
 Primary Endpoint: Prespecified Subgroups
Characteristics HR (95% CI) HR (95% CI) Characteristics HR (95% CI) HR (95% CI)

Overall Effect 0.74 (0.65, 0.85) Prior Hospitalization for HF

Age (years) Yes 0.67 (0.56, 0.80)

≤65 0.78 (0.63, 0.96) No 0.84 (0.69, 1.01)

>65 0.72 (0.60, 0.85) Main Etiology of HF

Sex Ischemic 0.77 (0.65, 0.92)

Male 0.73 (0.63, 0.85) Non-ischemic/

0.71 (0.58, 0.87)
unknown
Female 0.79 (0.59, 1.06)
BMI (kg/m2)
Race <30 0.78 (0.66, 0.92)
White 0.78 (0.66, 0.91) ≥30 0.69 (0.55, 0.86)
Black or African 0.62 (0.37, 1.04)
Asian 0.64 (0.48, 0.86)

Geographic Region
Asia 0.65 (0.49, 0.87)
Europe 0.84 (0.69, 1.01)
North America 0.73 (0.51, 1.03)
South America 0.64 (0.47, 0.88)

0.50 0.80 1.00 1.25 0.50 0.80 1.00 1.25

DAPA Better Placebo Better DAPA Better Placebo Better

A selection of subgroups is presented above.

BMI = body mass index; DAPA = dapagliflozin; HF = heart failure; HR = hazard ratio.
29 McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France. © AstraZeneca 2019
 Primary Endpoint: Subgroup Analyses
Prespecified Subgroup
Dapagliflozin Placebo
Characteristics (n=2373) (n=2371) HR (95% CI) HR (95% CI)
All Patients 386/2373 502/2371 0.74 (0.65, 0.85)
Type 2 Diabetes at Baseline*
Yes 215/1075 271/1064 0.75 (0.63, 0.90)
No 171/1298 231/1307 0.73 (0.60, 0.88)

0.50 0.80 1.00 1.25

DAPA Better Placebo Better

Post-hoc Subgroup
Dapagliflozin Placebo
Characteristics (n=2373) (n=2371) HR (95% CI) HR (95% CI)
All Patients 386/2373 502/2371 0.74 (0.65, 0.85)
Angiotensin Receptor Neprilysin Inhibitor (ARNI)
Yes 41/250 56/258 0.75 (0.50, 1.13)
No 345/2123 446/2113 0.74 (0.65, 0.86)

0.50 0.80 1.00 1.25

DAPA Better Placebo Better

*Defined as history of type 2 diabetes or HbA1c ≥6.5% at both enrollment and randomization visits.

30 McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France. © AstraZeneca 2019
Secondary Endpoints

In order of hierarchical testing

© AstraZeneca 2019
© AstraZeneca 2019
 Secondary Endpoint: CV Death or HF Hospitalization

35

30

Placebo 25% RRR

Cumulative Percentage (%)

25

DAPA HR 0.75 (0.65, 0.85)

20 p=0.00002

15

10

0
0 3 6 9 12 15 18 21 24
No. at Risk Months from Randomization
DAPA 2373 2306 2223 2153 2007 1563 1147 613 210
Placebo 2371 2264 2168 2082 1924 1438 1101 596 212

CV = cardiovascular; DAPA = dapagliflozin; HF = heart failure; HR = hazard ratio1101.

32 McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France. © AstraZeneca 2019
 Secondary Endpoint: Total HF Hospitalizations and CV Death
45

40
Placebo 25% RRR
Number of events per 100 patients

Rate Ratio 0.75 (0.65, 0.88)

35 DAPA
p=0.0002
30

25

20

15

10

0 3 6 9 12 15 18 21 24
Months since Randomization
Number at Risk
DAPA 2373 2339 2293 2248 2127 1664 1242 671 232
Placebo 2371 2330 2279 2230 2091 1636 1219 664 234
Including first and repeat hospitalizations
CV = cardiovascular; DAPA = dapagliflozin; HF = heart failure.
33 McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France. © AstraZeneca 2019
 Secondary Endpoint:
Kansas City Cardiomyopathy Questionnaire (KCCQ)
Total Symptom Score (TSS):
Change from baseline to 8 months*
Treatment Change Difference
DAPA +6.1 ± 18.6 2.8 points (95% CI 1.6, 4.0)
Placebo +3.3 ± 19.2 p<0.001†

Total Symptom Score:

Proportion with ≥5 point change from baseline to 8 months ‡
Treatment Dapagliflozin Placebo Odds ratio (95% CI)
1.15 (1.08, 1.23)
≥5 point improvement 58% 51%
p<0.001
0.84 (0.78, 0.90)
≥5 point deterioration 25% 33%
p<0.001

*Increase in score indicates an improvement

†
Calculated from win ratio, incorporating death. Win ratio = 1.18 (CI 1.11, 1.26). Win ratio >1 indicates superiority of dapagliflozin over placebo.
‡
Taking account of death
CI = confidence interval; DAPA = dapagliflozin.
34 McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France. © AstraZeneca 2019
 Secondary Endpoint: Worsening Renal Function

Composite of: Sustained* ≥50% reduction in eGFR,

end-stage renal disease (ESRD) or death from renal causes.
Treatment n (%) Hazard ratio (95% CI)

Dapagliflozin 28 (1.2)
0.71 (0.44, 1.16)
p=0.17
Placebo 39 (1.6)

ESRD consisted of sustained eGFR below 15 mL/min/1.73m2, sustained dialysis or kidney transplantation.
*Sustained = 28 days or more
eGFR = estimated glomerular filitration rate.
35 McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France. © AstraZeneca 2019
 Secondary Endpoint: All-cause Death
24

20
Placebo 17% RRR
Cumulative Percentage (%) 16
DAPA HR 0.83 (0.71, 0.97)
p=0.022*

12

0
0 3 6 9 12 15 18 21 24
No. at Risk Months from Randomization
DAPA 2373 2342 2296 2251 2130 1666 1243 672 233
Placebo 2371 2330 2279 2231 2092 1638 1221 665 235
* Nominal p-value.

DAPA = Dapagliflozin; HR = Hazard ratio.

36 McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France. © AstraZeneca 2019
Safety

© AstraZeneca 2019
© AstraZeneca 2019
 Safety/Adverse Events
Patients exposed to at least Dapagliflozin Placebo
one dose of study drug (n=2368) (n=2368) p-value
Adverse events (AE) of interest (%)
Volume depletion+ 7.5 6.8 0.40
Renal AE‡ 6.5 7.2 0.36
Fracture 2.1 2.1 1.00
Amputation 0.5 0.5 1.00
Major hypoglycaemia 0.2 0.2 -
Diabetic ketoacidosis 0.1 0.0 -
AE leading to treatment discontinuation (%) 4.7 4.9 0.79
Any serious adverse event (incl. death) (%) 38 42 <0.01

+
Volume depletion serious AEs in 29 dapagliflozin patients (1.2%) and 40 placebo patients (1.7%), p=0.23
‡
Renal serious AEs in 38 dapagliflozin patients (1.6%) and 65 placebo patients (2.7%), p=0.009

38 McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France. © AstraZeneca 2019
 DAPA-HF Summary
• DAPA-HF is the first heart failure outcomes trial with an SGLT2 inhibitor investigating the treatment of HF
in adults with HFrEF on top of standard of care (which includes medicines such as ACE-I, ARB, β-
blockers, MRA, and ARNI) in patients with and without T2D.1
• Dapagliflozin provided a statistically-significant and clinically meaningful reduction in the risk of
worsening heart failure events and cardiovascular death when compared to placebo, as well as
improvement in heart failure symptoms, when added to standard therapy. 1,2
• The safety findings of DAPA-HF were consistent with the well-established safety profile of dapagliflozin
and the rate of discontinuation was low.1,2

ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; ARNI = angiotensin receptor-neprilysin Inhibitor; β-blockers = beta-blockers; CV = cardiovascular; HF = heart failure; HFrEF = heart failure with reduced
ejection fraction; MRA = mineralocorticoid receptor antagonist; SGLT2 = sodium-glucose cotransporter 2; T2D = type 2 diabetes.
1. AstraZeneca Pharmaceuticals LP press release. Published August 20,2019. 2. McMurray J. Presentation at: European Society of Cardiology Congress. September 1, 2019; Paris, France. © AstraZeneca 2019
DAPA-HF Population Compared to HFrEF Registries and
Trials

© AstraZeneca 2019
 DAPA-HF Compared with HF Registries and Trials
• DAPA-HF study design is a representation of the real-world heart failure population
• Patients in DAPA-HF were also generally similar to those in recent HF trials with globally diverse enrollment
(particularly PARADIGM-HF and ATMOSPHERE)
• In DAPA-HF, 11% of patients were treated with the angiotensin receptor–neprilysin inhibitor combination,
sacubitril/valsartan, a finding consistent with the 13% receiving this therapy in the recent CHAMP-HF registry
• Identical rates of use of all key HFrEF therapies in patients with and without diabetes
– In DAPA-HF, the use of ACE inhibitors, ARBs and MRAs was as high in other patient subgroups, findings which were consistent with
reports from PARADIGM-HF, SHIFT and the ESC Long-Term Registry
– Consistent with other HF studies, patients with a history of T2D in the DAPA-HF trial were treated with oral glucose-lowering therapy
(oral therapy only in 53%), insulin (insulin alone in 12%) or both (15%), with 20% of patients receiving no glucose-lowering therapy

• DAPA-HF has enrolled patients with and without diabetes who have persisting symptoms, a reduced LVEF and an
elevated NT-proBNP level, who are similar to those enrolled in contemporary HFrEF registries and randomized in other
recent HFrEF trials

ACE = angiotensin-converting enzyme; ARB = angiotensin-receptor blocker; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection
fraction; MRA = mineralocorticoid receptor antagonist; NT pro-BNP = N-terminal pro-B-type natriuretic peptide.

1. McMurray JJV et al. Eur J Heart Fail. 2019;doi: 10.1002/ejhf.1548. Accessed July 16, 2019.
41 © AstraZeneca 2019
 Baseline Characteristics in Contemporary HF Registries & DAPA-HF
ESC Long Term Registry ASIAN-HF CHAMP-HF DAPA-HF
(n = 5460) (n =5276) (n = 3494) (n =4744)
Mean age, years 64 60 66 66
Female sex, n (%) 22 22 29 23
Median BMI, kg/m2 28 25 30 27
Mean systolic BP, mmHg 122 118 121 122
Mean heart rate, bpm 73 80 74 72
Mean LVEF, % 29 28 30 31
NYHA Class III/IV, % 31 33 32 32
Ischemic etiology, % 49 47 40 56
Diabetes, % 32 40 41 42
Atrial Fibrillation, % 37 18 36 40
Diuretic, % 84 82 61a 93
ACEi/ARB, % 92 75 73b 94b
Beta-blocker, % 93 79 83 96
MRA, % 68 59 33 71
Digoxin, % 24 31 14 19
Ivabradine, % 10 NR 1 5
ARNI, % 0 0 13 11

a
Loop diuretic only.
b
Includes sacubitril/valsartan.
ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor–neprilysin inhibitor; BP = blood pressure; bpm = beats per minute; BMI = body mass index; CHAMP-HF
= Change the Management of Patients with Heart Failure; DAPA-HF = Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure; ESC = European Society of Cardiology; HF = heart failure; LVEF= left
ventricular ejection fraction; MRA = mineralocorticoid receptor antagonist; NR = not reported; NYHA = New York Heart Association.
42 © AstraZeneca 2019
1. McMurray JJV et al. Eur J Heart Fail. 2019;doi: 10.1002/ejhf.1548. Accessed July 16, 2019.
DAPA-HF: In Context With Other HFrEF Outcome Trials

DAPA-HF and EMPEROR-Reduced Study Designs

DAPA-HF and PARADIGM-HF Comparison

© AstraZeneca 2019
 DAPA-HF and EMPEROR-Reduced Study Designs
DAPA-HF1 EMPEROR-Reduced2,3
• Patients ≥18 years of age with NYHA class II-IV heart failure with • Patients ≥18 years of age (Japan: ≥20 years of age) with NYHA class II-IV
reduced EF (<40%) and elevated NT-proBNP (HFrEF) heart failure with Reduced EF (<40%) and elevated
Patient population • eGFR ≥30 mL/min/1.73 m2 NT-proBNP (HFrEF)
• eGFR ≥20 mL/min/1.73 m2

Sample size N=4744 N=~3600

Study duration 24 months 38 months
Time to first occurrence of any component of the composite: Time to the first occurrence of any of the components of the composite:
• CV death • CV death
Primary outcome • hHF • hHF
• an urgent HF visit

• Time to first occurrence of either of the components of the • Total number of hHF
composite: CV death or hHF • eGFR slope change from baseline
• Total number of hHF and CV death • Time to occurrence of sustained reduction of eGFR
• Change in KCCQ at 8 months • Time to first hHF
Secondary • Time to the composite of ≥50% decline in eGFR, reaching ESRD or • Time to CV death
outcomes renal death • Time to all-cause mortality
• All-cause mortality • Time to diabetes onset
• Change in KCCQ at 12 months
• Total all-cause hospitalization

Background • Stable SoC HFrEF treatment • Stable SoC HFrEF treatment

Therapy

Status • COMPLETED • 2020

CV = cardiovascular; EF = ejection fraction; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; HF = heart failure; HFrEF = heart failure with reduced
ejection fraction; hHF = hospitalization for heart failure; KCCQ = Kansas City Cardiomyopathy Questionnaire; NT-proBNP = N-terminal proB-type natriuretic peptide; NYHA =
New York Heart Association.
1. https://clinicaltrials.gov/ct2/show/record/NCT03036124. Accessed August 20, 2019; 2. https://clinicaltrials.gov/ct2/show/record/NCT03057977. Accessed July 16, 2019; 3.
44 Anker SD et al. Abstract presented at: EASD Annual Meeting; October 1-5, 2018; Berlin, Germany. Abs 666. © AstraZeneca 2019
 DAPA-HF & PARADIGM-HF Comparison
STUDY DAPA-HF (N=4744)1,2 PARADIGM-HF (N=8442)1,3,4
Interventions • DAPA 10 mg/PBO (1:1) • Sacubitril-valsartan 200 mg BID/Enalapril 10 mg BID (1:1)
• ≥18 years of age
• NYHA class II-IV LVEF ≤40% (amended to ≤35% in December 2010)
• ≥18 years of age
• ACEI or ARB, beta-blocker (unless contraindicated or not tolerated) and MRA, if
• NYHA class II-IV HFrEF (<40%) > 2 months
indicated
• Elevated NT-proBNP ≥ 600 pg/ml
• BNP >150 pg/mL or NT-proBNP >600 pg/mL
• T2D and non-diabetes (T1D excluded)
• patients hospitalized in the preceding 12 months were eligible with a lower level:
• eGFR ≥30 mL/min/1.73 m2
BNP >100 pg/mL or NT-proBNP >400 pg/mL
Patient Population • eGFR ≥30 mL/min/1.73 m2
• Time to first occurrence of any of the components of the composite: CV death or hHF • Composite of CV death or first hHF
Primary Endpoint or an urgent HF visit
• Time to first occurrence of either of the components of the composite: CV death or • Death from any cause
hHF • Change in KCCQ at 8 mo
• Total number of hHF and CV death • Time to new onset of atrial fibrillation
• Change in KCCQ at 8 months • Renal composite of ESRD or eGFR reduction of ≥50% or eGFR reduction of >30
• Time to first occurrence of any of the components of the composite: ≥50% sustained mL/min/1.73 m2 to <60 mL/min/1.73 m2
Secondary Endpoints decline in eGFR or reaching ESRD or renal death
• 32% NYHA functional class III/IV • 24% NYHA functional class III/IV
• KCCQ: 68 • KCCQ: 73
• LVEF: 31% • LVEF: 29%
• NT-proBNP: 1437 pg/ml • NT-proBNP: 1615 pg/ml
HF Characteristics • Prior hHF: 47% • Prior hHF: 63%
• Hx of T2D: 42% • Hx of T2D: 34%
• BMI: 27 kg/m2 • BMI: 28 kg/m2
• Prior MI/Coronary Revasc:44% MI, 34% PCI and 17% CABG • Prior MI/Coronary Revasc: 43% for MI, 21% for PCI and 15% for CABG
• Hx of Stroke/HTN: 10%/74% • Hx of Stroke/HTN: 9%/71%
History & Co-Morbidity • Mean eGFR: 66 ml/min/1.73m2 • Mean eGFR: 68 ml/min/1.73m2
• Beta Blocker: 96%
• Beta Blocker:93%
• Digoxin:19%
• Digoxin:30%
• MRA: 71%
• MRA: 60%
• ACEi/ARB:94%
• ACEi/ARB:100%
• Diuretics:93%
• Diuretics:80%
Background Therapy • ARNI: 11%
Study Duration • 24 months • 4 years (early termination due to trial efficacy)
Status COMPLETED3 COMPLETED

This chart does not imply comparable or superior efficacy/safety profiles. Each study was placebo-controlled and no direct comparisons to other SGLT-2is were included. Please refer to study publications and
ClinicalTrials.gov for additional information.
1. McMurray JJV et al. Article and supplementary appendix. Eur J Heart Fail. 2019;doi: 10.1002/ejhf.1548. Access July 16, 2019. 2. https://clinicaltrials.gov/ct2/show/record/NCT03036124. Accessed August 20, 2019; 3. McMurray
45 JJV et al. N Engl J Med. 2014;371:993-1004; 4. https://clinicaltrials.gov/ct2/show/NCT01035255. Accessed August 30, 2019. © AstraZeneca 2019
Dapagliflozin HFpEF: In Context With Other HF Outcome
Trials

DELIVER Study Design

DELIVER and EMPEROR-Preserved Study Designs

© AstraZeneca 2019
 DELIVER:
Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure

4,700 Patients Placebo

• ≥40 years of age
+ standard of care

randomization
• Diagnosis of symptomatic HF (NYHA
functional class II-IV) and typical
signs/symptoms of HF ≥ 6 weeks before

1:1
enrollment with at least intermittent need for
diuretic treatment
• LVEF >40% and evidence of structural heart
disease within 12 months of enrollment Dapagliflozin 10 mg
• Elevated NT-proBNP levels + standard of care
• Both ambulatory and hospitalized patients off
IV HF therapy for 24 hours may be enrolled

Primary Endpoint Secondary Endpoints

• Time to first occurrence of any components of the • Total number of (first and recurrent) hospitalizations for HF and CV death
composite: CV death, hHF, urgent HF visit • Change from baseline in the total symptom score of the KCCQ at 8 months
• Proportion of patients with worsened NYHA class from baseline to 8 months
• Time to the occurrence of death from any cause

Estimated Completion: June 2021

BNP = B-type natriuretic peptide; hHF = hospitalization for heart failure; IV = intravenous; KCCQ = Kansas City Cardiomyopathy Questionnaire; LVEF = left ventricular ejection
fraction; NYHA = New York Heart Association.
47 ClinicalTrials.gov website. Identifier NCT03619213. Accessed March 7, 2019. © AstraZeneca 2019
 DELIVER and EMPEROR-Preserved Study Designs
DELIVER1 EMPEROR-Preserved2-4
• Patients ≥40 years of age with symptomatic NYHA class II-IV heart failure • Patients ≥18 years of age (Japan: ≥20 years of age) with NYHA class II-IV heart failure
and a medical history of symptoms/signs of HF present ≥6 weeks before • elevated NT-proBNP levels
enrollment with at least intermittent need for diuretics • LVEF >40% (HFpEF)
Patient population • Elevated NT-proBNP levels • Structural heart disease within 6 months or hHF within 12 months
• LVEF >40% (HFpEF) • eGFRa ≥20 mL/min/1.73 m2
• Evidence of structural heart disease documented within the last 12 months • Stable dose of diuretics, if prescribed
• eGFRa ≥25 mL/min/1.73 m2

Sample size N=~4700 N=~5250

Study duration 33 months 38 months

Time to first occurrence of any component of the composite: Time to first occurrence of any component of the composite:
• CV death • CV death
Primary outcome • hHF • hHF
• an urgent HF visit

• Total first and recurrent hHF and CV death • Occurrence of first and recurrent hHF
• Change from baseline in KCCQ at 8 months • eGFRa slope of change from baseline
• Proportion of patients with worsened NYHA class from baseline to 8 months • Time to first occurrence of sustained reduction of eGFR, chronic dialysis, or renal
• Time to all-cause mortality transplant
• Time to first hHF
Secondary outcomes
• Time to CV death
• Time to all-cause mortality
• Time to diabetes onset
• Change from baseline in KCCQ at 52 weeks
• Occurrence of all-cause hospitalization

Background Therapy • Stable SoC treatment • Stable SoC treatment

Status • 2021 • 2020

a
Based on the Chronic Kidney Disease-Epidemiology Collaboration Equation.
CV = cardiovascular; EF = ejection fraction; eGFR = estimated glomerular filtration rate; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; hHF = hospitalization for heart failure; KCCQ
= Kansas City Cardiomyopathy Questionnaire; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal proB-type natriuretic peptide; NYHA = New York Heart Association.
1. https://clinicaltrials.gov/ct2/show/record/NCT03619213. Accessed July 16, 2019; 2. https://clinicaltrials.gov/ct2/show/record/NCT03057951. Accessed July 16, 2019; 3. Butler et al. Eur J Heart Fail.
48 2018;20(Suppl S1):P972; 4. Anker SD et al. Abstract presented at: EASD Annual Meeting; October 1-5, 2018; Berlin, Germany. Abs 666. © AstraZeneca 2019