DECLARE-TIMI 58

Study Design

DECLARE-TIMI 58, Dapagliflozin Effect on CardiovascuLAR Events – Thrombolysis In Myocardial Infarction 58

 A Multinational, Randomized, Double-blind, Placebo-controlled, Phase IIIb Cardiovascular Outcomes Trial

Study Design1,2,3

Double-blind
17,160 patientsa Dapagliflozin 10 mg daily
T2D (6.5% ≤ HbA1c <12%),

1:1
≥55 yrs (men) or ≥60 yrs
(women) with ≥1 CV risk factor
OR ≥40 yrs with ASCVD Placebo daily
All other glucose-lowering agents per treating
physician

S Single-blind PBO run-in R Event-driven duration: ≥1390 MACE

(1-2 months) Median follow-up: 4.2 years

Primary safety endpoint Secondary endpoints Additional safety endpoints Data monitoring committee
• Composite of CV death, nonfatal
• Renal composite endpoint • Malignancies (eg, bladder cancer) • Periodically review safety
MI, or nonfatal ischemic stroke
(sustained ≥40% decrease in • Liver eventsb • Two preplanned efficacy reviews
(MACE)
eGFR to eGFR <60 mL/min/1.73 • DKA eventsb • Assess bladder cancer every
Primary efficacy endpoints m2 and/or ESRD and/or renal or CV • Amputations 8 events
• MACE death) • Fractures
• Composite of hospitalization for • All-cause mortality
heart failure or CV death
aA total of 17,190 patients were randomized; however, 30 patients were excluded from all analyses because of significant good clinical practice violations at a single site for a different trial; bBlinded adjudication of events.
ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; DKA, diabetic ketoacidosis; eGFR, estimated glomerular filtration rate; ESRD = end-stage renal disease; HbA1c, glycated hemoglobin;
MACE, major adverse cardiovascular events; MI, myocardial infarction; PBO, placebo; R, randomization; S, screening; T2D, type 2 diabetes; yrs, years.
1. Raz I et al. Diabetes Obes Metab. 2018;20:1102-1110; 2. Wiviott SD et al. Am Heart J. 2018;200:83-89; 3. Wiviott SD et al. N Engl J Med. 2019;380:347-357.
 DECLARE-TIMI 58
Primary Efficacy Endpoints

DECLARE-TIMI 58, Dapagliflozin Effect on CardiovascuLAR Events – Thrombolysis In Myocardial Infarction 58

Primary Endpoint: Composite of hHF or CV Death
6
HR 95% CI p-value Placebo (496 Events)
(superiority)

5 0.83 (0.73, 0.95) 0.005

DAPA 10 mg (417 Events)

Cumulative Incidence (%)

4

17%
2
RRR
1

0
0 180 360 540 720 900 1080 1260 1440
Days
No. at Risk
DAPA 10 mg 8582 8517 8415 8322 8224 8110 7970 7497 5445
Placebo 8578 8485 8387 8259 8127 8003 7880 7367 5362
CV, cardiovascular; DAPA, dapagliflozin; hHF, hospitalization for heart failure.
Wiviott SD et al. New Engl J Med. 2019;380:347-357.
© AstraZeneca 2019
Primary Endpoint
Composite of hHF or CV death and the Individual Components

Number of events

DAPA 10 mg Placebo
(N=8582) (N=8578) HR (95%CI) p-value

17%
Composite of hHF/CV death 417 496 0.83 (0.73, 0.95) 0.005 RRR

Hospitalization for HF
27%
212 286 0.73 (0.61, 0.88)
RRR

CV death 245 249 0.98 (0.82, 1.17)

0.6 0.7 0.8 0.9 1.0 1.1 1.2

Favors Favors
DAPA Placebo
Two-sided p-value is shown for the primary efficacy composite outcome of CV death or hHF.
CV, cardiovascular; DAPA, dapagliflozin; HF, heart failure; hHF, hospitalization for heart failure.
Wiviott SD et al. New Engl J Med. 2019;380:347-357. © AstraZeneca 2019
DECLARE-TIMI 58
Heart Failure Subgroup analysis
38%
RRR
 45%
RRR

36%
RRR
41%
RRR
 DECLARE-TIMI 58
MI Subgroup

DECLARE-TIMI 58, Dapagliflozin Effect on CardiovascuLAR Events – Thrombolysis In Myocardial Infarction 58

MACE Outcomes in Patients with Prior MI:
DECLARE Prior MI Subgroup Analysis

20
HR (95%CI) P value P interaction
Prior MI 0.84 (0.72, 0.99) 0.039 Prior MI PBO: 17.8%
0.11
No Prior MI 1.00 (0.88, 1.13) 0.97
Prior MI DAPA: 15.2%
15
Cumulative Incidence,

16%
10 RRR
%

No Prior MI PBO: 7.1%

No Prior MI DAPA: 7.1%

0
360 720 1080 1440

Days
No. at risk

Prior MI-PBO 1807 1698 1607 1498 989

Prior MI-DAPA 1777 1687 1591 1504 1011
No Prior MI-PBO 6771 6583 6362 6151 4169
No Prior MI-DAPA 6805 6616 6426 6204 4214

Prior MI was a pre-specified subgroup of interest in DECLARE TIMI-58

CV = cardiovascular; DAPA = dapagliflozin; HR = hazard ratio; MACE = major adverse cardiovascular event; MI = myocardial infarction; NNT = number needed to treat;
No. = number; PBO = placebo.
Furtado RHM et al. Online ahead of print. Circulation. 2019. Accessed March 18, 2019.
 MACE Outcomes Stratified by Time from Last MI: DECLARE
Prior MI Subgroup Analysis

DAPA (%/N) PBO %/N HR (95 % CI) P-interaction

(trend)

Overall 15.2%/1777 17.8%/1807 0.84 (0.72 to 0.99)

≤ 12 months 13.8%/217 20.3%/271 0.66 (0.42 to 1.03)

> 12 to 24 months 11.8%/169 25.7%/187 0.42 (0.25 to 0.71) 0.007

> 24 to 36 months 15.8%/158 18.8%/181 0.83 (0.50 to 1.40)

>36 months 15.8%/1233 15.8%/1167 1.01 (0.82 to 1.23)

0.25 2.50

DAPA Better PBO Better

In patients with previous MI, the effect of dapagliflozin to reduce the risk of MACE appeared greatest if
instituted within first 24 months after MI

CV = cardiovascular; DAPA = dapagliflozin; HR = hazard ratio; MACE = major adverse cardiac event; MI = myocardial infarction; PBO = placebo.
Furtado RHM et al. Online ahead of print. Circulation. 2019. Accessed March 18, 2019.
DECLARE-TIMI 58
Secondary Efficacy and Other Endpoints
Secondary Endpoint: Renal Composite Endpoint

6
HR 95% CI p-value
(nominal)2
Placebo (480 Events)
5 0.76 (0.67, 0.87) <0.001

Cumulative Incidence (%)1

DAPA 10 mg (370 Events)
4

3
24%
RRR
2 Renal
composite
with CV
death
1

0
0 180 360 540 720 900 1080 1260 1440
Days
No. at Risk
DAPA 10 mg 8582 8533 8436 8347 8248 8136 8009 7534 5472
Placebo 8578 8508 8422 8326 8200 8056 7932 7409 5389
Renal composite endpoint defined as confirmed sustained eGFR decrease ≥40% to eGFR <60 mL/min/1.73 m 2 using CKD-EPI equation and/or ESRD (dialysis ≥90 days or kidney transplantation, confirmed sustained
eGFR <15 mL/min/1.73 m2) and/or renal or CV death. CV, cardiovascular; DAPA, dapagliflozin; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HR, hazard ratio.
1. Wiviott SD et al. New Engl J Med. 2019;380:347-357; 2. Wiviott SD et al. Presented at: AHA Scientific Sessions; November 10, 2018. Chicago, IL.
© AstraZeneca 2019
Renal Composites and All-cause Mortality

DAPA 10 mg Placebo Hazard ratio

Outcome
(N=8582) (N=8578) (95% CI)
24%
Renal composites, % RRR
Renal
composite
≥40% decrease in eGFR to <60 mL/min/1.73 m2, with CV
4.3 5.6 0.76 (0.67,0.87) death
ESRD, or death from renal or cardiovascular cause, %a
≥40% decrease in eGFR to <60 mL/min/1.73 m2,
1.5 2.8 0.53 (0.43, 0.66)
ESRD, or death from renal cause, %b 47%
RRR
All-cause mortality, % 6.2 6.6 0.93 (0.82, 1.04) Renal
Composite
without CV
death

Secondary renal composite outcome; bPrespecified additional renal composite outcome.

a

DAPA, dapagliflozin; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease.
Wiviott SD et al. New Engl J Med. 2019;380:347-357. © AstraZeneca 2019
Updated ACC/AHA CV Disease Primary Prevention Guidelines in T2DM
 R EG CANVAS
PA- DEC
EM L AR
E

Zelnikker SGLT2Is CVOTs Meta-analysis

Finally, The guideline references SGLT-2is and GLP-1 receptor agonists as the only two classes to be used post metformin for the
primary prevention of CV disease in patients with T2D.
 SGLT2Is Information
Parameter Dapagliflazin¹ Empagliflozin²

Method of Dapagliflozin can be taken orally Empagliflozin should be taken orally

Administration /
Food Interaction once daily at any time of day with or once a day at the morning with or
without food without food
Given 10 mg once daily initially, but if
Dose Titration No dose titration is required (Given 10 tighter glycemic control is needed, dose
mg once daily) titrated to 25 mg daily, if patients well
tolerating 10 mg dose
Can be given in mild, moderate hepatic Can be given in mild, moderate hepatic
Use in Patients impairment at normal dose; in severe impairment at normal doses, but not
with Hepatic
Impairment
hepatic impairment, starting dose of 5 recommended in severe hepatic
mg is recommended, and if tolerated, impairment
may be increased to 10 mg

Bone Fracture No evidence of increased fracture rates No evidence of increased fracture rates

Lower Limb
Amputations
No increased risk No increased risk

1. Dapagliflozin SmPC. 2. Empagliflozin SmPC

 SGLT2Is Information

Parameter Dapagliflazin¹ Empagliflozin2

Largest experience with more
Worldwide Clinical Experience than 1.5 million patients Less experience
worldwide
The first SGLT2I with 4 years
Long Term Clinical Evidence
long term clinical evidence vs No long term efficacy data vs SU
vs SUs
SUs
52 weeks efficacy data in addition
The only SGLTI with 104 weeks
Long term use in addition to to multiple daily insulin
follow up in addition to multiple
Insulins 78 weeks efficacy data in addition
daily Insulins
to basal insulin only
Only SGLT2I approved as add
Add on to GLP1 RA Evidence on to GLP1 RA in Saudi No Yet Indicated

The only SGLT2I with evidence

to be used safely during
Use in Ramadan Evidence⁴ Ramadan (Reference for No DATA
SGLT2Is usage in IDF-DAR
Guidelines)
The only approved SGLT2I/Oral
medication for adults with T1DM
Use in T1DM (EMA & Japan approvals - Not Yet Indicated
2019)

1. Dapagliflozin SmPC. 2. Empagliflozin SmPC

 SGLT2i HF Data
Parameters Dapagliflazin Empagliflozin
Dapa HF
4744 Patient w/w out Diabetes
HFrEF (EF≤40%) Announced ESC2019 Emperor Reduced
outcome trials Published NEJM September Ongoing (June 2020)
2019

HFpEF (EF>40%) Deliver Emperor Preserved

outcome trials 4700 patients ongoing Ongoing

Mechanistic Trials
Define HF
HFrEF Biomarkers (NT- 263 Patients W/W out Diabetes
Announced AHA 2019 Not Studied
ProBNP)
Published in AHA circulation

Preserved HF
HFpEF Biomarkers (NT- Not Studied
320 Patients W/W out Diabetes
ProBNP)
Ongoing (Feb 2021)
DETERMINE-Reduced
312 Patients W/W out Diabetes Emperial-Reduced
HFrEF (6MWD)
Ongoing (Feb 2020) Announced (December 2019)

DETERMINE-Preserved
500 Patient W/W out Diabetes Emperial-Preserved
HFpEF (6MWD) Ongoing (July 2020) Announced (December 2019)
 Dapa HF Outcomes
Parameter Dapa HF
Number of patients 4744 (actual)
Intervention DAPA 10 mg vs PBO
Background SOC
Key inclusion criteria: general  Age ≥18 years
 eGFRa ≥30 mL/min/1.73 m2
Key inclusion criteria: HF status  NYHA class II-IV ≥2 mo
 LVEF ≤40% within last 12 mo
 Elevated NT-proBNP
 Optimized/stable HF therapy ≥4 wk
Key inclusion criteria: glycemic status  With or without T2D
Key exclusion criteria  T1D
 MI, UA, stroke, TIA, or CV procedure/surgery within 12 wk
 Acute decompensated HF
 SBP <95 mm Hg or symptomatic hypotension
 Recent treatment/intolerance to SGLT2 inhibitor

Primary endpoint  Time to first occurrence of any component of the composite of a

worsening HF event (hHF or urgent HF visit) or CV death ;RRR 26%
(p=0.00001)
Secondary endpoints  Composite of hHF or CV death; RRR 25% (p=0.00002)

 Total recurrent hHF and CV deaths; RRR 25% (p=0.0002)

 Change from BL in TSS of KCCQ at 8 month 2.8 points (p<0.001)

 Renal composite of ≥50% sustained eGFR reduction, ESRD, d or renal
death; RRR 29% (p=0.17)

 Death from any cause; RRR 17% (p=0.022)

 DECLARE Results Key to the Updated ACC/AHA CV Disease Primary Prevention
Guidelines in T2DM

In just over 3 months, the landmark results of DECLARE-TIMI 58 Trial “Dapagliflozin and Cardiovascular Outcomes in Type 2
Diabetes” have played a pivotal role in helping change clinical practice, as evidence by 17 th March 2019 updates to the 2019
American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Primary Prevention of Cardiovascular
Disease.
For the first time, SGLT-2 inhibitors are acknowledged in this guideline recommending these medicines be used in the primary
prevention of CV disease in patients with type-2 diabetes (T2D), calling out their important role in preventing heart failure.

Specifically, the guideline references DECLARE-TIMI 58, CANVAS and EMPA-REG by stating: “Three RCTs have shown a significant
reduction in ASCVD events and heart failure with use of an SGLT-2 inhibitor.”
 
Additionally, DECLARE-TIMI 58 is referenced in the following: “Although most patients studied had established CVD at baseline,
the reduction in heart failure has been shown to extend to primary prevention populations.”

 
http://www.onlinejacc.org/content/early/2019/03/13/j.jacc.2019.03.016
 
https://www.ahajournals.org/doi/10.1161/CIR.0000000000000678
THANK YOU

© AstraZeneca 2019