DECLARE TIMI Result:

from Glycemic Control to Cardio Renal Benefit

Mencermati Hasil Penelitian DECLARE TIMI-58:

dari Kontrol Glikemik menuju Ke Manfaat Kardio Renal

Made Ratna Saraswati

Divisi Endokrinologi dan Metabolisme, Departemen/SMF Penyakit Dalam

Fakultas Kedokteran Universitas Udayana, Denpasar Bali

Disampaikan pada Malang Endocrinology Update (MEU) 13 April 2019

 Disclosure information

Made Ratna Saraswati

has received speaker fees from: AztraZeneca, Boehringer Ingelheim, Elli Lilly, PT. Merck Tbk,
MSD, Novo Nordisk, Sanofi (PT Aventis Pharma), Servier;
has taken part in advisory boards for Novo Nordisk, Sanofi, Boehringer Ingelheim, and AstraZeneca;
and received research grant from AztraZeneca.
Point of view

 Burden of Diabetes

 CVOT in Diabetes – where do we go from here?

 DECLARE – TIMI 58

 From CVOT Result to Guideline

 Mechanistic Action of SGLT2i in Cardio – Renal Protection

Point of view

 Burden of Diabetes

 CVOT in Diabetes – where do we go from here?

 DECLARE – TIMI 58

 From CVOT Result to Guideline

 Mechanistic Action of SGLT2i in Cardio – Renal Protection

 Diabetes adalah penyakit yang progresif

UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with
conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853.
 Renal and cardiovascular disease are interconnected and should be
considered together

Renal and cardiac systems are linked1 CKD patients are more likely to die of
heart disease than advance to ESRD2
3.5

3
3

Rate per 100 person-years

2.5

1.5

0.5
0.5

0
ESRD CV
death

Therefore renal and cardiac systems and outcomes should be considered together
CKD, chronic kidney disease; CV, cardiovascular; ESRD, end-stage renal disease.
6 1. Ronco C, et al. J Am Coll Cardiol. 2008;52:1527. 2. Dalrymple L, et al. J Gen Intern Med. 2011;26:379.
 Rate of eGFR decline is significantly associated with risk of CV mortality in
patients with type 2 diabetes

CV survival according to yearly eGFR change • This study assessed the association
between renal function patterns and the
occurrence of CV events in 1,040
patients with type 2 diabetes
Probability of cardiovascular survival

1.0

0.8
• Rapid renal function deterioration was
defined as an eGFR slope ≥-5
Rapid renal function deterioration
0.6 mL/min/1.73 m2/year.
• A more rapid renal function decline was
0.4
associated with a higher risk of
occurrence of CV death
0.2
Change in eGFR slope of less then ≥-5mL/min/1.73 m2/year
Change in eGFR slope of <-5mL/min/1.73 m2/year
0
0 10 20 30 40 50 60 70 80

Time (months)

CV, cardiovascular; eGFR, estimated glomerular filtration rate; SCr, serum creatinine.
7 Ragot S, et al. Diabetes Care. 2016;39:1259-1266.
 Lower eGFR and higher albuminuria independently predict CV mortality
in patients with CKD, a pattern that is worse in patients with DKD

Cardiovascular mortality according to eGFR in Cardiovascular mortality according to ACR

participants with and without diabetes in participants with and without diabetes
8 8

Adjusted hazard ratio

Adjusted hazard ratio

4 4

2 2

1.5 1.5

1 1

0 0
15 30 45 60 75 90 105 120 2.5 5 10 30 300 1000
eGFR (mL/min per 1.73 m2) ACR (mg/g)
Diabetes Non-diabetes

ACR, albumin:creatinine ratio; CV, cardiovascular; eGFR, estimated glomerular filtration rate; T2D, type 2 diabetes; DKD, diabetic kidney disease.
8 Fox C, et al. Lancet. 2012;380:1662-1674.
 Mortality improvement has been seen in major CV disease and
atherosclerosis but not heart failure or arrhythmia
Data from the US National Health Interview Survey was used to analyse follow-up of 677,051 adults over a mean
period of 11.8 years
100
Change in mortality per 1000 person-

80
With diabetes
60 Without diabetes
years over 10 years (%)

40

20

-20

-40

-60 P=0.011 P=0.067 P=0.564 P=0.809 P=0.325

-80 Major CV Heart

IHD Stroke Arrhythmia
disease failure
-100

CV, cardiovascular; IHD, ischaemic heart disease.

Cheng YJ, et al. Diabetes Care. 2018. 2018;41:2306-2315.
 Myocardial damage leading to LV dysfunction and HF is an early
and often undetected complication of T2D1,2
68% of patients with T2D had evidence of Undiagnosed HF was detected in 28% of patients*
LV dysfunction 5 years after T2D diagnosis1 with diabetes (n=581) during cardiac screening2

Diastolic LVD
n=61 Heart
Normal LV 16% failure
function (HFpEF) 23%
n=124 32%
Heart
failure 5%
27% Systolic LVD 72% No heart
n=106 (HFrEF) failure

Systolic and 25%

diastolic LVD
n=95

Patients had no evidence of inducible ischaemia

HF is an early and forgotten complication of T2D patients1,2

*Western European cohort.
HF, heart failure; HFpEF, HF with preserved ejection fraction; HFrEF, HF with reduced ejection fraction; LV, left ventricular; LVD, LV dysfunction; T2D, type 2 diabetes.
1. Faden G, et al. Diabetes Res Clin Pract. 2013;101:309-316. 2. Boonman-de Winter LJ, et al. Diabetologia. 2012;55:2154-2162.
Diabetes can lead to HF through both atherosclerotic-
mediated and atherosclerotic-independent mechanisms

Patients with T2D are at risk for

atherosclerotic events like MIs,
which result in HFrEF due to
myocardial wall damage1
HEART
FAILURE

Patients with T2D are also at risk of HF

due to direct inflammatory effect in
the microvascular and myocardium
with subsequent fibrosis2

HF, heart failure; HFrEF, heart failure with reduced ejection fraction; T2D, type 2 diabetes.
1. de Simone G, et al. J Hypertens. 2010;28(2):353–360. 2. Redfield MM. N Engl J Med. 2016;375:1868-1877.
Point of view

 Burden of Diabetes

 CVOT in Diabetes – where do we go from here?

 DECLARE – TIMI 58

 From CVOT Result to Guideline

 Mechanistic Action of SGLT2i in Cardio – Renal Protection

•• For outcome clinical trials, in order to exclude
unacceptable CV risk, a two-sided 95 % CI upper
boundary of 1.8 risk ratio (pre-approval) and/or 1.3
risk ratio (post-approval) for major adverse events
(MACE) versus control group is required.

•• To satisfy the new statistical requirements, CV event

analysis might include a meta-analysis of all
placebocontrolled, add-on (drug vs. placebo, plus
standard therapy) and active-controlled trials, and/or an
additional single, large, safety CVOT can be conducted.

This, alone or in addition to other trials, needs to satisfy

the upper bound mentioned above before
approval.
Schnell O, Rydén L, Standl E, Ceriello A, on behalf of the D&CVD EASD
Study Group. Current perspectives on cardiovascular outcome trials in
diabetes. Diabetol (2016) 15:139. DOI 10.1186/s12933-016-0456-8.
Figrure. Completed and ongoing CVOTs
3-P= 3 point, 4-P= 4 point, DECLARE-TIMI 58=Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events, ESRD=end stage renal disease,
HARMONY Outcome= Effect of Albiglutide, When Added to Standard Blood Glucose Lowering Therapies on Major Cardiovascular Events in Subjects With Type 2 Diabetes Mellitus,
PIONEER 6= A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes, REWIND= Researching Cardiovascular Events With A Weekly
Incretin in Diabetes, VERTIS CV= Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Diasease

Cefalu WT et al. Cardiovascular Outcome Trials on Type 2 Diabetes: Where Do We Go From Here? Reflections From a Diabetes Care Editors’ Expert Forum.
Diabetes Care 2018;41:14-31.
Limitations of current CVOT structure
and opportunities for improvement
Point of view

 Burden of Diabetes

 CVOT in Diabetes – where do we go from here?

 DECLARE – TIMI 58

 From CVOT Result to Guideline

 Mechanistic Action of SGLT2i in Cardio – Renal Protection

 DECLARE assessed dapagliflozin’s CV and renal outcomes in a broad
population of T2D patients with eCVD and multiple risk factors1-4

17,160 patients Primary end points

Multiple (≥2) risk factors  Composite of CV death, MI,
 ≥55-year-old males and stroke (MACE)
≥60-year-old females plus Dapagliflozin  Composite of CV death or
 at least one of the following: (10 mg per day) hospitalization for heart failure

Double-blind

End points
dyslipidaemia, hypertension, or
T2D
current smoking Secondary endpoint
and
Renal end points
either: ≥40 years old with established
atherosclerotic CV disease: Confirmed sustained
 ischaemic heart disease, Placebo ≥40% decrease in eGFR to eGFR
 peripheral artery disease, or <60 mL/min/1.73 m2 and/or ESRD
 cerebrovascular disease and/or renal or CV death

Median duration ~4.2 years

• The mean eGFR* was 86.1 mL/min/1.73 m2, including 1,565 patients with eGFR <60 mL/min/1.73 m2.

*eGFR was calculated using the MDRD formula.

CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; MACE, major adverse cardiovascular event (CV death, nonfatal MI, and nonfatal stroke);
MI, myocardial infarction; T2D; type 2 diabetes.
1. AstraZeneca; https://clinicaltrials.gov/ct2/show/NCT01730534. 2. Raz I, et al. Diabetes Obes Metab. 2018;20(5):1102-1110. 3. Wiviott SD, et al. Am Heart J. 2018;200:83-89.4. Wiviott
SD et al. Online ahead of print. N Engl J Med. 2018
17
 The majority of T2D patients in the DECLARE trial are in an earlier stage
of the CV risk continuum and have better renal function

Multiple (≥2) risk factors Baseline Dapa Placebo

 ≥55-year-old males and ≥60-year-old Characteristics (N=8,582) (N=8,578)
females plus
 at least one of the following: dyslipidemia, Age, years, mean (SD) 63.9 (6.8) 64.0 (6.8)
hypertension or current smoking
DECLARE included BMI, kg/m2, mean (SD) 32.1 (6.0) 32.0 (6.1)
patients with T2D
HbA1c, %, mean (SD) 8.3 (1.2) 8.3 (1.2)
and either:
≥40 years old with established eGFR, mean (SD) 85.4 (15.8) 85.1 (16.0)
atherosclerotic CV disease:
 ischemic heart disease, Multiple risk factors, n (%) 10,186 (59.4%)
 peripheral artery disease, or
 cerebrovascular disease Est CV disease, n (%) 6,974 (40.6%)

The patients in the DECLARE1,2 DECLARE CANVAS EMPA-REG

trial had better baseline renal
eGFR, mean (mL/min/1.73 m2) 85.2 76.5 74.1
function than the EMPA-REG
OUTCOME3 or CANVAS4 trials* Micro-/macro-albuminuria (%) 30.2 30.2 40.6
* eGFR Calculations:
BMI, body mass index; CV, cardiovascular; CVD, cardiovascular disease; Dapa, dapagliflozin;
DECLARE CKD EPI
eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; SD, standard deviation; T2D, type 2 diabetes.
CANVAS MDRD
1. Raz I, et al. Diabetes Obes Metab. 2018;20:1102-1110. 2. Wiviott SD et al. Online ahead of print. N Engl J Med. 2018 .
EMPA-REG MDRD
19 3. Zinman B, et al. N Engl J Med. 2015;373:2117-2128. 4. Neal B, et al. N Engl J Med. 2017;377:644-657.
 DECLARE has the largest proportion and numbers of T2D patients
at low CV risk among the SGLT-2i CV outcomes studies to date
In the T2D patient population, most patients do not have established CV disease1

EMPA-REG OUTCOME2
(N=7,020)
>99% eCVD Placebo MACE rate
N=~6,950
43.9/1000 pt-yrs

CANVAS3
(N=10,142)
~65.6% eCVD ~34.4% MRF Placebo MACE rate
N=6,656 N=3,486
31.5/1000 pt-yrs

DECLARE4,5
(N=17,160)
~40.6% eCVD ~59.4% MRF Placebo MACE rate
N=6,974 N=10,186
24.2/1000 pt-yrs

CV, cardiovascular; eCVD, established CV disease; MACE, major CV events; SGLT-2i, sodium glucose co-transporter 2 inhibitor; T2D, type 2 diabetes
1. Einarson TR, et al. Cardiovasc Diabetol 2018;17:83; 2. Zinman B, et al. N Engl J Med 2015;373:2117–2128; 3. Neal B, et al. N Engl J Med 2017;377:644–657;
4. Raz I, et al. Diabetes Obes Metab 2018;20:1102–1110; 5 Wiviott SD et al. Online ahead of print. N Engl J Med. 2018
 Baseline medications in the DECLARE trial

77%
ACEi/ARB
CV Subgroup 77%

32%
Beta-blockers
~40% 67%
eCVD
39%
Aspirin
~60% 71%

≥2
64%
risk Statins
factors 82%

38%
Diuretics
39%

ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker;

eCVD, established cardiovascular disease.
22 Raz I, et al. Diabetes Obes Metab. 2018;20:1102-1110.
Primary end points

 Composite of CV death, MI, stroke (MACE)

 Composite of CV death or hospitalization for heart failure

Renal end points

Confirmed sustained
≥40% decrease in eGFR to eGFR
<60 mL/min/1.73 m2 and/or ESRD and/or renal or CV death
 For the primary safety outcome of MACE, DAPA was
Primary Endpoint: MACE noninferior to placebo (p<0.001 for noninferiority).

HR 95% CI p-value p-value

(superiority) (noninferiority)
10.0 Placebo (803 Events)
0.93 0.84, 1.03 0.17 <0.001
DAPA 10 mg (756 Events)
Cumulative Incidence (%)
7.5

5.0

2.5

0.0

0 180 360 540 720 900 1080 1260 1440

Days
N at risk
DAPA 10 mg 8582 8466 8303 8166 8017 7873 7708 7237 5225
Placebo 8578 8433 8281 8129 7969 7805 7649 7137 5158

Forxiga is not indicated for CV and Renal outcomes.

N at risk is the number of patients at risk at the beginning of the period.

DAPA, dapgliflozin; MACE, major adverse cardiovascular events.
Wiviott SD et al. Online ahead of print. New Engl J Med. 2018.
 Primary Endpoint:
Composite of MACE and the Individual Components
Number of events

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

MACE 756 803 0.93 (0.84,1.03) 0.17

Cardiovascular death 245 249 0.98 (0.82,1.17)

Myocardial infarction 393 441 0.89 (0.77,1.01)

Ischemic stroke 235 231 1.01 (0.84,1.21)

0.7 0.8 0.9 1.0 1.1 1.2

Forxiga is not indicated for CV and Renal outcomes. Favors Favors
DAPA Placebo
aTwo-sided p-value is shown for the primary efficacy outcome of MACE; p-value for noninferiority was p<0.001.
DAPA, dapagliflozin; MACE, major adverse cardiovascular events.
Wiviott SD et al. Online ahead of print. New Engl J Med. 2018.
 American College of Cardiology
Scientific Meeting 2019

Dapagliflozin and CV outcomes in

patients with type 2 diabetes and prior
myocardial infarction: a sub-analysis
from DECLARE TIMI-58
Remo H. M. Furtado, et al.
On behalf of the DECLARETIMI-58
Executive & Steering Committees and Investigators

NCT01730534
DECLARE TIMI-58 was funded by a grant from AstraZeneca to Brigham and Women’s Hospital
 MACE by time from last MI

Dapagliflozin Placebo P-interaction

HR
% % (trend)

Overall (N = 3,584) 15.2% 17.8% 0.84

≤ 12 months (N = 488) 13.8% 20.3% 0.66

12-24 months (N = 356) 11.8% 25.7% 0.42 0.007

24-36 months (N = 339) 15.8% 18.8% 0.83

> 36 months (N = 2,400) 15.8% 15.8% 1.01

Dapagliflozin better Placebo better

 Primary Endpoint: Composite of hHF or CV Death

6 HR 95% CI p-value Placebo (496 Events)

0.83 (0.73, 0.95) 0.005

Cumulative Incidence (%)
DAPA 10 mg (417 Events)

0 180 360 540 720 900 1080 1260 1440

Days
N at risk
DAPA 10 mg 8582 8517 8415 8322 8224 8110 7970 7497 5445
Placebo 8578 8485 8387 8259 8127 8003 7880 7367 5362

Forxiga is not indicated for CV and Renal outcomes.

N at risk is the number of patients at risk at the beginning of the period.
CV, cardiovascular; DAPA, dapagliflozin; hHF, hospitalization for heart failure.
Wiviott SD et al. Online ahead of print. New Engl J Med. 2018.
 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

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

Hospitalization for HF 212 286 0.73 (0.61, 0.88)

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
Forxiga is not indicated for CV and Renal outcomes. 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. Online ahead of print. New Engl J Med. 2018.
 While SGLT-2i’s reduce MACE in T2D patients with eCVD only,
hHF prevention occurs in a broader group of patients
MACE hHF
Established CVD HR (95% CI) Established CVD HR (95% CI)

EMPA-REG 0.86 (0.74, 0.99) EMPA-REG 0.65 (0.50, 0.85)

CANVAS 0.82 (0.72, 0.95) CANVAS 0.68 (0.51, 0.90)

DECLARE 0.90 (0.79, 1.02) DECLARE 0.78 (0.63, 0.97)

FE Model for eCVD 0.86 (0.80, 0.93) FE Model for eCVD 0.71 (0.62, 0.82)

MRF MRF

CANVAS 0.98 (0.74, 1.30) CANVAS 0.64 (0.35, 1.15)

DECLARE 1.01 (0.86, 1.20) DECLARE 0.64 (0.46, 0.88)

FE Model for MRF 1.00 (0.87, 1.16) FE Model for MRF 0.64 (0.48, 0.85)

0 0.5 1 1.5 0 0.5 1 1.5

Forxiga is not indicated for CV and Renal outcomes.

1. Zinman B, et al. N Engl J Med 2015;373:2117–2128; 2. Neal B, et al. N Engl J Med 2017;377:644–657 3. Wiviott SD et al. Online ahead of print. N Engl J Med. 2018; 4.
33 Zelnicker, T. Online ahead of print Lancet 2018
 Dapagliflozin prevents hHF consistently across a broad range of
T2D patients regardless of history of eCVD or HF

hHF by presence/absence of eCVD hHF by presence/absence of previous HF

Hospitalization for HF Hazard ratio (95% CI) Hospitalization for HF Hazard ratio (95% CI)

Established CV Disease Prior HF*

0.78 (0.63, 0.97) 0.73 (0.55, 0.96)
(eCVD)

Multiple Risk Factors No prior HF

(No eCVD) 0.64 (0.46, 0.88) 0.73 (0.58, 0.92)

0 0.5 1 1.5 0 0.5 1 1.5

Favors Favors Favors Favors

Dapagliflozin Placebo Dapagliflozin Placebo

*10% of patients in DECLARE had prior HF

Forxiga is not indicated for CV and Renal outcomes.

CV, cardiovascular; eCVD, established CV disease; HF, heart failure; hHF, hospitalized heart failure; SGLT-2i, SGLT co-transporter 2 inhibitor; T2D, type 2 diabetes
Wiviott SD et al. Online ahead of print. N Engl J Med. 2018
Effect of Dapagliflozin on Heart Failureand
Mortality in Type 2 DiabetesMellitus
Results form the DECLARE-TIMI 58 Trial

Eri T. Kato, Michael G. Silverman, Ofri Mosenzon, Thomas A. Zelniker, Avivit

Cahn, Remo H.M. Furtado, Julia Kuder, Sabina A. Murphy, Deepak L. Bhatt,
Lawrence A. Leiter, Darren K. McGuire, John P.H. Wilding, Marc P. Bonaca,
Christian T.Ruff, Akshay S.Desai, Shinya Goto, Peter A.Johansson,
Ingrid Gause-Nilsson, Per Johanson, Anna Maria Langkilde, Itamar Raz,
Marc S. Sabatine and Stephen D.Wiviott

On behalf of the DECLARE-TIMI 58Investigators

 Composite of hHF/CV death and components by renal function

hHF/CV death hHF CV death

Hazard ratio (95% CI) Hazard ratio (95% CI) Hazard ratio (95% CI)

Overall population 0.83 (0.73, 0.95)a Overall population 0.73 (0.61, 0.88) Overall population 0.98 (0.82, 1.17)

Baseline eGFRb Baseline eGFRb Baseline eGFRb

≥90 mL/min/1.73 m2 0.96 (0.77, 1.19) ≥90 mL/min/1.73 m2 0.94 (0.69, 1.26) ≥90 mL/min/1.73 m2 1.08 (0.80, 1.44)
60 to <90 mL/min/1.73 m2 0.79 (0.66, 0.95) 60 to <90 mL/min/1.73 m2 0.65 (0.51, 0.84) 60 to <90 mL/min/1.73 m2 0.96 (0.75, 1.24)
<60 mL/min/1.73 m2 0.78 (0.55, 1.09) <60 mL/min/1.73 m2 0.70 (0.44, 1.12) <60 mL/min/1.73 m2 0.90 (0.57, 1.44)

0.25 0.5 0.75 1 1.25 1.5 0.25 0.5 0.75 1 1.25 1.5 0.25 0.5 0.75 1 1.25 1.5

Favors Favors Favors Favors Favors Favors

Dapagliflozin Placebo Dapagliflozin Placebo Dapagliflozin Placebo

Interaction
Interaction Interaction
P value = 0.79
P value = 0.37 P value = 0.19

aP=0.005; bCalculated by the Chronic Kidney Disease Epidemiology Collaboration equation.

CV, cardiovascular; eGFR, estimated glomerular filtration rate; hHF, hospitalization for heart failure.
Wiviott SD et al. Article and supplementary appendix online ahead of print. N Engl J Med. 2018.
Primary end points
 Composite of CV death, MI, stroke (MACE)
 Composite of CV death or hospitalization for heart failure

Secondary end points: Renal end points

Confirmed sustained
≥40% decrease in eGFR to eGFR
<60 mL/min/1.73 m2 and/or ESRD and/or renal or CV death
 Dapagliflozin slowed renal disease progression in T2D patients
with relatively good baseline renal function
The patients in the Renal Composite† Placebo (480 Events)
DECLARE1,2 trial had better
6
baseline renal function than HR 95% CI P value
the EMPA-REG OUTCOME3 or 0.76 (0.67, 0.87) <0.001 (nominal)

Patients with Events (%)

CANVAS4 trials
4

EMPA-REG
DECLARE

CANVAS

DAPA 10 mg (370 Events)

2

eGFR,
mean
(mL/min/1
85.2 76.5 74.1
0
.73m2)
0 6 12 18 24 30 36 42 48 54 60
Micro-
/macro- Months from Randomization
30.2 30.2 40.6 N at risk*
albumin- 8582 8533 8436 8347 8248 8136 8009 7534 5472 1637 DAPA 10 mg
uria (%) 8578 8508 8422 8326 8200 8056 7932 7409 5389 1589 Placebo
Forxiga is not indicated for CV and Renal outcomes.
†Renal composite endpoint defined as sustained confirmed eGFR decrease ≥ 40% to eGFR < 60 ml/min/1.73m2 using CKD-EPI equation and/or ESRD (dialysis ≥ 90 days or kidney transplantation,
sustained confirmed eGFR < 15 ml/min/1.73m2) and/or renal or CV death (pre-specified secondary outcome)
CV, cardiovascular; CKD, chronic kidney disease; Dapa, dapagliflozin; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease
1. Raz I, et al. Diabetes Obes Metab 2018;20:1102–1110; 2. Wiviott SD et al. Online ahead of print. N Engl J Med. 2018; ; 3. Zinman B, et al. N Engl J Med 2015;373:2117–2128; 4. Neal B, et al. N Engl J
Med 2017;377:644–657
 DECLARE-TIMI 58 confirms the well-established safety profile of dapagliflozin
in a broad CV risk population
Adverse Events Dapa 10mg Placebo
(in T2D patients with CV risk) (N=8,574) (N=8,569)
Amputations, % 1.4% 1.3%

DKA (adjudicated), % 0.3% 0.1%

Fractures, % 5.3% 5.1%

Malignancies,% (IR):
• Overall malignancies 5.6% (14.32) 5.7% (14.52)
• Bladder cancer (adjudicated) 0.3% (0.76) 0.5% (1.32)
• Breast cancer (adjudicated) 0.4% (1.05) 0.4% (1.02)

Volume Depletion, % 2.5% 2.4%

Acute Kidney Injury, % 1.5% 2.0%

Genital Infections, % 0.9% 0.1%

UTI’s, % 1.5% 1.6%

Fournier’s Gangrene*, (N) 1 5

Major hypoglycaemia, % 0.7% 1.0%

*blinded review by TIMI/AZ
CV, cardiovascular; dapa, dapagliflozin; DKA, diabetic ketoacidosis; IR, incidence rate per 1000 patient-years; N, number; UTI, urinary tract infection Forxiga is not indicated for CV and Renal outcomes.
Wiviott SD et al. Online ahead of print. N Engl J Med. 2018;
 Conclusion

These data with dapagliflozin from DECLARE- TIMI 58 extend the benefit of SGLT2i to a
broader population of patients for primary and secondary prevention
Forxiga is not indicated for CV and Renal outcomes.

Verma S, Jüni P, Mazer CD, The Lancet 2018, in press

Pump, pipes and filter: dapagliflozin covers it all
Effects of dapagliflozin 10mg vs placebo1,2 MACE hHF/CV death RENAL
Prior MI < 2 years ago

Prior MI
NNT4 years NNT4 years
=39 =53

ASCVD but no prior MI

–
Primary Prevention

–
T2D population in DECLARE
ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; HHF = hospitalization for heart failure; MACE = major adverse cardiovascular events; MI =
myocardial infarction; NNT = number needed to treat.
1. Verma S et al. Online ahead of print. Circulation. 2019; 2. Furtado RHM et al. Online ahead of print. Circulation. 2019. © AstraZeneca 2019
Point of view

 Burden of Diabetes

 CVOT in Diabetes – where do we go from here?

 DECLARE – TIMI 58

 From CVOT Result to Guideline

 Mechanistic Action of SGLT2i in Cardio – Renal Protection

 First line therapy is Metformin and comprehensive lifestyle (including weight management and physical activity
First line therapy
If HbA1c aboveistarget
Metformin and comprehensive
proceed as below lifestyle (including weight management and physical activity
If HbA1c above target proceed as below

Established ASCVD or CKD

The 2018 ADA-EASD T2D consensus report reflects emerging evidence from
GLP-1 RA and SGLT2i CVOTs in patients with established CVD or CKD

First-line therapy is metformin and comprehensive lifestyle modification

(including weight management and physical activity)
If HbA1c above target, proceed as below
CONSENSUS RECOMMENDATIONS

Patients with T2D who have established

ASCVD:
SGLT2 inhibitors or GLP-1 RAs with proven
CV benefit recommended ASCVD HF or CKD
predominates predominates
Patients with ASCVD in whom HF coexists
or is of special concern:
SGLT2 inhibitors recommended PREFERABLY
EITHER/ SGLT2i with evidence of reducing
OR HF and/or CKD progression in CVOTs,
Patients with T2D and CKD, with or if eGFR adequate
without CVD: SGLT2i
Consider SGLT2 inhibitor or, if GLP-1 RA with proven OR
contraindicated/not preferred, GLP-1 RA with proven CVD benefit,
CVD benefit if eGFR If SGLT2i not tolerated or
shown to reduce CKD progression adequate contraindicated or if eGFR less than
adequate, add GLP-1 RA with
proven CVD benefit

ADA, American Diabetes Association; ASCVD, atherosclerotic cardiovascular disease; CANA, canagliflozin; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; CVOTs, cardiovascular
outcome trials; EASD, European Association for the Study of Diabetes; eGFR, estimated glomerular filtration rate; EMPA, empagliflozin; EQW, exenatide once-weekly; ESRD, end-stage renal disease; GLP-1 RA,
glucagon-like peptide-1 receptor agonist; HbA1c, glycated haemoglobin; HF, heart failure; LIRA, liraglutide; SEMA, semaglutide; SGLT2, sodium–glucose co-transporter 2; T2D, type 2 diabetes. Davies MJ, et al.
Online ahead of print. Diabetologia. 2018;61(12):2461-2498.
 ESC guidelines recommend early SGLT2 inhibitor use in patients
with T2D for disease prevention

ESC guidelines recommend early SGLT2 inhibitor use,

along side BP control and statin use

• In DM patients with existing CVD, the use of a sodium-

glucose co-transporter-2 (SGLT2) inhibitor substantially
lessened CVD and total mortality and HF
hospitalization without major adverse effects.
• SGLT2 inhibitors should be considered early in the
course of DM management in such patients

Forxiga is not indicated for CV and Renal outcomes.

BP, blood pressure; CVD, cardiovascular disease; DM, diabetes mellitus; ESC, European Society of Cardiology; HF, heart failure; SGLT2, sodium-glucose cotransporter 2; T2D, type 2 diabetes.
Piepoli MF, et al. Eur Heart J. 2016;37:2315-2381.
Point of view

 Burden of Diabetes

 CVOT in Diabetes – where do we go from here?

 DECLARE – TIMI 58

 From CVOT Result to Guideline

 Mechanistic Action of SGLT2i in Cardio – Renal Protection

 SGLT2 inhibitor ̶ mediated inhibition of sodium reabsorption in
the proximal tubule is renal protective1
2
Natriuresis
leads to
increased
Effects mediated by SGLT2i in the kidney
sodium delivery
to macula Natriuresis
densa1  ↓blood pressure1
3 TGF leads  ↓plasma volume1
to afferent
vasoconstriction,  ↓afterload3
↓ intraglomerular  ↓preload3
pressure and
↓ proteinuria1  ↓LV wall stress3
 ↓intraglomerular hypertension1
1  ↓intraglomerular hyperfiltration1
Blocks proximal
glucose and Glucoresis
sodium
reabsorption1
 ↓HbA1c1
 ↓total body fat mass1
 ↓plasma uric acid1

SGLT2, sodium-glucose cotransporter 2; TGF, tubuloglomerular feedback.

1. Rajasekeran H, et al. Kidney Int. 2016;89;524-526. 2. Alicic RZ, et al. Clin J Am Soc Nephrol. 2017;12:2032-2045. 3. Verma S. JAMA Cardiol. 2017;(9):939-940.
 In contrast to loop diuretics, SGLT2 inhibitors reduce interstitial volume more
so than intravascular volume

SGLT2 inhibitors Loop diuretics

• SGLT2 inhibitors may differentially regulate the interstitial vs intravascular compartment compared with loop diuretics
• Interstitial oedema is evident in patients with congestive heart failure (a)
• SGLT2 inhibitors may selectively reduce interstitial volume with minimal change in blood volume (b) whereas loop diuretics may
cause a reduction in both interstitial and intravascular volume (c)
• This differential volume regulation by SGLT2 inhibitors (interstitial > intravascular) may limit the aberrant reflex neurohumoral
stimulation that occurs in the setting of intravascular depletion SGLT2, sodium-glucose cotransporter 2.
Verma S, McMurray JJV. Diabetologia. 2018;61:2108-2117.
 There are a number of putative mechanisms to explain cardiorenal protection
with SGLT2 inhibitors
SGLT2i

KIDNEY CIRCULATION HEART

SGLT2i causes afferent ↓ Intravascular/ECF volume Reduction in preload, Improvement of

arteriolar constriction, leads to ↑ haematocrit and afterload and LV wall stress myocardial energetics1
decreasing intraglomerular ↓ systolic blood pressure1,2 improve filling conditions1,2
pressure1

Improved renal function2

ECF, extracellular fluid; LV, left ventricular; SGLT2, sodium-glucose cotransporter 2.

1. Verma S, et al. JAMA Cardiol. 2017;2:939-940. 2. Sattar N, et al. Diabetologia. 2016;59:1333-1339.
 Summary
 DECLARE-TIMI 58 is the first T2D CVOT with proven benefit on reducing hHF
and CV death in a large cohort of patients with CV risk factors or
established CV disease.1 DECLARE-TIMI 58 confirmed dapagliflozin known
safety profile including reduction of renal disease progression.
 Dapagliflozin benefits go beyond glucose control; it is both cardio- and
reno-effective for T2D patients as evidenced in the largest, broadest, and
longest SGLT2 inhibitor CVOT, DECLARE TIMI-58.1
 DECLARE results are in line with current guidelines on the prevention and
treatment of HF in patients with T2D. SGLT2 inhibitors should be considered
early in the course of T2D management in HF patients.2

CV, cardiovascular; CVOT, CV outcome trial; hHF, hospitalisation for HF; SGLT2, sodium-glucose cotransporter 2;
T2D, type 2 diabetes.
Forxiga is not indicated for CV and Renal outcomes.
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH,
Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, dan Sabatine MS, for the DECLARE–TIMI 58 Investigators . Dapagliflozin and
Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2019; 380:347-357.
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