CURRICULUM VITAE

SALLY AMAN NASUTION, MD, FINASIM, FACP

- Born in Medan, 8th August 1967

- Internist – Cardiologist

- Faculty Member Division of Cardiology, Department of Internal Medicine at Faculty of Medicine Universitas Indonesia, Jakarta

- Head of Intensive Coronary Care Unit (ICCU), Integrated Cardiac Services Cipto Mangunkusumo National General Hospital Jakarta

- President of the Indonesian Society of Internal Medicine

1

A Second Revolution in The Prevention of Cardiovascular Disease in Type 2 Diabetes

Dr dr SALLY AMAN NASUTION, SpPD-KKV, FINASIM, FACP

Division of Cardiology Department of Internal Medicine

Faculty of Medicine Universitas Indonesia

Cipto Mangunkusumo National General Hospital

Jakarta

HF was the first manifestation of T2D-relatedCV disease more often than was MI or stroke

16.2%

14.1%

11.5%10.3%

4.2%

PAD HF* NFMI CVA CV death

% e

ven

t as f

irst

CV

even

t

Cohort study of patients (n=1.9 million) with T2D

and incidence of CV disease

• In this large cohort, PAD and HF were the

two most common first presentations of

T2D-related CV disease

• Yet, myocardial infarction and stroke

continue to be chosen as primary outcomes

of major type 2 diabetes trials, as part of

the MACE endpoint

• This suggests that future studies should

assess CV events that occur earlier in

patients with T2D such as HF and PAD

CV, cardiovascular; CVA, cerebrovascular accident; HF, heart failure; NFMI, nonfatal myocardial infarction; PAD, peripheral arterial disease; T2D, type 2 diabetes.

Shah AD, et al. Lancet Diabetes Endocrinol. 2015;3:105-113, Appendix.

*Heart failure post MI was not included in this definition of HF

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Patients with HF are at risk for morbid and fatal events

CV = cardiovascular; HF = heart failure; hHF = hospitalization for heart failure.

1. Lloyd-Jones D et al. Circulation. 2002;106:3068-3072; 2. Vos T et al. Lancet. 2017;390:1211-1259; 3. Westphal JG et al. Interact Cardiovasc Thorac Surg. 2018;27:921-930; 4. Mamas MA et al. Eur J Heart Fail. 2017;19:1095-1104.

• As many as one in five people will develop HF during their lifetime.1

• HF was estimated to affect ~64 million people worldwide in 2016.2

• HF morbidity and mortality rates are high despite advances in therapy.3

• HF remains as malignant as some of the common cancers in both men and women.4

– HF survival was worse than prostate cancer survival in men and worse than breast cancer survival in women.

0%

20%

40%

60%

80%

100%

Pro

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(1 y

ear)

0%

20%

40%

60%

80%

100%

Pro

bab

ilit

y o

f su

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(1 y

ear)

Men

Women

Prostate Lung Colorectal Bladder HF

Breast Colorectal Lung Ovarian HF

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T2D increases the risk of developing HF symptoms and HF hospitalizations

HF = heart failure; T2D = type 2 diabetes.

Rørth R et al. Diabetes Care. 2018;41:1285-1291.

Development of heart failure Heart failure hospitalization

50

Cu

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in

cid

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(%

)

45

40

35

30

25

20

15

10

5

0

0 4321

Years since randomization

P<0.0001

50

Cu

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in

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(%

)

45

40

35

30

25

20

15

10

5

0

0 4321

Years since randomization

Diabetes

No diabetesP<0.0001

Diabetes

No diabetes

© AstraZeneca 2019

Diabetes can lead to HF through both atherosclerotic-mediated and atherosclerotic-independent mechanisms

HF = heart failure; T2D = type 2 diabetes.

1. de Simone G et al. J Hypertens. 2010;28:353-360; 2. Redfield MM. N Engl J Med. 2016;375:1868-1877.

Patients with T2D are at risk of HF,

partially due to atherosclerotic events like

myocardial infarctions1

HEART

FAILURE

Patients with T2D are also at risk of HF

due to direct inflammatory effect in the

microvascular endothelium and

myocardium with subsequent fibrosis2

When choosing an antidiabetic therapy, the impact on HF merits consideration

Class Study Impact on HF

Insulin Review of diabetes registry from Kaiser Permanente Northwest

Registry (n=8063) looking at incident HF diagnosis1

Increase >2-fold increase*

SU(2nd generation)

Analysis of UK General Practice Research Database

(n=91,521) looking at first occurrence of HF2

Increase HR 1.18 – 1.30

(P=0.01 and P<0.001)†

TZD Meta-analysis of patients with prediabetes and diabetes

(n=20,191). HF defined as requiring admission to hospital3Increase RR 1.72 [1.21-2.42]

(P=0.002)

DPP-4 Meta-analysis of RCT with DPP-4 inhibitors. HF defined as

requiring hospitalisation4

Increase OR 1.19 [1.03-1.37]

(P=0.015)

GLP-1 Meta-analysis of four CV outcome studies with GLP-1 receptor

antagonists. HF was defined as hospitalisation for HF5

No impact HR 0.93 [0.83-1.04]

(P=0.20)

*When insulin was added compared to when either metformin or SU was added. **Compared to metformin monotherapy.

CV, cardiovascular; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; HF, heart failure; HR, hazard ratio; OR, odds ratio; RCT, randomised

controlled trial; RR, relative risk.

1. Nichols GA, et al. Diabetes Metab Res Rev. 2005;21:51-57. 2. Tzoulaki I, et al. BMJ. 2009;339:b4731. 3. Lago RM, et al. Lancet. 2007; 370:1129-1136.

4. Monami M, et al. Nutr Meta Cardiovasc Dis. 2014;24:689-697. 5. Bethel MA, et al. Lancet Diabetes Endocrinol. 2018;6:105-113.

In CVD-REAL Nordic, dapagliflozin was associated with lower risk of

CV events compared with DPP4 inhibitors in a real-world clinical

setting

CI, confidence interval; CV, cardiovascular; DPP-4, dipeptidyl peptidase-4; hHF, heart failure hospitalisation; HR, hazard ratio; MACE, major adverse cardiovascular events

Persson F, et al. Diabetes Obes Metab 2018;20:344–351

MACE

Dapagliflozin vs DPP4 inhibitor

hHF

Dapagliflozin vs DPP4 inhibitor

Cu

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(%

) HR (95% Cl):

0.62 (0.50, 0.77)

0

0.0 0.5 1.0 1.5 2.0

1

2

3

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5

6

0.0 0.5 1.0 1.5 2.0

0

1

2

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HR (95% Cl):

0.79 (0.67, 0.94)

DPP4 inhibitor Dapagliflozin

DECLARE-TIMI 58 resulted in early cardio-protection for

T2DM patients

© AstraZeneca 2019

DECLARE-TIMI 58: Broad CV risk population & 2 clinically relevant and important CV primary endpoints in T2D1-3

aMedian follow-up times: CANVAS – 2.4yrs;4 EMPA-REG OUTCOME – 3.1yrs5; bDefined 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.

ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; GLD = glucose-lowering drug; hHF = hospitalization for heart failure; MACE = major adverse cardiovacular event; MI = myocardial infarction; T2D = type 2 diabetes.

1. Wiviott SD et al. N Engl J Med. 2019;380:347-357; 2. Raz I et al. Diabetes Obes Metab 2018;20:1102–1110; 3. Wiviott SD et al. Am Heart J 2018;200:83–89; 4. Neal B et al. N Engl J Med 2017;377:644–657; 5. Zinman B et al. N Engl J Med 2015;373:2117–2128.

Prior to the first interim analysis, the clinically relevant secondary endpoint of hHF was elevated to a composite primary

endpoint of hHF and CV death

DECLARE provides a comprehensive assessment of the impact of dapagliflozin on common and clinically important

diabetes-related CV events

Placebo

Dapagliflozin (10 mg per day)

1:1

Do

ub

le-b

lin

dT2D, ≥40 years plus:

Multiple (≥2) risk factors OR

Established ASCVD

N=17,160

Add on to background CV and GLD per treating physician

Follow-up visits every 6 months; phone contact every 3 months

Event-driven duration, with median follow-up of 4.2 yearsa

Pri

ma

ry E

nd

po

ints CV death, MI, stroke (MACE)

Hospitalization for heart failure

or CV death

Composite endpoint of

Composite endpoint of

Secondary Endpoints• Renal composite endpointb

• All-cause mortality

© AstraZeneca 2019

The majority of T2D patients in the DECLARE-TIMI 58 trial are in an earlier stage of the CV and renal risk continuum and at lower CV risk

a eGFR Calculations: DECLARE CKD; EPI CANVAS MDRD; EMPA-REG MDRD; b Based on a pre-final version of the database (N=7034).

ASCVD = atherosclerotic cardiovascular disease; BMI = body mass index; CV = cardiovascular; DAPA = dapagliflozin; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin; SD = standard deviation; T2D = type 2 diabetes.

1. Raz I, et al. Diabetes Obes Metab. 2018;20:1102-1110. 2. Wiviott SD et al. N Engl J Med. 2019;380:347-357; 3. Zinman B, et al. Supplementary appendix. N Engl J Med 2015;373:2117–2128 4. Zinman B et al. Cardiovasc Diabetol. 2014;13:102. http://dx.doi.org/10.1186/1475-2840-13-102. 5. Neal B, et al. N Engl J Med. 2017;377:644-657.

DECLARE CANVAS EMPA-REG

eGFR, mean (mL/min/1.73 m2) 85.2 76.5 74b

Micro-/macro-albuminuria (%) 30.2 30.2 39.6

Baseline

Characteristics

DAPA

(N=8,582)

Placebo

(N=8,578)

Age, years, mean (SD) 63.9 (6.8) 64.0 (6.8)

BMI, kg/m2, mean (SD) 32.1 (6.0) 32.0 (6.1)

HbA1c, %, mean (SD) 8.3 (1.2) 8.3 (1.2)

eGFR, mean (SD) 85.4 (15.8) 85.1 (16.0)

Multiple risk factors, n (%) 10,186 (59.4%)

Est. ASCVD, n (%) 6974 (40.6%)

The patients in the DECLARE1,2

trial had better baseline renal

function than the EMPA-REG

OUTCOME3,4 or CANVAS5 trialsa

≥40 years old with established

ASCVD: ischemic heart disease,

peripheral artery disease, or

cerebrovascular disease

Multiple (≥2) risk factors ≥55-year-old males and ≥60-year-old

females plus

at least one of the following:

dyslipidemia, hypertension, or current

smokingDECLARE included

patients with T2D

and either:

© AstraZeneca 2019

Baseline medication use in the DECLARE-TIMI 58 trial

ASCVD = atherosclerotic cardiovascular disease; ACEI = angiotensin converting-enzyme inhibitor; ARB = angiotensin-receptor blocker.

Raz I et al. Diabetes Obes Metab. 2018;20:1102-1110.

~60%

≥ 2 risk factors

~40%

ASCVD 39.1%

82.2%

71.1%

66.6%

77.7%

Diuretics

Statins

Aspirin

Beta-blockers

ACEI/ARB

38.2%

63.7%

39.1%

32.3%

76.7%

Diuretics

Statins

Aspirin

Beta-blockers

ACEI/ARB

Patient mix

© AstraZeneca 2019

DECLARE has the largest T2D primary prevention population among the

SGLT2 inhibitor CVOTs to date

ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; CVOT = cardiovascular outcome trial; MACE = major adverse cardiovascular event; MRF = multiple risk factors; SGLT2 = sodium glucose cotransporter 2; T2D = type 2 diabetes

1. Einarson TR et al. Cardiovasc Diabetol 2018:17:83; 2. Zinman B, et al. Article and online supplement. 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. N Engl J Med. 2019;380:347-357.

CANVAS3

DECLARE4,5

>99% ASCVDN=6964

EMPA-REG OUTCOME2

~65.6% ASCVDN=6656

~34.4% MRFN=3486

(N=7020)

(N=10,142)

(N=17,160)~40.6% ASCVD

N=6974

~59.4% MRFN=10,186

In the T2D patient population, most patients do not have established CV disease1

Placebo MACE rate

43.9/1000 pt-yrs

Placebo MACE rate

24.2/1000 pt-yrs

Placebo MACE rate

31.5/1000 pt-yrs

DECLARE demonstrated

CV safety with

dapagliflozin in this

broad CV risk T2D

population earlier in the

CV risk continuum5

© AstraZeneca 2019

Dapagliflozin patients in DECLARE had significant reduction in the composite of hHF/CV death and fewer MACE compared to placebo

N at risk is the number of subjects at risk at the beginning of the period. 2-sided p-value is displayed; HR, CI, and p-value are from cox proportional hazard model.

CV = cardiovascular; CVD = cardiovascular disease; DAPA = dapagliflozin; hHF = hospitalization for heart failure; MACE = major adverse cardiovacular event

Wiviott SD et al. N Engl J Med. 2019;380:347-357

8582 8466 8303 8166 8017 7873 7708 7237 52258578 8433 8281 8129 7969 7805 7649 7137 5158

N at riskDP

Days from Randomization

Cu

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(%

)

10

9

8

7

6

5

4

3

2

1

0

1440126010809007205403601800

DAPA 10 mg (756 Events)

Placebo (803 Events)

MACE

HR 95% CI p-value

0.83 (0.73, 0.95) 0.005

Cu

mu

lati

ve

In

cid

en

ce

(%

)

8582 8517 8415 8322 8224 8110 7970 7497 54458578 8485 8387 8259 8127 8003 7880 7367 5362

N at risk

DP

6

5

4

3

2

1

0

1440126010809007205403601800

DAPA 10 mg (417 Events)

Placebo (496 Events)

Days from Randomization

hHF/CV death

HR 95% CI p-value

0.93 (0.84, 1.03) 0.17

© AstraZeneca 2019

CI = confidence interval; DAPA = dapagliflozin; hHF = hospitalization for heart failure; HR = hazard ratio; N = number of patients.

In House Data, AstraZeneca Pharmaceuticals LP. CSR D1693C00001.

0 6 12 18 24 30 36 42 48 54 60

Months from Randomization

Cu

mu

lati

ve

%

4

2

1

0

3

N at risk

535873607874799881218256838084828578Placebo

543974897965810182188315840385098582DAPA 10 mg

1572

1626

HR (95% CI) p-value

0.73 (0.61, 0.88) <0.001

DAPA 10 mg (212 Events)

Placebo (286 Events)

DECLARE showed that dapagliflozin prevents hHF in a T2D population

© AstraZeneca 2019

Dapagliflozin prevents hHF regardless of history of HF or ejection fraction in patients with T2D

aDefined as EF <45% or severe/moderate LV systolic dysfunction, with or without history of HF. CV = cardiovascular; EF = ejection fraction; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; hHF = hospitalization for heart failure; LV = left ventricular.

1. Wiviott SD et al. N Engl J Med. 2019;380:347-357; 2. Kato ET et al. Online ahead of print. Circulation. 2019.

10% of patients in DECLARE had prior HF

0 0.5 1 1.5

0.73 (0.55, 0.96)

Hazard ratio (95% CI)

Favors

Dapagliflozin

Favors

Placebo

hHF: history of HF1

0.73 (0.58, 0.92)

Prior HF

No Prior HF

0 0.5 1 1.5

0.64 (0.43, 0.95)

Hazard ratio (95% CI)

Favors

Dapagliflozin

Favors

Placebo

hHF: ejection fraction2

0.76 (0.62, 0.92)

HFrEFa

Not HFrEF

- HF without known

reduced EF

- No history of HF

0.72 (0.50, 1.04)

0.77 (0.60, 0.97)

3.9% of patients in DECLARE had HFrEFa

© AstraZeneca 2019

The CV benefits of dapagliflozin appear early in T2D patients with HFrEFa

aDefined as EF <45% or severe/moderate LV systolic dysfunction, with or without history of HF. CV = cardiovascular; DAPA = dapagliflozin; EF =ejection fraction; HFrEF = heart failure with reduced ejection fraction; hHF = hospitalization for heart failure; HR = hazard ratio; LV = left ventricular; NNT = number needed to treat; PBO = placebo; T2D = type 2 diabetes; yrs = years.

Kato ET et al. Online ahead of print. Circulation. 2019.

Cu

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Rate

(%

) P

ati

en

ts w

ith

HF

rEF

a

DAPA PBO

30

25

20

15

10

5

0

0 180 360 540 720 900 1080 1260 1440

NNT (4yrs) = 11

20

15

10

5

0

0 180 360 540 720 900 1080 1260 1440

NNT (4yrs) = 16

20

0

15

10

5

0 180 360 540 720 900 1080 1260 1440

NNT (4yrs) = 19

0 180 360 540 720 900 1080 1260 1440

30

25

20

15

10

5

0

NNT (4yrs) = 18

hHF/CV death hHF CV death All-cause mortality

HR 95% CI

0.62 (0.45,

0.86)

HR 95% CI

0.64 (0.43,

0.95)

HR 95% CI

0.55 (0.34,

0.90)

HR 95% CI

0.59 (0.40,

0.88)

Days DaysDays Days

© AstraZeneca 2019

In high CV risk T2D patients with prior MI, dapagliflozin reduced MACE by 16% with a 4-year NNT of 39

Prior MI was a prespecified subgroup of interest in DECLARE TIMI-58. CV = cardiovascular; DAPA = dapagliflozin; HR = hazard ratio; MACE = major adverse cardiovascular events; MI = myocardial infarction; NNT = number needed to treat; PBO = placebo; T2D = type 2 diabetes.

Furtado RHM et al. Online ahead of print. Circulation. 2019.

Primary Outcome – MACE

Prior MI - PBO

Prior MI - DAPA

Patients with prior MI

HR (95% CI) = 0.84 (0.72 to 0.99)

Patients without prior MI

HR (95% CI) = 1.00 (0.88 to 1.13)

Absolute risk reduction (pts with events)

2.6% (prior MI) vs. 0% (no prior MI)

20%

15%

10%

5%

0%

360 720 1080 1440

Days

No Prior MI - PBONo Prior MI - DAPA

DAPA has a clear

beneficial MACE

outcome in high

CV risk T2D

patients with prior

MI’s

Cu

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© AstraZeneca 2019

It is clear that SGLT2 inhibitors prevent hHF in a broad group of T2D patients and reduce MACE only in high risk patients with ASCVD

ASCVD = atherosclerotic CV disease; CV = cardiovascular; FE = fixed effects; hHF = hospitalized for heart failure; HR = hazard ratio; MACE = major cardiovascular adverse event; MRF = multiple risk factors; SGLT2 = sodium glucose co-transporter 2; T2D = type 2 diabetes.

1. Zelniker TA et al. Article and supplementary appendix. Lancet. 2019;393:31-39; 2. Einarson TR et al. Cardiovasc Diabetol. 2018;17:83.

MACEhHF

0 0.5 1 1.5

EMPA-REG

CANVAS

DECLARE

0.65 (0.50, 0.85)

0.71 (0.62, 0.82)

0.64 (0.35, 1.15)

0.64 (0.46, 0.88)

0.68 (0.51, 0.90)

0.78 (0.63, 0.97)

FE Model for ASCVD

Multiple risk factors1

CANVAS

DECLARE

FE Model for MRF 0.64 (0.48, 0.85)

EMPA-REG No MRF patients

0 0.5 1 1.5

EMPA-REG

CANVAS

DECLARE

0.86 (0.74, 0.99)

0.86 (0.80, 0.93)

0.98 (0.74, 1.30)

1.01 (0.86, 1.20)

0.82 (0.72, 0.95)

0.90 (0.79, 1.02)

FE Model for ASCVD

Multiple risk factors1

CANVAS

DECLARE

FE Model for MRF 1.00 (0.87, 1.16)

EMPA-REG No MRF patients

Established ASCVD1 HR (95% CI) HR (95% CI)Established ASCVD1

Globally CV disease affects only about 30% of patients with T2D2

Favors placeboFavors treatment Favors placeboFavors treatment

© AstraZeneca 2019

Prior MI < 2 years ago

Prior MI

ASCVD but no prior MI

Primary Prevention

Pump, pipes and filter: dapagliflozin covers it all

ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; hHF = hospitalization for heart failure; MACE = major adverse cardiovascular events; MI = myocardial infarction; NNT = number needed to treat; T2D = type 2 diabetes.

1. Verma S et al. Online ahead of print. Circulation. 2019; 2. Furtado RHM et al. Online ahead of print. Circulation. 2019.

MACE hHF/CV

deathRENAL

–

–

Effects of dapagliflozin 10mg vs placebo1

T2D population in DECLARE

NNT 4

years2 = 39

NNT 4

years2 = 53

© AstraZeneca 2019

DECLARE results are key for adults with T2D in the 2019 ACC/AHACV Disease Primary Prevention Guideline

ACC = American College of Cardiology; AHA = American Heart Association; ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; GLP-1 RA = glucagon-like peptide-1; HF = heart failure; RCT = randomized controlled trials; SGLT2 = sodium-glucose co-transporter 2; T2D = type 2 diabetes.

Arnett DK et al. In press. J Am Coll Cardiol. 2019.

ACC/AHA Guideline on

Primary Prevention of

CV Disease

“Three RCTs have shown a

significant reduction in

ASCVD events and HF with

the use of an SGLT2

inhibitor. Although most

patients studied had

established ASCVD at

baseline, the reduction in

HF has been shown to

extend to primary

prevention populations.”

• Recommendations are expanding from secondary

to primary prevention of CV disease

• HF prevention benefit with SGLT2 inhibitors is

acknowledged in primary prevention populations

• SGLT2 inhibitors or GLP-1 receptor agonists may be

initiated in patients with T2D and additional ASCVD

risk factors who require glucose-lowering therapy

despite initial metformin therapy

2019 ESC Guidelines on diabetes, pre-diabetes,and cardiovascular diseases

ESC Guidelines onwith E

ovascular diseases in collaboration- doi/10.1093/eurheartj/ehz486)www.escardio.org/guidelines

C S©E

Diabetes, pre-diabetes and cardi Eur Heart Journal 2019 –ASD (European Heart Journal 2019 doi/10.1093/eurheartj/ezh486

New treatment algorithms

© AstraZeneca 2019

Summary and Conclusions

• HF represents a substantial global burden with significant unmet needs in terms of morbidity and

mortality. T2D is a major risk factor for the development of HF, which occurs early and is often

undetected in patients with T2D

• In DECLARE, dapagliflozin demonstrated cardiorenal protection (reductions in the composite of

hHF/CV death) and confirmed its well-established safety profile in a landmark trial of over 17,000

patients across 4.2 years, in a broad population representative of the everyday T2D patients

• DECLARE analyses support the consistency of the effect of dapagliflozin on hHF outcomes, and

show a robust effect on MACE in a high-risk prior MI subgroup

• With DECLARE, dapagliflozin provides the evidence for early cardiorenal event prevention beyond

glucose control in T2D

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