Soebagijo Adi S

Endocrine & Metabolic Division – Dep. Of Internal Medicine

Faculty of Medicine Airlangga University

Dr. Soetomo General Academic Hospital - Surabaya

Diabetic Kidney Disease: New Pathways New Treatment

Sympo 13

DECLARE as the largest and broadest CVOT in the SGLT-2i class to date has defined the cardio-renal benefit of dapagliflozin for patients with T2DM

• The DECLARE trial confirms in a broad patient population with good renal function over 4.2 years follow up that dapagliflozin is both renal- and cardio-protective

• DECLARE met its primary endpoint of reduction in hHF/CV death across the entire study population

• Dapagliflozin also demonstrated significant reduction in the prespecified composite secondary renal endpoint, sustained eGFR decrease of >40% to <60mL/min/1.73m2, ESRD, renal or CV death (nominally significant) in a large (n=17,160) and broad population of patients with T2DM and good baseline renal function (mean eGFR of 85.2mL/min/1.73m2). This benefit was demonstrated across eGFR subgroupsand in patients with both eCVD and MRFs

• Both increased albuminuria and declining eGFR are associated with increased CV mortality and risk of renal failure2. There is currently limited therapies to treat diabetic kidney disease and preventing new onset or worsening of diabetic kidney disease progression represents a significant opportunity to reduce both mortality and morbidity of patients with T2DM.

• Diabetic kidney disease is a major contributor to the CKD and renal replacement therapy burden globally3. The use of dapagliflozin early in patients with T2DM will not only control the patient’s HbA1c but also prevent renal disease progression and CV events.

CV, Cardiovascular; eCVD; Established CVD; eGFR, Estimated Glomerular Filtration Rate; ESRD, End Stage Renal Disease; HbA1c, Glycated Haemoglobin; MRF; Multiple Risk Factors, T2DM, Type 2

Diabetes Mellitus

1. Wiviott SD et al. Online ahead of print. N Engl J Med. 2018 2. Fox C, et al. Lancet 2012;380:1662–1674 3. International Diabetes Federation: IDF Diabetes Atlas, ed 7. Brussels, International Diabetes

Federation, 2015.

CKD and its significant economic and societal costs impact 1:10 people globally

3

CKD defined as states 3-5.

CKD, chronic kidney disease.

Hill MI, et al. Diabetes Care. 1992;15(7):815-819.

Canada |

USA

14.44%

Senegal | Congo |

South Africa

7.6%

Iran

11.68%

India | Bangladesh

6.76%

Australia

8.14%

Europe

11.86%Japan |

S Korea |

Oceania

11.73%

China | Taiwan |

Mongolia

10.06%

The number of people requiring RRT is high, and likely to double in just over 15 years due to increases in diabetes prevalence

4

CKD = chronic kidney disease; RRT = renal replacement therapy.

1. Liyanage T et al. Lancet. 2015;385:1975-1982; 2. Webster AC et al. Lancet. 2017;389:1238-1252; 3. International Diabetes Federation. IDF Diabetes Atlas: 8th edition.

1.0

Nu

mb

er

of

pa

tie

nts

re

ce

ivin

g R

RT

(m

illi

on

s)

Asia (0.968-2.162)

North America (0.637-1.260)

Europe (0.532-0.825)

Latin America, Caribbean (0.373-0.903)

Africa (0.083-0.236)

Oceania (0.025-0.053)

2010 2015 2020 2025 2030

3.0

2.0

0

• A 2010 report estimated 2.6 million people

were receiving RRT1

• This same report suggested that

~5 million actually required RRT1

• The number receiving RRT is estimated to

increase to more than 5 million by 20301

• This rise is largely driven by population

ageing and an increasing prevalence of

diabetes and hypertension1

• Diabetes accounts for 30%-50% of all CKD2

• The number of adults with diabetes is

projected to grow from 425 million in 2017 to

to over 600 million by the year 20453

Year

Progress reducing MI and stroke has been made; however, more needs to be done to address the burden of ESRD in T2D

ESRD, end-stage renal disease; T2D, type 2 diabetes.

Gregg EW, et al. N Engl J Med. 2014;370:1514-1523.

Even

ts p

er

10,0

00 a

du

lt p

op

ula

tio

n

wit

h d

iag

no

se

d d

iab

ete

s

Acute MI

Stroke

Amputation

ESRD

Death from hyperglycaemic crisis

Year

150

125

100

75

50

25

4

2

0

1990 1995 2000 2005 2010

6

Renal and cardiovascular disease are interconnected and should be considered together

7

CKD = chronic kidney disease; CV = cardiovascular; ESRD = end-stage renal disease.

1. Ronco C et al. J Am Coll Cardiol. 2008;52:1527-1539; 2. Dalrymple LS et al. J Gen Intern Med. 2011;26:379-385.

Therefore renal and cardiac systems and outcomes should be considered together

CKD patients are more likely to die of

heart disease than advance to ESRD2

Renal and cardiac systems are linked1

0.5

3

0

0.5

1

1.5

2

2.5

3

3.5

Ra

te p

er

10

0 p

ers

on

-ye

ars

ESRD CVdeath

PUMPPIPEFILTER

Lower eGFR and higher albuminuria independently predict CV mortality in patients with CKD, a pattern that is worse in patients with DKD

8

ACR, albumin:creatinine ratio; CV, cardiovascular; eGFR, estimated glomerular filtration rate; T2D, type 2 diabetes; DKD, diabetic kidney disease.

Fox C, et al. Lancet. 2012;380:1662-1674.

Diabetes Non-diabetes

eGFR (mL/min per 1.73 m2)

8

1.5

2

4

1

0

15 30 45 60 75 90 105 120

Ad

jus

ted

ha

za

rd r

ati

o

8

1.5

2

4

1

0

2.5 5 10 30 300 1000

Ad

jus

ted

ha

za

rd r

ati

o

ACR (mg/g)

Cardiovascular mortality according to ACR

in participants with and without diabetes

Cardiovascular mortality according to eGFR in

participants with and without diabetes

CV survival according to yearly eGFR change

Rate of eGFR decline is significantly associated with risk of CV mortality in patients with type 2 diabetes

9

Pro

ba

bilit

y o

f c

ard

iova

sc

ula

r s

urv

iva

l

Time (months)

Rapid renal function deterioration

Change in eGFR slope of <-5mL/min/1.73 m2/year

1.0

0.8

0.6

0.4

0.2

0

0 10 20 30 40 50 60 70 80

Change in eGFR slope of less then ≥-5mL/min/1.73 m2/year

CV, cardiovascular; eGFR, estimated glomerular filtration rate; SCr, serum creatinine.

Ragot S, et al. Diabetes Care. 2016;39:1259-1266.

• This study assessed the association

between renal function patterns and the

occurrence of CV events in 1,040

patients with type 2 diabetes

• Rapid renal function deterioration was

defined as an eGFR slope ≥-5

mL/min/1.73 m2/year.

• A more rapid renal function decline was

associated with a higher risk of

occurrence of CV death

Incidence rates of HF are higher in those with

microalbuminuria compared to those without

Incidence rates of HF are higher in those with CKD

compared to those without

Cu

mu

lati

ve

in

cid

en

ce

of

HF

Years

CKD HFrEF

CKD HFpEF

No CKD HFrEF

No CKD HFpEF

0 2 4 6 8 10 12

Declining renal function is associated with development of incident HF

10

CKD, chronic kidney disease; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.

Nayor M, et al. Eur J Heart Fail. 2017;19:615-623.

8%

6%

4%

2%

0%

Cu

mu

lati

ve

in

cid

en

ce

of

HF

Years

Microalbuminuria HFrEF

Microalbuminuria HFpEF

No microalbuminuria HFrEF

No microalbuminuria HFpEF

0 2 4 6 8 10 12

8%

6%

4%

2%

0%

Conversely, heart failure increases the risk of renal function decline and of adverse renal outcomes

11

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HF, heart failure.

George LK, et al. Circ Heart Fail. 2017;10:e003825.

69

165

14

40

0

20

40

60

80

100

120

140

160

180

Incident CKD Incident CKD or mortality

Inc

ide

nc

e p

er

10

00

pa

tie

nt

yea

rs

With HF Without HF

HF is associated with significantly higher risk of

incident CKD† and incident CKD or mortality

22%

9%

0%

5%

10%

15%

20%

25%

Rapid eGFR decline

Pre

vale

nce

of

rap

id e

GF

Rd

ecli

ne

%

With HF Without HF

HF is associated with a more rapid

decline in eGFR*

*Rapid rate of eGFR decline was defined as slopes steeper than -5 mL/min/1.73 m2/yr †Incident CKD was defined as two eGFR values of <60 mL/min/1.73 m2 occurring

≥3 months apart and a decrease from baseline eGFR of at least 25%.

SGLT2 inhibition blocks the proximal reabsorption of sodium and glucose, resulting in urinary glycosuria and changes in several risk factors1-4

a Dapagliflozin 5 mg and 10 mg

ACE = ace inhibitor; ARB = angiotensin 2 receptor blocker; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin; SGLT2 = sodium–glucose

cotransporter-2; SBP = systolic blood pressure; T2D = type 2 diabetes; urinary albumin to creatine ratio.

1. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. 2. Henry RR, et al. Int J Clin Pract. 2012;66:446-456. 3. Bailey CB, et al. Lancet. 2010;375:2223-2233. 4.

Heerspink HJ et al. Diabetes Obes Metab. 2016;18:590-597; 5. Del Prato S et al. Diabetes Obes Metab. 2015;17:581-590.

HbA1c

SBP

Weight

Proximal tubule

Glucose

Filtration ↑

in T2DSGLT2

Glucose

Sodium

Glucose

Reabsorption

↑ in T2D0.89% decrease from baseline

at 24 weeks1

~3 kg weight loss from baseline

at 24 weeksa,2

5.1 mm Hg reduction from baseline

at 24 weeks3

Modulation of traditional risk factors

Using dapagliflozin 10 mg

Impact on renal function with

dapagliflozin 10 mg

eGFR

UACR

Remains stable out to 4 years5

Improves albuminuria (-33.2%) on

top of ACEi/ARB at 12 weeks4

Glomerular hyperfiltration is well characterized in early diabetes

13

T2D = type 2 diabetes; TGF = tubuloglomerular feedback.

Alicic RZ et al. Clin J Am Soc Nephrol. 2017;12:2032-2045.

• Glomerular hyperfiltration, a consequence

of early diabetes, leads to glomerular

hypertension

• It is observed in up to 40% of patients with

T2D

• Decreased distal delivery of sodium to the

macula densa leads to a decrease in TGF

and dilates the afferent arteriole to

increase glomerular pressure

• Concurrently, high local production of

angiotensin II at the efferent arteriole

produces vasoconstriction

• The overall effect is high intraglomerular

pressure and glomerular hyperfiltration

Normal Diabetes

SGLT2 inhibition has a number of potential direct and downstream effects which may result in improved renal structural architecture and function

14

Na = sodium; SGLT2 = sodium–glucose co-transporter 2; TGF = tubuloglomerular feedback.

Heerspink HJL et al. Kidney Int. 2018;94:26-39.

Tubuloglomerular feedback restoration:

• Inhibits proximal glucose reabsorption

• Blocks proximal sodium reabsorption

• Leads to natriuresis and increased

Na delivery to the macula densa

• TGF constricts the afferent arteriole, resulting in

decreased glomerular hyperfiltration

Additional downstream effects:

• Decreased urinary albumin excretion may reduce

pro-inflammatory pathway activation and direct

tubular toxicity

• Improved cardiac function and increased

hematocrit concentration may result in increased

oxygen delivery to the kidney and improvements in

renal hypoxia

Natriuresis

leads to

increased

sodium delivery

to macula densa

Natriuresis

leads to

increased

sodium delivery

to macula densa

2

Blocks proximal

glucose and

sodium

reabsorption

Blocks proximal

glucose and

sodium

reabsorption

1

TGF leads

to afferent

constriction,

↓ intraglomerular

pressure and

↓ proteinuria

TGF leads

to afferent

constriction,

↓ intraglomerular

pressure and

↓ proteinuria

3

Haemodynamic hypothesis of SGLT2 inhibitor mediated improvement of the cardiorenal axis

15

ECF, extracellular fluid; SGLT2, sodium–glucose co-transporter 2.

Sattar N, et al. Diabetologia. 2016;59:1333-1339.

KIDNEY

↑ Glucose and sodium reabsorption

in proximal tubule

CIRCULATION

↓ Intravascular/ECF volume

↑ Haematocrit

↓ Systolic blood pressure

↑ Urinary

glucose loss

Weight loss

↑ Urinary

sodium loss

Improved TGF

and renal function

HEART (+ LUNGS)

↓ Cardiac afterload

↓ Cardiac preload

↑ Myocardial oxygen supply

± Improved cardiac metabolism?

Improved renal function

2 3

1

4

SGLT2 inhibition and RAAS blockade both reduce glomerular hyperfiltrationby complimentary mechanisms1-3

Na, sodium; RAAS, renin-angiotensin-aldosterone; SGLT2, sodium–glucose co-transporter 2.

1. Van Bommel EJ, et al. Clin J Am Soc Nephrol. 2017;12(4):700-710. 2. Seidu S, et al. Prim Care Diabetes. 2018;12(3):265-283. 3. Cherney DZ, et al. Circulation. 2014;129(5):587-597.4. Heerspink HJ, et al. Diabetes Care. 2011;34 Suppl 2:S325-S329. 5. Adapted from: Shiraishi M, et al. FASEB J. 2003;17(15):2284-2286.

CLINICAL IMPLICATIONS

Efferent vasodilation1

SGLT2 inhibitors

RAAS blockade

• Decreased glomerular pressure1,3

• Reduction in albuminuria1,2

• Decreased glomerular pressure1,3

• Reduction in albuminuria4

Afferent

constriction1-3

Due to increased Na+ delivery

to the macula densa1-3

Efferent arteriole

Afferent arteriole

Bowman’s capsuleGlomerular capillaries

Efferent arteriole

Afferent arteriole

Bowman’s capsuleGlomerular capillaries

16

Renal Outcomes

The DECLARE TIMI-58 Trial

In 2008, FDA required new anti-hyperglycaemic agents to demonstrate CV safety in patients with T2DM1,2

CV, cardiovascular; DPP-4, dipeptidyl peptidase-4; GLD, glucose-lowering drugs; GLP-1, glucagon-like peptide 1; SGLT2, sodium–glucose co-transporter 2; SGLT2i, SGLT2 inhibitor.

1. Neal B, et al. Diabetes Obes Metab. 2017;19:926-935. 2. Cohen D. BMJ. 2010;341:c4848. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Guidance for Industry. Diabetes mellitus—Evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. https://www.fda.gov/downloads/Drugs/Guidances/ucm071627.pdf.

• In December 2008, the US Food and Drug Administration (FDA) issued new guidance describing an enhanced strategy for ensuring the CV safety of drugs marketed for the management of diabetes1

• Three SGLT2i studies have reported1

• In addition to assessing CV safety, impact on renal outcomes was also investigated1,2

18

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

CONSENSUS RECOMMENDATIONS

Patients with T2D who have established

ASCVD:

SGLT2 inhibitors or GLP-1 RAs with proven

CV benefit recommended

Patients with ASCVD in whom HF coexists

or is of special concern:

SGLT2 inhibitors recommended

Patients with T2D and CKD, with or

without CVD:

Consider SGLT2 inhibitor or, if

contraindicated/not preferred, GLP-1 RA

shown to reduce CKD progression

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.

If SGLT2i not tolerated or contraindicated or if eGFR less than

adequate, add GLP-1 RA withproven CVD benefit

HF or CKD predominates

ASCVD predominates

GLP-1 RAwith provenCVD benefit

SGLT2iwith provenCVD benefit,

if eGFRadequate

SGLT2i with evidence of reducingHF and/or CKD progression in CVOTs,

if eGFR adequate

EITHER/OR

OR

PREFERABLY

First-line therapy is metformin and comprehensive lifestyle modification (including weight management and physical activity)

If HbA1c above target, proceed as below

19

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

20

*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. WiviottSD et al. Online ahead of print. N Engl J Med. 2018

≥40 years old with established

atherosclerotic CV disease: ischaemic 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:

dyslipidaemia, hypertension, or

current smokingT2D

and

either:

Dapagliflozin

(10 mg per day)

Placebo

Do

ub

le-b

lin

d

En

d p

oin

ts

Composite of CV death or

hospitalization for heart failure

Composite of CV death, MI,

stroke (MACE)

Primary end points

Median duration ~4.2 years

Confirmed sustained

≥40% decrease in eGFR to eGFR

<60 mL/min/1.73 m2 and/or ESRD

and/or renal or CV death

Renal end points

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

17,160 patients

The majority of T2D patients in the DECLARE trial are in an earlier stage of the CV risk continuum and have better renal function

21

BMI, body mass index; CV, cardiovascular; CVD, cardiovascular disease; 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. 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 CANVAS EMPA-REG

eGFR, mean (mL/min/1.73 m2) 85.2 76.5 74.1

Micro-/macro-albuminuria (%) 30.2 30.2 40.6

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 CV disease, n (%) 6,974 (40.6%)

The patients in the DECLARE1,2

trial had better baseline renal

function than the EMPA-REG

OUTCOME3 or CANVAS4 trials*

≥40 years old with established

atherosclerotic CV disease: 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 smoking

DECLARE included

patients with T2D

and either:

* eGFR Calculations:

DECLARE CKD EPI

CANVAS MDRD

EMPA-REG MDRD

DECLARE has the largest proportion and numbers of T2D patients

at low CV risk among the SGLT-2i CV outcomes studies to date

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

CANVAS3

DECLARE4,5

>99% eCVDN=~6,950

EMPA-REG OUTCOME2

~65.6% eCVDN=6,656

~34.4% MRFN=3,486

(N=7,020)

(N=10,142)

(N=17,160)~40.6% eCVD

N=6,974

~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

9%

51%

40%

19%

56%

25%26%

52%

22%

DECLARE CANVAS EMPA-REG OUTCOME

DECLARE has a greater proportion of T2D patients with normal eGFR than the EMPA-REG OUTCOME or CANVAS trials

eGFR Categories

<60 mL/min/1.73 m2 60 to <90 mL/min/1.73 m2 ≥90 mL/min/1.73 m2

eGFR, estimated glomerular filtration rate1. Raz I, et al. Diabetes Obes Metab 2018;20:1102–1110. 2. Zinman B, et al. N Engl J Med. 2015;373:2117–2128 Appendix. 3. The George Institute. CANVAS Program ADA Scientific Sessions 2017 Study Results Slides. http://www.georgeinstitute.org/sites/default/files/canvas-study-results-ada-2017.pdf (accessed 6 Nov 2018).23

eGFR calculated using CKD-EPI equation

CV, cardiovascular; CKD, chronic kidney disease; Dapa, dapagliflozin; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease

Wiviott SD et al. Online ahead of print. N Engl J Med. 2018

HR 95% CI P value

0.76 (0.67, 0.87) <0.001 (nominal)

Months from Randomization

Pa

tie

nts

wit

h E

ve

nts

(%

)

6

0 6 12 18 24 30 36 42 48 54 60

8582 8533 8436 8347 8248 8136 8009 7534 5472 16378578 8508 8422 8326 8200 8056 7932 7409 5389 1589

N at risk*DAPA 10 mg

Placebo

4

2

0

DAPA 10 mg (370 Events)

Placebo (480 Events)

Dapagliflozin slowed renal disease progression in T2D patients with good baseline renal function

† Renal composite endpoint

defined as:

Sustained confirmed eGFR

decrease ≥ 40% to eGFR < 60

ml/min/1.73m2 and/or

ESRD (dialysis ≥ 90 days or

kidney transplantation, sustained

confirmed eGFR < 15

ml/min/1.73m2) and/or

renal or CV death

Renal Composite †

© AstraZeneca 2018

INTERNAL MEDICAL USE ONLY

Renal Composites and All-cause Mortality

aSecondary renal composite outcome; bPrespecified additional renal composite outcome.

DAPA, dapagliflozin; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease.

Wiviott SD et al. Online ahead of print. New Engl J Med. 2018.

OutcomeDAPA 10 mg

(N=8582)

Placebo

(N=8578)

Hazard ratio

(95% CI)

Renal composites, %

≥40% decrease in eGFR to <60 mL/min/1.73 m2,

ESRD, or death from renal or cardiovascular cause, %a4.3 5.6 0.76 (0.67,0.87)

≥40% decrease in eGFR to <60 mL/min/1.73 m2,

ESRD, or death from renal cause, %b1.5 2.8 0.53 (0.43, 0.66)

All-cause mortality, % 6.2 6.6 0.93 (0.82, 1.04)

26

The renal protective effects of dapagliflozin were consistent across baseline eGFR subgroups

aCalculated by the Chronic Kidney Disease Epidemiology Collaboration equation; bSecondary outcome; cPrespecified additional renal composite outcome.

CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease.

Wiviott SD et al. Article and supplementary appendix online ahead of print. N Engl J Med. 2018.

Overall population

≥90 mL/min/1.73 m2

60 to <90 mL/min/1.73 m2

<60 mL/min/1.73 m2

0.25 0.5 0.75 1 1.25 1.5

Hazard ratio (95% CI)

Favors

Dapagliflozin

Favors

Placebo

Composite of ≥40% decrease in eGFRa to

<60 mL/min/1.73 m2, ESRD, or renal death or CV deathb

0.79 (0.63, 0.99)

0.76 (0.63, 0.93)

0.77 (0.54, 1.09)

Baseline eGFRa

0.76 (0.67, 0.87) Overall population

≥90 mL/min/1.73 m2

60 to <90 mL/min/1.73 m2

<60 mL/min/1.73 m2

0.25 0.5 0.75 1 1.25 1.5

Hazard ratio (95% CI)

Favors

Dapagliflozin

Favors

Placebo

Composite of ≥40% decrease in eGFRa to

<60 mL/min/1.73 m2, ESRD, or renal deathc

0.50 (0.34, 0.73)

0.54 (0.40, 0.73)

0.60 (0.35, 1.02)

Baseline eGFRa

0.53 (0.43, 0.66)

Interaction

P value = 0.97

Interaction

P value = 0.87

The renal protective effects of dapagliflozin were similar across baseline CV risk subgroup

aCalculated by the Chronic Kidney Disease Epidemiology Collaboration equation; bSecondary outcome; cPrespecified additional renal composite outcome.

CV, cardiovascular; eCVD, established cardiovascular disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; MRF, multiple CV risk factors.

Wiviott SD et al. Article and supplementary appendix online ahead of print. N Engl J Med. 2018.

Overall population

eCVD

MRF

0.25 0.5 0.75 1 1.25 1.5

Hazard ratio (95% CI)

Favors

Dapagliflozin

Favors

Placebo

Composite of ≥40% decrease in eGFRa to

<60 mL/min/1.73 m2, ESRD, or renal death or CV deathb

0.79 (0.66, 0.94)

0.74 (0.60, 0.91)

CV risk

0.76 (0.67, 0.87)

Interaction

P value = 0.67

Overall population

eCVD

MRF

0.25 0.5 0.75 1 1.25 1.5

Hazard ratio (95% CI)

Favors

Dapagliflozin

Favors

Placebo

Composite of ≥40% decrease in eGFRa to

<60 mL/min/1.73 m2, ESRD, or renal deathc

0.55 (0.41, 0.75)

0.51 (0.37, 0.69)

CV risk

0.53 (0.43, 0.66)

Interaction

P value = 0.72

INTERNAL MEDICAL USE ONLY28

*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

Wiviott SD et al. Online ahead of print. N Engl J Med. 2018 http://www.timi.org/index.php?page=declare-slide-sets downloaded November 10, 2018

Adverse Events

(in T2D patients with CV risk)

Dapa 10mg

(N=8,574)

Placebo

(N=8,569)

Amputations, % 1.4% 1.3%

DKA (adjudicated), % 0.3% 0.1%

Fractures, % 5.3% 5.1%

Malignancies,% (IR):

• Overall malignancies

• Bladder cancer (adjudicated)

• Breast cancer (adjudicated)

5.6% (14.32)

0.3% (0.76)

0.4% (1.05)

5.7% (14.52)

0.5% (1.32)

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%

DECLARE confirms the well-established safety profile of dapagliflozin in a broad CV risk population

CI, confidence interval; CV, cardiovascular; hHF, hospitalized heart failure; HR, hazard ratio; T2DM, Type 2 diabetes mellitus1. 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

DECLARE

CANVAS

EMPA-REG

>99

% e

CV

DN

=6

,96

4

~66%

eC

VD

N=

6,6

56

~3

4%

MR

F

N=

3,4

86

~4

1%

eC

VD

N=

6,9

74

~5

9%

MR

FN

=1

0,1

86

0.93 (0.84, 1.03)

0.86 (0.75, 0.97)

0.86 (0.74, 0.99)

0.98 (0.82, 1.17)

0.87 (0.72, 1.06)

0.62 (0.49, 0.77)

0.89 (0.77, 1.01)

0.85 (0.69, 1.05)

0.87 (0.70, 1.09)

1.01 (0.84, 1.21)

0.90 (0.71, 1.15)

1.24 (0.92, 1.67)

0.73 (0.61, 0.88)

0.67 (0.52, 0.87)

0.65 (0.50, 0.85)

0.83 (0.73, 0.95)

0.78 (0.67, 0.91)

0.66 (0.55, 0.79)

0.53 (0.43, 0.66)*

0.60 (0.47, 0.77)

0.54 (0.40, 0.75)Favors

placebo

Favors

empagliflozin

MACE Composite

Hazard ratio (95% CI)

CV death

Nonfatal MI

Nonfatal stroke

hHF/CVD

Favors

SGLT2i

Favors

Placebo

hHF

Renal Composite*

Endpoint

*excluding CV death

component for comparison

purposes

SGLT-2 inhibitors reduce CV events, in particular hHF, as well as show renal protective benefits in T2D

SGLT2 inhibitors have consistently shown a reduction in renal outcomes

30

CV, cardiovascular; T2D, type 2 diabetes, BP, blood pressure; LDL-C, low density lipoprotein – cholesterol; HF, heart failure.

1. Wanner, C. N Engl J Med. 2016;375:323-334. . 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

Impact of SGLT2i on composite renal outcomes

0 0.2 0.4 0.6 0.8 1

STUDY

EMPA-REG1

CANVAS2

DECLARE3

HR (95% CI)

0.54 (0.40, 0.75)

0.60 (0.47, 0.77)

0.53 (0.43, 0.66)

• EMPA-REG OUTCOME: incident or

worsening nephropathy, defined as

progression to macroalbuminuria (urinary

albuminto-creatinine ratio, >300 mg/g

• CANVAS: 40% reduction in eGFR, renal-

replacement therapy, or renal death

• DECLARE*: Confirmed sustained ≥40%

decrease in eGFR to eGFR <60

mL/min/1.73 m2 and/or ESRD and/or

renal death

*excluding CV death component for comparison purposes

Renal Endpoints:

DECLARE CANVAS EMPA-REG

eGFR, mean (mL/min/1.73 m2) 85.2 76.5 74.1

Micro-/macro-albuminuria (%) 30.2 30.2 40.6

INTERNAL MEDICAL USE ONLY

Learning from all SGLT2 CVOTs….

These data with dapagliflozin from DECLARE- TIMI 58 extend the benefit of SGLT2i to a broader population of patients for primary and secondary prevention

Pump, Pipes and Filter: do SGLT2 inhibitors have it all covered? Verma S, Jüni P, Mazer CD, The Lancet 2018, in press

32

• Diabetes accounts for 30%-50% of all CKD. The number of adults with diabetes is projected to grow from 425 million in 2017 to to over 600 million by the year 2045.

• The renal complication of diabetes occur early with over 25% of patients having microalbuminuria at time of diagnosis

• Renal and CV disease are connected. Worsening renal function adversely impact CV outcomes. CV diseases like heart failure worsen renal function.

• HF occurred more commonly than MI or CV death in diabetic kidney disease trials

• DECLARE assessed dapagliflozin’s CV and renal outcomes in a broad population of T2D. Patients enrolled in DECLARE were early in their CV risk continuum and had better preserved renal function compared to previous SGLT2i studies assessing the ability of dapagliflozin to demonstrate organ protection.

• DECLARE results showed that dapagliflozin reduced the composite of hHF/CV death by 17% and reduced a renal only composite endpoint by 47% (nominal p value). This benefit was consistent across baseline renal function subgroups.

• Dapagliflozin, when given to patients with preserved renal function and at lower CV risk demonstrate both cardiac and renal protection

Summary

33