CURRICULUM VITAE SAN - Translating...CURRICULUM VITAE SALLY AMAN NASUTION, MD, FINASIM, FACP - Born in Medan, 8th August 1967 -Internist – Cardiologist -Faculty Member Division of

CURRICULUM VITAE

SALLY AMAN NASUTION MD FINASIM FACP - Born in Medan 8th August 1967

- Internist ndash 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

Interim Result of EMPRISE Real World Data

Translating EMPA-REG OUTCOME

in Real World Setting

2

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

CVD is a significant global burden

3 CHD coronary heart disease CVD cardiovascular disease

1 WHO CVD Fact sheet Ndeg317 Jan 2015 httpwwwwhointmediacentrefactsheetsfs317en

31

due to

CVD

74 million

due to

CHD

67 million

due to

stroke

Total global deaths

in 2012 ~56 million1

People with diabetes and CV disease die earlier than

those without diabetes or CV disease

In this case CV disease is represented by MI or stroke

CV cardiovascular MI myocardial infarction

The Emerging Risk Factors Collaboration JAMA 201531452 4

A 60-year-old male patient dies on average 12 years earlier with diabetes and CV disease

compared with no diabetes and CV disease

60 End of life years

-6 years

-12 years

No diabetes

Diabetes

Diabetes + CV disease

HF is a Global Health Problem with a Prevalence of

Approximately 26 million Worldwide

5

Estimates based on a single centre or hospital

Ponikowski P et al Heart failure Preventing disease and death worldwide European Society of Cardiology

2014 wwwescardioorgstatic_fileEscardioSubspecialtyHFAWHFA-whitepaper-15-May-14pdf (accessed

Nov 2015)

North America1

Canada 15

USA 19

Latin America and Africa1

No population-based

estimates

Europe1

France 22

UK 13

Asia1

China 13

Japan 10

Malaysia 67

Singapore 45

Australasia1

Australia 13

Middle East1

Oman 05

Proportion of the population living with heart failure (HF) in individual countries across the world

1 Redfield MM et al N Engl J Med 20163751868 2 Bugger H et al Diabetologia 201457660

3 Borlaug BA Heart failure with preserved ejection fraction In Springer Verlag 2015213ndash230

4 Mann DL et al Braunwalds Heart Disease A Textbook of Cardiovascular Medicine Single Volume 10th Edition

Elsevier Saunders Philadelphia 2015

There are Two Categories of Heart Failure

6

Attributed to pro-inflammatory CV and

non-CV coexisting conditions1

Associated with hypertension obesity

diabetes metabolic syndrome lung

disease smoking and iron deficiency1

HFpEF is less well understood than

HFrEF12

Accounts for gt50 of all HF cases

1 per year increase in prevalence3

Occurs due to loss of systolic function4

Leading cause coronary artery

disease4

Associated with coronary artery

disease risk factors eg hypertension

diabetes advanced age smoking

dyslipidemia4

Accounts for 50 of all HF cases

Important classification for clinical management24

HF preserved EF1

LVEF ge502 (40ndash50 borderline)

HF reduced EF3

LVEF le402

7 7

Intervention HFrEF HFpEF

Beta blocker SENIORS1 OPTIMIZE-HF14

ACEiARB CHARM2 I-PRESERVE15

PEP-CHF16

ARNi

PARADIGM-HF PARAGON-HF

Digoxin DIG3 Dig-PEF17

PDE5 inhibitor RELAX-HF4 RELAX-HF4

MRA RALES5

EMPHASIS6

TOPCAT18

ALDO-HF19

HydralazineNi A-HeFT7

Cohn8 NEAT-HFpEF20

CRT MADIT-CRT9

COMPANION10 PROSPECT21

ICD IMPROVE-HF9

MADIT-I11 No studies available

Exercise HF-ACTION12

Thompson et al13 Pandey22

Evidence of

clinical efficacy

Clinical efficacy

uncertain

No evidence of

clinical efficacy

Therapies Successful in HFrEF have not

Demonstrated Success in HFpEF

Ongoing

T2D type 2 diabetes

1 World Health Organization httpwwwwhointdiabetesaction_onlinebasicsenindex3html

T2D is a major and independent risk factor for both

microvascular and macrovascular complications

8

Macrovascular

Microvascular

Endothelial dysfunction is common to

microvascular and macrovascular events

9 TIA transient ischaemic attack

Versari D et al Diabetes Care 200932(suppl 2)S314

Normal conditions Risk factors Subclinical organ factors Clinical events

Remodelling ndash hypertrophy

Remodelling ndash plaque

Microalbuminuriamild insufficiency

Endothelial function

Myocardial infarction

Heart failure

Peripheral artery disease

TIA stroke

Aortic aneurysm

Overt proteinuria

End-stage renal failure

Including TNFα IL-6 resistin PAI-1 angiotensinogen

IL-6 interleukin 6 PAI-1 plasminogen activator inhibitor-1 T2D type 2 diabetes

Lau DCW et al Am J Physiol Heart Circ Physiol 2005288H2031

Interactions are complex inter-related and not necessarily causal

Visceral adiposity is related to inflammation insulin

resistance dyslipidaemia and atherosclerosis

10

OBESITY

Adiponectin

Adipocytokines

inflammatory

cytokines

T2D

Insulin

resistance

Atherosclerosis

Dyslipidaemia

Endothelial

dysfunction

Age

Oxidative

stress

Hypertension

Diabetes is Common Among Patients with HF

11

HFpEF RCTs HFrEF RCTs Registries

Pre

va

len

ce

o

f d

iab

ete

s (

)

33

43

49

32 35

48

43 42 42

0

10

20

30

40

50

60

TOPCAT1

(n=3345)

SOCRATES-R6

(n=456)

RELAX2

(n=216)

EPHESUS4

(n=6642)

PARADIGM5

(n=8399)

SOCRATES -P3

(n=477)

OPTIMIZE8

(n=46612)

GWTG HF7

(n=21078)

ADHERE9

(n=46612

)

1Pitt B et al N Engl J Med 20143901383 2Redfield MM et al JAMA 20133091268 B et al Eur Heart J 2016381119 4Pitt B et al N Engl J Med 20033481309 5McMurray JJV et al N Engl J Med 2014371993 6Gheorghiade M et al JAMA 20153142251 7Luo N et al JACC Heart Fail 20175305 8Greenberg BH et al Heart J 2007154277e12277e8 9Peacock F et al N Engl J Med 2008 3582117ndash2126

Prevalence of DM in HF is 25-30 overall 40-45 in those hospitalized for HF

People with diabetes are at increased risk of

heart failure

12

Diabetes confers a 60ndash80 greater

probability of CV death and all-cause

mortality in those with established HF23

Synthesised based on data from two clinical studies ndash see Notes for details

CV cardiovascular HF heart failure

1 Kannel WB et al Am J Cardiol 19743429 2 Cubbon RM et al Diab Vasc Dis Res 201310330 3 MacDonald MR et al Eur Heart J 2008291377

People with diabetes

have a 2- to 5-fold higher

risk of developing HF1

2ndash5

bull KaplanndashMeier survival curves of HF patients hospitalised with LVEF ge50 (n=498) and lt50 (n=754)

HF heart failure LVEF left ventricular ejection fraction

Varela-Roman A et al Eur J Heart Failure 20057859

Poorer HF survival with diabetes than without diabetes

Diabetes worsens heart failure prognosis

13

Su

rviv

al

pro

po

rtio

n

Time (years)

p=00322 RR=141

LVEF ge50

Diabetes No diabetes

10

08

06

04

02

00 0 2 4 6 8 10 12

04

02

00 0 2 4 6 8 10 12

plt00001

RR=173

LVEF lt50


Time (years)

10

08

06

00

Circulation 2016 Jun 14133(24)2459-502 doi 101161CIRCULATIONAHA116022194

Clinical Update Cardiovascular Disease in Diabetes Mellitus Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes

Mellitus - Mechanisms Management and Clinical Considerations

Low Wang CC1 Hess CN1 Hiatt WR1 Goldfine AB2

Pathophysiological of Heart Failure in

Diabetes Mellitus

14

Diabetes-related CV complications have declined with

improved care but substantial burden remains

15

Years

0

50

100

150

1990 2000 2010

Even

ts p

er

100

00

ad

ult

po

pu

lati

on

wit

h d

iab

ete

s

MI Stroke ESRD

CV cardiovascular ESRD end-stage renal disease MI myocardial infarction

Adapted from Gregg EW et al N Engl J Med 20143701514

Turnbull FM et al Diabetologia 2009522288

Meta-analysis including 27049 participants and 2370 major vascular events

No evidence from prospective trials that more intensive glycaemic control reduces mortality

16

Hazard ratio (95 CI)

ACCORD 257 (141) 203 (114) -101

ADVANCE 498 (186) 533 (199) -072

UKPDS 123 (013) 53 (025) -066

VADT 102 (222) 95 (206) -116

Overall 980 884 -088

ACCORD 137 (079) 94 (056) -101

ADVANCE 253 (095) 289 (108) -072

UKPDS 71 (053) 29 (052) -066

VADT 38 (083) 29 (063) -116

Overall 497 441 -088

All-cause mortality

Cardiovascular death

Trials

Number of events (annual event rate )

More intensive Less intensive ∆HbA1c ()

Favours more intensive

Favours less intensive

Overall HR (95 CI)

104 (090 120)

110 (084 142)

05 20 10

Trials

Number of events (annual event rate ) ΔHbA1c () Hazard ratio (95 CI) Overall HR (95 CI)

More intensive Less intensive

Major cardiovascular events

ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)

Hospitalisedfatal heart failure

Overall 459 446 -088 100 (086 116)

Major CV events = CV death or non-fatal stroke or non-fatal MI daggerDiamonds incorporate point estimate (vertical dashed line) and encompass 95 CI of overall effect for each outcome Turnbull FM et al Diabetologia 2009522288


Meta-analysis shows modest benefit of intensive glycaemic control on macrovascular risk

10 05 20

dagger



Study1 Baseline HbA1c Control vs

intensive

Mean duration of diabetes at

baseline (years) Microvascular CVD Mortality

UKPDS 9 79 vs 7 Newly diagnosed darr harr harr

ACCORD1ndash3 83 75 vs 64 100 darr harr uarr

ADVANCE 75 73 vs 65 80 darr harr harr

VADT 94 84 vs 69 115 darr harr harr

No change in primary microvascular composite but significant decreases in micromacroalbuminuria23 No change in major clinical microvascular events but significant reduction in ESRD (p=0007)5 1 Table adapted from Bergenstal RM et al Am J Med 2010123374e9 2 Genuth S amp Ismail Beigi F Clin Endocrinol Metab 20129741 3 Ismail-Beigi F et al Lancet 2010376419 4 Hayward RA et al N Engl J Med 20153722197 5 Zoungas S et al N Engl J Med 20143711392

Glucose-lowering studies confirmed benefit on microvascular complications but mixed results on macrovascular outcomes

18

Long-term follow-up145

darr darr harr darr harr darr

darr harr uarr

darr harr

harr harr harr harr

darr harr darr harr harr

Therapeutic Effects of Glucose-Lowering Therapies

on HF and CV Outcomes

HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)

bull Empaglifozin (EMPA-REG OUTCOME)

bull Canagliflozin (CANVAS) bull Dapagliflozin (DECLARE-

TIMI)

+- (Null)

bull Liraglutide (LEADER) bull Semaglutide (SUSTAIN-6)

bull Insulin Glargine (ORIGIN) bull Acarbose (ACE) bull Lixisenatide (ELIXA) bull Exanetide (EXSCEL) bull Alogliptin (EXAMINE) bull Sitagliptin (TECOS)

- (Harm)

bull Pioglitazone (PROactive) bull Rosiglitazone (RECORD) bull Saxagliptin (SAVOR-TIMI

53)

Prevalence of Heart Failure in Recent Diabetes CVOTs

Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)

Heart failure not specified as an inclusion criterion in any trial

CV safety trials are being conducted for each compound within the newer classes

Trial disclosure dates for non-published trials from clinicaltrialsgov Adapted from Johansen OE World J Diabetes 201561092 (references 1ndash19 expanded in slide notes)

SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8

(n=5875) Albuminuria

EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE

Ertugliflozin CVOT19

(n=3900) 3P-MACE

DPP-4 inhibitor SGLT2 inhibitor GLP-1 agonist

KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE

EMPA-REG OUTCOMEreg5

(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13

(n=8300) 4P-MACE + renal

LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15

(n=3700) Renal + 5P-MACE

CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE

Hospitalisation for Heart Failure in DPP4i CVOTs

Updated FDA Label (82017)

Trial

Impact on HHF

compared with placebo

FDA Label

DPP4i

(saxagliptin) SAVOR-TIMI

HR 127 (95CI 107-151)2

p=0007

FDA guidance May increase the risk of

heart failure particularly in patients who

already have heart or kidney disease

(452016)3

DPP4i

(alogliptin) EXAMINE

HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098

Consider the risks and benefits prior to

initiating treatment in patients at risk for

heart failure such as those with a prior

history of heart failure and renal impairment

(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)

1 Pfeffer M A et al N Engl J Med 20153732247 2 Scirica BM et al N Engl J Med 20133691317 3 FDA Drug Safety Communication Available at httpwwwfdagovDrugsDrugSafetyucm486096htm (accessed April 2016) 4 Zannad F et al Lancet 20153852067 5 Green JB et al N Engl J Med 2015373232 6 Rosenstock J et al JAMA 201932169

In Indonesia Empagliflozin is not indicated for CV risk reduction and treatment of HF Zinman B et al N Engl J Med 20153732117ndash2128

Outcome Patients with event analyzed Hazard

ratio

95 CI P value

Empagliflozin Placebo

3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME

Empagliflozin Improved CV Outcomes in T2DM

Months

Pa

tie

nts

with

ev

en

t (

)

Reduction in risk of CV death occurred early and was

sustained throughout the trial

Empagliflozin is not indicated in all countries for CV risk reduction

RRR for CV death 38 ARR for CV death 22 rates of CV death 37 (empagliflozin) versus 59 (placebo)

Cumulative incidence function Nominal p-value ARR absolute risk reduction RRR relative risk reduction

Zinman B et al N Engl J Med 20153732117

24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1

Hospitalization for heart failure

HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5

Death from any cause

HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39

Patients with eventanalysed ()

Empagliflozin Placebo HR (95 CI) HR (95 CI)

HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)

EMPA-REG OUTCOME Reductions in HHF CV death and All-cause Mortality

Were Consistent in Patients with and without HF at Baseline

025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo

Favours empagliflozin In Indonesia Empagliflozin is not indicated for CV risk reduction and treatment of HF Fitchett D et al Eur Heart J 2016371526

2016 ESC Guidelines Recognise Empagliflozin for the Prevention or Delay of Heart Failure in T2D

Ponikowski P et al Eur Heart J 2016372129 Empagliflozin is not indicated for treatment for Heart Failure in Indonesia

Empagliflozin should be considered in patients with T2D in order to delay the onset of heart failure and prolong life

Class IIa

Level B

1 4S investigator Lancet 1994 344 1383-89 httpwwwtrialresultscenterorgstudy2590-4Shtm 2 HOPE investigator N Engl J Med 2000342145-53 httpwwwtrialresultscenterorgstudy2606-HOPEhtm Empagliflozin is not indicated in Indonesia for CV risk reduction the treatment of HF or kidney disease

Number needed to treat (NNT) to prevent one death across landmark trials in patients with high CV risk

28

Simvastatin1

for 54 years

High CV risk 5 diabetes 26 hypertension

1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin

Empagliflozin for 3 years

T2DM with high CV risk 92 hypertension

gt80 ACEiARB

gt75 statin

Clinical trial vs real world setting

EMPRISE background

CAD coronary artery disease CV cardiovascular HHF hospitalisation for heart failure T2D type 2 diabetes

1 ClinicalTrialsgov NCT03363464 (accessed Jul 2018) 2 Fitchett D et al J Am Coll Cardiol 201871364

3 Fitchett D et al ACC 2018 oral presentation 4 Iannazzo S et al Farmeconomia Health Economics and Therapeutic Pathways 20171843 30

Empagliflozin was launched as a treatment for T2D in the US in August 20141

In September 2015 the EMPA-REG OUTCOMEreg trial demonstrated that empagliflozin

reduced the risk of CV death HHF and all-cause mortality in patients with T2D and

established CV disease (most commonly CAD) on top of standard of care1

Additional analyses indicated that these effects were consistent across the

CV risk continuum within the EMPA-REG OUTCOMEreg population23

An economic analysis based on EMPA-REG OUTCOMEreg suggested that empagliflozin has

the potential to provide economic benefits to the healthcare system4

CV risk continuum in T2D

Comparison of studies should be interpreted with caution due to differences in study design populations and methodology

Definitions of CVD vary between studies daggerAnalysis of 60 studies with 4549481 patients with T2D CVD cardiovascular disease

T2D type 2 diabetes

1 Einarson TR et al Cardiovasc Diabetol 20181783 2 Zinman B et al N Engl J Med 20153732117

3 Patorno E et al Circulation 2019 doi 101161CIRCULATIONAHA118039177 31

EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3

Approximately one in three

patients with T2D have CVDdagger

20

18

lit

era

ture

revie

w1

Almost all patients had CVD in

EMPA-REG OUTCOMEreg

Patients with and without CVD

included in EMPRISE

10 of total

T2D population =

Objectives

DPP-4i dipeptidyl peptidase-4 inhibitor SGLT2i sodium-glucose co-transporter-2 inhibitor T2D type 2 diabetes

Patorno E et al Circulation 2019 doi 101161CIRCULATIONAHA118039177 EU PAS Register EUPAS20677

wwwenceppeuenceppviewResourcehtmid=21657 (accessed Jan 2019)

bull To assess effectiveness safety healthcare resource

utilisation and costs of care of empagliflozin versus

DPP-4i in patients with T2D

bull To assess effectiveness of SGLT2i versus


bull First 5 years of empagliflozin use 2014minus2019

bull Over 200000 patients projected to be included by

study completion

ndash gt100000 empagliflozin gt100000 DPP-4i

32

large USA databases 3

Research initiated and currently led by Professors Elisabetta Patorno and Sebastian Schneeweiss from the

Division of Pharmacoepidemiology Brigham and Womens Hospital and Harvard Medical School Boston USA

Built upon an academic collaboration between Brigham and Womens Hospital and Boehringer Ingelheim

Comprehensive clinical picture of empagliflozin

Sensitivity analyses SGLT2i versus DPP-4i daggerBladder cancers kidney cancers other urinary tract non-kidney or non-bladder cancers DaggerHypoglycaemia events requiring hospitalisation

3P-MACE 3-point major adverse cardiovascular events CV cardiovascular DPP-4i dipeptidyl peptidase-4 inhibitor ED emergency department ESRD end-stage renal disease

HCRU healthcare resource utilisation HHF hospitalisation for heart failure MI myocardial infarction SGLT2i sodium-glucose co-transporter-2 inhibitor

1 ClinicalTrialsgov NCT03363464 (accessed Jan 2019) 2 EU PAS Register EUPAS20677 wwwenceppeuenceppviewResourcehtmid=21657 (accessed Jan 2019)

33

Effectiveness1

Safety1

HCRU and costs2

CV mortality

Hospital admission for MI

Hospital admission for stroke

All-cause mortality

3P-MACE

HHF

Primary outcomes

Coronary revascularisation procedure

ESRD

Treatment for retinopathy

Secondary outcomes

Diabetic ketoacidosis Bone fracture

Urinary tract cancersdagger

Lower limb amputation

Acute kidney injury requiring dialysis Severe hypoglycaemiaDagger

All-cause and CV hospitalisation

Length of hospital stay

All-cause ED visits

Office visits

Other outpatient services

Inpatients Outpatients

Pharmacy

Medications filled

Costs

Total cost of care Inpatient costs

Emergency care costs

Outpatient costs Pharmacy costs

Secondary outcomes

HCRU

17551 new users of

DPP-4i

EMPRISE patient population (2014ndash2016)

Empagliflozin vs DPP-4i

34

347031 patients aged ge18 years initiating empagliflozin or a DPP-4i

with 12 months of continuous enrolment prior to cohort entry

17551 new users of

empagliflozin

306987 patients with T2D initiating

empagliflozin or a DPP-4i

35102 patients after 11 PS matching

(based on gt140 baseline covariates)

Exclusion criteria 40044 patients

excluded

PS matching

DPP-4i dipeptidyl peptidase-4 inhibitor PS propensity score T2D type 2 diabetes

Patorno E et al Circulation 2019 doi 101161CIRCULATIONAHA118039177

Mean follow-up 53 months

EMPA

vs

DPP-4i

Empagliflozin was associated with a reduced risk of HHF in routine clinical practice compared with DPP-

4i

11 propensity score matched cohorts

Broad HHF definition data shown with HHF defined as a discharge diagnosis of heart failure in any position (positive predictive value = 79ndash96)

DPP-4i dipeptidyl peptidase-4 inhibitor HHF hospitalisation for heart failure

Patorno E et al Circulation 2019 doi 101161CIRCULATIONAHA118039177 35

0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001

DPP-4i Empagliflozin

005

004

003

002

001

0

EMPA

vs

DPP-4i

Study

Empagliflozin Comparator

HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY


Empagliflozin vs placebo

1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Specific HHF 1617551

(NR) 20

4217551

(NR) 56

049

(027 089)

Broad HHFdagger 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Empagliflozin was associated with a reduced risk of HHF in routine clinical practice compared with DPP-4i

36

EMPRISE mean follow-up 53 months Comparison of studies should be interpreted with caution due to differences in study design populations

and methodology Definitions of HHF vary between studies

Defined as a discharge diagnosis of heart failure in the primary position (positive predictive value = 84ndash100) daggerDefined as a discharge diagnosis of heart failure in any position (positive predictive value = 79ndash96)

DPP-4i dipeptidyl peptidase-4 inhibitor HHF hospitalisation for heart failure NR not reported PY patient-years

1 Zinman B et al N Engl J Med 20153732117 2 Patorno E et al Circulation 2019 doi 101161CIRCULATIONAHA118039177

025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY

EMPA-REG OUTCOMEreg 1


1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)

The effect of empagliflozin vs DPP-4i on HHF was consistent in patients with and without CVD

37


Definitions of HHF vary between studies

CVD cardiovascular disease DPP-4i dipeptidyl peptidase-4 inhibitor HHF hospitalisation for heart failure NR not reported PY patient-

years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)

In EMPRISE the effect of empagliflozin vs DPP-4i on HHF was consistent between both doses



Broad HHF definition

DPP-4i dipeptidyl peptidase-4 inhibitor EMPA empagliflozin HHF hospitalisation for heart failure NR not reported PY patient-years

1 Zinman B et al N Engl J Med 20153732117 2 Patorno E et al Circulation 2019 doi 101161CIRCULATIONAHA118039177 38

025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Empagliflozin HHF results in the EMPRISE study complement the RCT

indicating these findings translate into routine clinical practice


Definitions of HHF vary between studies Broad HHF definition

DPP-4i dipeptidyl peptidase-4 inhibitor HHF hospitalisation for heart failure RCT randomised controlled trial

1 Patorno E et al Circulation 2019 doi 101161CIRCULATIONAHA118039177 2 Zinman B et al N Engl J Med 20153732117 39

7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months

EMPA-REG OUTCOMEreg2 EMPRISE1

Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001

Sitagliptin Empagliflozin

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin

HHF outcomes subgroups by baseline CVD status from EMPRISE and EMPA-REG OUTCOMEreg



CVD cardiovascular disease DPP-4i dipeptidyl peptidase-4 inhibitor HHF hospitalisation for heart failure MI myocardial infarction PY patient-years

1 Zinman B et al N Engl J Med 20153732117 2 Fitchett D et al ACC 2018 oral presentation 3 Boehringer Ingelheim Data on file 2018

4 Patorno E et al Circulation 2019 doi 101161CIRCULATIONAHA118039177

40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY

EMPA-REG OUTCOMEreg (empagliflozin vs placebo)

Overall population1 1264687 (27) 94 952333 (41) 145 065 (050 085)

History of MI or stroke23 05610

No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)

EMPRISE4 (empagliflozin vs sitagliptin)

Overall population 7816443 (NR) 105 15816443 (NR) 222 051 (039 068)

Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)

EMPRISE4 (empagliflozin vs DPP-4i)


Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2

HHF in EMPRISE and EMPA-REG OUTCOMEreg

Broad HHF definition daggerResults were consistent when comparing empagliflozin vs the DPP-4i class

DPP-4i dipeptidyl peptidase-4 inhibitor HHF hospitalisation for heart failure RRR relative risk reduction RCT randomised controlled trial

RWE real-world evidence

1 Patorno E et al Circulation 2019 doi 101161CIRCULATIONAHA118039177 2 Zinman B et al N Engl J Med 20153732117

41

EMPA-REG OUTCOMEreg RCT2 EMPRISE RWE study1

Patients with

HHF events

HHF assessment Unadjudicated

Treatment

allocation Routine clinical care

(not blinded or randomised)

Outcome

identification

236 of 32886 patientsdagger

(empagliflozin vs sitagliptin)

Detected through databases

with validated algorithm

Result

49 RRR of HHF associated with

empagliflozin vs sitagliptin

(results consistent when comparing

empagliflozin vs the DPP-4i class)

Adjudicated by endpoints committee

Blinded and randomised

221 of 7020 patients

Detected by study investigators

35 RRR of HHF demonstrated

with empagliflozin vs placebo

Empagliflozin may influence cardiac and renal function via changes in energy supply

References 1 Ferrannini G et al Diabetes Care 2015381730 2 Heise T et al Diab Obes Metab 201315613 3 Rossmeislovaacute L et al Int J Obes (Lond) 201337640 4 Heilbronn LK et al JAMA 20062951539 5 Dwyer JT et al in Endotext [Internet] 2015 Ch 11 httpswwwncbinlmnihgovbooksNBK278991diet-treatment-obestoc-11-summary-of-weight-loss-phase

(Accessed Mar 2017) 6 Ferrannini E et al J Clin Invest 2014124499 7 Habegger KM et al Nat Rev Endocrinol 20106689 8 Mudaliar S et al Diabetes Care 2016391115 9 Kitabchi AE et al Diabetes Care 2006292739 10 Laffel L Diabetes Metab Res Rev 199915412 11 Aubert G et al Circulation 2016133698

12 Veech RL et al IUBMB Life 200151247 13 Ronco C et al J Am Coll Cardiol 2008521527 14 McCullogh PA et al Contrib Nephro 201318282

Empagliflozin is not indicated in Indonesia for CV risk reduction and is not indicated for the treatment of HF or kidney disease

Empagliflozin may influence arterial wall structurefunction by modulating lipid synthesis and insulin resistance

References 1 Ferrannini G et al Diabetes Care 2015381730 2 Heise T et al Diab Obes Metab 201315613 3Rossmeislovaacute L et al Int J Obes (Lond) 201337640 4 Halter JB et al J Clin Endocrinol Metab 197948946 5Koutsari C et al Diabetes 2013622386 6Ebbert JO et al Nutrients 201354987 Fernandez ML et al J Nutr 20051352075 8Nielsen S Karpe F Curr Opin Lipidol 2012233219 Taskinen MR Diabetologia 200346733 10Henriksen JE et al Diabetes 2000491209 11 Giannini C et al Diabetes Care 2011341869 12 Chapman MJ et al Eur Heart J 2011321345 13 Nolan CJ et al Diabetes 201564673 14 Guiducci L et al Endocr Res 2011369 15 Jacobson TA et al J Clin Lipidol 20159129 Empagliflozin is not indicated in Indonesia for CV risk reduction and is not indicated for the treatment of HF or kidney disease

Empagliflozin enhances the excretion of glucose sodium and water into the urine

bull By blocking the action of SGLT2 Empagliflozin reduces renal glucose reabsorption and increases urinary glucose excretion This is accompanied by transient natriuresis and increases in urine volume

44

H2O Proximal

tubule lumen

Blood

lumen

Heise T et al Clin Ther 2016382265 Heerspink HJ et al Circulation 20161345

Haemodynamic renal mechanisms may have an important role in the effects of Empagliflozin

Solid lines represent pathways supported by existing data dashed lines represent possible areas for future research ACE2 angiotensin-converting enzyme-2 Ang 17 angiotensin 17 Rajasekeran H et al Kidney Int 201689522

darr Intraglomerular hypertension

darr Hyperfiltration

Activation of ACE2 ndash Ang17

darr Ventricular arrhythmias

Vascular effects

darr Inflammation

darr Fibrosis

uarr Cardiac contractility

darr Epicardial fat darr Atherosclerosis

darr Myocardial stretch

darr Arterial stiffness

Afferent arteriole constriction

darr Inflammation

darr Glucose toxicity

darr Total body fat mass

darr Plasma uric acid

darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure

uarr Tubulo-glomerular feedback

Natriuresis

SGLT2i

Phase III randomised double-blind placebo-controlled studies

Two dedicated HF trials are now investigating the HF benefit

of empagliflozin in patients with and without T2D

Aim To investigate the safety and efficacy of empagliflozin versus placebo on top of guideline-directed

medical therapy in patients with HF with reduced1 and preserved2 ejection fraction

Population T2D and non-T2D age ge18 years chronic HF (NYHA IIndashIV)

EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care

Empagliflozin 10 mg qd

+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p

Estimated follow-up on

treatment ~38 months

Guideline-directed medical therapy

HF heart failure LVEF left ventricular ejection fraction NYHA New York Heart Association T2D type 2 diabetes

1 ClinicalTrialsgov NCT03057977 2 ClinicalTrialsgov NCT03057951

Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47

bull Cardiovascular disease is a significant global burden

bull T2D is a major and independent risk factor for both microvascular and

macrovascular complication

bull People with T2D has increase risk of heart failure and diabetes worsen the

prognosis of heart failure both in preserved and reduce ejection fraction

bull Major historic T2D CV outcomes trials focused on intensive vs

conventional glycaemic control confirmed benefit on microvascular

complications but mixed results on macrovascular outcomes

bull Empagliflozin in EMPA-REG OUTCOME may suggest beyond glycemic

control effect with various potential mechanism explaining the effect

3P-MACE

EMPA-REG OUTCOME Relative risk reduction

darr14

CV death All-cause mortality HHF

Incident or

worsening

nephropathy

darr38 darr32 darr35 darr39



Summary

48

bull An interim analysis of ~33000 patients in EMPRISE showed that

in routine clinical practice empagliflozin was associated with a 44

relative risk reduction of HHF compared with DPP4i in patients

with T2D1

bull Results were consistent in EMPRISE analyses comparing

Empagliflozin vs the DPP-4i class1

bull EMPRISE which includes three-quarters of patients without CVD

showed that the reduced risk of HHF with empagliflozin was

consistent in patients with and without established CVD1

Interim Result of EMPRISE Real World Data

Translating EMPA-REG OUTCOME

in Real World Setting

2

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




31

due to

CVD

74 million

due to

CHD

67 million

due to

stroke

Total global deaths










-6 years

-12 years

No diabetes

Diabetes




5




Nov 2015)

North America1

Canada 15

USA 19


No population-based

estimates

Europe1

France 22

UK 13

Asia1

China 13

Japan 10

Malaysia 67

Singapore 45

Australasia1

Australia 13

Middle East1

Oman 05







6







HFrEF12





disease4




dyslipidemia4



HF preserved EF1


HF reduced EF3

LVEF le402

7 7




PEP-CHF16

ARNi




MRA RALES5

EMPHASIS6

TOPCAT18

ALDO-HF19


Cohn8 NEAT-HFpEF20

CRT MADIT-CRT9


ICD IMPROVE-HF9




Evidence of

clinical efficacy

Clinical efficacy

uncertain

No evidence of

clinical efficacy



Ongoing

T2D type 2 diabetes




8

Macrovascular

Microvascular











Heart failure


TIA stroke

Aortic aneurysm

Overt proteinuria








10

OBESITY

Adiponectin

Adipocytokines

inflammatory

cytokines

T2D

Insulin

resistance

Atherosclerosis

Dyslipidaemia

Endothelial

dysfunction

Age

Oxidative

stress

Hypertension


11


Pre

va

len

ce

o

f d

iab

ete

s (

)

33

43

49

32 35

48

43 42 42

0

10

20

30

40

50

60

TOPCAT1

(n=3345)

SOCRATES-R6

(n=456)

RELAX2

(n=216)

EPHESUS4

(n=6642)

PARADIGM5

(n=8399)

SOCRATES -P3

(n=477)

OPTIMIZE8

(n=46612)

GWTG HF7

(n=21078)

ADHERE9

(n=46612

)




heart failure

12










2ndash5






13

Su

rviv

al

pro

po

rtio

n

Time (years)

p=00322 RR=141

LVEF ge50


10

08

06

04

02

00 0 2 4 6 8 10 12

04

02

00 0 2 4 6 8 10 12

plt00001

RR=173

LVEF lt50


Time (years)

10

08

06

00






Diabetes Mellitus

14



15

Years

0

50

100

150

1990 2000 2010

Even

ts p

er

100

00

ad

ult

po

pu

lati

on

wit

h d

iab

ete

s

MI Stroke ESRD






16


ACCORD 257 (141) 203 (114) -101

ADVANCE 498 (186) 533 (199) -072

UKPDS 123 (013) 53 (025) -066

VADT 102 (222) 95 (206) -116

Overall 980 884 -088

ACCORD 137 (079) 94 (056) -101

ADVANCE 253 (095) 289 (108) -072

UKPDS 71 (053) 29 (052) -066

VADT 38 (083) 29 (063) -116

Overall 497 441 -088

All-cause mortality


Trials





Overall HR (95 CI)

104 (090 120)

110 (084 142)

05 20 10

Trials




ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)


Overall 459 446 -088 100 (086 116)




10 05 20

dagger




intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1









31

due to

CVD

74 million

due to

CHD

67 million

due to

stroke

Total global deaths










-6 years

-12 years

No diabetes

Diabetes




5




Nov 2015)

North America1

Canada 15

USA 19


No population-based

estimates

Europe1

France 22

UK 13

Asia1

China 13

Japan 10

Malaysia 67

Singapore 45

Australasia1

Australia 13

Middle East1

Oman 05







6







HFrEF12





disease4




dyslipidemia4



HF preserved EF1


HF reduced EF3

LVEF le402

7 7




PEP-CHF16

ARNi




MRA RALES5

EMPHASIS6

TOPCAT18

ALDO-HF19


Cohn8 NEAT-HFpEF20

CRT MADIT-CRT9


ICD IMPROVE-HF9




Evidence of

clinical efficacy

Clinical efficacy

uncertain

No evidence of

clinical efficacy



Ongoing

T2D type 2 diabetes




8

Macrovascular

Microvascular











Heart failure


TIA stroke

Aortic aneurysm

Overt proteinuria








10

OBESITY

Adiponectin

Adipocytokines

inflammatory

cytokines

T2D

Insulin

resistance

Atherosclerosis

Dyslipidaemia

Endothelial

dysfunction

Age

Oxidative

stress

Hypertension


11


Pre

va

len

ce

o

f d

iab

ete

s (

)

33

43

49

32 35

48

43 42 42

0

10

20

30

40

50

60

TOPCAT1

(n=3345)

SOCRATES-R6

(n=456)

RELAX2

(n=216)

EPHESUS4

(n=6642)

PARADIGM5

(n=8399)

SOCRATES -P3

(n=477)

OPTIMIZE8

(n=46612)

GWTG HF7

(n=21078)

ADHERE9

(n=46612

)




heart failure

12










2ndash5






13

Su

rviv

al

pro

po

rtio

n

Time (years)

p=00322 RR=141

LVEF ge50


10

08

06

04

02

00 0 2 4 6 8 10 12

04

02

00 0 2 4 6 8 10 12

plt00001

RR=173

LVEF lt50


Time (years)

10

08

06

00






Diabetes Mellitus

14



15

Years

0

50

100

150

1990 2000 2010

Even

ts p

er

100

00

ad

ult

po

pu

lati

on

wit

h d

iab

ete

s

MI Stroke ESRD






16


ACCORD 257 (141) 203 (114) -101

ADVANCE 498 (186) 533 (199) -072

UKPDS 123 (013) 53 (025) -066

VADT 102 (222) 95 (206) -116

Overall 980 884 -088

ACCORD 137 (079) 94 (056) -101

ADVANCE 253 (095) 289 (108) -072

UKPDS 71 (053) 29 (052) -066

VADT 38 (083) 29 (063) -116

Overall 497 441 -088

All-cause mortality


Trials





Overall HR (95 CI)

104 (090 120)

110 (084 142)

05 20 10

Trials




ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)


Overall 459 446 -088 100 (086 116)




10 05 20

dagger




intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1














-6 years

-12 years

No diabetes

Diabetes




5




Nov 2015)

North America1

Canada 15

USA 19


No population-based

estimates

Europe1

France 22

UK 13

Asia1

China 13

Japan 10

Malaysia 67

Singapore 45

Australasia1

Australia 13

Middle East1

Oman 05







6







HFrEF12





disease4




dyslipidemia4



HF preserved EF1


HF reduced EF3

LVEF le402

7 7




PEP-CHF16

ARNi




MRA RALES5

EMPHASIS6

TOPCAT18

ALDO-HF19


Cohn8 NEAT-HFpEF20

CRT MADIT-CRT9


ICD IMPROVE-HF9




Evidence of

clinical efficacy

Clinical efficacy

uncertain

No evidence of

clinical efficacy



Ongoing

T2D type 2 diabetes




8

Macrovascular

Microvascular











Heart failure


TIA stroke

Aortic aneurysm

Overt proteinuria








10

OBESITY

Adiponectin

Adipocytokines

inflammatory

cytokines

T2D

Insulin

resistance

Atherosclerosis

Dyslipidaemia

Endothelial

dysfunction

Age

Oxidative

stress

Hypertension


11


Pre

va

len

ce

o

f d

iab

ete

s (

)

33

43

49

32 35

48

43 42 42

0

10

20

30

40

50

60

TOPCAT1

(n=3345)

SOCRATES-R6

(n=456)

RELAX2

(n=216)

EPHESUS4

(n=6642)

PARADIGM5

(n=8399)

SOCRATES -P3

(n=477)

OPTIMIZE8

(n=46612)

GWTG HF7

(n=21078)

ADHERE9

(n=46612

)




heart failure

12










2ndash5






13

Su

rviv

al

pro

po

rtio

n

Time (years)

p=00322 RR=141

LVEF ge50


10

08

06

04

02

00 0 2 4 6 8 10 12

04

02

00 0 2 4 6 8 10 12

plt00001

RR=173

LVEF lt50


Time (years)

10

08

06

00






Diabetes Mellitus

14



15

Years

0

50

100

150

1990 2000 2010

Even

ts p

er

100

00

ad

ult

po

pu

lati

on

wit

h d

iab

ete

s

MI Stroke ESRD






16


ACCORD 257 (141) 203 (114) -101

ADVANCE 498 (186) 533 (199) -072

UKPDS 123 (013) 53 (025) -066

VADT 102 (222) 95 (206) -116

Overall 980 884 -088

ACCORD 137 (079) 94 (056) -101

ADVANCE 253 (095) 289 (108) -072

UKPDS 71 (053) 29 (052) -066

VADT 38 (083) 29 (063) -116

Overall 497 441 -088

All-cause mortality


Trials





Overall HR (95 CI)

104 (090 120)

110 (084 142)

05 20 10

Trials




ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)


Overall 459 446 -088 100 (086 116)




10 05 20

dagger




intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1








5




Nov 2015)

North America1

Canada 15

USA 19


No population-based

estimates

Europe1

France 22

UK 13

Asia1

China 13

Japan 10

Malaysia 67

Singapore 45

Australasia1

Australia 13

Middle East1

Oman 05







6







HFrEF12





disease4




dyslipidemia4



HF preserved EF1


HF reduced EF3

LVEF le402

7 7




PEP-CHF16

ARNi




MRA RALES5

EMPHASIS6

TOPCAT18

ALDO-HF19


Cohn8 NEAT-HFpEF20

CRT MADIT-CRT9


ICD IMPROVE-HF9




Evidence of

clinical efficacy

Clinical efficacy

uncertain

No evidence of

clinical efficacy



Ongoing

T2D type 2 diabetes




8

Macrovascular

Microvascular











Heart failure


TIA stroke

Aortic aneurysm

Overt proteinuria








10

OBESITY

Adiponectin

Adipocytokines

inflammatory

cytokines

T2D

Insulin

resistance

Atherosclerosis

Dyslipidaemia

Endothelial

dysfunction

Age

Oxidative

stress

Hypertension


11


Pre

va

len

ce

o

f d

iab

ete

s (

)

33

43

49

32 35

48

43 42 42

0

10

20

30

40

50

60

TOPCAT1

(n=3345)

SOCRATES-R6

(n=456)

RELAX2

(n=216)

EPHESUS4

(n=6642)

PARADIGM5

(n=8399)

SOCRATES -P3

(n=477)

OPTIMIZE8

(n=46612)

GWTG HF7

(n=21078)

ADHERE9

(n=46612

)




heart failure

12










2ndash5






13

Su

rviv

al

pro

po

rtio

n

Time (years)

p=00322 RR=141

LVEF ge50


10

08

06

04

02

00 0 2 4 6 8 10 12

04

02

00 0 2 4 6 8 10 12

plt00001

RR=173

LVEF lt50


Time (years)

10

08

06

00






Diabetes Mellitus

14



15

Years

0

50

100

150

1990 2000 2010

Even

ts p

er

100

00

ad

ult

po

pu

lati

on

wit

h d

iab

ete

s

MI Stroke ESRD






16


ACCORD 257 (141) 203 (114) -101

ADVANCE 498 (186) 533 (199) -072

UKPDS 123 (013) 53 (025) -066

VADT 102 (222) 95 (206) -116

Overall 980 884 -088

ACCORD 137 (079) 94 (056) -101

ADVANCE 253 (095) 289 (108) -072

UKPDS 71 (053) 29 (052) -066

VADT 38 (083) 29 (063) -116

Overall 497 441 -088

All-cause mortality


Trials





Overall HR (95 CI)

104 (090 120)

110 (084 142)

05 20 10

Trials




ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)


Overall 459 446 -088 100 (086 116)




10 05 20

dagger




intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1











6







HFrEF12





disease4




dyslipidemia4



HF preserved EF1


HF reduced EF3

LVEF le402

7 7




PEP-CHF16

ARNi




MRA RALES5

EMPHASIS6

TOPCAT18

ALDO-HF19


Cohn8 NEAT-HFpEF20

CRT MADIT-CRT9


ICD IMPROVE-HF9




Evidence of

clinical efficacy

Clinical efficacy

uncertain

No evidence of

clinical efficacy



Ongoing

T2D type 2 diabetes




8

Macrovascular

Microvascular











Heart failure


TIA stroke

Aortic aneurysm

Overt proteinuria








10

OBESITY

Adiponectin

Adipocytokines

inflammatory

cytokines

T2D

Insulin

resistance

Atherosclerosis

Dyslipidaemia

Endothelial

dysfunction

Age

Oxidative

stress

Hypertension


11


Pre

va

len

ce

o

f d

iab

ete

s (

)

33

43

49

32 35

48

43 42 42

0

10

20

30

40

50

60

TOPCAT1

(n=3345)

SOCRATES-R6

(n=456)

RELAX2

(n=216)

EPHESUS4

(n=6642)

PARADIGM5

(n=8399)

SOCRATES -P3

(n=477)

OPTIMIZE8

(n=46612)

GWTG HF7

(n=21078)

ADHERE9

(n=46612

)




heart failure

12










2ndash5






13

Su

rviv

al

pro

po

rtio

n

Time (years)

p=00322 RR=141

LVEF ge50


10

08

06

04

02

00 0 2 4 6 8 10 12

04

02

00 0 2 4 6 8 10 12

plt00001

RR=173

LVEF lt50


Time (years)

10

08

06

00






Diabetes Mellitus

14



15

Years

0

50

100

150

1990 2000 2010

Even

ts p

er

100

00

ad

ult

po

pu

lati

on

wit

h d

iab

ete

s

MI Stroke ESRD






16


ACCORD 257 (141) 203 (114) -101

ADVANCE 498 (186) 533 (199) -072

UKPDS 123 (013) 53 (025) -066

VADT 102 (222) 95 (206) -116

Overall 980 884 -088

ACCORD 137 (079) 94 (056) -101

ADVANCE 253 (095) 289 (108) -072

UKPDS 71 (053) 29 (052) -066

VADT 38 (083) 29 (063) -116

Overall 497 441 -088

All-cause mortality


Trials





Overall HR (95 CI)

104 (090 120)

110 (084 142)

05 20 10

Trials




ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)


Overall 459 446 -088 100 (086 116)




10 05 20

dagger




intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1






7 7




PEP-CHF16

ARNi




MRA RALES5

EMPHASIS6

TOPCAT18

ALDO-HF19


Cohn8 NEAT-HFpEF20

CRT MADIT-CRT9


ICD IMPROVE-HF9




Evidence of

clinical efficacy

Clinical efficacy

uncertain

No evidence of

clinical efficacy



Ongoing

T2D type 2 diabetes




8

Macrovascular

Microvascular











Heart failure


TIA stroke

Aortic aneurysm

Overt proteinuria








10

OBESITY

Adiponectin

Adipocytokines

inflammatory

cytokines

T2D

Insulin

resistance

Atherosclerosis

Dyslipidaemia

Endothelial

dysfunction

Age

Oxidative

stress

Hypertension


11


Pre

va

len

ce

o

f d

iab

ete

s (

)

33

43

49

32 35

48

43 42 42

0

10

20

30

40

50

60

TOPCAT1

(n=3345)

SOCRATES-R6

(n=456)

RELAX2

(n=216)

EPHESUS4

(n=6642)

PARADIGM5

(n=8399)

SOCRATES -P3

(n=477)

OPTIMIZE8

(n=46612)

GWTG HF7

(n=21078)

ADHERE9

(n=46612

)




heart failure

12










2ndash5






13

Su

rviv

al

pro

po

rtio

n

Time (years)

p=00322 RR=141

LVEF ge50


10

08

06

04

02

00 0 2 4 6 8 10 12

04

02

00 0 2 4 6 8 10 12

plt00001

RR=173

LVEF lt50


Time (years)

10

08

06

00






Diabetes Mellitus

14



15

Years

0

50

100

150

1990 2000 2010

Even

ts p

er

100

00

ad

ult

po

pu

lati

on

wit

h d

iab

ete

s

MI Stroke ESRD






16


ACCORD 257 (141) 203 (114) -101

ADVANCE 498 (186) 533 (199) -072

UKPDS 123 (013) 53 (025) -066

VADT 102 (222) 95 (206) -116

Overall 980 884 -088

ACCORD 137 (079) 94 (056) -101

ADVANCE 253 (095) 289 (108) -072

UKPDS 71 (053) 29 (052) -066

VADT 38 (083) 29 (063) -116

Overall 497 441 -088

All-cause mortality


Trials





Overall HR (95 CI)

104 (090 120)

110 (084 142)

05 20 10

Trials




ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)


Overall 459 446 -088 100 (086 116)




10 05 20

dagger




intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1






T2D type 2 diabetes




8

Macrovascular

Microvascular











Heart failure


TIA stroke

Aortic aneurysm

Overt proteinuria








10

OBESITY

Adiponectin

Adipocytokines

inflammatory

cytokines

T2D

Insulin

resistance

Atherosclerosis

Dyslipidaemia

Endothelial

dysfunction

Age

Oxidative

stress

Hypertension


11


Pre

va

len

ce

o

f d

iab

ete

s (

)

33

43

49

32 35

48

43 42 42

0

10

20

30

40

50

60

TOPCAT1

(n=3345)

SOCRATES-R6

(n=456)

RELAX2

(n=216)

EPHESUS4

(n=6642)

PARADIGM5

(n=8399)

SOCRATES -P3

(n=477)

OPTIMIZE8

(n=46612)

GWTG HF7

(n=21078)

ADHERE9

(n=46612

)




heart failure

12










2ndash5






13

Su

rviv

al

pro

po

rtio

n

Time (years)

p=00322 RR=141

LVEF ge50


10

08

06

04

02

00 0 2 4 6 8 10 12

04

02

00 0 2 4 6 8 10 12

plt00001

RR=173

LVEF lt50


Time (years)

10

08

06

00






Diabetes Mellitus

14



15

Years

0

50

100

150

1990 2000 2010

Even

ts p

er

100

00

ad

ult

po

pu

lati

on

wit

h d

iab

ete

s

MI Stroke ESRD






16


ACCORD 257 (141) 203 (114) -101

ADVANCE 498 (186) 533 (199) -072

UKPDS 123 (013) 53 (025) -066

VADT 102 (222) 95 (206) -116

Overall 980 884 -088

ACCORD 137 (079) 94 (056) -101

ADVANCE 253 (095) 289 (108) -072

UKPDS 71 (053) 29 (052) -066

VADT 38 (083) 29 (063) -116

Overall 497 441 -088

All-cause mortality


Trials





Overall HR (95 CI)

104 (090 120)

110 (084 142)

05 20 10

Trials




ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)


Overall 459 446 -088 100 (086 116)




10 05 20

dagger




intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1
















Heart failure


TIA stroke

Aortic aneurysm

Overt proteinuria








10

OBESITY

Adiponectin

Adipocytokines

inflammatory

cytokines

T2D

Insulin

resistance

Atherosclerosis

Dyslipidaemia

Endothelial

dysfunction

Age

Oxidative

stress

Hypertension


11


Pre

va

len

ce

o

f d

iab

ete

s (

)

33

43

49

32 35

48

43 42 42

0

10

20

30

40

50

60

TOPCAT1

(n=3345)

SOCRATES-R6

(n=456)

RELAX2

(n=216)

EPHESUS4

(n=6642)

PARADIGM5

(n=8399)

SOCRATES -P3

(n=477)

OPTIMIZE8

(n=46612)

GWTG HF7

(n=21078)

ADHERE9

(n=46612

)




heart failure

12










2ndash5






13

Su

rviv

al

pro

po

rtio

n

Time (years)

p=00322 RR=141

LVEF ge50


10

08

06

04

02

00 0 2 4 6 8 10 12

04

02

00 0 2 4 6 8 10 12

plt00001

RR=173

LVEF lt50


Time (years)

10

08

06

00






Diabetes Mellitus

14



15

Years

0

50

100

150

1990 2000 2010

Even

ts p

er

100

00

ad

ult

po

pu

lati

on

wit

h d

iab

ete

s

MI Stroke ESRD






16


ACCORD 257 (141) 203 (114) -101

ADVANCE 498 (186) 533 (199) -072

UKPDS 123 (013) 53 (025) -066

VADT 102 (222) 95 (206) -116

Overall 980 884 -088

ACCORD 137 (079) 94 (056) -101

ADVANCE 253 (095) 289 (108) -072

UKPDS 71 (053) 29 (052) -066

VADT 38 (083) 29 (063) -116

Overall 497 441 -088

All-cause mortality


Trials





Overall HR (95 CI)

104 (090 120)

110 (084 142)

05 20 10

Trials




ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)


Overall 459 446 -088 100 (086 116)




10 05 20

dagger




intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1












10

OBESITY

Adiponectin

Adipocytokines

inflammatory

cytokines

T2D

Insulin

resistance

Atherosclerosis

Dyslipidaemia

Endothelial

dysfunction

Age

Oxidative

stress

Hypertension


11


Pre

va

len

ce

o

f d

iab

ete

s (

)

33

43

49

32 35

48

43 42 42

0

10

20

30

40

50

60

TOPCAT1

(n=3345)

SOCRATES-R6

(n=456)

RELAX2

(n=216)

EPHESUS4

(n=6642)

PARADIGM5

(n=8399)

SOCRATES -P3

(n=477)

OPTIMIZE8

(n=46612)

GWTG HF7

(n=21078)

ADHERE9

(n=46612

)




heart failure

12










2ndash5






13

Su

rviv

al

pro

po

rtio

n

Time (years)

p=00322 RR=141

LVEF ge50


10

08

06

04

02

00 0 2 4 6 8 10 12

04

02

00 0 2 4 6 8 10 12

plt00001

RR=173

LVEF lt50


Time (years)

10

08

06

00






Diabetes Mellitus

14



15

Years

0

50

100

150

1990 2000 2010

Even

ts p

er

100

00

ad

ult

po

pu

lati

on

wit

h d

iab

ete

s

MI Stroke ESRD






16


ACCORD 257 (141) 203 (114) -101

ADVANCE 498 (186) 533 (199) -072

UKPDS 123 (013) 53 (025) -066

VADT 102 (222) 95 (206) -116

Overall 980 884 -088

ACCORD 137 (079) 94 (056) -101

ADVANCE 253 (095) 289 (108) -072

UKPDS 71 (053) 29 (052) -066

VADT 38 (083) 29 (063) -116

Overall 497 441 -088

All-cause mortality


Trials





Overall HR (95 CI)

104 (090 120)

110 (084 142)

05 20 10

Trials




ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)


Overall 459 446 -088 100 (086 116)




10 05 20

dagger




intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1







11


Pre

va

len

ce

o

f d

iab

ete

s (

)

33

43

49

32 35

48

43 42 42

0

10

20

30

40

50

60

TOPCAT1

(n=3345)

SOCRATES-R6

(n=456)

RELAX2

(n=216)

EPHESUS4

(n=6642)

PARADIGM5

(n=8399)

SOCRATES -P3

(n=477)

OPTIMIZE8

(n=46612)

GWTG HF7

(n=21078)

ADHERE9

(n=46612

)




heart failure

12










2ndash5






13

Su

rviv

al

pro

po

rtio

n

Time (years)

p=00322 RR=141

LVEF ge50


10

08

06

04

02

00 0 2 4 6 8 10 12

04

02

00 0 2 4 6 8 10 12

plt00001

RR=173

LVEF lt50


Time (years)

10

08

06

00






Diabetes Mellitus

14



15

Years

0

50

100

150

1990 2000 2010

Even

ts p

er

100

00

ad

ult

po

pu

lati

on

wit

h d

iab

ete

s

MI Stroke ESRD






16


ACCORD 257 (141) 203 (114) -101

ADVANCE 498 (186) 533 (199) -072

UKPDS 123 (013) 53 (025) -066

VADT 102 (222) 95 (206) -116

Overall 980 884 -088

ACCORD 137 (079) 94 (056) -101

ADVANCE 253 (095) 289 (108) -072

UKPDS 71 (053) 29 (052) -066

VADT 38 (083) 29 (063) -116

Overall 497 441 -088

All-cause mortality


Trials





Overall HR (95 CI)

104 (090 120)

110 (084 142)

05 20 10

Trials




ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)


Overall 459 446 -088 100 (086 116)




10 05 20

dagger




intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1







heart failure

12










2ndash5






13

Su

rviv

al

pro

po

rtio

n

Time (years)

p=00322 RR=141

LVEF ge50


10

08

06

04

02

00 0 2 4 6 8 10 12

04

02

00 0 2 4 6 8 10 12

plt00001

RR=173

LVEF lt50


Time (years)

10

08

06

00






Diabetes Mellitus

14



15

Years

0

50

100

150

1990 2000 2010

Even

ts p

er

100

00

ad

ult

po

pu

lati

on

wit

h d

iab

ete

s

MI Stroke ESRD






16


ACCORD 257 (141) 203 (114) -101

ADVANCE 498 (186) 533 (199) -072

UKPDS 123 (013) 53 (025) -066

VADT 102 (222) 95 (206) -116

Overall 980 884 -088

ACCORD 137 (079) 94 (056) -101

ADVANCE 253 (095) 289 (108) -072

UKPDS 71 (053) 29 (052) -066

VADT 38 (083) 29 (063) -116

Overall 497 441 -088

All-cause mortality


Trials





Overall HR (95 CI)

104 (090 120)

110 (084 142)

05 20 10

Trials




ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)


Overall 459 446 -088 100 (086 116)




10 05 20

dagger




intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1











13

Su

rviv

al

pro

po

rtio

n

Time (years)

p=00322 RR=141

LVEF ge50


10

08

06

04

02

00 0 2 4 6 8 10 12

04

02

00 0 2 4 6 8 10 12

plt00001

RR=173

LVEF lt50


Time (years)

10

08

06

00






Diabetes Mellitus

14



15

Years

0

50

100

150

1990 2000 2010

Even

ts p

er

100

00

ad

ult

po

pu

lati

on

wit

h d

iab

ete

s

MI Stroke ESRD






16


ACCORD 257 (141) 203 (114) -101

ADVANCE 498 (186) 533 (199) -072

UKPDS 123 (013) 53 (025) -066

VADT 102 (222) 95 (206) -116

Overall 980 884 -088

ACCORD 137 (079) 94 (056) -101

ADVANCE 253 (095) 289 (108) -072

UKPDS 71 (053) 29 (052) -066

VADT 38 (083) 29 (063) -116

Overall 497 441 -088

All-cause mortality


Trials





Overall HR (95 CI)

104 (090 120)

110 (084 142)

05 20 10

Trials




ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)


Overall 459 446 -088 100 (086 116)




10 05 20

dagger




intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1











Diabetes Mellitus

14



15

Years

0

50

100

150

1990 2000 2010

Even

ts p

er

100

00

ad

ult

po

pu

lati

on

wit

h d

iab

ete

s

MI Stroke ESRD






16


ACCORD 257 (141) 203 (114) -101

ADVANCE 498 (186) 533 (199) -072

UKPDS 123 (013) 53 (025) -066

VADT 102 (222) 95 (206) -116

Overall 980 884 -088

ACCORD 137 (079) 94 (056) -101

ADVANCE 253 (095) 289 (108) -072

UKPDS 71 (053) 29 (052) -066

VADT 38 (083) 29 (063) -116

Overall 497 441 -088

All-cause mortality


Trials





Overall HR (95 CI)

104 (090 120)

110 (084 142)

05 20 10

Trials




ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)


Overall 459 446 -088 100 (086 116)




10 05 20

dagger




intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1








15

Years

0

50

100

150

1990 2000 2010

Even

ts p

er

100

00

ad

ult

po

pu

lati

on

wit

h d

iab

ete

s

MI Stroke ESRD






16


ACCORD 257 (141) 203 (114) -101

ADVANCE 498 (186) 533 (199) -072

UKPDS 123 (013) 53 (025) -066

VADT 102 (222) 95 (206) -116

Overall 980 884 -088

ACCORD 137 (079) 94 (056) -101

ADVANCE 253 (095) 289 (108) -072

UKPDS 71 (053) 29 (052) -066

VADT 38 (083) 29 (063) -116

Overall 497 441 -088

All-cause mortality


Trials





Overall HR (95 CI)

104 (090 120)

110 (084 142)

05 20 10

Trials




ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)


Overall 459 446 -088 100 (086 116)




10 05 20

dagger




intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1









16


ACCORD 257 (141) 203 (114) -101

ADVANCE 498 (186) 533 (199) -072

UKPDS 123 (013) 53 (025) -066

VADT 102 (222) 95 (206) -116

Overall 980 884 -088

ACCORD 137 (079) 94 (056) -101

ADVANCE 253 (095) 289 (108) -072

UKPDS 71 (053) 29 (052) -066

VADT 38 (083) 29 (063) -116

Overall 497 441 -088

All-cause mortality


Trials





Overall HR (95 CI)

104 (090 120)

110 (084 142)

05 20 10

Trials




ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)


Overall 459 446 -088 100 (086 116)




10 05 20

dagger




intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1






Trials




ACCORD 352 (211) 371 (229) -101

ADVANCE 557 (215) 590 (228) -072

UKPDS 169 (130) 87 (160) -066

VADT 116 (268) 128 (298) -116

Overall 1194 1176 -088 091 (084 099)

Stroke

Overall 378 370 -088 096 (083 110)


Overall 730 745 -088 085 (076 094)


Overall 459 446 -088 100 (086 116)




10 05 20

dagger




intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1







intensive









18



darr harr uarr

darr harr

harr harr harr harr




HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1








HF Outcomes

CV Outcomes

+ (Benefit)

+- (Null)

- (Harm)

+ (Benefit)



TIMI)

+- (Null)



- (Harm)


53)


Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1







Trial FU y

(median)

Age

y BMI

Male

()

Duration

of DM y HO of CVD

Baseline

HO HF

HbA1c

baseline (D)

SAVOR 21 651 287 67 103 78 13 80 (-03)

EXAMINE 15 61 295 68 71 100 28 80 (-03)

TECOS 4 66 302 71 116 74 18 72 (-03)

ELIXA 2 61 30 69 93 100 22 77 (-03)

LEADER 38 643 325 64 127 81 18 87 (-04)

SUSTAIN-6 21 646 313 61 139 59 24 87 (-07 -10)

EXCSEL 32 62 318 62 12 73 16 80 (-05)

EMPA-REG 31 631 306 72 gt10y

(57) 99 10 81 (-03)

CANVAS 24 633 32 64 135 66 14 82 (-06)




SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1








SAVOR-TIMI 531

(n=16492) 1222 3P-MACE

EXAMINE2

(n=5380) 621 3P-MACE

ELIXA3

(n=6068) 805 4P-MACE

TECOS4

(n=14671) 1690 4P-MACE

SUSTAIN-67

(n=3297) 3P-MACE

CANVAS-R8


EXSCEL12

(n=14000) ge1591 3P-MACE

FREEDOM-CVO14

(n=4000) 4P-MACE

REWIND18

(n=9622) ge1067 3P-MACE

HARMONY Outcomes16

(n=9400) 3P-MACE


(n=3900) 3P-MACE


KEY

DECLARE-TIMI 5817

(n=17276) ge1390 3P-MACE


(n=7020) 772 3P-MACE

CAROLINAreg9

(n=6000) ge411 4P-MACE

CARMELINAreg13


LEADER6

(n=9341) ge611 3P-MACE

CREDENCE15


CANVAS10

(n=4418) ge420 3P-MACE

2013 2014 2015 2016 2017 2018 2019 2020

OMNEON11

(n=4202) 4P-MACE



Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1








Trial

Impact on HHF


FDA Label

DPP4i


HR 127 (95CI 107-151)2

p=0007




(452016)3

DPP4i


HR 119 (95CI 090-158)4

p=0220




(452016)3

DPP4i

(sitagliptin) TECOS

HR 100 (95CI 083-120)5

p=098





(8102017)

DPP4i

(linagliptin)

CAROLINA

CARMELINA

CARMELINA

HR 090 (95CI 074-108)6

p=026





(8102017)




ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1








ratio

95 CI P value


3-point MACE 4904687 2822333 086 074 099 00382

CV death 1724687 1372333 062 049 077 lt00001

Nonfatal MI 2134687 1212333 087 070 109 02189

Nonfatal stroke 1504687 602333 124 092 167 01638

Hospitalization for

heart failure 1264687 952333 065 050 085 00017

03 05 10 20

EMPA-REG OUTCOME


Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1






Months

Pa

tie

nts

with

ev

en

t (

)







24

HR 062 (95 CI 049 077)

plt0001

EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1






EMPA-REG OUTCOME


7

0

6

5

4

3

2

1


HR=065 (95 CI 050 085) P=0002

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

4687

2333

4614

2271

4523

2226

4427

2173

3988

1932

2950

1424

2487

1202

1634

775

395

168 Placebo

Empagliflozin

No at risk P

ati

en

ts w

ith

eve

nt

()

0

15

10

5


HR=068 (95 CI 057 082) Plt0001

Placebo

Empagliflozin

0

Month

6 12 18 24 30 36 42 48

Pa

tie

nts

wit

h e

ve

nt

()

4687

2333

4651

2303

4608

2280

4556

2243

4128

2012

3079

1503

2617

1281

1722

825

414

177 Placebo

Empagliflozin

No at risk


NNT 39



HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1








HHF or CV death

All patients 2654687 (57) 1982333 (85) 066 (055 079)

HF at baseline

No 1904225 (45) 1492089 (71) 063 (051 078)

Yes 75462 (162) 49244 (201) 072 (050 104)

HHF

All patients 1264687 (27) 952333 (41) 065 (050 085)

HF at baseline

No 784225 (18) 652089 (31) 059 (043 082)

Yes 48462 (104) 30244 (123) 075 (048 119)

CV death

All patients 1724687 (37) 1372333 (59) 062 (049 077)

HF at baseline

No 1344225 (32) 1102089 (53) 060 (047 077)

Yes 38462 (82) 27244 (111) 071 (043 116)

All-cause mortality

All patients 2694687 (57) 1942333 (83) 068 (057 082)

HF at baseline

No 2134225 (50) 1592089 (76) 066 (051 081)

Yes 56462 (121) 35244 (143) 079 (052 120)



025 05 1 2

All

treatment

by

subgroup

interaction

pgt041

Favours

placebo





Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1









Class IIa

Level B



28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1








28

Simvastatin1

for 54 years


1994 2000 2015

Pre-statin era


Ramipril2

for 5 years

Pre-ACEiARB era

lt29 statin



gt80 ACEiARB

gt75 statin


EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1







EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1






EMPRISE background















T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1









T2D type 2 diabetes



EM

PA

-RE

G

OU

TC

OM

Ereg

2

EM

PR

ISE

3



20

18

lit

era

ture

revie

w1


EMPA-REG OUTCOMEreg


included in EMPRISE

10 of total

T2D population =

Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1






Objectives











study completion


32










33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1











33

Effectiveness1

Safety1

HCRU and costs2

CV mortality



All-cause mortality

3P-MACE

HHF

Primary outcomes


ESRD


Secondary outcomes







All-cause ED visits

Office visits



Pharmacy

Medications filled

Costs




Secondary outcomes

HCRU

17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1






17551 new users of

DPP-4i



34



17551 new users of

empagliflozin






excluded

PS matching




EMPA

vs

DPP-4i


4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1







4i





0 3 6 9 12 15 18 21 24

Cu

mu

lati

ve

in

cid

en

ce

Months

HR 056

(95 CI 043 073)

plt00001


005

004

003

002

001

0

EMPA

vs

DPP-4i

Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1






Study


HR (95 CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2



(NR) 20

4217551

(NR) 56

049

(027 089)


(NR) 103

14617551

(NR) 196

056

(043 073)


36






025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1






Study


HR (95

CI)

n event

N analysed

()

Rate

1000 PY

n event

N analysed

()

Rate

1000 PY



1264687

(27) 94

952333

(41) 145

065

(050 085)

EMPRISE2


Broad HHF 8217551

(NR) 103

14617551

(NR) 196

056

(043 073)

Without CVD 1713238

(NR) 28

3613238

(NR) 63

046

(026 083)

With CVD 644245

(NR) 354

1154245

(NR) 650

056

(041 076)


37




years


025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i

Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1






Study


HR (95 CI) p-value

n event

N analysed ()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY



EMPA 10 mg 602345 (26) NR 952333 (41) 145 062 (045 086) 0004

EMPA 25 mg 662342 (28) NR 952333 (41) 145 068 (050 093) 002

EMPRISE2


EMPA 10 mg 4610620 (NR) 105 9510620 (NR) 206 055 (039 078)

EMPA 25 mg 357744 (NR) 101 567744 (NR) 173 062 (041 095)







025 1 4

Favours

empagliflozin

Favours

comparator

EMPA

vs

DPP-4i







7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1












7

6

5

4

2

0

0 6 12 18 24 30 36 42 48

1

3

HR 065

(95 CI 050 085)

p=0002

Pa

tie

nts

wit

h e

ve

nt

()

Months


Placebo

005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 051

(95 CI 039 068)

plt00001


005

004

003

002

001

0 3 6 9 12 15 18 21 24 0

HR 056

(95 CI 043 073)

plt00001


Cu

mu

lati

ve

in

cid

en

ce

Months

Empagliflozin







40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1












40

Study


HR (95 CI)

p-value for

interaction

n event

N analysed

()

Rate

1000 PY

n event

N analysed ()

Rate

1000 PY




No 321639 (20) 68 28815 (34) 122 057 (035 095)

Yes 943048 (31) 108 671518 (44) 157 068 (050 094)



Without CVD 1612342 (NR) 28 4012342 (NR) 74 040 (022 073)

With CVD 604034 (NR) 351 1064034 (NR) 607 060 (044 083)



Without CVD 1713238 (NR) 28 3613238 (NR) 63 046 (026 083)

With CVD 644245 (NR) 354 1154245 (NR) 650 056 (041 076)

Favours

empagliflozin

Favours

comparator

0125 025 05 1 2






41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1











41


Patients with

HHF events


Treatment



Outcome

identification





Result




















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1















44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1










44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1








44

H2O Proximal

tubule lumen

Blood

lumen








Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1












Vascular effects

darr Inflammation

darr Fibrosis






darr Inflammation




darr HbA1c Negative

caloric balance

uarr Uricosuria

Glycosuria

darr Plasma volume

darr Blood pressure


Natriuresis

SGLT2i







EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1












EMPEROR-reduced1

LVEF le40

EMPEROR-preserved2

LVEF gt40

Placebo qd

+ standard of care


+ standard of care

Screening

Placebo qd

+ standard of care


+ standard of care

30

-da

y

follo

w-u

p

Screening

30

-da

y

follo

w-u

p






Planned recruitment

2850 patients

Planned recruitment

4126 patients

46




Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1








Summary

47











3P-MACE


darr14


Incident or

worsening

nephropathy




Summary

48




with T2D1








Summary

48




with T2D1






Documents

CURRICULUM VITAE SAN - Translating...CURRICULUM VITAE SALLY AMAN NASUTION, MD, FINASIM, FACP - Born in Medan, 8th August 1967 -Internist – Cardiologist -Faculty Member Division of