David Fitchett MD

St Michael’s Hospital

Toronto

Challenges in the Management of Heart Failure in People with Type 2 Diabetes

A Cardiologist’s Perspective

Faculty Disclosure

Faculty: David Fitchett MD,, FRCP(C) Associate Professor of Medicine, University of Toronto Cardiologist, St. Michael’s Hospital

Potential Conflicts of Interest CME and Consultation honoraria: Boehringer Ingelheim, Lilly, Astra Zeneca, Novartis, Merck, EMPA Reg Outcome steering committee DSMB Chair: Sustain 6 and PIONEER 6 for NovoNordisk

53 year old male

• Known DM for 2 years

– DM diagnosed at time of Acute Inferior wall MI

• Primary PCI to RCA

– BP 145/85

– Weight 103kg (BMI 35) Smokes 1ppd

– Echocardiogram: Inferobasal akinesis LVEF 50%

– A1C 7.5%, Creatinine 115, Proteinuria 2+

• Medications

Metformin 1G bid, Glyburide (Glibenclamide) 2.5mg qd ,

Atorvastatin 80mg qd, Atenolol 50mg qd, Ramipril 5mg qd

• No CV symptoms

3 years ago: Sees cardiologist

53 year old male

• Presents to GP with SOB with mild exertion

– BP 155/70 HR 85 reg JVP +15, Creps, Mild

ankle oedema

– Weight 105 kg BMI 36

– Creatinine 135, eGFR 50 LDL-C 1.6

– A1C 7.4%

– Echocardiogram: Inferobasal akinesis, LVEF 50%

• Started on furosemide 40mg daily

• Improved symptoms

Now

53 year old male

New Challenges

• Optimise Risk factor control

– Smoking cessation, BP, weight control

• Optimise HF management

– HF preserved EF

• Select DM medication with CV / renal

benefit

Heart Failure: Impact of Diabetes • Frequent in T2 DM

– T2DM > 65 yrs old HF prevalence 22%

• Often unrecognized

• At least 50% are HFpEF

• High mortality

– 5 year survival of < 50%

• Optimal management of T2DM and HF a challenge

– Antiglycemic drugs may promote weight gain / fluid retention

– TZD and Saxagliptin increase risk of HF

• Until recently no glycemic drug favourably modified HF outcomes

Central Role of T2 DM in Heart Failure

T2 DM

Impact of Accelerated Atherosclerosis and Heart Failure

Accelerated Atherogenesis

Volume overload Myocardial Fibrosis

Stroke MI

Risk

Heart Failure

Risk

Sudden Death

MI Stroke Heart

Failure

Age Associated Prevalence of Heart Failure in Diabetic and Non-Diabetic Individuals

Nichols et al Diabetes Care 2004;27:1879

5 Year Survival in 115,803 Subjects

with Diabetes by Incident Heart Failure

Bertoni et al Diabetes Care 2004;27:699

Study 1994-1999

Prevalence HF 22.2%

Incident HF 1994-99

Increased with

• Age

• CHD

• CKD

• PVD

5 yr Mortality 32.7 / 100 pt / yrs

5 yr Mortality 3.7 / 100 pt yrs

Diabetes

Heart Failure Free

Diabetes

With Heart Failure

13

Cu

mu

lative

in

cid

en

ce

(%

)

60

40

20

0

0 0.5 1 1.5 2 2.5 3 3.5

Follow-up (years)

Diabetes increases risk of hospitalization or death

due to heart failure

HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction.

MacDonald et al. Eur Heart J 2008;29:1377-85.

No diabetes (HFpEF)

HFpEF: adjusted HR 2.0

95% CI 1.70–2.36; p<0.0001 Diabetes (HFpEF)

HFpEF

No diabetes (HFrEF)

HFrEF: adjusted HR 1.60

95% CI 1.44–1.77; p<0.0001 Diabetes (HFrEF)

HFrEF

In patients with T2 DM and CVD

Heart Failure is more frequent than MI

and has a greater impact on CV Mortality

Incidence per 100 patient-

yrs

CV mortality

(%) After event

Deaths

Heart

Failure (HF admission +

Investigator

reported HF)

3.7 24.2% 61

Non-fatal

MI

1.9 21.5% 26

Zinman et al N Engl J Med 2015; Fitchett et al Eur Heart J 2016;

Placebo group of EMPA REG Outcome

3000 Patients with DM and CV Disease

Observed 3 years

HF was the first manifestation of T2D-related CV disease: more often than MI or stroke

16.2%

14.1%

11.5%

10.3%

4.2%

PAD HF* NFMI CVA CV death

% e

ven

t as

fir

st C

V e

ven

t Cohort study of patients (n=34,198) with

T2D and incidence of CV disease

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

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

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

16%

27%

25%

32%

Systolic LVD

n=106

Systolic and

diastolic LVD

n=95

Normal LV

function

n=124

Diastolic LVD

n=61

Left ventricular dysfunction occurs in the absence of atherosclerosis

68% of patients with T2D had evidence of

LV dysfunction 5 years after T2D diagnosis1 • Multicentre study evaluating

clinical and echocardiographic

characteristics of individuals

with T2D (n=386)

• Patients had no evidence of

inducible ischaemia by stress

testing at baseline

• This suggests the earliest defect

in the diabetic heart is that of

diastolic dysfunction, not

atherothrombosis2

LV, left ventricular; LVD, LV dysfunction; T2D, type 2 diabetes.

1. Faden G et al. Diabetes Res Clin Pract. 2013;101:309-316. 2. Borlaug BA, Paulus WJ. Eur Heart J. 2011;32(6):670-679.

HF remains under-diagnosed in patients with T2D,

A high index of suspicion is required

HFrEF HFpEF All HF

Unrecognised

Heart Failure

4.8% 22.9% 27.7%

95% CI 24-31%

Systolic

dysfunction

Diastolic

dysfunction

All HF

Unrecognised

LV dysfunction

0.7% 25.1% 25.8%

95% CI 22-28%

Boonman de Winter et al Diabetologia 2012;55:2154-62

Cross-sectional study

605 subjects with T2 DM and no history of HF

ESC Criteria for HF: Judged by expert panel

Echocardiogram: Evidence of diastolic or systolic dysfunction The prevalence of undiagnosed HF was higher:

− With increasing age

− In females

− In patients with BMI ≥30 kg/m2

− In patients with dyspnea

− In patients complaining of fatigue

− In patients with hypertension

Cardiovascular Outcomes Have Improved in Diabetes: Heart Failure Remains the Largest CVD Problem

Burns et al Diab Care 2018;42:293-302

HF HF

ACS

ACS

Management of Patient with (or at risk for)

HF with Diabetes

• Prevention

• Symptom control

• Guideline recommended treatment to improve

survival and prevent HF decompensation

• Diabetes management with agents that

– reduce risk of HF decompensation

– Improve survival / Reduce hospital admissions

Use a Multifaceted Vascular Protection

Strategy to Reduce Cardiovascular Risk

BP <130/80

A1C ≤7%

Rx

Statins

ACEi/ARB

Healthy

Lifestyle/weight

Smoking

Cessation

Physical

Activity

Impact of Multifaceted Strategy on CV

Events in Patients with Diabetes

STENO 2 Gaede et al. NEJM. 2003: 348;383-393

NNT = 5

Months of Follow-up

12 24 36 48 60 72 84 96 0

10

20

30

40

50

60

P = 0.007

Conventional therapy

Intensive therapy

53 %

RRR

CV Event

Intensive Goals Exercise program

Smoking cessation

Diet

Total chol < 4.6

SBP < 130

A1C < 6.5

ACE I / ARB

ASA

Reduced Heart Failure Hospitalisation after

Intensive Risk Factor Management

Oellgard et al Diabetologia 2018;61:1724

Conventional therapy

Intensive therapy

HR 0.51 (95% CI 0.34-0.76)

STENO 2

Long Term Outcomes after

Intensive Risk Factor Management

Mortality CVD Events + Mortality

Gaede et al Diabetologia 2016

Survival 7.9 years longer

In intensively treated group

STENO 2

Heart Failure with Reduced Ejection Fraction

The Building Blocks of Therapy

Transplant

VAD

CRT

ICD

Beta Blocker ACE Inhibitor

ARB MRA

Hydralazine / IDN

Digoxin

CABG

Ivabradine

IV Iron

All treatments are equally effective

in patients with and without diabetes

ARNI

Heart Failure with Reduced Ejection Fraction

The Building Blocks of Therapy

Transplant

VAD

CRT

ICD

Beta Blocker ACE Inhibitor

ARB MRA

Hydralazine / IDN

Digoxin

CABG

Ivabradine

IV Iron

Choice of Glucose Lowering Agents

Guideline management of HFpEF focuses on treatment of comorbidities

T2D, hypertension, coronary artery disease, and obesity

ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; AF, atrial fibrillation; CAD, coronary artery

disease; COR, class of recommendation; GDMT, guidelines-directed medical therapy; HF, heart failure; HFpEF, heart

failure with preserved ejection fraction; LOE, level of evidence; T2D, type 2 diabetes.

Yancy CW, et al. Circulation. 2013;128:1810-1852.

COR I: treatment is recommended; COR IIa: treatment is reasonable; COR IIb: treatment may be

considered.

LOE B: date derived from single study or non-randomized studies; LOE C: limited patient population

evaluated (case study, consensus).

Recommendations COR LOE

Systolic and diastolic blood pressure should be controlled

according to published clinical practice guidelines I B

Diuretics should be used for relief of symptoms due to volume

overload I C

Coronary revascularization for patients with CAD in whom

angina or demonstrable myocardial ischemia is present despite

GDMT

IIa C

Management of AF according to published clinical practice

guidelines for HFpEF to improve symptomatic HF IIa C

Use of beta-blocking agents, ACE inhibitors, and ARBs for

hypertension in HFpEF IIa C

ARBs might be considered to decrease hospitalisation in HFpEF IIb B

Nutritional supplementation is not recommended in HFpEF III: No Benefit C

Choice of Glucose Lowering Agents

Risk of Heart Failure Related to A1C

Lack of Intensive Glycemic Control on Heart Failure Admission or Death

Control et al Diabetalogia 2009

Glucose Lowering: Impact on Heart Failure

Glycemic Agent / Control

benefit 0 neutral harm

Insulin 0

Metformin ?

Sulphonylurea / Glinide ?

TZD

DPP4 i 0 (saxagliptin )

GLP1 agonist 0

SGLT2 inhibitor

http://dx.doi.org/10.1093/eurheartj/ehv728

Baseline Characteristics (n= 7034)

• Age 63.1 (9% > 75 yrs)

• Male 72%

• Current / ex smoker 46%

• Diabetes > 10yrs 57%

• eGFR 74 ml/min/1.73m2

– 26 % 30-60 ml/min/1.73m2

• Coronary disease 75%

• Prior MI 47%

• Multivessel CAD 47%

• CABG 25%

• Stroke 23%

• Heart failure 10.5%

Zinman et al N Engl J Med 2015 DOI: 10.1056/NEJMoa1504720

CV death

34

CI, confidence interval; HR, hazard ratio.

Zinman et al. N Engl J Med 2015:373:2117-

HR 0.62 (95% CI 0.49, 0.77)

p<0.0001

Empagliflozin in Indonesia is not indicated to reduce CV Death

Further information refer to local prescribing information

Hospitalisation for heart failure

35

HR 0.65 (95% CI 0.50, 0.85)

p=0.0017

Cumulative incidence function. HR, hazard ratio

Heart failure Hospitalisation

and Cardiovascular Mortality

36

Patients with event/analysed (%)

Empagliflozin Placebo HR (95% CI)

Adjudicated HHF 126/4687

(2.7)

95/2333

(4.1)

0.65 (0.50,

0.85)

Investigator-reported heart

failure*

204/4687

(4.4)

143/2333

(6.1)

0.70 (0.56,

0.87)

Introduction of loop

diuretics

340/3962

(8.6)

262/1969

(13.3)

0.62 (0.53,

0.73)

0.5 1 2

Effects of empagliflozin on various presentations

of heart failure

37

Cox regression analysis in patients treated with ≥1 dose of study drug.

*Investigator-reported heart failure was based on the narrow standardised MedDRA query ‘cardiac

failure’.

HHF, hospitalisation for heart failure.

Fitchett D et al. ESC 2016 Clinical Trial Update (2237)

Favours empagliflozin

Favours placebo

Patients hospitalized

for heart failure

(%)

Hospitalization for HF in patients with HF vs without

HF at baseline

HR 0.75

(95% CI 0.48, 1.19)

HR 0.59

(95% CI 0.43, 0.82)

38

Cox regression analysis. CI, confidence interval; HR, hazard ratio

Inzucchi SE. AHA 2015. Oral presentation

Impact of Empagliflozin on HF Rehospitalisation

39 Savarese et al ACC 2018

Reduction of CV Mortality in Overall Population

and in Patients with ‘HF Burden’

HFH Heart Failure Hospitalisation, HFBL Heart Failure at baseline,

HFI Investigator reported Heart Failure

41

Placebo Empagliflozin HR

(95% CI)

CV

deaths

(%)

Absolute

Mortality

Reduction

Overall

population

137 / 2333

(5.9%)

172 / 4687

(3.7%)

0.62

(0.49,

0.77)

100% 2.2%

HF Burden

(HFH, HFBL,

HFI)

54 / 353

(15.3%)

63/605

(10.4%)

0.67

(0.47,

0.97)

37.9% 4.9%

No HF

burden

83/1980

(4.1%)

109/4082

(2.7%)

0.63

(0.48,

0.84)

62.1% 1.4%

Fitchett et al Eur J Cardiol 2017 doi: 10.1093/eurheartj/ehx511.

44% reduction of CV deaths by Empagliflozin

in HF burden patients (15% of population)

CANVAS Outcomes

CV death, nonfatal myocardial infarction, or nonfatal stroke

CV death

Nonfatal myocardial infarction

Nonfatal stroke

Hospitalization for heart failure

CV death or hospitalization for heart failure

All-cause mortality

Progression of albuminuria

Renal composite

Favors Placebo Favors

0.5 1.0

Canagliflozin

2.0

Hazard ratio (95% CI)

p <0.0001 noninferiority

p = 0.0158 superiority

CANVAS: Heart Failure Outcomes

43

CANVAS: Possible greater benefit in patients with a history of HF

Relative Risk Absolute Risk

Radholm et al Circulation 2018;137

CV Death or Hospitalisation for HF

EMPA REG, CANVAS, DECLARE

Comparisons

46

Patients

enrolle

d

FU

Yrs

MACE

ARR p

RRR

Mortality

ARR p

RRR

CV mortality

/HF

ARR p

RRR

HF Hosp

ARR p

RRR

EMPA REG Empagliflozin

CVD 3 1.6% 0.04

14% 2.6% <0.001

32% NNT 3yrs 40

1.04%

34%

1.4% <0.002

35%

CANVAS Canagliflozin

CVD

+ 30%

High

risk

3.2 1.5% 0.02

14%

0.7% ns

13%

4.5%

22%

1.0% <0.05

33%

DECLARE Dapagliflozin

CVD

+ 60%

High

risk

4.3 0.6% ns 0.4% ns 1.0% 0.005

17%

0.92%

27%

ARR Absolute risk reduction, RRR Relative risk reduction HFH Heart failure hospitalisation

CV Benefits of SGLT2 Inhibition in patients with Established CVD vs Risk Factors only

HR 95% CI HR 95% CI

Established ASCVD Risk Factors only

CV Death

0.80 (0.71-0.91) 1.02 (0.80-1.30

Non fatal MI 0.85 (0.76-0.95)

0.99 (0.79-1.24)

Non fatal Stroke 0.97 (0.86-1.10)

1.01 (0.80-1.28)

Heart Failure Hospitalisation

0.71 (0.62-0.82) 0.64 (0.48-0.85)

CV Death / HFH 0.76 (0.69-0.84) 0.84 (0.69-1.01)

Zelniker et al Lancet 2018

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

†Broad definition HHF data shown

1:1 propensity score-matched cohorts; DPP-4i, dipeptidyl peptidase-4 inhibitor; HHF, hospitalisation for heart failure

Patorno E et al. AHA 2018; poster 1112 49

Month

HR 0.56

(95% CI 0.43, 0.73)

p<0.0001

Cu

mu

lati

ve

in

cid

en

ce

0.05

0.04

0.03

0.02

0.01

0

0 3 6 9 12 15 18 21 24

DPP-4i Empagliflozin

Direct comparison of studies should be interpreted with caution due to differences in study design, populations

and methodology. Definitions of HHF vary between studies. †Broad definition HHF data shown

CVD, cardiovascular disease; DPP-4i, dipeptidyl peptidase-4 inhibitor; HHF, hospitalisation for heart failure; MI, myocardial infarction;

PY, patient-years; RCT, randomised controlled trial; RWE, real-world evidence;

1. Zinman B et al. N Engl J Med 2015;373:2117 (supplemental appendix); 2. Fitchett D et al. ACC 2018; oral presentation; 3. Patorno E et al. AHA 2018; poster 1112

Study Empagliflozin Comparator HR (95% CI)

EMPRISE (empagliflozin vs DPP-4i in Real World Setting)

Overall

population

83/17,539

(0.5) 10.5

150/17,539

(0.9) 19.9

0.56

(0.43, 0.73)† 44%

↓ Risk

Without

CVD 17/13,243 2.8 47/13,243 8.3

0.35

(0.20, 0.61)†

With CVD 63/4,217 35.2 120/4,217 68.0 0.53

(0.39, 0.72)†

0.125 0.25 0.5 1 2

Favours

Placebo

Favours

Empagliflozin

HHF in EMPRISE Suggests Patients with and without CVD Benefit from EMPAGLIFLOZIN

Impact of SGLT2i on CV Outcomes by the presence or absence of established CVD

51

Verma et al Lancet 2018

Prevention of Hypotension when Prescribing an SGLT2 inhibitor

52

HYPERVOLEMIA• Con nuediure cand

monitorBP/Cr/weight/assumingnothypotensive

• Cau onwithmul plediure cs

VOLUMECONTRACTION• Stopdiure icand

monitor• Ini ateSGLT2when

euvolemic

EUVOLEMIA

HYPERTENSIVEBP>130/80• Con nue

diure candmonitorBP/lytes/Cr/weight

NORMOTENSIVEBP110-130/70-90• Con nueor

discon nuediure candmonitorBP/lytes/Cr/weight

1. Whatisthevolumestatus?• Posturalhypotensivesymptoms• CheckBPonstanding

HYPOTENSIVESBP<110• Cau on,holdor

reducediure candre-ins tuteifrequired

2.Whatisthebloodpressure?

Cherney D, Udell J.

Circulation. 2016;134:1915-1917

Practical Considerations for the Use of SGLT2 Inhibitors

Renal function – threshold for treatment

• Empagliflozin eGFR > 45, Canagliflozin eGFR > 45, Dapagliflozin eGFR > 60

Intercurrent illness / Major trauma or surgery

• “Sick day” Temporary discontinuation to prevent acute kidney injury or DKA

DKA

• Check for plasma ketones in any patient unwell / nauseated irrespective of

plasma glucose

Risk of hypoglycemia is low but

• Consider reducing SU and or insulin dose especially if high risk

Elderly, history of hypoglycemia, Severe obesity, Irregular eating habits

Mycotic Genital Infections

• Encourage genital hygiene, changing pads / tampons frequently, avoid tight

synthetic underwear

Amputation risk

• Only observed with canagliflozin

• Avoid SGLT2i in patients with prior amputation or ischemic feet

53

Recent guidelines recognise empagliflozin for the prevention

or delay of heart failure in T2D

Empagliflozin is not indicated for the treatment of heart failure

CV, cardiovascular; HF, heart failure; RCT, randomised controlled trial; T2DM, type 2 diabetes

Seferovic PM et al. Eur J Heart Failure 2018;20:853

• ESC Heart Failure Association position statement – February 2018

Prevention of heart failure by type 2 antidiabetic

drugs (p12)

“A significant breakthrough in contemporary

cardiology was the finding that some T2DM drugs are

associated with a lower risk of HF hospitalization in

patients with CV disease or at high risk of CV disease”

“Two large RCTs that assessed CV safety of the

sodium–glucose co-transporter type 2 (SGLT2)

inhibitors, empagliflozin and canagliflozin, have shown

a significant reduction in HF hospitalization with both

drugs”

55

Consider SGLT2i in patients with

Multiple CV Risk Factors

ADA /EASD Guidelines 2018

HF or CKD

Predominates

Heart Failure Risk Assessed by ABC Heart Failure Risk Score

56

0

10

20

30

40

50

60

70

80

Placebo Empagliflozin

<10%

10-20%

>20%

Heart

Fa

ilure

/ C

V M

ort

alit

y R

isk /

1000

ABC Heart failure Score

Parameters

• Age

• Coronary heart disease

• SBP

• Heart rate

• ECG LVH

• Smoking

• Albumin level

• Fasting glucose

• Creatinine

Butler et al Circ HF 2008;1:125

Heart Failure Hospitalisation / CV Mortality

ABC HF Risk

Fitchett et al Eur Heart J 2018;39:313

53 year old male

Management Strategy

• Risk factors

– Smoking cessation, weight loss, BP control

• Optimise HF management

– MRA Eplerenone

• Select DM medication with CV / HF benefit

– Discontinue Glyburide. Start Empagliflozin 10mg daily

Would he have developed HF if he had been started

on empagliflozin after the MI?

EMPEROR-Reduced and EMPEROR-Preserved Heart Failure Outcome Trials

HF with Reduced Ejection

Fraction (HFrEF)

• T2D and non-T2D

• Event driven trial

• 2850 pts

HF with Preserved Ejection

Fraction (HFpEF)

• T2D and non-T2D

• Event driven trial

• 4126 pts

+

EMPEROR-Reduced1 EMPEROR-Preserved2

1. NCT03057977 2. NCT03057951 www.clinicaltrials.gov

Diabetes and Heart Failure (HF) • HF hospitalisation more frequent than ACS / CVA

– Higher mortality rates in HFH than ACS

• Specific glucose lowering drugs increase risk of HF

– TZDs -Saxagliptin

• SGLT2 Inhibition – with Empagliflozin reduces HF and CV death – With Canagliflozin and Dapagliflozin reduces HF

• Empagliflozin should be considered in patients with

T2DM & CVD to prevent heart failure and CV death

• The HF trials with SGLT2i will provide efficacy and safety data in patients with established HF with defined phenotypes in patients with and without T2DM

62

*HRs refer to the risk of CV death or HHF in patients with diabetes versus non-diabetes

MacDonald MR et al. Eur Heart J 2008;29:1377

CV death or HHF in patients with or without diabetes

The presence of diabetes worsens HF prognosis

63

20

0

60

40

0 0.5 1 1.5 2 2.5 3 3.5

HFrEF: unadjusted HR 1.60

(95% CI 1.44, 1.77); p<0.0001

HFpEF: unadjusted HR 2.0

(95% CI 1.70, 2.36); p<0.0001

HFrEF

HFpEF

HFrEF

HFpEF

Cu

mu

lati

ve

in

cid

en

ce

(%

)

Follow-up (years)

No diabetes Diabetes

Left Ventricular Function in Diabetes

• Impaired diastolic function in 40% Poulsen et al Circ Card Imag 2010;3:24

• Abnormal systolic function yet normal EF in

43% Nakai et al Eur J Echo 2009;10:926

• Reduced LV ejection fraction

– Silent MI

– “Diabetic cardiomyopathy”

Fluid retention

• Diabetic nephropathy

• Medications Heart Failure

+

SGLT2 Inhibitors and Heart Failure

• EMPA REG Outcome (10% HF at baseline)

– Hospitalisation for heart failure: Adjudicated

– Investigator reported HF: Not adjudicated AE

– New use of loop diuretic: Surrogate for HF

• CANVAS Program (11% HF at baseline)

– Hospitalisation for HF

Neither study phenotyped Heart Failure • No NYHA class • No BNP • No measure of LV function

Hospitalisation for heart failure

66

HR 0.65 (95% CI 0.50, 0.85)

p=0.0017

Cumulative incidence function. HR, hazard ratio

Patients with

heart failure hospitalization

or CV death

(%)

HR 0.72

(95% CI 0.50, 1.04)

HR 0.63

(95% CI 0.51, 0.78)

HF hospitalization or CV death in patients with HF

vs without HF at baseline

67

Cox regression analysis. CI, confidence interval; HR, hazard ratio

Inzucchi SE. AHA 2015. Oral presentation

0.25 0.5 1 2

HR (95% CI)

Hospitalisation for heart

failure

eGFR

<60 ml/min/1.73 m2

≥60 ml/min/1.73 m2

Reduced risk for hospitalisation for HF was maintained in

patients with eGFR <60 ml/min/1.73 m2 at baseline

Empagliflozin is not indicated in all countries for CV risk reduction, and is not indicated for the treatment of

HF

CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure

Wanner C et al. ERA-EDTA 2016; oral presentation

68

HR 0.59

(95% CI 0.39, 0.88)

Hospitalisation for heart failure in patients with eGFR <60 ml/min/1.73 m2

Hospitalisation for heart failure according to baseline eGFR

Favours

empagliflozin

Favours

placebo

Patients with event/analysed (%)

Empagliflozin Placebo HR (95% CI)

Adjudicated HHF 126/4687

(2.7)

95/2333

(4.1)

0.65 (0.50,

0.85)

Investigator-reported heart

failure*

204/4687

(4.4)

143/2333

(6.1)

0.70 (0.56,

0.87)

Adjudicated HHF or

investigator-reported heart

failure*

217/4687

(4.6)

151/2333

(6.5)

0.70 (0.57,

0.87)

Introduction of loop

diuretics

340/3962

(8.6)

262/1969

(13.3)

0.62 (0.53,

0.73)

Introduction of loop

diuretics or adjudicated

HHF

411/4027

(10.2)

313/2013

(15.5)

0.63 (0.54,

0.73)

0.5 1 2

Effects of empagliflozin on various outcomes

reflecting heart failure burden

69

Cox regression analysis in patients treated with ≥1 dose of study drug.

*Investigator-reported heart failure was based on the narrow standardised MedDRA query ‘cardiac failure’.

HHF, hospitalisation for heart failure.

Fitchett D et al. ESC 2016 Clinical Trial Update (2237)

Favours empagliflozin

Favours placebo

CV Death in overall population and in

patients with “HF burden”

70

Placebo Empagliflozin HR (95% CI)

CV deaths (%)

Absolute mortality reduction

Overall population

137/2333 (5.9%)

172/4687 (3.7%)

0.62 (0.49, 0.77)

100% 2.2%

HF Burden (HFH, HFBL, HFAE)

54/353 (15.3%)

63/605 (10.4%)

0.67 (0.47, 0.97)

37.9% 4.9%

No HF burden 83/1980 (4.1%)

109/4082 (2.7%)

0.63 (0.48, 0.84)

62.1% 1.4%

HFH, HF hospitalization; HFBL, HF at baseline; HFAE, HF as an investigator-reported adverse event.

Protection of Renal Function with Empagliflozin in

Patients with and without Baseline Heart Failure

71

Butler et al ESC 2018

Impact of Empagliflozin on Renal Endpoints in

Patients with and without Baseline Heart Failure

72 Butler et al ESC 2018

2017 2018 2019 2020

DPP-4 inhibitor

SGLT2 inhibitor

GLP-1 agonist

KEY

….and further trials are on the horizon

73

CAROLINA®

N=6072

≥631 3P-MACE

Linagliptin vs SU

CARMELINA®

N=7053

3P-MACE + renal

Linagliptin

CREDENCE

N=4200

Renal + 5P-MACE

Canagliflozin

DECLARE-TIMI 58

N=25,880; 3P-MACE

Dapagliflozin

N=3176; 3P-MACE

PIONEER-6

Semaglutide (oral)

HARMONY Outcomes

N=9400; 3P-MACE

Albiglutide

N=9622; 3P-MACE

REWIND

Dulaglutide

DAPA-HF

N=4500; CV death, HHF

or urgent HF visit

Dapagliflozin

VERTIS CV

Ertugliflozin

N=8000

3P-MACE

DAPA-CKD

Dapagliflozin

N=4000

≥50% decline eGFR

EMPEROR-Preserved

Empagliflozin

N~4126; CV death or HHF

EMPEROR-Reduced

N~2850; CV death or HHF

Empagliflozin

N~5000

Empagliflozin

Empagliflozin CKD trial

EXSCEL

Exenatide

N=14,780

1360 3P-MACE

EMPEROR-Reduced and EMPEROR-Preserved Heart Failure Outcome Phase III Trials

HF with Reduced Ejection

Fraction (HFrEF)

• T2D and non-T2D

• Event driven trial

• 2850 pts

HF with Preserved Ejection

Fraction (HFpEF)

• T2D and non-T2D

• Event driven trial

• 4126 pts

+

EMPEROR-Reduced1 EMPEROR-Preserved2

1. NCT03057977 2. NCT03057951 www.clinicaltrials.gov

Diabetes and Heart Failure (HF) • HF hospitalisation more frequent than ACS / CVA

– Higher mortality rates in HFH than ACS

• Specific glucose lowering drugs increase risk of HF

– TZDs -Saxagliptin

• SGLT2 Inhibition – with Empagliflozin reduces HF and CV death – With Canagliflozin reduces HF

• Empagliflozin should be considered in patients with

T2DM & CVD to prevent heart failure and CV death

• The HF trials with SGLT2i will provide efficacy and safety data in patients with established HF with defined phenotypes in patients with and without T2DM