Congestive Heart Failure: The Complication That Gets No Respect

Sanjay Kaul, MD, FACC, FAHADivision of Cardiology

Cedars-Sinai Medical CenterLos Angeles, California

65th Advanced Postgraduate Course February 9 - 11, 2018, San Francisco, CA

Faculty/Presenter DisclosureFaculty Name: Sanjay Kaul, MD

• Advisor/Consultant

- United States FDA

• Consultant

- Boehringer Ingelheim

- Sanofi

- Novo Nordisk

- Johnson & Johnson

• Stocks/Equity

- Johnson & Johnson

Congestive Heart Failure (in T2DM):

The Complication That Gets No Respect

Congestive Heart Failure (in T2DM):

The Complication That Gets No Respect

• Impact of heart failure

• Classification, prognosis, and medical management

• Epidemiology of T2DM and heart failure

• Pathophysiology of T2DM and heart failure

• Glucose-lowering medications and heart failure

• Heart failure outcomes in recent CVOTs in T2DM

• Possible mechanisms for cardiovascular benefits

• Current trials with SGLT2 inhibitors in heart failure

• ‘Take-home’ points

Outline

HF is a Global Health Problem with a Prevalence of

Approximately 26 million Worldwide

*Estimates based on a single centre or hospital Ponikowski P et al. Heart failure: Preventing disease and death worldwide. European Society of Cardiology, 2014. www.escardio.org/static_file/Escardio/Subspecialty/HFA/WHFA-whitepaper-15-May-14.pdf (accessed Nov 2015)

North America1

Canada 1.5%

USA 1.9%

Latin America and Africa1

No population-based estimates

Europe1

France 2.2%

UK 1.3%

Asia1

China* 1.3%

Japan 1.0%

Malaysia* 6.7%

Singapore* 4.5%

Australasia1

Australia 1.3%

Middle East1

Oman* 0.5%

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

The Prevalence and Cost of HF is Projected to Increase Further

0

10

20

30

40

50

60

70

80

2012 2030

Cost of HF*(US)

0

1

2

3

4

5

6

7

8

9

2012 2030

Prevalence of HF(US)

Nu

mb

er

of A

me

rica

ns w

ith

HF

(m

illio

ns)

Pro

jecte

d c

ost o

f H

F (

bill

ion

s o

f d

olla

rs)

5.8m

8.5m

$31b

$70b

Heidenreich et al., AHA Policy Statement: Forecasting the Impact of Heart Failure in the United States. Circ Heart Fail. 2013;6:606–619

* 80% of costs are related to hospitalization

Scientific Evidence Underlying The ACC/AHA Clinical Practice Guidelines

Caveat Emptor, Caveat Lector

1. Redfield MM et al. N Engl J Med 2016;375:1868; 2. Bugger H et al. Diabetologia 2014;57:660;3. Borlaug BA. Heart failure with preserved ejection fraction. In: Springer Verlag; 2015;213–230.4. Mann DL et al. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, Single Volume, 10th Edition.

Elsevier Saunders, Philadelphia 2015

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 HFrEF1,2

Accounts for >50% 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, e.g. hypertension, diabetes, advanced age, smoking, dyslipidemia4

Accounts for 50% of all HF cases

Important classification for clinical management2,4

HF preserved EF1

LVEF ≥50%*,2 (40–50 borderline)

HF reduced EF3

LVEF ≤40%2

There are Two Categories of Heart Failure Scientific Evidence Underlying The ACC/AHA Clinical Practice Guidelines

Caveat Emptor, Caveat Lector

There are Two Categories of Heart Failure

HFpEF

• Preserved systolic LV function

• No LV dilation

• Concentric LV remodeling

• Diastolic LV dysfunction

HFrEF

• Systolic LV dysfunction

• LV dilation

• Eccentric LV remodeling

• Diastolic LV dysfunction

Classification of HF: ACCF/AHA stage vs NYHA classification

NYHA: New York Heart Association, HF: heart failure Yancy CW, et al. Circulation. 2013 ;128(16):e240–327.

ACCF/AHA Stage NYHA Classification

A

At high risk for HF but without

structural heart disease or

symptoms of HFNone

BStructural heart disease but

without signs or symptoms of HFI

No limitation of physical activity. Ordinary physical activity

does not cause symptoms of HF.

CStructural heart disease with prior

or current symptoms of HF

I Same as above

IISlight limitation of physical activity. Comfortable at rest,

but ordinary physical activity results in symptoms of HF.

IIIMarked limitation of physical activity. Comfortable at rest

but less than ordinary activity causes symptoms of HF.

IVUnable to carry on any physical activity without

symptoms of HF or symptoms of HF at rest.

DRefractory HF requiring

specialized interventionsIV

Unable to carry on any physical activity without

symptoms of HF or symptoms of HF at rest.

Heart Failure Risk Factors

The Framingham Heart StudyAge and Risk-factor Adjusted HR

39% (PAR)59% (PAR)

34% (PAR)

13% (PAR)

6% (PAR)12% (PAR)

Levy D, et al. JAMA 1996;275:1557–156

Hypertension and CAD are the most common risk factors for HF

Not all Heart Failure Patients have a History of CAD

HFpEF Study CAD HFrEF Study CAD

TOPCAT1 (n=3445) 59% PARADIGM-HF7 (n=8442) 60%

I-Preserve2 (n=4133) 48% RALES8 (n=1663) 55%

CHARM-Preserved3 (n=3023) 60% COPERNICUS9 (n=2289) 67%

DIG-PEF4 (n=988) 56% MERIT-HF10 (n=3991) 65%

PEP-CHF5 (n=850) 27% CHARM-ALT11 (n=2028) 68%

SENIORS6 (n=752) 77% SOLVD12 (n=2569) 71%

1Pitt, B. et al. N Engl J Med. 2014;370:1383–1392; 2Massie, B. et al. N Engl J Med 2008;359:2456–2467; 3Yusuf, S. et al. Lancet. 2003 Sep 6; 362(9386):777–781; 4Ahmed A, et al. Circulation 2006;114:397–403; 5Cleland, J, et al. Eur Heart J. 2006 Oct;27(19):2338–2345; 6 Flather, M et al. Eur Heart J. 2005 Feb;26(3):215–225; 7McMurray, J. et al. N Engl J Med 2014; 371:993–1004; 8Pitt, B. et al. N Engl J Med 1999:341:709–717; 9Packer et al. N Engl J Med. 2001; 344:1651–1658; 10Merit HF Study Group. The Lancet. 1999;353:2001-2001; 11Granger, C et al. Lancet 2003; 362:772–776; 12SOLVD Study Investigators N Engl J Med 1991;325:293–302.

1. Loehr LR et al. Am J Cardiol 2008;101:1016; 2. Chen J et al. JAMA 2011;306:1669

10

22

42

0

20

40

60

Day 30 Year 1 Year 5

Dea

ths

(% p

atie

nts

)

Time after hospitalization

Mortality rates after HHF

(ARIC study)1

Mortality rates after HHF

(US Acute Care)2*

31 31 30 28 30

0

10

20

30

40

2000 2002 2004 2006 2008

Ris

k-ad

just

ed 1

-yea

r m

ort

alit

y (%

)

*Risk-adjusted rates relative to

1999 1-year mortality of 31.7%

Prognosis after hospitalization for HF (HHF) is poor

Mortality Rates after HHF – Results from Two

Population-Based Cohort Studies

Repeat Hospitalization Leads to Worse Patient Outcomes

Adapted from Solomon SD et al. Circulation. 2007;116:1482–1487

3rd HF Hospitalization

1st HF Hospitalization2nd HF

Hospitalization

0

2

4

6

8

10

12

14

16

Hazard

rati

o (

mo

rtality

)

Time since discharge (months)

0-1 1-3 3-6 6-12 12+

40% of patients died after discharge from HF hospitalization

Guidelines for Management of HFrEF (Stage C/D)2017 ACC/AHA/HFSA Focused Update

Yancy CW et al, Circulation. 2017 ACC/AHA/HFSA HF Focused Update of the 2012 ACCF/AHA Guidelines for the Management of Heart Failure. DOI: 10.1161/CIR.0000000000000509.

Class I

Benefit>>>Risk

Class IIa

Benefit >>Risk

Magnitude of Benefit Demonstrated in RCTsClass I LOE A Recommended Therapy

Guideline-directed therapyRR reduction in

mortality1,2

NNT for mortality reduction

(over 1 year)1

RR reductionin HHF2

ACE inhibitor or ARB 17% 77 31%

Beta blocker 34% 28 41%

Aldosterone antagonist 30% 18 35%

Hydralazine/nitrate 43% 21 33%

ARNI 16% 80 21%3

1Fonarow,G. et al. JAMA Cardiol. 2016;1(6):714-717; 2Yancy CW et al. Circulation. 2013;128:e240–e327; 3McMurray, J. et al. N Engl J Med 2014; 371:993–1004

15

Benefit of therapy evident on the background of standard of care (incremental treatment effects)

Recommendations3 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

IIaC

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 hospitalizations in HFpEF IIb B

In appropriately selected patients* with HFpEF aldosterone receptor antagonists

might be considered to decrease hospitalizations4 IIb B-R

*Appropriately selected patients: with EF ≥45%, elevated BNP levels or HF admission within 1 year, estimated

glomerular filtration rate >30 mL/min, creatinine <2.5 mg/dL, potassium <5.0 mEq/L

Yancy CW et al, Circulation. 2017 ACC/AHA/HFSA HF Focused Update of the 2012 ACCF/AHA Guidelines for the Management of Heart Failure. DOI: 10.1161/CIR.0000000000000509.

Guidelines for Management of HFpEF2017 ACC/AHA/HFSA Focused Update

No treatment has yet been shown, convincingly, to reduce

morbidity and mortality in patients with HFpEF

Therapies Successful in HFrEF Have Not

Demonstrated Success in HFpEF

Intervention HFrEF HFpEF

Beta blocker SENIORS1 OPTIMIZE-HF14

ACEi/ARB CHARM2 I-PRESERVE15

PEP-CHF16

Digoxin DIG3 Dig-PEF17

PDE5 inhibitor RELAX-HF4 RELAX-HF4

MRARALES5

EMPHASIS6

TOPCAT18

ALDO-HF19

Hydralazine/NiA-HeFT7

Cohn8NEAT-HFpEF20

CRTMADIT-CRT9

COMPANION10PROSPECT21

ICDIMPROVE-HF9

MADIT-I11No studies available

ExerciseHF-ACTION12

Thompson et al.13Pandey*22

✓

✓

✓

✓

✓

✓

✓

✓

✓ Evidence of

clinical efficacy

Clinical efficacy

uncertain

No evidence of

clinical efficacy

HFpEF RCTs HFrEF RCTs Registries

Pre

vale

nce

of d

iab

ete

s (%

)

33

43

49

3235

48

4342 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=46,612)GWTG HF7

(n=21,078)ADHERE9

(n=46,612)

1Pitt B et al. N Engl J Med 2014;390:1383; 2Redfield MM et al. JAMA 2013;309:1268; B et al. Eur Heart J 2016;38:1119; 4Pitt B et al. N Engl J Med 2003;348:1309; 5McMurray JJV et al. N Engl J Med 2014;371:993; 6Gheorghiade M et al. JAMA 2015;314:2251; 7Luo N et al. JACC Heart Fail 2017;5:305; 8Greenberg BH et al. Heart J 2007;154:277.e12277.e8; 9Peacock F, et al. N Engl J Med 2008; 358:2117–2126.

Diabetes is Common Among Patients with HF

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

There is a Strong Relationship Between

Heart Failure and Diabetes

1. Kannel WB et al. Am J Cardiol 1974;34:292. Cubbon RM et al. Diab Vasc Dis Res 2013;10:3303. MacDonald MR et al. Eur Heart J 2008;29:1377

People with diabetes have a 2- to 5-fold higher risk

of developing HF(independent of IHD or HTN)1

Diabetes confers 60–80% greater probability of CV death and

all-cause mortality in those with established HF2,3*

2–52–5

T2DM Confers Higher Risk of CV death, Hospitalization for

Heart Failure and All-cause Mortality

MacDonald MR, et al. Eur Heart J 2008;29:1377–1385

CV death or

hospitalization due to heart failure

CV death

Hospitalization

due to heart failure

All-cause

mortality

Low EF

Low EF

Low EF

Low EF

657/1306

(50.3%)

413/1306

(31.6%)

449/1306

(34.4%)

496/1306

(38.0%)

1104/3270

(33.8%)

707/3270

(21.6%)

709/3270

(21.7%)

854/3270

(26.1%)

Diabetes No diabetes

CV death or hospitalization due to heart failure60

40

20

00.5 1 1.5 2 2.5 3 3.50

Cu

mu

lati

ve in

cid

en

ce (%

)

Follow-up (years)

a

Diabetes(Low EF)

No Diabetes (Low EF)

Cu

mu

lati

ve in

cid

en

ce (%

)

60

40

20

00.5 1 1.5 2 2.5 3 3.50

Follow-up (years)

Diabetes (Low EF)

No Diabetes (Low EF)

All-cause mortality

Diabetes Increases Risk in HFpEF to Approximate Risk

in HFrEF in Non-DM

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

Increased risk of hospitalization or death due to HF with HFrEF vs HFpEF

0

60

40

20

0 0.5 1 1.5 2 2.5 3 3.5

1HFrEF: adjusted HR 1.60

95% CI 1.4, 1.77; p<0.0001

2HFpEF: adjusted HR 2.0

95% CI 1.70, 2.36; p<0.0001

HFrEF

HFpEF2

HFrEF1

HFpEF

Cum

ula

tive incid

ence o

f

CV

death

or

HH

F (

%)

Follow-up (years)

DiabetesNon-Diabetes

Patients with Heart Failure have Similar

Pathophysiological Features as Patients with Diabetes

Mitochondrial

dysfunction

Endothelial

dysfunction

Insulin resistance

RAAS activation

Inflammation

Heart failure

Neurohormonal

activation

Impaired contractility

Cardiomyocyte

apoptosis/fibrosis

Shared pathological features Diabetes

LV remodelling

Hyperglycaemia

Advanced glycated

end-product toxicity

↓ Pancreatic

beta-cell function

Neuronal degeneration/

demyelination

LV, left ventricular; RAAS, renin-angiotensin-aldosterone systemAdapted from: Sena CM et al. BBA Mol Basis Dis 2013;1832:2216; Aroor AR et al. Heart Fail Clin 2012;8:609; Anker SD et al. Heart 2004;90:464; Sivitz WI et al. Antioxid Redox Signal 2010;12:557; Bauters C et al. Cardiovasc Diabetol 2003;2:1

Diabetes Contributes to the Progression of Heart Failure

Perrone-Filardi P et al. Eur Heart J. 2015;36(39):2630–2634

HFpEF in 2018: Phenotypic Diversity

Kitzman D, Shah SJ. JACC 2016Borlaug B. Nat Rev Cardiol 2014

Lung Chest wall restriction, reduced vital capacity,

impaired ventilation and diffusion Obstructive sleep apnea Pulmonary hypertension

Liver Non-alcoholic fatty liver disease

Promotes generalized inflammatory state

Visceral adiposity Inflammatory cytokines

Adverse neurohormones Increased BNP clearance

Kidney Direct toxic effects of perinephric fat

Glomerulomegaly with glomerular dysfunction

Skeletal muscle Increased adipose infiltration

Impaired perfusion Decreased diffusive O2 transport Mitochondrial dysfunction

Heart Direct and indirect myocardial lipotoxicity

Worsened cardiac mechanics Diastolic dysfunction; increased filling pressures/ volume overload, increased afterload

Obesity-related HFpEF is the most common phenotype of heart failure in T2DM

Intensive Glycaemic Control* Has Not

Been Shown to Significantly Impact the Risk of HF

Number of events (yearly rate, %)DHbA1c

(%)HR (95% CI)

More intensive Less intensive

Admission to hospital/fatal HF

ACCORD 152 (0.90) 124 (0.75) –1.01 1.18 (0.93, 1.49)

ADVANCE 220 (0.83) 231 (0.88) –0.72 0.95 (0.79, 1.14)

UKPDS 8 (0.06) 6 (0.11) –0.66 0.55 (0.19, 1.60)

VADT 79 (1.80) 85 (1.94) –1.16 0.92 (0.68, 1.25)

Overall 459 446 –0.88 1.00 (0.86, 1.16)†

0.5 1.0 2.0

Favours more

intensive controlFavours less

intensive control

*Versus less-intensive glycaemic control; †p=0.31 for heterogeneity from Q test

with significance cut off of p=0.1

Turnbull FM et al. Diabetologia 2009;52:2288

Previous CV Outcomes Trials with Glucose-Lowering Agents

Have Not Shown a Benefit for HF Outcomes

TrialStudy drug Comparator

HR (95% CI)n (%) n (%)

ORIGIN (HHF) 310 (4.9) 343 (5.5) 0.90 (0.77, 1.05)

SAVOR-TIMI 53 (HHF) 289 (3.5) 228 (2.8) 1.27 (1.07, 1.51)

EXAMINE (HHF) 106 (3.9) 89 (3.3) 1.19 (0.90, 1.58)

TECOS (HHF) 228 (3.1) 229 (3.1) 1.00 (0.83, 1.20)

TECOS (HHF or CV death) 538 (7.3) 525 (7.2) 1.02 (0.90, 1.15)

ELIXA (HHF) 122 (4.0) 127 (4.2) 0.96 (0.75, 1.23)

ELIXA (HHF or 4P-MACE) 456 (15.0) 469 (15.5) 0.97 (0.85, 1.10)

PROactive (HHF or HF death) 149 (5.7) 108 (4.1) 1.41(1.10, 1.80)

RECORD (HHF or CHF death) 61 (2.7) 29 (1.3) 2.10 (1.35, 3.27)

DD

P-4

inh

ibit

ors

*

GL

P-1

R

ag

on

ists

*In

su

lin

*T

ZD

s*

0.3 1.0 4.0

Favours study drug Favours comparator

Vildagliptin increased ventricular end-diastolic volume in pts with reduced LV fx (VIVIDD)

Liraglutide increased (ns) the rate of death or hHF in pts recently hospitalized for HF (FIGHT)

Excess adverse cardiac events with Liraglutide in chronic HF with or without DM (LIVE)

Metformin in Heart FailureCompared With Other Treatments For All-cause Mortality

Eurich DT, et al. Circ Heart Fail 2013;6:395–402

Study or

subgroup log[risk ratio] SE Weight

Risk ratio

IV, random,95% CI Year

Favors

Metformin ● Control

Evans –0.5108 0.25 2.6% 0.60 (0.37, 0.98) 2005

Eurich –0.4156 0.2 4.1% 0.66 (0.45, 0.98) 2005

Masoudi –0.1393 0.06 29.0% 0.87 (0.77, 0.98) 2005

Inzucchi –0.0834 0.13 8.9% 0.92 (0.71, 1.19) 2005

Shah –0.2357 0.4 1.1% 0.79 (0.36, 1.73) 2010

MacDonald –0.4308 0.15 6.9% 0.65 (0.48, 0.87) 2010

Roussel –0.3711 0.13 8.9% 0.69 (0.53, 0.89) 2010

Andersson –0.1625 0.0682 24.6% 0.85 (0.74, 0.97) 2010

Aguilar –0.2744 0.1 13.9% 0.76 (0.62, 0.92) 2011

Total (95% CI) 100.0% 0.80 (0.74, 0.87)

0.5 0.7 1 1.5 2Heterogeneity: Tau2=0.00; Chi2=9.45, df=8 (P=0.31); I2=15%

Test for overall effect: Z=5.35 (P<0.00001)

Congestive Heart Failure (in T2DM):

The Complication That Gets No Respect

• Impact of heart failure

• Classification, prognosis, and medical management

• Epidemiology of T2DM and heart failure

• Pathophysiology of T2DM and heart failure

• Glucose-lowering medications and heart failure

• Heart failure outcomes in recent CVOTs in T2DM

• Possible mechanisms for cardiovascular benefits

• Current trials with SGLT2 inhibitors in heart failure

• ‘Take-home’ points

2008 FDA Diabetes GuidanceRecommendations

• Primary evidence for regulatory approval: glycemic control

• Demonstrate that therapy will not result in an unacceptable increase in CV risk (noninferiority, rule out HR 1.3)

• Phase 2/3 design should permit a pre-specified meta-analysis of major cardiovascular events (3p-MACE: CV death, non-fatal MI, or non-fatal stroke; 4-p MACE = 3-p MACE + hosp. for UA or CR) (4p-MACE to r/o 1.8, 3p-MACE to r/o 1.3)

• Independent committee should prospectively and blindly adjudicate MACE

• Trials should include patients at increased risk for cardiovascular disease (advanced CVD, CKD, elderly)

• Trial duration(s) should be longer than 3-6 months to obtain enough events and provide long-term data (~2yrs)

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116994.htm

No mention of heart failure outcome assessment in Diabetes Guidance!

CVOTs in T2DM: Evidentiary Landscape25 Trials (9 Completed), N=200,000 since 2013

2013

TECOSn = 14,6714-P MACE

CAROLINAn = 6,1153-P MACE

CARMELINAn = 8,300

3-P MACE,renal

composite

REWINDn = 9,9013-P MACE

2015 2016 2017 2018 2019 2020

SAVOR-TIMI 53n = 16,4923-P MACE

EXAMINEn = 5,3803-P MACE

EMPA-REG OUTCOMEn = 7,0203-P MACE

ELIXAn = 6,0684-P MACE

SUSTAIN-6n = 3,2973-P MACE

LEADERn = 9,3403-P MACE

DEVOTE

n = 7,6373-P MACE

CANVAS Program

n = 10,1423-P MACE

FREEDOM-CVOn = 4,0004-P MACE

EXSCELn = 14,7523-P MACE

ACEn = 6,5265-P MACE

(3-P MACE + hospitalization

for HF or unstable angina)

VERTIS CVn = 8,0003-P MACE

HARMONY Outcomesn = 9,4003-P MACE

Dapa-HFn = 4,500

CV death, HF hospitalization, HF urgent visit

CREDENCEn = 4,200

ESRD, doubling of creatinine,

renal/CV death

DECLARE-TIMI 58n = 17,150

3-P MACE, CVD

EMPEROR-Preservedn = 4,126

CV death or HF hospitalization

EMPEROR-Reducedn = 2,850

CV death or HF hospitalization

Dapa-CKDn = 4,000

≥50% sustained decline in eGFR

or reaching ESRDor

CV death orrenal death

PIONEER 6n = 3,1763-P MACE

IRISn = 3,876

Fatal or nonfatal stroke or MI

DPP-4 inhibitors

SGLT2 inhibitors

GLP-1 receptor agonists

α-Glucosidase inhibitor

TZD

Insulin

*

*

*

*

Spectrum of CV Risk of Target Patient Population

of Key CVOTs of Glucose-Lowering Therapies

EMPEROR-Reduced

EMPEROR-Preserved

Dapa-HF

DECLARE-TIMI 58

Borrowed from Javed Butler, MD (Circulation 2018, In Press)

Select Therapeutic Effects of Glucose-Lowering Therapies

on HF and CV Outcomes

HF Outcomes

CV Outcomes

+ (Benefit)

+/-(Null)

-(Harm)

+(Benefit)

• Empaglifozin(EMPA-REG OUTCOME)

• Canagliflozin (CANVAS)

+/-(Null)

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

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

-(Harm)

• Pioglitazone (PROactive)• Rosiglitazone (RECORD)• Saxagliptin (SAVOR-TIMI 53)

Prevalence of Heart Failure in Recent Diabetes CVOTs

TrialF/U, y

(median)

Age,

yBMI

Male

(%)

Duration

of DM, yH/O of CVD

Baseline

H/O HF

HbA1c,

baseline (D)

SAVOR 2.1 65.1 28.7 67 10.3 78% 13% 8.0 (-0.3)

EXAMINE 1.5 61 29.5 68 7.1 100% 28% 8.0 (-0.3)

TECOS 4 66 30.2 71 11.6 74% 18% 7.2 (-0.3)

ELIXA 2 61 30 69 9.3 100% 22% 7.7 (-0.3)

LEADER 3.8 64.3 32.5 64 12.7 81% 18% 8.7 (-0.4)

SUSTAIN-6 2.1 64.6 31.3 61 13.9 59% 24% 8.7 (-0.7, -1.0)

EXCSEL 3.2 62 31.8 62 12 73% 16% 8.0 (-0.5)

EMPA-REG 3.1 63.1 30.6 72>10y

(57%)99% 10% 8.1 (-0.3)

CANVAS 2.4 63.3 32 64 13.5 66% 14% 8.2 (-0.6)

Heart failure not specified as an inclusion criterion in any trial!

Heart Failure Outcomes in Recent Diabetes CVOTs

Trial PEPSEP (prespecified)

Yes Powered

SAVOR No Yes No

EXAMINE* No No No

TECOS No Yes No

ELIXA No Yes No

LEADER No Yes No

SUSTAIN-6 No Yes No

EXCSEL No Yes No

EMPA-REG No Yes No

CANVAS Program No Yes No

Hospitalization for heart failure (HHF) not prespecified as a

primary endpoint or as a powered secondary endpoint in any trial!

*post hoc

Heart Failure Outcomes in Recent IGT/T2DM CVOTs

Trial Primary endpoint

NAVIGATOR (NEJM 2010)

(Valsartan/nateglinide vs placebo in pts with

impaired glucose tolerance and established CV

disease or risk factors)

• Development of diabetes

• CV death, nonfatal MI, nonfatal stroke, arterial revascularization,

hospitalization for heart failure, or hospitalization for unstable angina

• CV death, nonfatal MI, nonfatal stroke, hospitalization for heart

failure

ORIGIN (NEJM 2012)

(Insulin glargine vs standard of care in pts with CV

risk factors plus impaired fasting glucose, impaired

glucose tolerance T2DM)

• CV death, nonfatal MI, nonfatal stroke

• CV death, nonfatal MI, nonfatal stroke, revascularization,

hospitalization for heart failure

ACE (Lancet 2017)

(Acarbose vs placebo in Chinese pts with coronary

heart disease and impaired glucose tolerance)

• CV death, nonfatal MI, nonfatal stroke, hospitalization for heart

failure, or hospitalization for unstable angina

Hospitalization for heart failure (HHF) prespecified as a component of

primary composite endpoint in 2 trials of IGT and 1 trial of IGT/T2DM!

CVOTs in T2DM: HF Outcome as Primary Endpoint25 Trials (9 Completed), N=200,000 since 2013

2013

TECOSn = 14,6714-P MACE

CAROLINAn = 6,1153-P MACE

CARMELINAn = 8,300

3-P MACE,renal

composite

REWINDn = 9,9013-P MACE

2015 2016 2017 2018 2019 2020

SAVOR-TIMI 53n = 16,4923-P MACE

EXAMINEn = 5,3803-P MACE

EMPA-REG OUTCOMEn = 7,0203-P MACE

ELIXAn = 6,0684-P MACE

SUSTAIN-6n = 3,2973-P MACE

LEADERn = 9,3403-P MACE

DEVOTE

n = 7,6373-P MACE

CANVAS Program

n = 10,1423-P MACE

FREEDOM-CVOn = 4,0004-P MACE

EXSCELn = 14,7523-P MACE

ACEn = 6,5265-P MACE

(3-P MACE + hospitalization

for HF or unstable angina)

VERTIS CVn = 8,0003-P MACE

HARMONY Outcomesn = 9,4003-P MACE

Dapa-HFn = 4,500

CV death, HF hospitalization, HF urgent visit

CREDENCEn = 4,200

ESRD, doubling of creatinine,

renal/CV death

DECLARE-TIMI 58n = 17,150

3-P MACE, CVD

EMPEROR-Preservedn = 4,126

CV death or HF hospitalization

EMPEROR-Reducedn = 2,850

CV death or HF hospitalization

Dapa-CKDn = 4,000

≥50% sustained decline in eGFR

or reaching ESRDor

CV death orrenal death

PIONEER 6n = 3,1763-P MACE

IRISn = 3,876

Fatal or nonfatal stroke or MI

DPP-4 inhibitors

SGLT2 inhibitors

GLP-1 receptor agonists

α-Glucosidase inhibitor

TZD

Insulin

Co-primary endpoint in DECLARE-TIMI 58:

CV death or HHF

Heart Failure Outcomes in Recent Diabetes CVOTs

TrialPEP

(MACE)CV death MI Stroke

Hosp.

for HF (HHF)

SAVOR 1222 529 543 298 517

EXAMINE* 621 200 360 61 195

TECOS 1690 602 561 306 457

ELIXA 805 314 531 127 249

LEADER 1302 453 374 274 466

SUSTAIN-6 254 90 111 71 113

EXCSEL 1744 487 925 332 450

EMPA-REG 772 309 334 210 126

CANVAS Program 1011 453 374 274 243

HHF as common as other nonfatal MACE endpoints

*post hoc

Heart Failure Outcomes in Recent Diabetes CVOTs

Trial

Hospitalization for Heart Failure (HHF)

Drug

%, IR/100PY

Control

%, IR/100PYHR (95%CI)

SAVOR 289 (3.5%) 228 (2.8%) 1.27 (1-07-1.51)

EXAMINE 106 (3.9%) 89 (3.3%) 1.19 (0.89-1.58)

TECOS 228 (1.07) 229 (1.09) 1.00 (0.83-1.20)

ELIXA 127 (4.2) 122 (4.0) 0.96 (0.75–1.23)

LEADER 218 (1.2) 248 (1.4) 0.87 (0.73–1.05)

SUSTAIN-6 59 (3.6) 54 (3.3) 1.11 (0.77–1.61)

EXCSEL 219 (3.0%) 231 (3.1%) 0.94 (0.78–1.13)

EMPA-REG 95 (0.94) 221 (1.45) 0.65 (0.50–0.85)

CANVAS Program 123 (0.55) 120 (0.87) 0.67 (0.52–0.87)

↑ risk of HHF with DPP4i, null outcomes with GLP-1 RA,

↓ risk with SGLT2 inhibitors

Hospitalisation for Heart Failure in DPP4i CVOTs

Updated FDA Label

Trial

Impact on HHF compared with placebo FDA Label

DPP4i

(saxagliptin)SAVOR-TIMI

HR 1.27; (95%CI 1.07-1.51)2

p=0.007

FDA guidance: May increase the risk of heart

failure, particularly in patients who already

have heart or kidney disease (4/5/2016).3

DPP4i

(alogliptin)EXAMINE

HR 1.19; (95%CI 0.90-1.58)4

p=0.220

FDA guidance: May increase the risk of heart

failure, particularly in patients who already

have heart or kidney disease (4/5/2016).3

DPP4i

(sitagliptin)TECOS

HR 1.00; (95%CI 0.83-1.20)5

p=0.98

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 (8/10/2017)

DPP4i

(linagliptin)CAROLINA

CARMELINANot completed

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 (8/10/2017)

1. Pfeffer M A et al., N Engl J Med 2015;373:2247; 2. Scirica BM et al. N Engl J Med 2013;369:1317; 3. FDA Drug Safety Communication, Available at: http://www.fda.gov/Drugs/DrugSafety/ucm486096.htm (accessed April 2016). 4. Zannad F et al. Lancet 2015;385:2067; 5. Green JB et al. N Engl J Med 2015;373:232;

Incretins in Heart Failure: Phase 2 Trials

0.00

0.10

0.20

0.30

0.40

0.50Liraglutide vs placebo

HR=1.296 (95% CI: 0.92, 1.83; P=0.142)

Liraglutide

Placebo

Days post-randomization

0 30 60 90 120 150 180

Death

or

heart

failu

re r

e-h

osp

italizati

on

rate

Margulies, KB et al, JAMA. 2016;316:500-8.

Eur J Heart Fail. 2017;19:69-77 (LIVE)JACC Heart Fail. 2017 (VIVIDD).

FIGHT (Phase 2, LV EF <40%, n=300)

• LIVE- Phase 2, chronic HF, EF <45% with orwithout DM, n= 241, 24 wks

- Excess adverse cardiac events with Liraglutide (12 v 3)

• VIVIDD- Phase 2, Class I-III HF, EF <40% with

DM, n= 254, 24 wks- No difference in HF events

- increased ventricular end-diastolic volume with vildagliptin

Zinman B, et al. N Engl J Med 2015;373:2117–2128

Outcome Patients with event / analyzed Hazard

ratio

95% CI P value

Empagliflozin Placebo

3-point MACE 490/4687 282/2333 0.86 0.74, 0.99* 0.0382

CV death 172/4687 137/2333 0.62 0.49, 0.77 <0.0001

Nonfatal MI 213/4687 121/2333 0.87 0.70, 1.09 0.2189

Nonfatal stroke 150/4687 60/2333 1.24 0.92, 1.67 0.1638

Hospitalization for

heart failure126/4687 95/2333 0.65 0.50, 0.85 0.0017

0.3 0.5 1.0 2.0

EMPA-REG OUTCOME:

Empagliflozin Improved CV Outcomes in T2DM

Zinman B, et al. N Engl J Med 2015;373:2117–2128

EMPA-REG OUTCOME:

Empagliflozin Improved CV Outcomes in T2DM

7

0

6

5

4

3

2

1

Hospitalization for heart failure

HR=0.65 (95% CI: 0.50, 0.85)P=0.002

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

168Placebo

Empagliflozin

No. at risk

Pa

tie

nts

with

ev

en

t (%

)

0

15

10

5

Death from any cause

HR=0.68 (95% CI: 0.57, 0.82)P<0.001

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

177Placebo

Empagliflozin

No. at risk

Patients with event/analysed (%)

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

HHF or CV death

All patients 265/4687 (5.7) 198/2333 (8.5) 0.66 (0.55, 0.79)

HF at baseline

No 190/4225 (4.5) 149/2089 (7.1) 0.63 (0.51, 0.78)

Yes 75/462 (16.2) 49/244 (20.1) 0.72 (0.50, 1.04)

HHF

All patients 126/4687 (2.7) 95/2333 (4.1) 0.65 (0.50, 0.85)

HF at baseline

No 78/4225 (1.8) 65/2089 (3.1) 0.59 (0.43, 0.82)

Yes 48/462 (10.4) 30/244 (12.3) 0.75 (0.48, 1.19)

CV death

All patients 172/4687 (3.7) 137/2333 (5.9) 0.62 (0.49, 0.77)

HF at baseline

No 134/4225 (3.2) 110/2089 (5.3) 0.60 (0.47, 0.77)

Yes 38/462 (8.2) 27/244 (11.1) 0.71 (0.43, 1.16)

All-cause mortality

All patients 269/4687 (5.7) 194/2333 (8.3) 0.68 (0.57, 0.82)

HF at baseline

No 213/4225 (5.0) 159/2089 (7.6) 0.66 (0.51, 0.81)

Yes 56/462 (12.1) 35/244 (14.3) 0.79 (0.52, 1.20)

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

Were Consistent in Patients with and without HF at Baseline

0.25 0.5 1 2

All treatment

by subgroup

interaction

p>0.41

Favours placeboFavours empagliflozin

Fitchett D et al. Eur Heart J 2016;37:1526

2016 ESC Guidelines Recognise Empagliflozin for

the Prevention or Delay of Heart Failure in T2D

Empagliflozin is not indicated for the treatment of heart failure

Ponikowski P et al. Eur Heart J 2016;37:2129

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

Class IIa

Level B

Heart Failure Outcome in EMPA-REG OUTCOMEIssues for Discussion

• Exploratory endpoint with no control for Type 1 error

• Endpoints redefined during trial

• Intensification of oral diuretic regimen used as a qualifying criteria

• Study not designed to explore effect on heart failure

- Baseline prevalence (10%) likely under-reported

- Functional class, EF, biomarkers not assessed

- Concomitant medications and doses not well captured

• Heart failure outcome data not pivotal for label change or claim

• “Hypothesis-generating” that requires validation in future studies

Patients with

event/analysed

Canagliflozin Placebo HR (95% CI) p-value

3P-MACE 585/5795 426/43470.86

(0.75, 0.97)

<0.001 (non-inferiority)

0.02 (superiority)

CV death 268/5795 185/43470.87

(0.72, 1.06)NR*

Non-fatal MI 215/5795 159/43470.85

(0.69, 1.05)NR*

Non-fatal

stroke158/5795 116/4347

0.90

(0.71, 1.15)NR*

Favours canagliflozin Favours placebo

CANVAS Program

Canagliflozin Improved CV Outcomes in T2DM

Neal B et al. N Engl J Med 2017; doi:10.1056/NEJMoa1611925

0.5 1.0 2.0

Superiority for

3P-MACE not

prespecified in the

testing hierarchy

*P values not reported because all-cause mortality

endpoint not met in the hierarchical test strategy

CANVAS Program

Hospitalization for Heart Failure

Neal B et al. N Engl J Med 2017; doi:10.1056/NEJMoa1611925

No. at risk

Canagliflozin 5795 5732 5653 5564 4437 3059 2643 2610 2572 2540 2498 2451 1782 490

Placebo 4347 4267 4198 4123 3011 1667 1274 1256 1236 1210 1180 1158 829 233

Intention-to-treat analysis. Exploratory outcome, no p-value is reported, only nominal effect estimate is given

Weeks since randomisation

Pa

tie

nts

wit

h a

n e

ve

nt

(%)

0 26 52 78 104 130 156 182 208 234 260 286 312 338

0

1

2

3

4

5

6

7

8

HR 0.67 (95% CI 0.52, 0.87)

Placebo Canagliflozin

Heart Failure Outcome in CANVASIssues for Discussion

• Exploratory endpoint with no control for Type 1 error

• Study not designed to explore effect on heart failure

- Baseline prevalence (14%) likely under-reported

- Functional class, EF, biomarkers not assessed

- Concomitant medications and doses not well captured

• Heart failure outcome data not pivotal for label change or claim

• “Hypothesis-generating” that requires validation in future studies

Kosiborod M et al. Circulation. 2017;doi.org/10.1161/CIRCULATIONAHA.117.029190

SGLT2i in Real World Practice: CVD-Real Registry

Primary Outcomes

P<0.001

Phetero 0.169

P<0.001

Phetero

0.089

Hospitalization for Heart Failure (HR 0.61)(Cana 53%, Dapa 42%, Empa 5%)

All-cause Death (HR 0.49)(Cana 42%, Dapa 51%, Empa 7%)

Inconsistent results for all-cause mortality, but not hospitalization for heart failure between CANVAS and CVD-Real!

Borrowed from Javed Butler, MD (Circulation 2018, In Press)

Potential Mechanistic Links Between Glucose-

Lowering Therapies and Heart Failure Risk

Renal events

CV death

Hospitalisation for heart failure

Arrhythmia

Afterload

Preload

Cardiometabolic

efficiency

Arterial wall structure/function

Cardiac function

Mechanism1−4 Possible cardio−renal effects5,6 CV/renal outcomes observed in

EMPA-REG OUTCOME7,8

Renal function

SGLT2 inhibition1,2

Glucoseremoval

Na+ removal

Metabolism

Sodium

Osmotic diuresis

Potential CV & Renal Function Preservation Mechanisms

of SGLT2i that May Benefit Heart Failure

1. Heise T et al. Diabetes Obes Metab 2013;15:613; 2. Heise T et al. Clin Ther 2016;38:2265; 3. Ferrannini G et al. Diabetes Care 2015;38:1730; 4. Briand F et al. Diabetes 2016;65:2032; 5. Heerspink HJ et al. Circulation 2016;134:752; 6. Inzucchi S et al. Diab Vasc Dis Res 2015;12:90; 7. Zinman B et al. N Engl J Med 2015;373:2117; 8. Wanner C et al. N Engl J Med 2016;375:323

1 EMPEROR-Preserved1 EMPEROR-Reduced2 Dapa-HF3

Sample size 4126 2850* 4500

Key inclusion

criteria

• Patients with chronic HF†

• Elevated NT-proBNP

• eGFR ≥20 ml/min/1.73 m2

• Symptomatic HFrEF†

• Elevated NT-proBNP

• eGFR ≥30 ml/min/1.73 m2

HFpEF (LVEF >40%) HFrEF (LVEF ≤40%) HFrEF (LVEF ≤40%)

Primary endpoint • Time to first event of adjudicated CV death or adjudicated HHF• Time to first occurrence of CV

death, HHF or urgent HF visit

Key secondary

endpoints

• Individual components of primary endpoint

• All-cause mortality

• All-cause hospitalisation

• Time to first occurrence of sustained reduction of eGFR

• Change from baseline in KCCQ

• Total number of HHF or CV death

• All-cause mortality

• Composite of ≥50% sustained

eGFR decline ESRD or renal

death

• Change from baseline in KCCQ

Start date:

Expected

completion date:

March 2017

June 2020

March 2017

June 2020

February 2017

December 2019

1. ClinicalTrials.gov NCT03057951; 2. ClinicalTrials.gov NCT03057977; 3. ClinicalTrials.gov NCT03036124

Randomised Controlled Trials of SGLT2 Inhibitors in HF

Diabetes and Heart Failure‘Take Home’ Points

• Heart failure is a complex disease, with various etiologies and poor prognosis – many

treatments are available for HFrEF, but few are available for HFpEF

• T2DM is a major risk factor for heart failure, and the prevalence of both is increasing

• Outcomes of patients with heart failure are poor, and worse with T2DM, so there is a critical

need for novel management strategies to improve outcomes in this high-risk group

• SGLT2 inhibitors have been shown to improve cardiovascular outcomes in patients with

T2DM, regardless of glycemic response

• Mechanisms of cardiovascular protection with SGLT2 inhibitors are likely to include increased

natriuresis, increased hematopoiesis, and a possible shift in heart fuel metabolism

• Large trials of cardiovascular outcomes with SGLT2 inhibitors, as well as dedicated trials in

patients with heart failure and a number of mechanistic studies, are ongoing. These trials will

provide further insight into the cardiovascular and renal protective signals seen with this class

of drugs