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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
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