The New Standard of Care__Leveraging the Benefits of SGLT2 Inhibitors Across the Heart Failure Spectrum.pptx

Sunday, October 8, 2023
7:00 AM - 8:15 AM ET
Room 5
Huntington Convention Center
300 Lakeside Ave E.
Cleveland, Ohio
The New Standard of Care: Leveraging the
Benefits of SGLT2 Inhibitors Across the
Heart Failure Spectrum
Provided by Clinical Care Options, LLC in partnership with the Heart Failure Society of America
This activity is supported by independent educational grants from
Boehringer Ingelheim Pharmaceuticals, Inc. and Eli Lilly and Company.

Faculty
Javed Butler, MD, MPH, MBA
President
Baylor Scott and White Research Institute
Dallas, Texas
Distinguished Professor of Medicine
Department of Medicine
University of Mississippi Medical Center
Jackson, Mississippi
Lee R. Goldberg, MD, MPH, FACC, FAHA, FHFSA
Vice Chair of Medicine for Informatics
Section Chief, Advanced Heart Failure and Cardiac Transplant
Professor of Medicine
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, Pennsylvania

Disclosures
The faculty reported the following relevant financial relationships or
relationships to products or devices they have with ineligible companies
related to the content of this educational activity:
Javed Butler, MD, MPH, MBA: consultant/advisor/speaker: Abbott,
American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer,
Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx,
Cytokinetics, Edwards, Element Science, Imbria, Impulse Dynamics, Innolife,
Inventiva, Janssen, Lilly, LivaNova, Lexicon, Medtronics, Merck, Novartis,
Novo Nordisk, Occlutech, Pfizer, Pharmacosmos, Roche, Sequana,
SQ Innovation, Vifor.
Lee R. Goldberg, MD, MPH, FACC, FAHA, FHFSA: consultant/advisor/speaker:
Abbott, Viscardia, Zoll/Respicardia.

Learning Objectives
 Use the most recent real-world evidence and current clinical guidelines
to initiate and optimize guideline-directed medical therapy for patients
with HF
 Discuss the latest clinical trial evidence in support of the safety and
efficacy of SGLT2 inhibition as key treatments for patients across the
HF spectrum
 Design and implement strategies that incorporate the SGLT2 inhibitor
drug class as a key component of guideline-directed medical therapy
for a range of patients with HF

Out With the Old:
New HF Staging, Classification, and
Treatment Recommendations

Slide credit: clinicaloptions.com
 NYHA class changes over time
 Heart failure is cellular disease
 Despite symptomatic improvement,
neurohormonal, cytokine, and
cellular changes continue to occur
and allow heart failure to progress
 Ejection fraction does not correlate
with functional capacity (NYHA class)
2022 Guideline Update: Evolution in
Approach to Heart Failure
 Heart failure is hemodynamic disorder
 Volume control is cornerstone of
therapy
 Patients “go into heart failure,” but
when symptoms improve, they are
“out of heart failure”
 Patients classified by NYHA class or
functional capacity alone
Traditional Paradigm Challenging Tradition
Heidenreich. J Am Coll Cardiol. 2022;79:e263. Greene. JAMA Cardiol. 2021;6:522.
Zhu. Biomedicines. 2022;10:402. Sabbah. Eur J Heart Fail. 2017;19:469. 5. Castro. Clin Cardiol. 2019;42:1181.

Shifting to Chronic Disease Model: A Staging System
 New system emphasizes:
‒ Heart failure (ventricular dysfunction) is chronic disease
‒ Focusing on prevention of disease or disease progression has biggest
impact on both patient and society
‒ Specific risk factors can be identified and managed to prevent heart
failure
‒ Current medical and device therapies have changed natural history of
heart failure and are most effective when initiated early
Bozkurt. J Card Fail. 2021;S1071-9164(21)00050-6.

Classification of HF: Stage and NYHA Class Overlay
Heidenreich. J Am Coll Cardiol. 2022;79:e263.
ACC/AHA Stage (Course of Disease)* NYHA Functional Classification (Symptom Status)†
A
(At Risk for HF)
At high risk for HF but without structural
heart disease or symptoms of HF
None
B
(Pre HF)
Structural heart disease, evidence of elevated
LV pressures, or elevated natriuretic peptides
or cardiac troponins (in patients with risk
factors) but without signs or symptoms of HF
I No limitation of physical activity
Ordinary physical activity does not cause HF symptoms
C
(Symptomatic HF)
Structural heart disease with prior or current
symptoms of HF
I No limitation of physical activity
Ordinary physical activity does not cause HF symptoms
II Slight limitation of physical activity; comfortable at rest,
but ordinary physical activity results in HF symptoms
III Marked limitation of physical activity; comfortable at rest,
but less than ordinary activity causes HF symptoms
IV Unable to carry on any physical activity without HF symptoms,
or symptoms at rest
D
(Advanced HF)
Refractory HF requiring specialized
interventions
IV Unable to carry on any physical activity without HF symptoms, or
symptoms at rest
*Patients should be treated to prevent progression and reduce
morbidity and mortality.
†Patients should be treated to reduce symptoms or referred for advanced
therapies or hospice.

NYHA Class vs ACC/AHA Staging System
 NYHA classification represents symptoms at the moment
‒ NYHA classification can change quickly
‒ Example: a 64-yr-old man with left ventricular ejection fraction 35%
 Admitted to hospital at NYHA class IV
 Following diuresis and medication optimization, discharged NYHA class II
 ACC/AHA staging represents course of disease and recommended therapies
‒ Identifies therapies to prevent progression, reverse remodel ventricle,
reduce symptoms, and reduce mortality regardless of current symptoms
‒ 64-yr-old man is ACC/AHA stage C, regardless of current symptoms
 He would benefit from at least the core 4 medication classes recommended for
stage C HFrEF

Heart Failure Classification Based on LVEF:
New Definitions
Bozkurt. J Card Fail. 2021;27:P387.
 HF with LVEF ≤40%
HF with reduced EF (HFrEF)
 HF with LVEF 41% to 49%
HF with mildly reduced EF (HFmrEF)
 HF with LVEF ≥50%
HF with preserved EF (HFpEF)
 HF with baseline LVEF ≤40%, ≥10-point increase from baseline LVEF, and
second measurement of LVEF >40%
HF with improved EF (HFimpEF)

2022 AHA/ACC/HFSA HF Guideline Updates
11
Stage A
At Risk for HF
Stage B
Pre HF
Stage C and D
Stage C: Symptomatic HF and Stage D: Advanced HF
HFrEF: LVEF ≤40%
Diuretics
as needed
Class 1
ARNI in NYHA II-III;
ACEI or ARB in NYHA II-IV
Class 1
β-blocker
Class 1
MRA
Class 1
SGLT2i
Class 1
Hydral-nitrates for
NYHA III-IV in
Black patients
Class 1
SGLT2i in patients with DM
Class 1
Class 1
ACEI
Class 1
ARB if ACEI intolerant
Class 1
β-blocker
Class 1
HFmrEF: LVEF 41-49%
Diuretics, as needed
Class 1
SGLT2i
Class 2a
ACEI, ARB, ARNI
Class 2b
β-blocker
Class 2b
MRA
Class 2b
GDMT
of major
medication
classes
GDMT Across HF Stages
HFpEF: LVEF ≥50%
Class 1
SGLT2i
Class 2a
ARNI
Class 2b
ARB
Class 2b
MRA
Class 2b
Management of risk factors
for HF

New Kids on the Block: SGLT2 Inhibitors
Recommended Across All Stages and Ejection Fraction
12
Stage A
At Risk for HF
Stage B
Pre HF
Stage C and D
Stage C: Symptomatic HF and Stage D: Advanced HF
HFrEF: LVEF ≤40%
Diuretics
as needed
Class 1
ARNI in NYHA II-III;
ACEI or ARB in NYHA II-IV
Class 1
β-blocker
Class 1
MRA
Class 1
SGLT2i
Class 1
Hydral-nitrates for
NYHA III-IV in
Black patients
Class 1
Class 1
Class 1
ACEI
Class 1
ARB if ACEI intolerant
Class 1
β-blocker
Class 1
HFmrEF: LVEF 41-49%
Class 1
SGLT2i
Class 2a
ACEI, ARB, ARNI
Class 2b
β-blocker
Class 2b
MRA
Class 2b
GDMT
of major
medication
classes
GDMT Across HF Stages
HFpEF: LVEF ≥50%
Class 1
SGLT2i
Class 2a
ARNI
Class 2b
ARB
Class 2b
MRA
Class 2b
Management of risk factors
for HF

SGLT2 Inhibitors: Direct and Indirect Actions Likely
Produce Cardio, Renal, and Metabolic Benefits
Givens. Heart Failure: A Comprehensive Guide to Pathophysiology and Clinical Care. Springer; 2017. p. 1.
Ronco. J Am Coll Cardiol. 2008;52:1527. Santos-Ferreira. Cardiology. 2020;145:311. Cowie. Nat Rev Cardiol. 2020;17:761.
Scheen. Nat Rev Endocrinol. 2020;16:556.
CRM
disease
↑ CRM
disease
↓ SNS
↓ RAAS
↓ Oxidative
stress
↓ Inflammation
SGLT2
inhibition
↑ Natriuresis
↑ Tubuloglomerular feedback
↓ Albuminuria
↓ Fluid retention/edema
↓ Uric acid
↓ Body mass
↑ Ketones
↑ Lipolysis/triglycerides
↓ Glucose and insulin resistance
↑ Endothelial function
↓ Vascular stiffness
↓ Systemic blood pressure
↓ Fluid overload
↑ Hematocrit/O2 supply
↓ Cardiac preload
↓ Ventricular remodeling
↓ Atrial remodeling
↓ Systolic dysfunction
↓ Diastolic abnormalities
↓ Fibrosis
cv
cv

Therapies in HFrEF (LVEF ≤40%):
SGLT2 Inhibitors as Fourth Pillar
1
4
Bassi. JAMA Cardiol. 2020;5:948 Rahamim. J Clin Med. 2021;10:4409.
 Cumulative risk reduction in all-cause mortality if all 4 evidence-based medical therapies
are used
– Relative risk reduction 72.9%; absolute risk reduction: 25.5%; NNT: 3.9, over 24 mo
4 Pillars of
Survival-Enhancing
Medical Therapy for
HFrEF

Therapies in HFmrEF (LVEF 41%-49%)
 May be reasonable to treat
these patients as HFrEF
‒ Particularly in lower-range
HFmrEF
15
Treatment of HFmrEF
Symptomatic HF
with LVEF 41%-49%
Diuretics as needed
(1)
SGLT2i
(2a)
ACEi, ARB, ARNI
(2b)
MRA
(2b)
Evidence-based BB for HFrEF
(2b)

Guideline Recommendations in HFmrEF
 Guidelines recommend:
‒ Diuretics: as needed for volume control and symptoms
‒ SGLT2 inhibitors: associated with decreased risk of heart failure
hospitalizations, cardiovascular events, and mortality
‒ ACE/ARB/ARNI: data suggest that all 3 are effective in this group of
patients; PARAGLIDE trial showed benefit of ARNI in EF between 40%
and 60%
‒ MRA: data suggest that MRAs are beneficial across spectrum of left
ventricular ejection fraction
‒ Beta blocker: benefit for LVEF 41% to 50% in sinus rhythm
Cleland. Eur Heart J. 2018;39:26. Mentz. J Am Coll Cardiol. 2023;82:1. Heidenreich. J Am Coll Cardiol. 2022;79:e263.
Class 2B

Therapies in HFpEF (EF ≥50%)
 Treat underlying contributing
comorbidities
‒ Iron deficiency anemia
‒ Atrial fibrillation
‒ Hypertension
‒ Ischemic disease, etc
 Exercise program and cardiac
rehab
17
Treatment of HFpEF
Symptomatic HF
with LVEF ≥50%
Diuretics as needed
(1)
SGLT2i
(2a)
ARNI
(2b)
MRA
(2b)
ARB
(2b)

Guideline Recommendations in HFpEF
 New recommendations
‒ SGLT2i (Class of Recommendation 2a)
‒ MRAs (Class of Recommendation 2b)
‒ ARNI (Class of Recommendation 2b)
 Several prior recommendations have been renewed
‒ Treatment of hypertension (Class of Recommendation 1)
‒ Treatment of atrial fibrillation (Class of Recommendation 2a)
‒ Use of ARBs (Class of Recommendation 2b)
‒ Avoidance of routine use of nitrates or phosphodiesterase-5 inhibitors
(Class of Recommendation 3: No Benefit)

 Randomized, open-label pilot trial evaluating phased withdrawal of HF medications in asymptomatic
patients with previous dilated cardiomyopathy whose LVEF improved from ≤40% to ≥50%
Asymptomatic patients
with history of dilated
cardiomyopathy; LVEF
improved from ≤40%
to ≥50%; LVEDV
normalized;
NT-proBNP <250 ng/L
(N = 51)
6-mo follow-up
Continuing treatment (n = 26)
Treatment withdrawal (n = 25)
PRIMARY ENDPOINT
Relapse of dilated cardiomyopathy within
6 mo: Reduction in LVEF by >10% to <50%,
increased LVEDV by >10% to higher-than-normal
range, 2-fold rise in NT-proBNP to
>400 ng/L, clinical evidence of HF
KEY SECONDARY ENDPOINTS
 Composite safety endpoint
 Sustained atrial or ventricular arrhythmias
TRED-HF: Medication Therapy in HFimpEF
Halliday. Lancet. 2019;393:61.

TRED-HF Trial
20
The Lancet 2019 39361-73DOI: (10.1016/S0140-6736(18)32484-X)
Halliday. Lancet. 2019;393:61.
50
Events
(%)
40
30
20
10
0
0 1 2 3 4 5 6
Mo Since Randomization
Treatment withdrawal group
Control group
Event rate: 45.7% (95% CI: 28.5%-67.2%; P = .0001)
Patients at Risk, n
Control group 26 26 26 26 26 26 26
Treatment
withdrawal group
25 22 22 21 16 16 13
These patients should continue their HFrEF treatment

Clinical Evidence for
SGLT2 Inhibitors in HFrEF

DAPA-HF: placebo-controlled, randomized phase III trial
Patients 18+ yr of age
with NYHA class II-IV HF,
EF ≤40%, NT-proBNP
≥600 pg/mL (≥400 pg/mL
if hospitalized for
HF within past 12 mo, or
≥900 pg/mL in patients
with AF)
(N = 4744)
Placebo + recommended
therapy
(n = 2371)
Dapagliflozin 10 mg daily
(n = 2373)
Primary endpoint: worsening HF or death from
cardiovascular causes
Key secondary endpoints: number of hospitalizations,
worsening symptoms and renal function, all-cause
mortality
Clinical Trials of SGLT2 Inhibitors in Ambulatory Patients
With HFrEF: DAPA-HF and EMPEROR-Reduced
EMPEROR-Reduced: randomized, double-blind,
placebo-controlled trial
McMurray. NEJM. 2019;381:1995. Packer. NEJM. 2020;383:1413.
Primary endpoint: composite of hospitalization for HF
and cardiovascular death
Key secondary endpoints: occurrence of all
hospitalizations for HF, rate of decline in estimated GFR
Patients 18+ yr
with NYHA class II, III,
or IV HF, LVEF ≤40%;
if EF ≥30%,
hospitalization for HF
in past 12 mo required
(N = 3730)
Placebo + usual HF therapy
(n = 1867)
Empagliflozin 10 mg daily
(n = 1863)

Placebo
Empagliflozin
HR: 0.75
(95% CI: 0.65-0.86;
P <.001)
CV Death/HF Hospitalization
DAPA-HF EMPEROR-Reduced
HR: 0.75
(95% CI: 0.65-0.85;
P <.001)
Placebo
Dapagliflozin
CV Death/HF Hospitalization
NNT = 21 over
18.2 mo median follow-up
SGLT2 Inhibitors in Ambulatory Patients With HFrEF
Cumulative
Percentage
Months Since Randomization
0
5
10
15
20
25
30
35
40
0 3 6 9 12 15 18 21 24
Cumulative
Incidence
(%)
Days After Randomization
810
720
540 630
450
360
270
180
90
0
0
10
20
30
40
McMurray. NEJM. 2019;381:1995. Packer. NEJM. 2020;383:1413.

DAPA-HF and EMPEROR-Reduced: Reduction in
CV Death/HF Hospitalization With or Without T2D
24
Zannad. Lancet. 2020;396:819.
No. With Event/No. of Patients (%) HR (95% CI)
SGLT2 Inhibitor Placebo
With diabetes
EMPEROR-Reduced
DAPA-HF
Subtotal
200/927 (21.6)
215/1075 (20.0)
265/929 (28.5)
271/1064 (25.5)
0.72 (0.60-0.87)
0.75 (0.63-0.90)
0.74 (0.65-0.84)
Test for overall treatment effect, P <.0001
Test for heterogeneity of effect, P = .76
Without diabetes
EMPEROR-Reduced
DAPA-HF
Subtotal
161/936 (17.2)
171/1298 (13.2)
197/938 (21.0)
231/1307 (17.7)
0.78 (0.64-0.97)
0.73 (0.60-0.88)
0.75 (0.65-0.87)
Test for treatment by subgroup
interaction,
P = .81
0.25 0.50 0.75 1.00 1.25
Favors SGLT2 Inhibitors Favors Placebo

No. With Event/No. of Patients (%) HR (95% CI)
SGLT2 Inhibitor Placebo
Receiving ARNI
EMPEROR-Reduced
DAPA-HF
Subtotal
51/340 (15.0)
41/250 (16.4)
93/387 (24.0)
56/258 (21.7)
0.64 (0.45-0.89)
0.75 (0.50-1.13)
0.68 (0.53-0.89)
Test for overall treatment effect, P = .0043
Not receiving ARNI
EMPEROR-Reduced
DAPA-HF
Subtotal
310/1523 (20.4)
345/2123 (16.3)
369/1480 (24.9)
446/2113 (21.1)
0.77 (0.66-0.90)
0.74 (0.65-0.86)
0.75 (0.68-0.84)
Test for treatment by subgroup interaction, P = .50
DAPA-HF and EMPEROR-Reduced: Adding SGLT2i to ARNI
Zannad. Lancet. 2020;396:819.
First Hospitalization for Heart Failure or Cardiovascular Death
0.25 0.50 0.75 1.00 1.25
Favors SGLT2 Inhibitors Favors Placebo

KCCQ-CSS broadly reflects impact of HF symptoms in daily life
Impact of empagliflozin on KCCQ-CSS was
prespecified secondary endpoint
CSS
Clinical summary score
TSS
Total symptom score
OSS
Overall summary score
KCCQ Domains
Symptom frequency
Symptom burden
Physical limitation
Quality of life
Social limitation
KCCQ Summary Scores and Domains
Spertus. J Am Coll Cardiol. 2020;76:2379.

DAPA-HF: Clinically Meaningful Change in KCCQ-TSS
Kosiborod. Circulation. 2020;141:90.
Proportions With ≥5-Point change in Kansas City Cardiomyopathy
Questionnaire-Total Symptom Score From Baseline to 8 Mo
70
60
50
40
30
20
10
0
≥5 points ≥5 points ≥10 points ≥15 points
Improvement
Deterioration
OR
(95% CI)
0.84
(0.78-0.90)
1.15
(1.08-1.23)
1.15
(1.08-1.22)
1.14
(1.07-1.22)
Placebo
Dapagliflozin
P <.0001
P <.0001
P <.0001 P <.0001
32.9%
25.3%
58.3%
50.9% 54.5%
47.6% 48.2%
54.0%

Clinical Evidence for
SGLT2 Inhibitors in HFpEF

Patients ≥18 yr of age,
NYHA class II-IV,
LVEF >40%, eGFR
≥20 mL/min/1.73 m2,
structural heart disease
or HHF within 12 mo of
screening
(N = 5988)
Median follow-up = 26.2 mo
Placebo once daily
(n = 2991)
Empagliflozin 10 mg once daily
(n = 2997)
COMPOSITE PRIMARY ENDPOINT
Time to first event of adjudicated
cardiovascular death or adjudicated HFH
SECONDARY ENDPOINTS
 First and recurrent adjudicated HF
hospitalization events
 Slope of change in eGFR (CKD-EPI)
First randomized, double-blind, placebo-controlled phase III trial
to show benefit in mortality and HFH
EMPEROR-Preserved: Empagliflozin for Treatment of
HFpEF in Addition to SoC, Regardless of DM Status
Anker. NEJM. 2021;385:1451.

EMPEROR-Preserved: Effects of Empagliflozin on
Composite of CV Death or HFH in HFpEF
Anker. NEJM. 2021;385:1451.
Mo
Cumulative
Incidence
(%)
100
80
60
40
20
0
36
0 3 6 9 12 15 18 21 24 27 30 33
EMPEROR-Preserved
(N = 5988)
25
20
15
10
5
0
36
0 3 6 9 12 15 18 21 24 27 30 33
HR: 0.79 (95% CI: 0.69-0.90;
P <.001) Placebo
Empagliflozin

Event rate
active vs control
8.6 vs 9.1 NA 5.48 vs 5.74
NA‡
(5.9 vs 6.6)
NA†
(12.8 vs 14.1)
6.7 vs 8.0
HR (95% CI)
0.95
(0.79-1.14)
0.92
(0.71-1.20)
0.96
(0.84-1.09)
0.93
(0.79-1.10)
0.94
(0.82-1.08)
0.83
(0.71-0.98)
*I-PRESERVE: patients with LVEF ≥45%. †PARAGON-HF: patients with LVEF >50%; event rate is for total HHF or CV death.
†Event rate is for patients with LVEF ≥45%.
Effect of Different HF Therapies in Specific Trials
Aiming to Recruit Patients With HFpEF (LVEF ≥50%)
Endpoint Studied: First Event of CV Death or HHF
% reduction of composite of
first event of CV death or HHF
18
16
14
12
10
8
6
4
2
0
CHARM-Preserved
(2003)
DIG (ancillary)
(2006)
I-PRESERVE
(2008)*
TOPCAT
(2014)
PARAGON-HF
(2019)†
EMPEROR-Preserved
(2021)
vs placebo vs placebo vs placebo vs placebo vs valsartan vs placebo
5%
8%
4%
7%
6%
17%

Placebo-controlled, randomized, multicenter phase IV clinical trial
Primary endpoint: total symptom score of KCCQ
Key secondary endpoints: 6-min walk test, KCCQ Overall Summary Score, clinically relevant changes
in KCCQ-CS and -OS, change from baseline in weight, natriuretic peptides, glycated hemoglobin, and
systolic blood pressure
PRESERVED-HF: Dapagliflozin in HFpEF
Patients ≥19 yr of age, NYHA class II-IV
and EF ≥45%, NT-proBNP ≥225 pg/mL
or BNP ≥75 pg/mL; patients with atrial
fibrillation must have BNP ≥100 pg/mL
or NT-proBNP ≥375 pg/mL
(N = 324)
Placebo 10 mg daily for 12 wk
(n = 162)
Dapagliflozin 10 mg daily for 12 wk
(n = 162)
Nassif. Nat Med. 2021;27:1954.

KCCQ Clinical Summary Score
Mean
KCCQ-CS
Score
Baseline (n = 324) Wk 12 (n = 304)
0
55
60
65
70
75
Effect size:
5.8 (2.3-9.2)
points
P = .001
PRESERVED-HF: Dapagliflozin Improves
KCCQ Total Symptom Score
Mean
KCCQ-TS
Score
0
55
60
65
70
75
Baseline (n = 324) Wk 12 (n = 304)
Effect size:
5.8 (2.0-9.6) points
P = .003
Placebo
Dapagliflozin
Proportion of Patients With Clinically Meaningful Change at 12 Wk
Patients
(%)
0
5
10
15
20
25
30
35
40
Deterioration No
Change
Small-
Moderate
Improvement
Moderate-
Large
Improvement
Very Large
Improvement
Dapagliflozin Placebo
P = .01
NNT = 9

Effect size:
5.3 (0.7-10.0) points
P = .026
KCCQ Physical Limitation Score
Mean
KCCQ-PL
Score
0
55
60
65
70
75
Baseline (n = 324) Wk 12 (n = 293)
Placebo
Dapagliflozin
6-Min Walk Test
Mean
6MWT
Distance
(m)
0
230
240
250
260
270
Placebo
Dapagliflozin
Effect size:
20.1 (5.6-34.7) m
P = .007
Baseline (n = 319) Wk 12 (n = 291)
PRESERVED-HF: Dapagliflozin Improves Morbidity

Placebo-controlled, randomized, double-blind, international, multicenter phase III clinical trial
Primary endpoint: composite of worsening HF (hospitalization or urgent visit) or cardiovascular death
Key secondary endpoints: total number of worsening HF events and cardiovascular death, change in
total symptom score on KCCQ, all-cause mortality
DELIVER: Dapagliflozin for Patients With HFpEF
Patients ≥40 yr of age, stabilized
HF, LVEF ≥40%, evidence of SHD,
elevated natriuretic peptide level;
patients with prior LVEF ≤40% were
eligible if LVEF ≥40% at enrollment
(N = 6263)
Placebo 10 mg daily +
usual therapy
(n = 3132)
Dapagliflozin 10 mg
daily + usual therapy
(n = 3131)
Solomon. NEJM. 2022;387:1089.
Median follow-up:
2.3 yr

DELIVER: Composite of Cardiovascular Death or
Worsening HF in Mildly Reduced or Preserved EF
Solomon. NEJM. 2022;387:1089.
Days
Cumulative
Incidence
(%) 100
80
60
40
20
0
1080
0 90 180 270 360 450 540 630 720 810 900 990
N = 6263
25
20
15
10
5
0
1080
0 90 180 270 360 450 540 630720 810 900 990
HR: 0.82 (95% CI: 0.73-0.92;
P <.001)
Placebo
Dapagliflozin

DELIVER: Outcomes by Ejection Fraction
Outcomes by LVEF <60% or LVEF ≥60%
Primary Composite
Worsening HF Event
Hospitalization for Heart Failure
CV Death
All-Cause
Death
HR
All Patients
LVEF <60%
LVEF ≥60%
0.82 (0.73-0.92)
0.83 (0.73-0.95)
0.78 (0.62-0.98)
All Patients
LVEF <60%
LVEF ≥60%
All Patients
LVEF <60%
LVEF ≥60%
All Patients
LVEF <60%
LVEF ≥60%
All Patients
LVEF <60%
LVEF ≥60%
0.79 (0.69-0.91)
0.77 (0.66-0.91)
0.83 (0.64-1.07)
0.77 (0.67-0.89)
0.75 (0.63-0.89)
0.82 (0.62-1.07)
0.88 (0.74-1.05)
0.95 (0.78-1.16)
0.68 (0.47-1.00)
0.94 (0.83-1.07)
0.97 (0.84-1.13)
0.86 (0.68-1.09)
Favors Dapagliflozin Favors Placebo
0.5 0.75 1.25 1.5
1
All Patients n = 6263
LVEF <60% n = 4372 (70%)
LVEF ≥60% n = 1891 (30%)
Solomon. NEJM. 2022;387:1089.

DELIVER and EMPEROR-Preserved Meta-Analysis
↓20% (13%-27%) Relative Risk Reduction of Primary Endpoint
With Consistent Reductions in Both Components
Cardiovascular Death or First Hospitalization for HF HR (95% CI)
0.50 0.75 1 1.25
DELIVER
EMPEROR-Preserved
Overall
0.80 (0.71-0.91)
0.79 (0.69-0.90)
HR: 0.80 (95% CI: 0.73-0.87;
P <.0001)
Cardiovascular Death (Excluding Unknown Death) HR (95% CI)
DELIVER
EMPEROR-Preserved
Overall
0.88 (0.74-1.05)
0.88 (0.73-1.07)
HR: 0.88 (95% CI: 0.77-1.00;
P = .052)
0.50 0.75 1.25
1
Hospitalization for HF HR (95% CI)
DELIVER
EMPEROR-Preserved
Overall
0.77 (0.67-0.89)
0.71 (0.60-0.84)
HR: 0.74 (95% CI: 0.67-0.83;
P <.0001)
0.50 0.75 1.25
1
Pheterogeneity >.40 for all endpoints
Kotit. Glob Cardiol Sci Pract. 2023;2023:e202314.

DELIVER and EMPEROR-Preserved Meta-Analysis
Consistent Reductions in Primary Endpoint Across
LVEF ≥40% Range, Including Among LVEF ≥60%
LVEF Range HR (95% CI)
0.50 0.75 1 1.25
LVEF 41%-49%
LVEF 50%-59%
LVEF ≥60%
DELIVER (n = 2116)
EMPEROR-Preserved (n = 1983)
Overall
0.84 (0.69-1.02)
0.71 (0.57-0.88)
HR: 0.78 (95% CI: 0.67-0.90;
P <.001)
0.79 (0.64-0.98)
0.80 (0.64-0.99)
HR: 0.79 (95% CI: 0.68-0.93;
P = .003)
0.76 (0.60-0.96)
0.87 (0.69-1.10)
HR: 0.81 (95% CI: 0.69-0.96;
P = .01)
DELIVER (n = 2256)
Overall
DELIVER (n = 1891)
Overall
Pheterogeneity = .42

Clinical Evidence for SGLT2 Inhibitors
Across EF Spectrum

Placebo-controlled, randomized, double-blind phase III clinical trial
Primary endpoint: composite of total deaths from cardiovascular causes, hospitalizations, and
urgent care visits for heart failure
Key secondary endpoints: total hospitalizations and urgent care visits for heart failure, incidence of death
from cardiovascular causes, all-cause mortality, KCCQ score
Patients 18-85 yr of age with
previous hospitalization for HF,
treatment with IV diuretic therapy,
and diagnosed type 2 diabetes or
laboratory evidence of T2D
(N = 1222)
Placebo daily
(n = 614)
Sotagliflozin 200 mg daily
with dose increase to 400 mg
(n = 608)
Solomon. NEJM. 2022;387:1089.
Median follow-up:
9.2 mo
SOLOIST-WHF: Efficacy of Sotagliflozin, a SGLT1 and
SGLT2 Inhibitor, for Patients With T2D and Worsening HF

SOLOIST-WHF: Total Deaths From CV Causes,
Hospitalizations, and Urgent Care Visits for HF
Bhatt. NEJM. 2021;384:117.
HR: 0.67 (95% CI: 0.52-0.85; P <.001)
ARR: 25.3 events/100 patient-yr
Mo Since Randomization
Events/100
Patients
100
80
60
40
20
0
0 3 6 9 12 15 18
Placebo
Sotagliflozin
608 sotagliflozin
614 placebo
N = 1222

Meta-Analysis of 5 Large Placebo-Controlled Trials
↓23% (18%-28%) Relative Risk Reduction of
Primary Endpoint (CV Death or HF Hospitalization)
Study HR (95% CI)
DAPA-HF
DELIVER
EMPEROR-Preserved
EMPEROR-Reduced
SOLOIST-WHF
Overall
0.75 (0.65-0.85)
0.80 (0.71-0.91)
0.79 (0.69-0.90)
0.75 (0.65-0.86)
0.71 (0.56-0.90)
HR: 0.77 (95% CI: 0.72-0.82;
P <.0001)
NNT = 25
0.50 0.75 1 1.25

Meta-Analysis of 5 Large Placebo-Controlled Trials
↓13% (5%-21%) Relative Risk Reduction of CV Death
Study HR (95% CI)
DAPA-HF
DELIVER
EMPEROR-Preserved
EMPEROR-Reduced
SOLOIST-WHF
Overall
0.82 (0.69-0.98)
0.88 (0.74-1.05)
0.88 (0.73-1.07)
0.92 (0.75-1.12)
0.84 (0.58-1.22)
HR: 0.87 (95% CI: 0.79-0.95;
P = .002)
0.50 0.75 1 1.25

Strategies for Incorporating SGLT2 Inhibitors
Into Patient Care

DAPA-HF
Chronic HFrEF
with or without T2D
Acute HF: The Missing Link
EMPEROR-Reduced
Chronic HFrEF with or without T2D
SOLOIST
Pre/post discharge after acute HF
with T2D
EMPEROR-Preserved
Chronic HFpEF
with or without T2D
EMPULSE
Acute HF
with or without T2D
In HFrEF or HFpEF
Voors. AHA Scientific Sessions 2021.

Multicenter, randomized, double-blind superiority trial
Primary endpoint: clinical benefit—composite of death, total HF events, time to first HF event, change in
KCCQ Total Symptom Score
Key secondary endpoints: time to cardiovascular death or first HF event, change in KCCQ Total Symptom
Score, change in NT-proBNP concentration
Patients ≥18 yr of age, hospitalized and
treated for acute HF and fulfilling
stabilization criteria: no hypotension,
no increase in IV diuretic dose,
no IV vasodilators, no IV inotropic drugs
(N = 530)
Placebo daily
(n = 265)
Empagliflozin 10 mg daily
(n = 265)
90-day follow-up
EMPULSE: Empagliflozin for Stable Patients
Hospitalized for Acute HF
Voors. AHA Scientific Sessions 2021. Voors. Nat Med. 2022;28:568.

Death:
Empagliflozin: 4.2%
Placebo: 8.3%
HF event:
Empagliflozin 10.6%
Placebo 14.7%
EMPULSE: Composite Death, Total HF Events, Time to
First HF Event, Change in KCCQ Total Symptom Score
 Patients receiving empagliflozin were 36% more likely to experience
clinical benefit compared with patients receiving placebo
6.4%
6.4%
27.5%
0.6%
7.7%
4.0%
39.7%
35.9%
0.2%
10.6%
7.2%
53.9%
Ties, none of
the previous
KCCQ-TSS
Time to HFE
HFE frequency
Time to death
Clinical benefit
Empagliflozin winner
Placebo winner
Ties
Stratified Win
Ratio: 1.36
(95% CI: 1.09-1.68;
P = .0054)
0.25 1.0 4.0
0.5 2.0
Empagliflozin Better
Placebo Better
Voors. AHA Scientific Sessions 2021. Voors. Nat Med. 2022;28:568.

Challenging Traditional GDMT Initiation
Typically started with vasodilator to “unload” ventricle
Titrated to maximally tolerated dose (more recently “low to moderate” dose)
Β-blocker added
Starting at low dose and titrating upward
Additional medications added “if needed” for symptoms, blood pressure, or
heart rate control
Yancy. J Am Coll Cardiol. 2013:15;62:e147.

Consequences of Traditional Sequencing
Missed
mortality
benefit
Long time to
optimize GDMT
No clinical benefits of multiple
agents on board
Many GDMT agents have impact at
relatively low dose
Many GDMT agents
have morbidity and
mortality benefit
quickly after
initiation
Mebazaa. Lancet. 2022;400:P1938. Heidenreich. J Am Coll Cardiol. 2022;79:e263.

Step 1
Step 2
Step 3
Step 4
Step 5
Step 1
Step 2
Step 3
The Need for Speed
Packer. Eur J Heart Fail. 2021;23:882.
Conventional Sequencing Rapid Sequencing
All 3 steps achieved within 4 wk
Uptitration to target doses thereafter
Uptitration to target doses at each step
Typically requires 6 mo or more
ACE inhibitor or angiotensin receptor blocker
β-blocker
ARNI
SGLT2 inhibitor
β-blocker SGLT2 inhibitor
ARNI
Mineralocorticoid receptor antagonist
+
Mineralocorticoid receptor antagonist

Why Is Rapid Initiation in HFrEF Important?
Greene. JAMA Cardiol. 2021;6:743.
Clinical benefits of all medications are apparent within 30 days of initiation!
Medication Class Outcome Relative Risk
β-blocker Death ↓ 25%
ARNI CV death or HF hospitalization ↓ 42%
MRA CV death or HF hospitalization ↓ 37%
SGLT2i
Death, HF hospitalization, or emergency/urgent
visit for worsening HF
↓ 58%
Clinical benefits of all medications are apparent within 30 days of initiation!

Multinational, open-label, randomized, parallel-group trial
Primary endpoint: 180-day HF readmission or all-cause mortality
Key secondary endpoints: change in QoL, 180-day all-cause mortality, 90-day HF readmission or
all-cause mortality
Patients 18-85 yr of age,
currently hospitalized
and not yet treated with
full doses of GDMT
(N = 1085)
Usual Care
(n = 536)
Treatment intensification with
β-blocker, ACE inhibitor (or ARB, or
ARNI), and MRA; first dose increase to
half optimal dose immediately after
randomization
(n = 542)
180-day follow-up
STRONG-HF: Uptitration of Guideline-Directed
Medical Therapies for Acute Heart Failure
Mebazaa. Lancet. 2022;400:P1938.

STRONG-HF: Target GDMT Doses in High-Intensity
vs Usual Care
 More patients in
high-intensity group
received target GDMT
dosages at 90 days
‒ ARNI/ACEI/ARB:
55% vs 2%
‒ β-blocker: 49% vs 4%
‒ MRA: 84% vs 46%
Mebazaa. Lancet. 2022;400:P1938. Study Timepoint
100
80
60
40
20
0
Patients
(%)
β-Blocker MRA
ACEI, ARB, or ARNI
High-Intensity Care Group
None
Less than half of full optimal dose
Half to less than full optimal dose
Full optimal dose or more
Usual Care Group
None
Less than half of full optimal dose
Half to less than full optimal dose
Full optimal dose or more

Probability
of
Event-Free
Survival
(%)
STRONG-HF: All-Cause Mortality
 More patients in high-intensity group
felt better and lived longer
‒ NYHA class I/II at 90 days: 83% vs 75%
‒ Primary endpoint of reduction in
death/HFH at 180 days: 15% vs 23%
‒ Heart failure readmission by Day 180:
9.5% vs 17%
55
Terminated early because of larger than expected
difference in groups; withholding intensive
treatment strategy would be unethical
Time Since Randomization (Days)
180
0 15 30 45 60 75 90 105 120 135 150 165
180-day adjusted risk difference: 8.9%
(95% CI: 3.9%-14.0%; P = .0005)
Usual care group
High-intensity care group
Mebazaa. Lancet. 2022;400:P1938.

Patient Considerations for SGLT2 Inhibitors

Concerns in Patients With and Without T2D
When Using SGLT2 Inhibitors
Hypoglycemia GU infections
Euglycemic
DKA

SGLT2 Inhibitors and GU Infections in Patients With HF
Packer. NEJM. 2020;383:1413. Anker. Circulation. 2021;143:337.
Anker. NEJM. 2021;385:1451. Filippatos. EASD 2021.
EMPEROR-Reduced
1.7% 0.6%
Empagliflozin Placebo
EMPEROR-Preserved
2.2% 0.7%
Rates of Genital Infections in EMPEROR-Reduced and EMPEROR-Preserved Trials
 In both trials, higher proportion of patients in empagliflozin group had genital infections vs patients in
placebo group
 However, number of patients with complicated genital infections was low, and rates were same for both
treatment groups in both trials (0.3% of patients)
T2D 1.9%
No T2D 1.4%
T2D 0.4%
No T2D 0.9%
T2D 2.5%
No T2D 2.0%
T2D 1.0%
No T2D 0.5%

GU Infection Prevention in SGLT2 Inhibitor Use
Wilding. Diabetes Ther. 2018;9:1757. Engelhardt. Ann Pharmacother. 2021;55:543.
Raise awareness at start of SGLT2 inhibitor treatment to
manage expectations and promote early intervention
Provide practical hygiene advice to patients (and their
partners) to prevent genital infections, including advice to rinse
and dry genital area after using toilet and before going to sleep
Topical treatments or appropriate oral treatments can be used for
mild to moderate infections
 When candidiasis occurs, it is often mild, responsive to treatment, and does not require
discontinuation of medication
 Recurrent infections despite repeated hygiene advice may necessitate reassessment of therapy

SGLT2 Inhibitors and UTI Occurrence in Patients With HF
*Including pyelonephritis and urosepsis.
Packer. NEJM. 2020;383:1413. Anker. NEJM. 2021;385:1451. Empagliflozin PI.
EMPEROR-Reduced
4.9% 4.5%
EMPEROR-Preserved
9.9% 8.1%
 Similar proportion of patients had UTIs in each
treatment group
 Proportion of patients with complicated UTIs was low
− EMPEROR-Reduced: empagliflozin (1.0%),
placebo (0.8%)
− EMPEROR-Preserved: empagliflozin (1.9%),
placebo (1.5%)
In patients with complicated UTIs,* temporary
interruption of empagliflozin should be considered

Hypoglycemia Rates With SGLT2i in Patients Without T2D
*Hypoglycaemic AEs with plasma glucose value of ≤70 mg/dL or that required assistance.
Packer. NEJM. 2020;383:1413. Anker. Circulation. 2021;143:337. Anker. NEJM. 2021;385:1451. Filippatos. EASD 2021.
EMPEROR-Reduced EMPEROR-Preserved
 In both trials, similar proportion of patients had hypoglycemic events* between empagliflozin and placebo
groups
 Empagliflozin has been shown to reduce A1C in patients with diabetes, but not in patients without diabetes
2.2% 2.4%
No T2D 0.3% No T2D 0.3%
4.3% 4.5%
No T2D 0.7% No T2D 0.8%

Initiating SGLT2i and Diabetes Medication Adjustments
*Hypoglycemic AEs with plasma glucose value of ≤70 mg/dL or that required assistance.
Packer. NEJM. 2020;383:1413. Anker. NEJM. 2021;385:1451.
Sulfonylureas and Insulin May Increase Risk of Hypoglycemia
 This risk has not been observed with other oral antidiabetics, such as metformin, pioglitazone,
and linagliptin
 Lower dose of insulin or insulin secretagogues (sulfonylureas) may be required to reduce risk
of hypoglycemia when used in combination with empagliflozin
Hypoglycemic Events in EMPEROR Trials
Hypoglycemic Events, %* EMPEROR-Reduced EMPEROR-Preserved
Empa Placebo Empa Placebo
Patients with T2D 2.2 2.4 4.3 4.5
Patients without T2D 0.7 0.6 0.7 0.8

Proposed Insulin and Other Diabetes Medication
Adjustments When Initiating SGLT2 Inhibitor Therapy
McDonald. Can J Cardiol. 2021;37:531. Giaccari. Int J Cardiol. 2022;351:66.
 SGLT2 inhibitors rarely cause hypoglycemia in absence of concomitant insulin and/or
secretagogue therapy
 Background therapies might need to be adjusted to prevent hypoglycemia, particularly in the
following scenarios:
A1C <7.5% Reduce dose of hypoglycemic agent
eGFR <45 mL/min/1.73 m2 Verify possible hypoglycemia by self-monitored blood glucose
If so, reduce dose of hypoglycemic agent
History of hypoglycemia Reduce dose of hypoglycemic agent
SUs, repaglinide or insulin Possible risk of hypoglycemia—verify eGFR and A1C

Ketoacidosis Concerns With SGLT2 Inhibitors
Empagliflozin PI. McDonald. Can J Cardiol. 2021;37:531.
 Ketoacidosis is rare but potentially
life-threatening
 Increased risk seen with restricted
food intake, severe dehydration, acute
medical illness, surgery, or alcohol use
 Patients might present with normal or
only modestly elevated blood glucose
levels
 Serum ketones should be measured to
help detect rare cases of normal anion
gap acidosis
If ketoacidosis is
suspected or diagnosed,
treatment with
empagliflozin should be
discontinued
immediately, and
immediate medical
attention should be
sought
Confusion
Symptoms include:
Nausea
Vomiting
Anorexia
Abdominal pain
Excess thirst
Difficulty
breathing
Fatigue

Dosing Considerations
 For HF treatment, standard empagliflozin dose is 10 mg once daily
‒ Are there exceptions?
 In patients with T2D: Initiate at 10-mg dose for treatment of HF
‒ In patients tolerating empagliflozin 10 mg who have eGFR ≥60 mL/min/1.73 m2
and need tighter glycemic control, dose can be increased to 25 mg once daily
Empagliflozin PI.
Recommended daily dose is 10 mg empagliflozin for patients with eGFR ≥20 mL/min/1.73 m2
Once daily Single dose No titration
Empagliflozin 10 mg

Diuretic Considerations
*Data for volume depletion were not reported in primary publication of the EMPEROR-Preserved trial.
McDonald. Can J Cardiol. 2021;37:531. Docherty. Heart. 2022;108:312.
Packer. NEJM. 2020;383:1413. Anker. NEJM. 2021;385:1451.
Attention to volume status is required when SGLT2 inhibitors, ARNIs, and loop diuretics are used in
combination because of their concomitant effects to promote diuresis
Rates of symptomatic hypotension with
empagliflozin treatment:
5.7% 5.5%
Empagliflozin
EMPEROR-Reduced
Placebo
6.6% 5.2%
Empagliflozin
EMPEROR-Preserved
Placebo
Dose of loop diuretic may not need to
be routinely reduced
Initiation of
SGLT2 inhibitor
therapy
Assess at
2 wk
~5% of patients will require
reduction in loop diuretic dose
Rates of volume depletion in
EMPEROR-Reduced
10.6% 9.9%

0
0.1
0.2
0.3
0.4
0.5
0.6
Diuretic Dose Adjustments
*Compared with placebo. †Total number of study visits that reported interval outpatient intensification
of diuretics for worsening heart failure.
Packer. Circulation. 2021;143:326. Packer. Circulation. 2021;144:1284.
Adjustment of Diuretic Dose in EMPEROR-Reduced and EMPEROR-Preserved Trials
Empagliflozin reduced requirement for intensification of diuretics due to worsening heart failure*†
EMPEROR-Reduced EMPEROR-Preserved
Days After Randomization
0 90 180 270 360 450 540 630 720 810
Mean
No.
of
Events
per
Patient
0
0.1
0.2
0.3
0.4
0.5
0.6
HR: 0.67
(95% CI: 0.57-0.78;
P <.0001) Placebo
Empagliflozin
0 3 6 9 12 15 18 21 24 27 30 33 36
Placebo
Study Mo
Empagliflozin
Mean
No.
of
Events
per
Patient
HR: 0.73
(95% CI: 0.65-0.82;
P <.0001)

Surgery Considerations With SGLT2 Inhibitors
Empagliflozin PI.
selondonccg.nhs.uk/wp-content/uploads/dlm_uploads/2021/09/Heart-Failure-Dapagliflozin-HFrEF-non-DM-FINAL-July-2021.pdf.
wsh.nhs.uk/CMS-Documents/Patient-leaflets/DiabetesUnit/5830-3-Diabetes-Management-of-diabetes-before-and-after-surgery-or-
procedure.pdf.
Patients with conditions leading to restricted food intake or dehydration, or who have
change in insulin requirements due to surgery, are at higher risk for ketoacidosis
In patients with diabetes, blood glucose may be higher than usual for ~1 day; their blood sugar should be
checked more regularly, if possible, until their levels are within range and have stabilized
Treatment should be interrupted, and monitoring
of blood ketones is recommended
Restart SGLT2 inhibitor therapy once patient's
condition has stabilized, blood ketone levels return to
normal, and patient has eaten normally for at least
24 hr (providing no new contraindications exist)
Surgery Restarting treatment

When Should SGLT2 Inhibitor Therapy Be Paused?
selondonccg.nhs.uk/wp-content/uploads/dlm_uploads/2021/09/Heart-Failure-Dapagliflozin-HFrEF-non-DM-FINAL-July-2021.pdf.
Empagliflozin PI.
 Unable to eat and drink normally
 Vomiting/diarrhea
 Fever
Have a major infection, including infection of the kidney or
urinary tract with fever
Have a condition that leads to volume depletion or dehydration, eg:
Are hospitalized for major surgical procedures
Restart SGLT2 inhibitor therapy once the patient’s condition has stabilized,
blood ketone levels return to normal, and patient has eaten normally for at
least 24 hr (providing no new contraindications exist)
Have an acute serious medical illness, eg, acute worsening of CHF
Patients should pause SGLT2 inhibitor therapy if they:

Key Takeaways
 SGLT2 inhibitors are important piece of HF GDMT across spectrum of
LVEF
 Using all GDMT agents, when possible, can improve both morbidity and
mortality for patients with HF
 Develop systems that promote initiation, titration, and maintenance of
all classes of medications, particularly in HFrEF with heavy medication
burden
‒ Should consider starting while in hospital for initiation
 Modify patient and family education to emphasize importance of
SGLT2 inhibitors and strategies to manage adverse events

Thank You For Attending!
Go Online for More CCO Coverage of Heart Failure
On-demand webcast of this symposium
Additional CME/CE-certified slideset on heart failure and integrating SGLT2 inhibitors across
the spectrum of heart failure
ClinicalThought commentaries on adverse event prevention, management, and strategies to
adjust additional medications such as antiglycemics and diuretics
clinicaloptions.com/CE-CME/cardiology

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