The unmet needs of patients with heart failure meeting 17 Feb 2022.pptx

Dr Adel Sallam
MD. FCMR. FSCCT
Cardiologist and Advanced Cardiovascular Image Specialist
What’s new in 2021:
An updated standard of care for HFrEF
SGLT2 inhibitors and Heart Failure

Case #1: outpatient, “Referral case
45 year old male
• NYHA II for past year
• Hospital discharge 2 day back
• LVEF 40%,sever MS ,mod AR
• Non-ischemic etiology
Medications:
• Sacubitril-valsartan 49/51mg bid
• Bisoprolol 2.5 mg/d
• Empagliflozin 10 mg OD
• Frusemide 40 mg OD
• Hyperkalemia to 5.2 with spironolactone
• HR 74 bpm, BP 90/50
• Generalized anasarca
• Baseline SCr 110 µmol/L, K+ 5.2
• ECG shows NSR with QRS of 136ms
• Active, still working-Driver
• Occ SOBOE, weight up/down 1-2kg
• Takes oral Lasix when needed
His questions today:
• Do I need to take all these meds?
• I feel dizzy ,fatigue
• Hade severe scrotal swelling
• My daughter says I may need a surgery – do I?
How should we answer these questions?

Why guideline therapy matters:
• In HFrEF, treatment effects of
comprehensive therapy (ARNI,
beta- blocker, MRA, SGLT2i) was
compared to conventional therapy
(ACEI/ARB, beta-blocker) in cross
trial analyses
• Significant improvement with
comprehensive therapy observed in
both overall survival and event-free
survival across all age groups
• In a 55-year-old man,
comprehensive therapy would
improve event-free survival by 8.3
years and overall survival by 6.3
years
Vaduganathan M et al. Lancet 2020
16
14
12
10
8
6
4
2
0
55 60 65 70 75 80
A
Event-free
survival
(yrs)
Age (yrs)
Comprehensive therapy
Conventional therapy
B
Overall
survival
(yrs)
Age (yrs)
16
14
12
10
8
6
4
2
0
55 60 65 70 75 80
20
18
10
8
6
4
2
55 60 65 70 75 80
C
Difference
in
event-free
survival
(yrs)
Age (yrs)
D
Difference
in
overall
survival
(yrs)
Age (yrs)
10
8
6
4
2
55 60 65 70 75 80
0
Comprehensive treatment improves survival in HFrEF
CCS/CHFS Heart Failure Guidelines

9
What are the challenges we face when treating our
patients with heart failure?
Balancing the desires to
‘do more’ and ‘do no harm’
Desire to do more
Desire to do more
Improve outcomes
Manage symptom frequency
and burden
Increase options for elderly
patients with multiple
comorbidities
Simplify dosing schedule
Without doing harm
Minimal contraindications
due to polypharmacy
Good safety profile
with minimal AEs
Preservation of
kidney function
AE, adverse event.

Theory vs Practice
Greene SJ et al. JACC 2018; 72: 351-66 and Jefferies JL et al. JACC 2018; 72:367-369.
GDMT is not implemented GDMT is not titrated

27%
21%
2% 4%
15%
4%
25%
0
10
20
30
40
50
60
70
80
90
100
Kidney
dysfunction
Patient
resistance/
noncompliance
Hypotension Low
albumin
Best clinical
compromise/
chronic
oedema
Plan for
outpatient
diuresis
Other*
Reasons
documented
for
discharge
with
residual
congestion
(%)
13
Kidney dysfunction limits optimal implementation
of guideline-directed therapy in heart failure
Multiple reasons for failure to comply with guidelines could be documented for each discharge.
*Other reasons for discharge with residual congestion included: severe tricuspid regurgitation secondary to severe pulmonary hypertension (n=2), severe tricuspid regurgitation
secondary to biventricular HF (n=2), oedema caused by peripheral vascular disease (n=4), aortic stenosis (n=1), restrictive cardiomyopathy (n=1), noncardiac rales (n=1) and
hospice (n=1).
Gilstrap LG et al. J Am Heart Assoc. 2018;7:e008789.

Reasons for deviation from b-blocker guidelines
14

Reasons for deviation from angiotensin-converting enzyme
inhibitor (ACEi) or angiotensin II
receptor blocker (ARB) guidelines
15

End-stage kidney disease
16
Before SGLT2 inhibitors, no treatment options provided sufficient
reduction in kidney function decline in patients with HF
RAASi, renin-angiotensin-aldosterone system inhibitor; SGLT2, sodium-glucose co-transporter-2.
Adapted from Mullens W et al. Eur J Heart Fail. 2020;22:584.
End-stage kidney disease
RAAS blockade does
not improve eGFR in
patients with HF
135
120
105
90
75
60
45
30
15
0
eGFR
(mL/min/1.73
m
2
)
Young age Older age
HF start (acute event)
HF slope
Start RAASi
Zoom in
Start RAASi
1. Acute drop in eGFR with RAASi
2. Slope remains parallel
3. Unknown if becomes less steep
with long follow-up slope
Average HF decline
Acute drop + slope after RAASi
Slope with sacubitril/valsartan
1
2
3
1 mL/min/1.73 m2 per year (normal rate)
2–3 mL/min/1.73 m2 per year (average rate in people with HF)

Evaluation of kidney function throughout the heart failure
trajectory – a position statement from the Heart Failure
Association of the European Society of Cardiology
European J of Heart Fail, Volume: 22, Issue: 4, Pages: 584-603, First published: 07 January 2020, DOI: (10.1002/ejhf.1697)

19
Thirty- and 90-day all-cause readmission rates
based on congestion status and use of
neurohormonal therapy at discharge.

Empagliflozin in HFrEF treatment:
Efficacy results

EMPEROR-Reduced: Phase III, randomized, double-blind,
placebo-controlled trial
*Guideline-directed medical therapy: All patients received appropriate treatments for heart failure, including diuretics, inhibitors of the renin⎼angiotensin system and neprilysin, beta blockers,
mineralocorticoid receptor antagonists and, when indicated, cardiac devices. †With elevated NT-proBNP (value dependent on EF and presence/absence of atrial fibrillation).
EF, ejection fraction; eGFR, estimated glomerular filtration rate; HHF, hospitalization for heart failure; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal prohormone of brain
natriuretic peptide; NYHA, New York Heart Association; OD, once daily; T2D, type 2 diabetes.
ClinicalTrials.gov. NCT03057977. Available at: https://clinicaltrials.gov/ct2/show/NCT03057977 (accessed June 2021); Packer M et al. Eur J Heart Fail. 2019;21:1270;
Packer M et al. N Engl J Med. 2020;383:1413. 21
Aim
Investigate the safety and efficacy of
empagliflozin vs placebo on top of guideline-
directed medical therapy* in patients with HF
with reduced ejection fraction
Population
3730 patients with and
without T2D, aged ≥18 years,
with chronic HF (NYHA class
II–IV), LVEF ≤40%†
Confirmatory endpoints
Composite primary endpoint
• Time to first event of adjudicated CV death
or HHF
Secondary endpoints
• First and recurrent adjudicated HHF events
• Slope of change in eGFR from baseline
Empagliflozin 10 mg OD + standard of care*
Placebo OD + standard of care*
Randomization
Median follow-up
16 months (event-driven)

Trial inclusion and exclusion criteria
Inclusion criteria1,2 Exclusion criteria1,2
Age ≥18 years (Japan, age ≥20 years) at screening MI, coronary artery bypass graft surgery or other major CV
surgery, stroke or TIA ≤90 days before Visit 1
Chronic HF NYHA class II−IV
Heart transplant recipient, or listed for heart transplant
HFrEF (LVEF ≤40%) and elevated NT-proBNP
EF (%)
NT-proBNP (pg/ml)
Patients without AF*
Acute decompensated HF
≥36 to ≤40 ≥2500
≥31 to ≤35 ≥1000
SBP ≥180 mmHg at Visit 2
≤30 ≥600
≤40% + HHF within
12 months
≥600
Symptomatic hypotension and/or a SBP <100 mmHg
Dose of medical therapy for HF that is consistent with
CV guidelines stable for ≥1 week prior to screening
and throughout screening period eGFR <20 ml/min/1.73 m2 or requiring dialysis
Further inclusion criteria apply Further exclusion criteria apply

Empagliflozin Outcome Trial in Patients With Chronic
Heart Failure and a Reduced Ejection Fraction -
EMPEROR-Reduced
Total screened: 7,220
Total number of enrollees: 3730
Duration of follow-up: 16 months (median)
Mean patient age: 67 years
Percentage female: 24%
• Inclusion criteria:
• Age ≥18 years
• Chronic HF, New York Heart Association (NYHA)
functional class II/III/IV
• Left ventricular EF (LVEF) ≤40%
• HF hospitalization within 12 months
• N-terminal pro–B-type natriuretic peptide (NT-
proBNP) ≥600 pg/ml if EF ≤30%; ≥1000 pg/ml if EF
31-35%; ≥2500 pg/ml if EF >35%
• If concomitant atrial fibrillation, then above thresholds
were doubled)
Exclusion criteria:
• Acute coronary syndrome, stroke, or transient ischemic attack (TIA) within 90 days
• Listed for orthotopic heart transplantation, currently implanted LV assist device (LVAD)
• Cardiomyopathy based on infiltrative/accumulation diseases, muscular dystrophies, reversible
causes, hypertrophic cardiomyopathy, pericardial restriction, peripartum, cardiomyopathy
caused by chemotherapy within 12 months
• Severe valvular heart disease
• Acute decompensated HF
• Implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy (CRT) within 3
months
Other salient features/characteristics:
• White 70%, Asian 18%
• North America: 11%, Europe: 36%, Asia: 13%, Latin America: 34%
• NYHA functional class II: 75%
• Mean LVEF: 27%
• Type 2 diabetes: 50%
• Estimated glomerular filtration rate (eGFR) <60: 48%
• Medications: angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker: 70%, angiotensin
receptor-neprilysin inhibitor: 19%, mineralocorticoid receptor antagonist (MRA): 71%, beta-blocker:
94%
• ICD: 31%, CRT 12%
23

Baseline characteristics (II)
24
Characteristic Empagliflozin
(n=1863)
Placebo
(n=1867)
Body mass index (kg/m2) – mean ± SD 28.0 ± 5.5 27.8 ± 5.3
Heart rate (beats/min) – mean ± SD 71.0 ± 11.7 71.5 ± 11.8
Systolic blood pressure (mmHg) – mean ± SD 122.6 ± 15.9 121.4 ± 15.4
LV ejection fraction (%) 27.7 ± 6.0 27.2 ± 6.1
N (%) with LV ejection fraction ≤30 1337 (71.8) 1392 (74.6)
NT-proBNP (pg/ml) – median (IQR), 1887 (1077, 3429) 1926 (1153, 3525)
N (%) with NTproBNP ≥1000 pg/ml 1463/1862 (78.6) 1488/1866 (79.7)
Principal cause of heart failure – number (%)
Ischaemic 983 (52.8) 946 (50.7)
Non-ischaemic 880 (47.2) 921 (49.3)
Cardiovascular history – N (%)
Hospitalisation for heart failure within 12 months 577 (31.0) 574 (30.7)
Atrial fibrillation 664 (35.6) 705 (37.8)
Diabetes mellitus 927 (49.8) 929 (49.8)
Hypertension 1349 (72.4) 1349 (72.3)
eGFR (ml/min/1.73 m2) – mean ± SD 61.8 ± 21.7 62.2 ± 21.5
N (%) with eGFR <60 893/1862 (48.0) 906/1866 (48.6)

Baseline characteristics (III)
25
Characteristic Empagliflozin
(n=1863)
Placebo
(n=1867)
Heart failure medication – N (%)
Angiotensin-converting enzyme (ACE) inhibitor 867 (46.5) 836 (44.8)
Angiotensin receptor blocker (ARB) 451 (24.2) 457 (24.5)
Angiotensin receptor neprilysin inhibitor (ARNI) 340 (18.3) 387 (20.7)
Mineralocorticoid receptor antagonist (MRA) 1306 (70.1) 1355 (72.6)
Beta blocker 1765 (94.7) 1768 (94.7)
Device therapy – N (%)
Implantable cardioverter-defibrillator* (ICD) 578 (31.0) 593 (31.8)
Cardiac resynchronisation therapy† (CRT) 220 (11.8) 222 (11.9)

Standard of care +
placebo
Standard of care +
empagliflozin
Days after randomization
Estimated
cumulative
incidence
function
(%)
HR: 0.75 (95% CI: 0.65, 0.86)
p<0.001
40
30
20
10
0
90 180 270 360 450 540 630 720 810
0
Cox regression model including covariates age, baseline eGFR, geographic region, baseline diabetes status, sex, LVEF and treatment.
ARR, absolute risk reduction; CI, confidence interval; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; NNT, number needed to treat.
19
RRR ARR
25% 5.2%
NNT
All
pts
Primary endpoint: Empagliflozin significantly lowered rates
of CV death or first HHF in patients with HFrEF

Standard of care +
placebo
Standard of care +
empagliflozin
Estimated
cumulative
incidence
function
(%)
HR: 0.75 (95% CI: 0.65, 0.86)
p<0.001
40
30
20
10
0
90 180 270 360 450 540 630 720 810
0
19
RRR ARR
25% 5.2%
NNT
All
pts
Early and sustained
risk reduction in CV
death or HHF

Standard of care +
placebo
Empagliflozin
+ standard of care
HR 0.75 (95% CI 0.65, 0.86)
p<0.001
Estimated
cumulative
incidence
function
(%)
40
30
20
10
0
90 180 270 360 450 540 630 720 810
0
19
28
RRR ARR
25% 5.2%
22% 3.7%
28% 6.9%
Empagliflozin No
T2D
NNT
T2D
All
pts
Empagliflozin reduced
the risk of CV death or
HHF regardless of
diabetes status
Interaction
p=0.57
Packer M et al. N Engl J Med. 2020;383:1413; Anker SD et al. Circulation. 2021;143:337.

Empagliflozin effect on individual components of
the primary endpoint
Empagliflozin (n=1863) Placebo (n=1867)
Number of
events (%)
Events per 100
patient-years
Number of
events (%)
Events per 100
patient-years
Hazard ratio (95% CI) p-value
Primary composite endpoint 361 (19.4) 15.8 462 (24.7) 21.0 0.75 (0.65, 0.86) <0.001
• First hospitalization for HF 246 (13.2) 10.7 342 (18.3) 15.5 0.69 (0.59, 0.81)
• CV death 187 (10.0) 7.6 202 (10.8) 8.1 0.92 (0.75, 1.12)

Key secondary endpoint: Empagliflozin significantly
lowered rates of total HHF (first and recurrent) in patients
with HFrEF
Analysis of first and recurrent HHF accounting for CV death as terminal event using a joint frailty model. Model includes covariates age, baseline eGFR, treatment, region,
baseline diabetes status, sex, baseline LVEF, estimated dependence between adjudicated HHF and adjudicated CV death, and variance of frailty.
Packer M et al. N Engl J Med. 2020;383:1413.
0.60
0.50
0.40
0.30
0.20
0.10
0.00
0 90 180 270 360 450 540 630 720 810 900
Mean
number
of
events
per
patient
Empagliflozin: 388 events
Placebo: 553 events
HR: 0.70 (95% CI: 0.58, 0.85)
p<0.001
30
RRR
30%
Standard of care +
placebo
Standard of care +
empagliflozin

31
Key secondary endpoint: Empagliflozin protected the
kidney by slowing the decline in kidney function over
time in patients with HFrEF
*All patients received appropriate treatments for heart failure, including diuretics, inhibitors of the renin⎼angiotensin system and neprilysin, beta blockers, mineralocorticoid
receptor antagonists and, when indicated, cardiac devices. eGFR slope is analysed based on on-treatment data using a random coefficient model including age and baseline
eGFR as linear covariates and sex, region, baseline LVEF, baseline diabetes status, and baseline by time and treatment by time interactions as fixed effects; the model allows for
randomly varying slope and intercept between patients. SE, standard error. Packer M et al. N Engl J Med. 2020;383:1413.
Annual mean change in eGFR slope
Adjusted
mean
(SE)
eGFR
slope
(mL/min/1.73
m
2
)/year
Standard of care*
+ empagliflozin
Standard of care*
+ placebo
0
-0.5
-1
-1.5
-2
-2.5
-2.28
-0.55
4x slower decline in
kidney function

Primary outcomes* in SGLT2i-HF trials were
consistent irrespective of baseline MRA use
SGLT2i, n/N (%) Placebo, n/N (%) HR (95% CI) HR (95% CI)
EMPEROR-Reduced1
Yes 118/557 (21.2) 132/512 (25.8) 0.76 (0.59, 0.97)
No 243/1306 (18.6) 330/1355 (24.4) 0.75 (0.63, 0.88)
Baseline use of MRA
0 0.5 1 1.5
Favours drug Favours placebo
DAPA-HF2
Yes 281/1696 (16.5) 361/1674 (21.6) 0.74 (0.63, 0.87)
No 105/677 (15.5) 141/697 (20.2) 0.74 (0.57, 0.95)
0 0.5 1 1.5

Primary outcomes* in SGLT2i-HF trials were
consistent irrespective of baseline ARNi use
SGLT2i, n/N (%) Placebo, n/N (%) HR (95% CI) HR (95% CI)
EMPEROR-Reduced1
Yes 310/1523 (20.4) 369/1480 (24.9) 0.64 (0.66, 0.90)
No 51/340 (15.0) 93/387 (24.0) 0.77 (0.45, 0.89)
Baseline use of ARNi
0 0.5 1 1.5
DAPA-HF2
Yes 41/250 (16.4) 56/258 (21.7) 0.75 (0.50, 1.13)
No 345/2123 (16.3) 446/2113 (21.1) 0.74 (0.65, 0.86)
0 0.5 1 1.5

36
EMPEROR-Reduced also assessed health status
HFrEF, heart failure with reduced ejection fraction; KCCQ, Kansas City Cardiomyopathy Questionnaire.
Butler J et al. Eur Heart J. 2021;42:1203.
In addition to the risk for mortality and hospitalizations, patients with HFrEF also suffer from
impaired health status
Improvements in health-related quality of life constitute a major treatment goal
The KCCQ reflects key health status domains, including:
HF symptom burden
and frequency
Physical function Quality of life Social function
Total symptom score
Clinical summary score
Overall summary score

Empagliflozin improved health status across various domains, and
this benefit was sustained during long-term follow-up in patients
with HFrEF
37
3 months
Adjusted mean difference (95% CI)
8 months
12 months
KCCQ scores
Clinical summary score 1.94 (0.96, 2.93) 1.35 (0.28, 2.42) 1.61 (0.39, 2.84)
Total symptom score 2.52 (1.46, 3.59) 1.64 (0.48, 2.79) 1.69 (0.40, 2.98)
Overall summary score 1.77 (0.81, 2.73) 1.30 (0.22, 2.38) 1.52 (0.29, 2.74)
KCCQ subdomains
Symptom frequency 2.76 (1.60, 3.92) 1.58 (0.34, 2.82) 1.84 (0.43, 3.26)
Symptom burden 2.26 (1.15, 3.37) 1.67 (0.47, 2.87) 1.49 (0.17, 2.81)
Physical limitation 1.38 (0.19, 2.57) 1.11 (–0.17, 2.39) 1.41 (–0.08, 2.90)
QoL 1.88 (0.69, 3.08) 1.43 (0.11, 2.75) 1.10 (–0.27, 2.64)
Social limitation 1.10 (–0.33, 2.53) 0.94 (–0.66, 2.53) 1.33 (–0.47, 3.13)
-1 0 1 2 3 4 -1 0 1 2 3 4
Favours
empagliflozin
Favours
placebo
Favours
empagliflozin
Favours
placebo
Favours
empagliflozin
Favours
placebo
-1 0 1 2 3 4
HFrEF, heart failure with reduced ejection fraction; QoL, quality of life.

Improvement in health-related quality of life with
empagliflozin vs placebo in patients with HFrEF
CSS, Clinical Summary Score; HFrEF, heart failure with reduced ejection fraction
• Improvement and less deterioration in all scores-
• Effects observed as early as 3 months and sustained for 12 months
3 months
Odds ratio (95% CI)
8 months
Odds ratio (95% CI)
12 months
Odds ratio (95% CI)
Improvement
CSS ≥5 points 1.20 (1.05, 1.37) 1.20 (1.04, 1.37) 1.22 (1.05, 1.41)
CSS ≥10 points 1.26 (1.10, 1.44) 1.21 (1.06, 1.38) 1.22 (1.06, 1.40)
CSS ≥15 points 1.29 (1.12,1.48) 1.20 (1.05, 1.38) 1.17 (1.01, 1.35)
0.5 1 1.5 0.5 1 1.5 0.5 1 1.5
Deterioration
CSS ≥5 points 0.75 (0.64, 0.87) 0.85 (0.73, 0.99) 0.84 (0.72, 0.98)
0.5
1
1.5 0.5
1
1.5 0.5
1
1.5
Favours
empagliflozin
Favours
placebo
Favours
empagliflozin
Favours
placebo
Favours
empagliflozin
Favours
placebo
38

39
Early improvement and less deterioration of empagliflozin on
NYHA class apparent after only 4 weeks in patients with HFrEF
Packer M et al. Circulation. 2021;143:326; Data on file.
Improvement Odds ratio (95% CI) p-value
4 weeks 1.38 (1.11, 1.72) 0.004
12 weeks 1.22 (1.01, 1.46) 0.04
32 weeks 1.30 (1.10, 1.55) 0.003
52 weeks 1.31 (1.08, 1.58) 0.005
Deterioration
4 weeks 0.70 (0.50, 0.97) 0.03
12 weeks 0.67 (0.51, 0.87) 0.003
32 weeks 0.81 (0.66, 0.99) 0.04
52 weeks 0.83 (0.68, 1.00) 0.05
0.8 1 1.2 1.4 1.6 1.8
0.4
0.6
0.8
1
1.2
Favours empagliflozin
Favours placebo
Favours empagliflozin
Favours placebo
Odds ratios for
empagliflozin vs placebo for
improvement in NYHA
functional class
Odds ratios for
empagliflozin vs placebo for
deterioration in NYHA
functional class

41
Empagliflozin consistently reduced CV death or HHF
across a broad range of patients with HFrEF
CKD, chronic kidney disease; HFrEF, heart failure with reduced ejection fraction
Anker SD et al. Circulation. 2021;143:337; Zannad F et al. Circulation. 2021;143:310.
Pre-existing
conditions
Diabetes
CKD
CV death
or HHF
Empagliflozin
n/N (%)
Placebo
n/N (%)
HR
(95% CI)
p-value
for trend
All patients 361/1863 (19.4) 462/1867 (24.7)
No diabetes 161/936 (17.2) 197/938 (21.0)
Diabetes 200/927 (21.6) 265/929 (28.5)
No CKD 142/879 (16.2) 187/867 (21.6)
CKD 219/981 (22.3) 273/997 (27.4)
0.57
Favours empagliflozin Favours placebo
0 0.5 1 1.5
0.63

42
HFrEF, heart failure with reduced ejection fraction.
Packer M et al. Eur Heart J. 2021;42:671; Ferreira JP et al. J Am Coll Cardiol. 2021;77:1397.
CV death
or HHF
Empagliflozin
n/N (%)
Placebo
n/N (%)
HR
(95% CI)
p-value
for trend
All patients 361/1863 (19.4) 462/1867 (24.7)
ARNI 51/340 (15.0) 93/387 (24.0)
No ARNI 310/1523 (20.9) 369/1480 (24.9)
MRA 243/1306 (18.6) 330/1355 (24.4)
No MRA 118/557 (21.2) 132/512 (25.8)
Concomitant
medication
ARNI
MRA
0 0.5 1 1.5
0.31
0.93

43
HFrEF, heart failure with reduced ejection fraction
Zannad F et al. Circulation. 2021;143:310.
CV death
or HHF
Empagliflozin
n/N (%)
Placebo
n/N (%)
HR
(95% CI)
p-value
for trend
All patients 361/1863 (19.4) 462/1867 (24.7)
≥90 31/229 (13.5) 55/220 (25.0)
60 to <90 128/740 (13.5) 169/740 (22.8)
45 to <60 80/433 (18.5) 108/467 (23.1)
30 to <45 87/345 (25.2) 96/349 (27.5)
<30 35/115 (30.4) 33/90 (36.7)
Kidney function
eGFR (mL/min/1.73 m2)
0.12
0 0.5 1 1.5

44
HFrEF, heart failure with reduced ejection fraction.
Anker SD et al. Circulation. 2021;143:337; Zannad F et al. Circulation. 2021;143:310; Packer M et al. Eur Heart J. 2021;42:671; Ferreira JP et al. J Am Coll Cardiol. 2021;77:1397.
MRA
Regardless of
pre-existing conditions
Diabetes
CKD
Regardless of
concomitant medication
ARNI
Regardless of
kidney function
Findings were consistent with the main analysis
eGFR

The primary outcome,
The primary outcome, cardiovascular death
or HF hospitalization, for empagliflozin vs.
placebo, was 19.4% vs. 24.7% (hazard ratio
[HR] 0.75, 95% confidence interval [CI] 0.65-
0.86, p < 0.001)
• Cardiovascular death: 10% vs. 10.8%
(HR 0.92, 95% CI 0.75-1.12)
• HF hospitalization: 13.2% vs. 18.3% (HR
0.69, 95% CI 0.59-0.81)
Secondary outcomes:
• Total hospitalizations: 388 vs. 553 (p < 0.001)
• Composite renal outcome (chronic haemodialysis, renal transplantation,
profound sustained reduction in eGFR): 1.6 vs. 3.1 (HR 0.50, 95% CI 0.32-0.77,
p < 0.01)
• All-cause mortality: 13.4% vs. 14.2% (HR 0.92, 95% CI 0.77-1.10, p > 0.05)
• New-onset type 2 diabetes among patients with prediabetes: 11.2% vs.
12.6% (p > 0.05)
• Change in haemoglobin A1c between baseline and week 52 (patients with
diabetes): -0.28 vs. -0.12% (p < 0.05)
• Systolic blood pressure -2.4 vs. -1.7 mm Hg (p > 0.05)
• Confirmed hypoglycaemic event: 1.4% vs. 1.5%
• Death/HF hospitalization/emergent or urgent HF visit requiring intravenous
treatment or diuretic intensification/deterioration of NYHA class: 32.7% vs. 43%
(p < 0.0001)
• Intensification of diuretics: 15.9% vs. 22.2% (p < 0.0001)
• Emergent or urgent HF visit requiring intravenous treatment: 6.8% vs. 9.9% (p =
0.0004)
• Hospitalization for HF requiring cardiac care unit/intensive care unit care:
4.8% vs. 5.7% (p = 0.002)
EMPEROR-Reduced ---Principal Findings
45

46
Summary: Efficacy
Empagliflozin achieved a remarkable 25% RRR in the primary composite
endpoint of CV death or first HHF, on top of SOC
Empagliflozin reduced first and recurrent HHF by 30% in a confirmatory
secondary endpoint analysis
Empagliflozin significantly reduced HF outcomes and kidney function decline
The results were consistent across a broad range of patients regardless
of background therapy, comorbidities and renal function
HF, heart failure
Packer M et al. N Engl J Med. 2020;383:1413; Anker SD et al. Circulation. 2021;143:337; Zannad F et al. Circulation. 2021;143:310; Packer M et al. Eur Heart J. 2021;42:671;
Ferreira JP et al. J Am Coll Cardiol. 2021;77:1397.
For patients with HFrEF:

Empagliflozin in HFrEF treatment:
Safety results

10.6%
9.4%
5.7%
1.0%
0.3%
1.4%
9.9%
8.7%
5.5%
0.8%
0.3%
1.5%
In EMPEROR-Reduced, AE rates were similar between
the empagliflozin and placebo treatment arms
Shown are AEs up to 7 days following discontinuation of study medication.
*Hypoglycaemic AEs with a plasma glucose value of ≤70 mg/dL or that required treatment. CV, cardiovascular; UTI, urinary tract infection.
Empagliflozin (n=1863)
Placebo (n=1863)
Volume depletion
Hypotension
Symptomatic
hypotension
Urinary tract infections
(complicated)
Genital tract infections
(complicated)
Hypoglycaemia*
Selected CV-related adverse events of interest
48
No clinically meaningful increases
in hypovolaemia, hypotension,
UTIs, hypoglycaemia or
hyperkalaemia
Selected non-CV-related adverse events of interest

In EMPEROR-Reduced, diabetes-related AE rates were
similar in the empagliflozin and placebo treatment arms
*Hypoglycaemic AEs with a plasma glucose value of ≤70 mg/dL or that required treatment. †Rare cases of diabetic ketoacidosis and necrotizing fasciitis of the perineum
(Fournier’s gangrene), including life-threatening and fatal cases, have been reported in post marketing experience in patients taking SGLT2 inhibitors including empagliflozin.
Anker SD et al. Circulation. 2021;143:337.
No diabetes Diabetes
49
1.4%
0.3%
0
0
0.90%
0.3%
0
0
Severe
hypoglycaemic events
Confirmed*
Diabetic
ketoacidosis†
1.9%
2.2%
0.6%
0
0.4%
2.4%
0.8%
0
Placebo (n=302)
Placebo (n=926)
Genital tract
infection
Genital tract infections may be
addressed with proactive
monitoring and management

In EMPEROR-Reduced, diabetes-related AE rates were
similar in the empagliflozin and placebo treatment arms
*Hypoglycaemic AEs with a plasma glucose value of ≤70 mg/dL or that required treatment. †Rare cases of diabetic ketoacidosis and necrotizing fasciitis of the perineum
(Fournier’s gangrene), including life-threatening and fatal cases, have been reported in post marketing experience in patients taking SGLT2 inhibitors including empagliflozin.
No diabetes Diabetes
50
1.4%
0.3%
0
0
0.90%
0.3%
0
0
Severe
Confirmed*
Diabetic
ketoacidosis†
1.9%
2.2%
0.6%
0
0.4%
2.4%
0.8%
0
Placebo (n=302)
Placebo (n=926)
Genital tract
infection
No severe hypoglycaemia in patients
without diabetes
No ketoacidosis in any patient

-8
-7
-6
-5
-4
-3
-2
-1
0
Last value on double-
blind treatment
Off treatment for
23–45 days
Empagliflozin significantly reduced the decline in kidney
function vs placebo in patients with HFrEF
MMRM includes age and baseline eGFR (CKD-EPI) as linear covariates and baseline score by visit, visit by treatment, sex, region, baseline LVEF, week reachable and baseline
diabetes as fixed effects. *Analysis was performed in 966 patients with paired data. CI, confidence interval; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR,
estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; MMRM, mixed model for repeated measures. 1. Packer M et al. N Engl J Med. 2020;383:1413; 2. Data
on file.
Standard of care +
placebo
Standard of care +
empagliflozin
Empagliflozin vs placebo
(after withdrawal)
+3.3 mL/min/1.73 m2
(95% CI: 1.8, 4.9)
p<0.001
During double-blind treatment1 Withdrawal after end of study*2
-8
-7
-6
-5
-4
-3
-2
-1
0
0 26 52 78 104 130
Mean
change
from
baseline
in
eGFR
(mL/min/1.73
m
2
)
Weeks since randomization
51
Standard of care +
placebo
Standard of care +
empagliflozin
Off treatment for
23–45 days
Last value on double-
blind treatment
Mean
change
from
baseline
in
eGFR
(mL/min/1.73
m
2
)

Key secondary endpoint: eGFR slope
Empagliflozin protected the kidney by slowing the progression of kidney disease
-7
-6
-5
-4
-3
-2
-1
0
0 10 20 30 40 50 60 70 80 90 100 110 120 130
Mean
change
from
baseline
in
eGFR
(ml/min/1.73
m
2
)
Week
Early difference between empagliflozin
and placebo due to the previously
reported initial drop with SGLT2i
Empagliflozin: Yearly decline of
-0.55 ml/min/1.73 m2 per year
Placebo: Yearly decline of
-2.28 ml/min/1.73 m2 per year
1-year 2-year 3-year
eGFR slope = rate of decline
eGFR slope is a measure for
long-term renal function
+1.73
eGFR slope difference
ml/min/1.73 m2 per year
p<0.001

Estimated
cumulative
incidence
function
(%)
6
4
2
0
180 270 360 450 540 720 810
0 90 630
Composite renal endpoint*: Empagliflozin reduced the
relative risk of adverse kidney outcomes by 50% vs
placebo in patients with HFrEF
53
ARR
Standard of care
+ placebo
*Composite renal outcome was an exploratory endpoint of the EMPEROR-Reduced trial, defined as as chronic dialysis, renal transplant, sustained reduction of ≥40% eGFR or
sustained eGFR <15 mL/min/1.73 m2 for patients with eGFR ≥30 mL/min/1.73 m2 at baseline (<10 mL/min/1.73 m2 for patients with eGFR <30 mL/min/1.73 m2 at baseline). Dialysis
is regarded as chronic if the frequency of dialysis is twice or more per week for at least 90 days. Cox regression model including covariates age, baseline eGFR (CKD-EPI), region,
baseline diabetes status, sex and baseline LVEF.
ARR, absolute risk reduction; HR, hazard ratio; RRR, relative risk reduction. Packer M et al. N Engl J Med. 2020;383:1413;
Packer M. Circ Heart Fail. 2021;doi:10.1161/CIRCHEARTFAILURE.121.008537.
RRR
1.5%
50%
Standard of care
+ empagliflozin
HR: 0.50 (95% CI: 0.32, 0.77)

54
The favourable effects of empagliflozin on renal outcomes
were consistent across a broad range of HFrEF patients
*Composite exploratory endpoint included chronic dialysis or renal transplant or sustained reduction of ≥40% in eGFR or sustained eGFR (CKD-EPI) <15 mL/min/1.73 m2 (for
patients with baseline eGFR ≥30 mL/min/1.73 m2) or sustained eGFR <10 mL/min/1.73 m2 (for patients with baseline eGFR <30 mL/min/1.73 m2).
CKD, chronic kidney disease. Anker SD et al. Circulation. 2021;143:337; Zannad F et al. Circulation. 2021;143:310.
Pre-existing
conditions
Diabetes
CKD
Composite
renal outcome
Empagliflozin
n/N (%)
Placebo
n/N (%)
HR
(95% CI)
p-value
for trend
All patients 30/1863 (1.6) 58/1867 (3.1)
No diabetes 8/936 (0.9) 19/938 (2.0)
Diabetes 22/927 (2.4) 39/929 (4.2)
No CKD 10/879 (1.1) 20/867 (2.3)
CKD 20/981 (2.0) 38/997 (3.8)
0.65
0 0.5 1 1.5
0.78
*

55
patients with baseline eGFR ≥30 mL/min/1.73 m2) or sustained eGFR <10 mL/min/1.73 m2 (for patients with baseline eGFR <30 mL/min/1.73 m2).
ARNI, angiotensin receptor–neprilysin inhibitor; MRA, mineralocorticoid receptor antagonist. Packer M et al. Eur Heart J. 2021;42:671; Ferreira JP et al. J Am Coll Cardiol.
2021;77:1397.
Composite
renal outcome
Empagliflozin
n/N (%)
Placebo
n/N (%)
HR
(95% CI)
p-value
for trend
All patients 30/1863 (1.6) 58/1867 (3.1)
ARNI 3/340 (0.9) 9/387 (2.3)
No ARNI 27/1523 (1.8) 49/1480 (3.3)
MRA 19/1306 (1.5) 46/1355 (3.4)
No MRA 11/557 (2.0) 12/512 (2.3)
Concomitant
medication
ARNI
MRA
0.71
0.18
0 0.5 1 1.5
*

57
patients with baseline eGFR ≥30 mL/min/1.73 m2) or sustained eGFR <10 mL/min/1.73 m2 (for patients with baseline eGFR <30 mL/min/1.73 m2);
†Not calculated as less than 14 events in this subgroup.
Zannad F et al. Circulation. 2021;143:310.
Composite
renal outcome
Empagliflozin
n/N (%)
Placebo
n/N (%)
HR
(95% CI)
p-value
for trend
All patients 30/1863 (1.6) 58/1867 (3.1)
≥90 1/229 (0.4) 4/220 (1.8)
60 to <90 12/740 (1.6) 22/740 (3.0)
45 to <60 9/433 (2.1) 12/467 (2.6)
30 to <45 5/345 (1.4) 15/349 (4.3)
<30 3/115 (2.6) 5/90 (5.6)
Kidney function
0.74
Not calculated†
Not calculated†
*
eGFR (mL/min/1.73 m2)
0 0.5 1 1.5

58
Anker SD et al. Circulation. 2021;143:337; Zannad F et al. Circulation. 2021;143:310; Packer M et al. Eur Heart J. 2021;42:671; Ferreira JP et al. J Am Coll Cardiol.
2021;77:1397.
Findings were consistent with the main analysis
MRA
Diabetes
CKD
Regardless of
concomitant medication
ARNI
Regardless of
kidney function
Regardless of
pre-existing conditions
eGFR

59
Safety Summary
The safety profile was similar to the known safety profile of empagliflozin.
There was no clinically meaningful increase in hypovolaemia and hypotension
or hypoglycaemic events
Empagliflozin protected the kidney by significantly slowing the decline in
kidney function and reducing relative risk of adverse kidney
outcomes by 50%
The favourable effects of empagliflozin on safety outcomes including kidney
outcomes were consistent across a broad range of patients regardless of
background therapy, comorbidities and renal function
Packer M et al. N Engl J Med. 2020;383:1413; Anker SD et al. Circulation. 2021;143:337; Zannad F et al. Circulation. 2021;143:310; Packer M et al. Eur Heart J. 2021;42:671;
Ferreira JP et al. J Am Coll Cardiol. 2021;77:1397.
In EMPEROR-Reduced:

What guidance is available on the use
of SGLT2 inhibitors in HFrEF?

McDonald, Virani, et al., Canadian Journal of Cardiology: https://doi.org/10.1016/j.cjca.2021.01.017 © Canadian Cardiovascular Society. 2021. All rights reserved.
Why guideline therapy matters:
• In HFrEF, treatment effects of
comprehensive therapy (ARNI, beta-
blocker, MRA, SGLT2i) was compared to
conventional therapy (ACEI/ARB, beta-
blocker) in cross trial analyses
• Significant improvement with
comprehensive therapy observed in both
overall survival and event-free survival
across all age groups
• In a 55-year-old man, comprehensive
therapy would improve event-free survival
by 8.3 years and overall survival by 6.3
years
Vaduganathan M et al. Lancet 2020
16
14
12
10
8
6
4
2
0
55 60 65 70 75 80
A
Event-free
survival
(yrs)
Age (yrs)
B
Overall
survival
(yrs)
Age (yrs)
16
14
12
10
8
6
4
2
0
55 60 65 70 75 80
20
18
10
8
6
4
2
55 60 65 70 75 80
C
Difference
in
event-free
survival
(yrs)
Age (yrs)
D
Difference
in
overall
survival
(yrs)
Age (yrs)
10
8
6
4
2
55 60 65 70 75 80
0
Comprehensive treatment improves survival in HFrEF
CCS/CHFS Heart Failure Guidelines

McDonald, Virani, et al., Canadian Journal of Cardiology: https://doi.org/10.1016/j.cjca.2021.01.017 © Canadian Cardiovascular Society. 2021. All rights reserved.
What people are talking about: how best to
prescribe?
McMurray and Packer, Circulation 2021

What Do ExpertsSay?
Packer M and McMurray J .Eur Heart Journal 2021.
Real‐lifeproblems. . .
• Cost: can the patient afford the SGLT2i, the
ARNI?
• Tolerability: which one is causing the side effect?
Greene SJ, Butler J, Fonarow GC. JAMA Cardiol. March 31,2021

My Take:Rapid Initiation >>> Simultaneous Initiation
Sacubitril/valsartan 24/26 BID
Metoprolol XL 25 QD
Spironolactone 25 QD
Dapagliflozin 10 QD
1
‐
2
weeks
1
‐
2
weeks
1
‐
2
weeks
Sac/val 49/51 BID
Metoprolol XL 50 QD
4 pillars by 4
‐
8
weeks!
Sac/val 97/103 BID
Metoprolol XL 100 QD Metop XL 200
QD
2 weeks 2 weeks 2 weeks 2 weeks
Maximumtolerated doses of 4
pillars of GDMT 8 weeks later!
Real‐lifesolutions. ..
•Ensure patients can afford meds stepwise‐and if they can’t
prioritize ARNI>ACEI>ARB + BB+ MRA > SGLT2i
• Ensure tolerability of meds
• Use telehealth for frequent follow‐up!
Titrate to: symptoms, HR, BP,K, Cr
START TITRAT
E

What Should YouRemember?
Quadruple therapy saves lives!
Ask yourself: If not on it, why not?
4 pillars at low doses is better than < 4 at higher doses
Great Science + Effective Implementation = Lives Saved

No need for titration with SGLT2 inhibitors in HFrEF
81
Ensure eGFR ≥20 mL/min/1.73 m2 for empagliflozin and ≥30 mL/min/1.73 m2 for dapagliflozin before initiation of SGLT2 inhibitor.
Maddox TM et al. J Am Coll Cardiol. 2021;77:772.
No titration or dose adjustment is needed for SGLT2 inhibitors in HFrEF
Achieving target or maximally tolerated doses of other drugs
is not necessary before adding SGLT2 inhibitors

Prepare ThePatient
• Watch out for
• Volume depletion
• Ketoacidosis
• Urosepsis/pyelonephritis
• Genital mycotic infections
• Necrotizing fasciitis
Vaduganathan M et al. Circulation HF 2020; 13.

When to phonea friendily endocrinologist)
• Does the patient have type 1 or
type 2 diabetes?
• How should other oral diabetic
therapy be adjusted?
• How should insulin therapy be
adjusted?
Vaduganathan M et al. Circulation HF 2020; 13.

86
Summary: Treatment guidance
SGLT2 inhibitors, ARNIs, evidence-based beta blockers and aldosterone
antagonists are first-line medications for all populations with HFrEF
No need for titration or additional monitoring when initiating
patients with HFrEF on SGLT2 inhibitors
Expert guidance already includes SGLT2 inhibitors for HFrEF, and
upcoming guidelines are currently being updated with insights into how to
incorporate SGLT2 inhibitors for patients with HFrEF in clinical practice
Maddox TM et al. J Am Coll Cardiol. 2021;77:772; Rosano GMC et al. Eur J Heart Failure. 2021. doi:10.1002/ejhf.2206.

Aldosterone antagonist for patients
with eGFR ≥30 mL/min/1.73 m2 or
creatinine ≤2.5 mg/dL in males or
≤2.0 mg/dL in females or
K+ ≤5.0 mEq/L, NYHA class II–IV
SGLT2 inhibitor for patients
meeting eGFR criteria,†
NYHA class II–IV
Ivabradine for patients with resting HR ≥70 bpm, on maximally
tolerated beta-blocker dose in sinus rhythm, NYHA class II–III
Titrate diuretic agent for patients
with persistent volume overload,
NYHA class II–IV
HYD/ISDN for persistently symptomatic
Black patients despite ARNI/beta
blocker/MRA/SGLT2 inhibitor, NYHA
class III–IV
Initiate, add or switch: SGLT2 inhibitors are included as
first-line therapy for HFrEF
*ARNI is preferred. ACEi/ARB should only be considered in patients with contraindications, intolerance or inaccessibility to ARNI.
†Ensure eGFR ≥30 mL/min/1.73 m2 (dapagliflozin) or ≥20 mL/min/1.73 m2 (empagliflozin).
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor–neprilysin inhibitor; bpm, beats per minute; eGFR, estimated
glomerular filtration rate; HR, heart rate; HYD/ISDN, hydralazine/isosorbide dinitrate; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association.
ARNI/ACEi/ARB*
and evidence-based
beta blocker
with diuretic agent as
needed
+
+
+
+
+
87

Beta blockers
Mineralocorticoid receptor antagonists
Renin–angiotensin system inhibitors
SGLT2 inhibitors
SGLT2 inhibitors can be considered a new foundational
treatment in HFrEF1–8
1. Maddox TM et al. J Am Coll Cardiol. 2021;77:772; 2. Bhatt DL et al. Cell Metab. 2019;30:847; 3. Felker GM. Circulation. 2020;141:112; 4. Bauersachs J et al. Eur Heart J.
2021;426:681; 5. Lam CSP, Butler J. Circulation. 2020;142:1129; 6. McMurray J, Packer M. Circulation. 2021;143:875; 7. McDonald M et al. Can J Cardiol. 2021;37:531;
Rosano GMC et al. Eur J Heart Failure. 2021. doi:10.1002/ejhf.2206. 88

See slide notes for full list of references
*(A) refers to the level of evidence in the ADA evidence-grading system: see slide 61 for full definition
ADA guidelines have evolved to recommend SGLT2 inhibitors and
GLP-1 RAs with proven CV and kidney benefits in patients with T2D and
cardio–renal comorbidities (1/5)
2016
Glucose lowering1
2018 2020
Agents with
demonstrated
CVD benefit are
recommended
independent of HbA1c
(A)*3
Incorporate an agent
proven to reduce CV
events and mortality
(A)*2
2021
Agents with
demonstrated
CVD benefit are
recommended
independent of HbA1c
and in consideration of
specific-risk factors (A)*4

Applying guidance to practice:
Who is the appropriate patient
for empagliflozin?

BID, twice daily; CV, cardiovascular; eGFR, estimated glomerular filtration rate; LDL-Chol., low-density lipoprotein cholesterol; LV, left ventricular; MI, myocardial infarction;
NYHA, New York Heart Association. 91
Case study
Male patient, 65
Experiencing worsening
heart failure symptoms
Presented with worsening
symptoms of shortness of breath
and fatigue after mild exercise;
no fluid retention
CV history
• Hypertension
• Anterior MI
• LV ejection fraction: 33%
• NYHA class II, progressing
to class III
Lab results
LDL-Chol. 110 mg/dL
eGFR 56 mL/min/1.73 m²
Potassium 4.8 mmol/L
Current medication
• Ramipril 5 mg BID
• Bisoprolol 5 mg/day
• Furosemide 80 mg/day
• Aspirin 100 mg/day
• Rosuvastatin 20 mg/day

92
Case study
Male patient, 65
Why is empagliflozin a
suitable treatment option for
this patient?

EMPEROR-Reduced: Empagliflozin significantly lowered
rates of key outcomes vs placebo in patients with HFrEF
*Composite renal endpoint is defined as chronic dialysis, renal transplant, sustained reduction of ≥40% eGFR or sustained eGFR <15 mL/min/1.73 m2 for patients with eGFR ≥30
mL/min/1.73 m2 at baseline (<10 mL/min/1.73 m2 for patients with eGFR <20 mL/min/1.73 m2 at baseline). Dialysis is regarded as chronic if the frequency of dialysis is twice or
more per week for at least 90 days. Cox regression model including covariates age, baseline eGFR (Chronic Kidney Disease Epidemiology Collaboration), region, baseline
diabetes status, sex and baseline LVEF. HHF, hospitalization for heart failure.
Relative risk reduction
Primary endpoint:
Adjudicated CV death or
HHF
p<0.001
Key secondary endpoint:
Adjudicated first and recurrent
HHF
p<0.001
Other secondary endpoint:
Composite renal endpoint*
25%
30%
50%
93

EMPEROR-Reduced: Benefits on all-cause death, HHF or
emergent/urgent HF care* seen after only 12 days of treatment
Placebo
Empagliflozin
Probability
of
event
(%)
5
4
3
2
0
1
0 10 20 30 40
Day 12 Day 34
Statistical significance
reached first time
Statistical significance
sustained
HR: 0.42 (95% CI: 0.19, 0.92)
p=0.029
HR: 0.67 (95% CI: 0.44, 1.00)
p=0.048
94
1867 1852 1830 1811 1792
1863 1855 1845 1826 1815
Placebo
Empagliflozin
Patients at risk
*For worsening HF.
Packer M et al. Circulation. 2021;143:326.

Improvement in health-related quality of life with
empagliflozin vs placebo in patients with HFrEF
CSS, Clinical Summary Score.
• Improvement and less deterioration in all scores-
• Effects observed as early as 3 months and sustained for 12 months
3 months
Odds ratio (95% CI)
8 months
Odds ratio (95% CI)
12 months
Odds ratio (95% CI)
Improvement
CSS ≥5 points 1.20 (1.05, 1.37) 1.20 (1.04, 1.37) 1.22 (1.05, 1.41)
CSS ≥10 points 1.26 (1.10, 1.44) 1.21 (1.06, 1.38) 1.22 (1.06, 1.40)
CSS ≥15 points 1.29 (1.12,1.48) 1.20 (1.05, 1.38) 1.17 (1.01, 1.35)
0.5 1 1.5 0.5 1 1.5 0.5 1 1.5
Deterioration
CSS ≥5 points 0.75 (0.64, 0.87) 0.85 (0.73, 0.99) 0.84 (0.72, 0.98)
0.5
1
1.5 0.5
1
1.5 0.5
1
1.5
Favours
empagliflozin
Favours
placebo
Favours
empagliflozin
Favours
placebo
Favours
empagliflozin
Favours
placebo
95

Simple dosing regimen for SGLT2 inhibitors
in patients with HFrEF
96
Boehringer Ingelheim Pharmaceuticals, Inc. Jardiance® (empagliflozin) Summary of Product Characteristics, June 2021; Maddox TM et al. J Am Coll Cardiol. 2021;77:772.
Single
dose
Once
daily
No
titration

NYHA class II–IV
Ivabradine for patients with resting HR ≥70, on maximally tolerated
beta-blocker dose in sinus rhythm, NYHA class II–III
NYHA class II–IV
class III–IV
97
2021 ACC Expert Consensus: SGLT2 inhibitors are
included as first-line therapy for HFrEF
HYD/ISDN, hydralazine/isosorbide dinitrate.
ARNI/ACEi/ARB*
and evidence-based
beta blocker
needed
+
+
+
+
+

NYHA class II–IV
Ivabradine for patients with resting HR ≥70, on maximally tolerated
beta blocker dose in sinus rhythm, NYHA class II–III
NYHA class II–IV
class III–IV
98
2021 ACC Expert Consensus: SGLT2 inhibitors are
included as first-line therapy for HFrEF
HYD/ISDN, hydralazine/isosorbide dinitrate.
ARNI/ACEi/ARB*
and evidence-based
beta blocker
needed
+
+
+
+
+
ARNI/ACEi/ARB, beta blocker
and aldosterone antagonist:
Serial evaluation and titration of
medications intensification within 6 months
in ~2-week cycles
• If volume status requires treatment, adjust
diuretics, with regular follow-up
• If euvolaemic and stable, start/increase/switch
GDMT, follow up ~2 weeks
• Repeat cycle until no further changes are
possible or tolerated
SGLT2 inhibitors::
No need for titration or additional monitoring after initiation

99
Case study
Male patient, 65
How do we appropriately
initiate empagliflozin?

Empagliflozin significantly reduced the decline in
kidney function vs placebo
eGFR slope is analysed based on on-treatment data using a random coefficient model including age and baseline eGFR as linear covariates and sex, region, baseline LVEF,
baseline diabetes status, and baseline by time and treatment by time interactions as fixed effects; the model allows for randomly varying slope and intercept between patients.
eGFR slope = rate of decline
eGFR slope is a measure for
long-term renal function
+1.73
eGFR slope difference
mL/min/1.73 m2 per year
p<0.001
100
Annual mean change in eGFR slope
Adjusted
mean
(SE)
eGFR
slope
(mL/min/1.73
m
2
)/year
Standard of care*
+ empagliflozin
Standard of care*
+ placebo
0
-0.5
-1
-1.5
-2
-2.5
-2.28
-0.55
4x slower decline in kidney function
with empagliflozin vs placebo

In EMPEROR-Reduced, AE rates were similar between
the empagliflozin and placebo treatment arms
Selected adverse events of interest
101
Shown are adverse events (AEs) up to 7 days following discontinuation of study medication.
*Hypoglycaemic AEs with a plasma glucose value of ≤70 mg/dL or that required treatment. UTI, urinary tract infection.
No clinically meaningful increases in
hypovolaemia, hypotension, UTIs or
hypoglycaemia
Empagliflozin (n=1863) Placebo (n=1863)
10.6%
9.4%
5.7%
1.0%
0.3%
1.7%
1.4%
9.9%
8.7%
5.5%
0.8%
0.3%
0.6%
1.5%
Volume
depletion
Hypotension
Symptomatic
hypotension
Urinary tract
infections
(complicated)
Genital tract
infections
(uncomplicated)
Hypoglycaemia* Genital tract
infections
(complicated)

Genital infections with SGLT2 inhibitors are common,
typically mild to moderate in severity and easily managed1–4
T2D, type 2 diabetes. 1. Wilding J et al. Diabetes Ther. 2018;9:1757; 2. Boehringer Ingelheim Pharmaceuticals, Inc. Jardiance® (empagliflozin) Summary of Product Characteristics,
June 2021; 3. Janssen International. Invokana® (canagliflozin) Summary of Product Characteristics, Jul 2020; 4. AstraZeneca. Forxiga® (dapagliflozin) Summary of Product
Characteristics, May 2021; 5. Packer M et al. N Engl J Med. 2020;383:1413; 6. Zinman B et al. N Engl J Med. 2015;373:2117.
Genital infections are a common AE associated with SGLT2 inhibitors in patients with and without T2D1,5,6
Genital infections usually occur early during treatment exposure and are not serious1
Management and treatment
Raise awareness at the start of SGLT2 inhibitor treatment to manage
expectations and promote early intervention1
Topical treatments or appropriate oral treatments can be used for
mild to moderate infections1
Provide practical hygiene advice to patients and their partners to
prevent genital infections1
102

Selected specific non-cardiorenal drug-related
adverse reactions* of different heart failure treatments
*Non-exhaustive list of non-cardiorenal drug-related adverse reactions. †Patients with diabetes.
1. GSK. Coreg® (carvedilol) Prescribing Information, Sep 2018; 2. Sanofi. Tritace® (ramipril) Summary of Product Characteristics, Jun 2021; 3. Novartis. Entresto® (sacubitril and
valsartan) Prescribing Information, Jun 2021; 4. Pfizer. Aldactone® (spironolactone) Prescribing Information, Jul 2020; 5. AstraZeneca. Forxiga® (dapagliflozin) Summary of
Product Characteristics, May 2021; 6. Boehringer Ingelheim Pharmaceuticals, Inc. Jardiance® (empagliflozin) Summary of Product Characteristics, June 2021.
10%
1%
0.1%
<0.01%
BETA BLOCKERS1 Erectile
dysfunction
Asthma
(in predisposed patients)
ACE INHIBITORS2 Neutropenia/
Agranulocytosis
ARNIs3 Angioedema
SPIRONOLACTONE4 Gynaecomastia
SGLT2 INHIBITORS5,6 Fournier’s
gangrene†
Diabetic
ketoacidosis†
Genital
infections
Angioedema
INCIDENCE Very rare Rare Uncommon Common
3%
103

104
Case study
Male patient, 65
Would you change your
treatment approach if this
patient had additional
comorbidities such as T2D or
CKD?
CKD, chronic kidney disease.

105
ADA, American Diabetes Association; ECDP, Expert Consensus Decision Pathway.
2021 ACC Expert Consensus: SGLT2 inhibitors can be used
regardless of T2D or CKD in patients with HFrEF
Comorbidity
Association with HF
outcomes
Clinical trial evidence for
modulating comorbidity
Suggested action
Diabetes Strong Strong
• Optimize therapy
• Administer SGLT2 inhibitor
• Consider consult with endocrinologist
• Treat according to the ACC ECDP on novel therapies for
CV risk reduction in patients with T2D and ADA
standards of medical care in diabetes
CKD Strong Strong
• Optimize RAAS inhibitor therapy
• Use HYD/ISDN if an ARNI/ACEi/ARB cannot be used
• Administer SGLT2 inhibitor
• Consider nephrology consult

No additional safety concerns, regardless of T2D status
106
*Hypoglycaemic AEs with a plasma glucose value of ≤70 mg/dL or that required treatment. †Data are for patients with no diabetes: empagliflozin n=936; placebo n=937.
1.4%
0.3%
0
0
0.9%
0.3%
0
0
Diabetic
ketoacidosis
Severe
Confirmed*
Genital tract
infection†
No diabetes Empagliflozin (n=304) Placebo (n=302)
1.9%
2.2%
0.6%
0 0.4%
2.4%
0.8%
0
Diabetic
ketoacidosis
Severe
Confirmed*
Genital tract
infection
Diabetes Empagliflozin (n=927) Placebo (n=926)

Diabetic ketoacidosis is rare in T2D and risk can
be mitigated
*Patients with LADA have autoimmune diabetes; therefore, they do not require insulin initially. †This may vary according to local label.
DKA, diabetic ketoacidosis; LADA, latent autoimmune diabetes in adults; T1D, type 1 diabetes.
1. Boehringer Ingelheim Pharmaceuticals, Inc. Jardiance® (empagliflozin) Summary of Product Characteristics, June 2021;
2. AstraZeneca. Forxiga® (dapagliflozin) Summary of Product Characteristics, May 2021.
RISK INCREASED IN
PATIENTS WITH:
• Low beta-cell function reserve, e.g. patients with T2D and low C-peptide or LADA* or
patients with a history of pancreatitis
‒ Restricted carbohydrate intake
‒ Severe dehydration
‒ Insulin dose reduction or inability to increase insulin due to an acute medical illness, surgery
or alcohol abuse
107
RECOMMENDATIONS†
• SGLT2 inhibitors should be used with caution in patients with increased risk of DKA1,2
• DKA may occur in patients treated with SGLT2 inhibitors with blood glucose in the euglycaemic
range (<14 mmol/L or <250 mg/dL)2
• Empagliflozin should not be used in patients with T1D or those who have or may have DKA
• Interrupt SGLT2 inhibitor treatment if hospitalized for major surgery or acute serious medical
illnesses. Monitoring of ketones is recommended in these patients. Measurement of blood
ketone levels is preferred to urine1,2
• SGLT2 inhibitors should be discontinued immediately if DKA is suspected1,2

The safety profile of SGLT2 inhibitors in glycaemia
is well established1–3
SU, sulphonylurea.
1. Petrie M et al. JAMA 2020;323:1353; 2. Ferrannini E et al. Diabetes. 2016;65:1190; 3. Boehringer Ingelheim Pharmaceuticals, Inc. Jardiance® (empagliflozin) Summary of
Product Characteristics, June 2021.
HYPO-
GLYCAEMIA
108
When an SGLT2 inhibitor is used in combination with an SU
or insulin, a lower dose of SU or insulin may be considered
to reduce the risk of hypoglycaemia3
There is no relevant blood glucose-lowering effect in
patients without T2D1,2
There is an increased risk of hypoglycaemia when used
in combination with an SU or insulin in patients with T2D3

109
Case study
Male patient, 65
Recommended actions
• Add empagliflozin 10 mg OD, regardless of T2D or CKD
status
• To reduce the risk of CV death or hospitalization
for heart failure with reduced ejection fraction
• To preserve kidney function by reducing the rate of
kidney function decline
OD, once daily.

Summary
Empagliflozin is simple to use: one dose, once-daily with no need for dose
titration or additional monitoring. Empagliflozin is therefore easy to
incorporate into clinical practice when treating patients with HFrEF
Empagliflozin can benefit patients with HFrEF by reducing the risk of CV
death or hospitalization for heart failure, slowing the decline in their renal
function and improving their health-related quality of life
Due to its consistent and favourable efficacy and safety profile,
empagliflozin can be used across a broad range of patients,
regardless of their T2D status
110
Maddox TM et al. J Am Coll Cardiol. 2021;77:772; Packer M et al. N Engl J Med. 2020;383:1413.

In EMPEROR-Reduced, empagliflozin demonstrated
positive safety and efficacy profiles in patients with HFrEF
CV, cardiovascular; HHF, hospitalization for heart failure.
Balancing the desires to
‘do more’ and ‘do no harm’
Desire to do more
Empagliflozin efficacy
vs placebo
Significant 25% relative
risk reduction in CV
death or first HHF
Improved health status
with sustained benefit
over long-term follow-up
Empagliflozin safety
vs placebo
Safety profile similar to
known safety profile for
empagliflozin
50% relative risk
reduction in adverse
kidney outcomes

Beta blockers
Mineralocorticoid receptor antagonists
Renin–angiotensin system inhibitors
SGLT2 inhibitors
SGLT2 inhibitors can be considered a new foundational
treatment in HFrEF1–8
1. Maddox TM et al. J Am Coll Cardiol. 2021;77:772; 2. Bhatt DL et al. Cell Metab. 2019;30:847; 3. Felker GM. Circulation. 2020;141:112; 4. Bauersachs J et al. Eur Heart J.
2021;426:681; 5. Lam CSP, Butler J. Circulation. 2020;142:1129; 6. McMurray J, Packer M. Circulation. 2021;143:875; 7. McDonald M et al. Can J Cardiol. 2021;37:531;
8. Rosano GMC et al. Eur J Heart Failure. 2021. doi:10.1002/ejhf.2206. 113

Summary
For patients with HFrEF, empagliflozin achieved a remarkable 25% RRR in
the primary composite endpoint of CV death or first HHF, on top of SOC, and
protected the kidney by significantly slowing the decline in kidney function
Expert guidance already includes SGLT2 inhibitors for HFrEF, and upcoming
guidelines are currently being updated with insights into how to incorporate
SGLT2 inhibitors for patients with HFrEF in clinical practice
Empagliflozin is simple to use as it is given once daily with no need for dose
titration or additional monitoring. Empagliflozin is therefore easy to
incorporate into clinical practice when treating patients with HFrEF
114
CV, cardiovascular; HHF, hospitalization for heart failure.
Packer M et al. N Engl J Med. 2020;383:1413; Maddox TM et al. J Am Coll Cardiol. 2021;77:772; Rosano GMC et al. Eur J Heart Failure. 2021. doi:10.1002/ejhf.2206.

Stephen J. Greene et al. J Am Coll Cardiol 2021; 77:1408-1411.
2021 American College of Cardiology Foundation

116
REALY we are ready to transition from a traditional and more singular focus on
possibility of overlapping side effects (i.e., “medications not getting along”) to
recognition that medications can potentially enhance tolerance and persistence of
each other (i.e., “medications working together”).
Specifically, we now have multiple examples where the 2 newest members of
quadruple therapy, ARNI and SGLT-2 inhibitors, may serve a secondary role in
enabling tolerance and persistence of other lifesaving HFrEF medications

Evaluation of kidney function throughout the heart failure trajectory – a
position statement from the Heart Failure Association of the European
Society of Cardiology

Evaluation of kidney function throughout the heart failure trajectory –
a position statement from the Heart Failure Association of the
European Society of Cardiology

The unmet needs of patients with heart failure meeting 17 Feb 2022.pptx

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