Empagliflozin: The Foundation Therapy in

Heart Failure
Dr Akhil Sharma MD,DM,FSCAI.
Professor (Jr.)
Department of Cardiology
KGMU Lucknow.
 Outline

Case presentation with HFrEF, HFmrEF, HFpEF

HF Burden and management guidelines

SGLT2i in HF

Clinical Evidence in Patients with Chronic HFrEF, HFmrEF,

HFpEF

Initiation in Stabilized Acute HF and Early Outcomes

Optimization of Place in Heart-Failure Therapy

 Case (HFrEF)

• A 54-year-old woman presented with shortness of breath (SOB) for 4 months

• SOB progressed to an extent that she was unable to perform daily activities.

• She also used 3 pillows to sleep and often woke up from sleep due to difficulty
catching her breath.

H/O Current
• Hypertension, medications
No significant
dyslipidemia, • Aspirin,
social or family
diabetes Atorvastatin, history was
mellitus, and Telmisartan, noted
history of Bisoprolol, and
triple bypass Metformin.
surgery 4 years
ago.
 Examination

• Bilateral diffuse crackles in lungs, elevated jugular venous pressure, and 2+

pitting lower extremity edema.
• ECG showed normal sinus rhythm with left ventricular hypertrophy.

• Chest x-ray showed vascular congestion.

• Laboratory results showed a pro-B-type natriuretic peptide (pro-BNP) level

of 874 pg/mL and troponin level of 0.22 ng/mL.
• Thyroid panel was normal.

• An echocardiogram demonstrated systolic dysfunction, mild mitral

regurgitation, a dilated left atrium, and an ejection fraction (EF) of 33%
 Case 2 : (HFmrEF)

History and Examination

• A 60-year-old female patient, non-alcoholic and non-smoker
• K/c/o T2DM for 10 years and Hypertension for 20 years
• On probing, increasing breathlessness on exertion since past 6 months
• BMI: 33 Kg/m2; waist-circumference: 102 cm
• BP: 130 / 84 mmHg
• Receiving Metformin 1g + Glimepiride 2mg BD; Telmisartan 40mg +
Amlodipine 5mg + Hydrochlorothiazide 6.25mg BD + Rosuvastatin 10mg
OD
 Laboratory Investigations

• HbA1c 8.1%; FPG 114 mg/dL

• Total-cholesterol 149 mg/dL;

• LDL-c 84 mg/dL;

• HDL-c 40 mg/dL;

• TG 125 mg/dL

• Sr. creatinine 1.0 mg/dL (eGFRCKD-EPI: 64 mL/min/1.73m2);

• UACR 220 mg/gCr s/o moderate-grade albuminuria

• Chest X-ray s/o enlarged cardiac silhouette, edema at lung-bases

• NT-proBNP 410 pg/mL

• Echocardiography s/o LVEF 46%, Grade-2 diastolic dysfunction

 Case (HFpEF)

• An 82-year-old woman with longstanding hypertension, obesity, and

type 2 diabetes mellitus presents for dyspnea on exertion, which has
increased over several months & has mild ankle edema.

• Her local internist referred her for additional evaluation and

management.

Current medications

• Metoprolol 25 mg bid,
• Amlodipine 5 mg q day,
• Telmisartan 40 mg,
• Glimepiride 1 mg PO bid,
• Rosuvastatin 10 mg
 Case continue..

• ECG did not demonstrate ischemic changes.

• Her baseline echocardiogram
• showed mild left ventricular (LV) hypertrophy, with septal & posterior wall thickness of 12 mm
& LV end-diastolic dimension of 4.9 cm, with EF of 60%
• Mitral inflow pattern
• showed an E:A ratio of 1.3 that changed with Valsalva to an impaired relaxed
pattern with a septal annular E' velocity of 7.8 cm/sec.

• Her resting right ventricular (RV) systolic pressure was 47 mm Hg.

• She exercised for 2 minutes and 50 seconds (2.4 MET) on a Bruce protocol stress
echocardiogram, stopping for extreme shortness of breath.

• Her resting blood pressure was 150/70 mm Hg and her heart rate was 74 bpm.
• At peak exercise, her BP was 196/90 mm Hg, with a peak HR of 95 bpm.

• Echocardiographic images at the end of exercise demonstrated augmentation of

contractility of all walls with mild mitral regurgitation.
• Her right ventricular systolic pressure at the end of exercise had increased to 65 mm
Hg, and Doppler inflow pattern showed a monolithic E wave with a velocity of 180
cm/sec and a septal annular E' velocity of 8 cm/sec.
 Outline

Case presentation with HFrEF, HFmrEF, HFpEF

HF Burden and management guidelines

SGLT2i in HF

Clinical Evidence in Patients with Chronic HFrEF, HFmrEF,

HFpEF

Initiation in Stabilized Acute HF and Early Outcomes

Optimization of Place in Heart-Failure Therapy

 Heart Failure
India is now the Chronic Heart Disease capital of the world’ warns CSI

• Heart Failure is public health challenge in India

• Incidence of HF in India vary widely from 1.3 to
23 million

S. Mishra et al. / Indian Heart Journal 70 (2018) 105–127

 How are Indian HF patients different??

Indian patients present with HF at a younger age than those in the West (THFR,
Medanta Registry and the INTER-CHF (Indian subset) study was 61.2, 58.9 and
56 years, respectively, as compared to 72.4 years in ADHERE Registry of USA)

Male to female ratio is also different in India (70:30 as per the THFR and 83:17
in the Medanta registry) compared to USA

Prevalence of risk factor as DM is much more prevalent among Indians than

those in the West

Prognosis of HF in Indian patients appears to be worse than those in the West.

 New backbone of heart failure care?

Mineralo-
SGLT-
RAS Beta
2
Inhibition
Inhibition Blockade corticoid
Receptor
?
Inhibition

N Engl J Med 381;21. N Engl J Med 383;15. Lancet 2020; 396:819-29.

RAS: renin angiotensin system; SGLT-2: sodium-glucose co-transporter
AHA/ACC/HFSA 2022 Guideline Recommendations for
Patients At Risk for HF (Primary Prevention)

COR: Category of Recommendation; LOE: Level of Evidence

 AHA/ACC/HFSA 2022 Guideline Recommendations
Patients with Heart Failure and Preserved Ejection Fraction

COR: Category of Recommendation; LOE: Level of Evidence

 isWhat
new is
(21)
new (21)
Recommendations
Recommendations
for management
for management
of patients with
of patients
HF and diabetes
with HF and diabetes
2021 HF Guidelines
2021 HF Guidelines Class Class2016 HF Guidelines
2016 HF Guidelines
Class Class
inhibitors
SGLT2 inhibitors
(canagliflozin,
(canagliflozin,
iflozin, empagliflozin,
dapagliflozin, ertugliflozin,
empagliflozin, ertugliflozin,
EmpagliflozinEmpagliflozin
should be considered
shouldinbe considered in
flozin) are recommended
sotagliflozin) in
are recommended in
patients with patients
T2DM in order to prevent
with T2DM in order to prevent
tspatients
with T2DM with
at risk
T2DM of CV
atevents
risk of CV Ievents I IIa IIa
or delay the onset of HFthe
or delay andonset
prolong
of HF and prolong
ucetohospitalizations for HF, major
reduce hospitalizations for HF, major
life. life.
ents,
CVend-stage renal dysfunction,
events, end-stage renal dysfunction,
V and
death.CV death.

©ESC
 Outline

Case presentation with HFrEF, HFmrEF, HFpEF

HF Burden and management guidelines

SGLT2i in HF

Clinical Evidence in Patients with Chronic HFrEF, HFmrEF,

HFpEF

Initiation in Stabilized Acute HF and Early Outcomes

Optimization of Place in Heart-Failure Therapy

 The Proof of Concept
Effects of SGLT2-inhibition on Pathophysiology of HF

•Preload Reduction
• ↑ in Free-water clearance
• ↓ in Stressed blood-volume
• ↓ in Pulmonary vascular pressures
• ↓ in Intraglomerular pressure

Effects on Myocardium
• ↑ in Metabolic efficiency
Improved
SGLT2- • ↑ in Diastolic relaxation Cardiac
inhibition • ↑ in O2 demand-supply balance Structure and
• ↓ in LV Hypertrophy Function
• ↓ in LV Remodeling, Fibrosis
Afterload Reduction
• ↑ in Endothelial function
• ↓ in Vascular stiffness
• ↓ in Neurohormonal stimulation
• ↑ in Autonomic balance

Adapted: Lan NSR et al. ESC Heart Fail. 2019;6:927; Requena-

Ibáñez JA et al. JACC Heart Fail. 2021 Aug;9(8):578-89; Mordi NA
et al. Circulation. 2020; 142: 1713-24; Omar M et al. Circ Heart
Fail. 2021 Nov. doi: 10.1161/CIRCHEARTFAILURE.121.009156.
 Outline

Case presentation with HFrEF, HFmrEF, HFpEF

HF Burden and management guidelines

SGLT2i in HF

Clinical Evidence in Patients with Chronic HFrEF, HFmrEF,

HFpEF

Initiation in Stabilized Acute HF and Early Outcomes

Optimization of Place in Heart-Failure Therapy

 Long-term CV safety of empagliflozin is evaluated in a large,
multicentre trial (EMPA-REG OUTCOME)

Europe
41%

North 19% Asia

America /
Western Pacific
*
20%
4% Africa

15% 42 Countries 7034 Patients

Latin America Countries with study centres
involved in the EMPA-REG
592 Clinical sites OUTCOME® trial

• *Cumulative percentage for North America, Australia and New Zealand.

• 1. Zinman et al. Cardiovasc Diabetol 2014;13:102. 2. NCT01131676.
21
 EMPA-REG OUTCOME: Summary

Empagliflozin in addition to standard of care reduced CV risk and improved

overall survival in adults with T2D at high CV risk

14% 38% 32% 35%

↓ 3P-MACE ↓ CV death ↓ All-cause ↓ Heart failure

mortality hospitalisations

The overall safety profile of empagliflozin was consistent with previous clinical trials and
current label information

In patients with T2DM & high risk for cardiovascular events who received
empagliflozin had significantly lower rates of the primary composite
cardiovascular outcome and of death from any cause than did those in the placebo
group when the study drugs were added to standard care.
 In Patients with Atherosclerotic CVD (ASCVD) & T2DM
CVOTs Have Demonstrated Improvements in CV Outcomes

Represents significant reduction Adapted: McGuire DK et al. JAMA Cardiol. doi:10.1001/jamacardio.2020.4511. Published Online, Oct 7 2020.
 EMPEROR-Reduced Study

Phase-III Randomized, Double-blind, Placebo-Controlled Trial

Study on Efficacy and Safety of Empagliflozin in Adult Patients with Chronic HFrEF,
with or without Type-2 Diabetes, and with eGFR ≥20 mL/min/1.73m2

Study design1-3 Confirmatory endpoints1,2

PRIMARY OUTCOME
Empagliflozin 10 mg OD +
SOC* CV Death or HHF (first adjudicated
EMPEROR-Reduced event)
LVEF ≤40% KEY SECONDARY OUTCOMES
Placebo OD + SOC*
3730 patients • Total HHF (first + recurrent adjudicated
events)
Median follow-up = 15.7 months
• Slowing of Kidney-function
(event-driven)
Decline (Change in Slope of eGFRCKD-EPI from
baseline)

*SOC: Standard of Care

CV, cardiovascular; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; HF, heart
failure; HHF, hospitalisation for heart failure; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; qd, once daily;
SOC, standard of care; T2D, type 2 diabetes
1. ClinicalTrials.gov. NCT03057977; 2. Packer M et al. Eur J Heart Fail 2019;21:1270; 3. Packer et al. NEJM 2020. DOI:
10.1056/NEJMoa2022190.
 Empagliflozin Improves HF Outcomes in Patients with HFrEF
CV Death or Hospitalization for HF, with Empagliflozin versus Placebo

40

RRR ARR
NNT = 19
incidence function (%)
Estimated cumulative

30
Placebo 25% 5.2%

20

Empagliflozin HR 0.75
10 (95% CI 0.65, 0.86)
p<0.001

0
Empagliflozin:
0 90 180 270 360 450 540 630 720 810 361 patients with event
Days after randomisation Rate: 15.8/100 patient-years
Patients at risk
Placebo 1867 1715 1612 1345 1108 854 611 410 224 109 Placebo:
Empagliflozin 1863 1763 1677 1424 1172 909 645 423 231 101 462 patients with event
Rate: 21.0/100 patient-years

Cox regression model including covariates age, baseline eGFR, geographic region, baseline diabetes status, sex, LVEF and treatment
CV, cardiovascular; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; ARR, absolute risk reduction; RRR, relative risk reduction. NNT: Number needed to treat
Packer et al. NEJM 2020. DOI: 10.1056/NEJMoa2022190.
EMPA: Consistently Benefits Patient-groups with HFrEF
CV Death or HHF Reduction, by Status of T2D, Age, ARNi, MRA Use

Adapted: Packer et al. NEJM 2020. DOI: 10.1056/NEJMoa2022190.

 Empagliflozin Does Not Worsen Overall Safety Outcomes
in Patients of HFrEF, with/without Type-2 Diabetes

Patients without Diabetes Empagliflozin (n = 304) Placebo (n = 302)

0.9 1.4
0.0 0.0 0.3 0.3 % %
% 0 % 0 % %
Diabetic Severe* Confirmed† Genital
ketoacidosi hypoglycaemic hypoglycaemic tract
s events events infection

Patients with Diabetes Empagliflozin (n = 927) Placebo (n = 926)

2.4 2.2 1.9
% % %
0.8 0.6 0.4
0.0 0.0 % %
% % %
Diabetic Severe* Confirmed† Genital
ketoacidosi hypoglycaemic hypoglycaemic tract
s events events infection

*Defined as a hypoglycemic episode requiring assistance; †Hypoglycaemic AEs with a plasma glucose value of ≤70 mg/dL or that required
treatment.

Anker SD et al. Circulation. 2021;143:337.

 Empagliflozin Lowers Risk of Serious Kidney Events in HFrEF
End-Stage Kidney Disease or Sustained Profound ↓ in eGFR
incidence
(%) (%)

6
cumulative

RRR ARR
function

50% 1.5%
cumulative

4 Placebo
function
Estimated
incidence

HR 0.50
Estimated

2
(95% CI 0.32, 0.77)
Empagliflozin
Empagliflozin
0 30 patients with event
0 90 180 270 360 450 540 630 720 Rate:
810 1.6/100 patient-years
Daysafter
Days after randomisation
randomisation Placebo
Patients at risk 58 patients with event
Placebo 1867 1592 1501 1136 1058 681 357 259
Empagliflozin 1863 1599 1532 1155 1062 687 391 276
Rate: 3.1/100 patient-years

Composite renal endpoint is defined as chronic dialysis, renal transplant, sustained reduction of ≥40% eGFR or sustained eGFR <15 ml/min/1.73 m 2
for patients with eGFR ≥30 ml/min/1.73 m 2 at baseline (<10 ml/min/1.73 m2 for patients with eGFR <30 ml/min/1.73 m 2 at baseline). Dialysis is
regarded as chronic if the frequency of dialysis is twice or more per week for at least 90 days. ARR, absolute risk reduction; RRR, relative risk
reduction. Zannad F et al. Circulation. 2021 Jan 26;143(4):310-21.
 Empagliflozin in Heart Failure with a Preserved Ejection Fraction-
EMPEROR PRESERVED

Aim: To investigate the safety and efficacy of empagliflozin versus placebo in patients with HF
and LVEF >40%, and compare and contrast the results in true HFpEF vs HFmrEF

Randomized, double-blind, placebo-controlled trial

Population: T2D and non-T2D, aged ≥18 years, chronic HF, and eGFR ≥20 mL/min/1.73m 2

*Randomized, double-blind, placebo-controlled trial; eGFR, estimated glomerular filtration rate.

Anker S et al. N Engl J Med. 2021 Aug 27. doi: 10.1056/NEJMoa2107038. Anker S. Presented at AHA Scientific Sessions, Nov 2021.

N Engl J Med 2021;385:1451-61.

 Empagliflozin Shows Consistent Efficacy in HFmrEF and HFpEF
EMPEROR-Preserved Results in Patients with LVEF 41-49% or LVEF ≥50%

RRR = Relative Risk-reduction; ARR = Absolute Risk-reduction; NNT = Number needed to treat to prevent 1 additional event
over 26.2 months
Anker S. Presented at AHA Scientific Sessions, Nov 2021.
Empagliflozin Consistently Benefits Patient-groups with HFpEF / HFmrEF
CV Death or HHF Risk-Reduction, by Status of T2D, Age, CKD, A-Fib/AF

Adapted: Anker S et al. N Engl J Med. 2021 Aug 27. doi: 10.1056/NEJMoa2107038.
 Empagliflozin Lowers Risk of CV Death or HF Hospitalizations
in Patients Across the Spectrum of Heart Failure (EMPEROR Pooled Analysis)

CV Death or Hospitalization for Heart Failure, by Baseline LV Ejection Fraction

Empagliflozin Placebo

LVEF n with event/N HR (95% CI) HR (95% CI)

<25% 117/476 154/523 0.77 (0.60, 0.98)
≥25 to <35% 191/1115 255/1115 0.72 (0.59, 0.87) Interaction
p-value = 0.7610
≥35 to <45% 115/659 128/613 0.82 (0.63, 1.05)
≥45 to <55% 159/1111 215/1149 0.74 (0.61, 0.91)
≥55 to <65% 134/1071 161/1021 0.78 (0.62, 0.97)
≥65% 60/428 60/437 0.98 (0.68, 1.40)
0.25 2.5

Favours empagliflozin Favours placebo

Butler J et al. Eur Heart J. 2021 Dec 8;ehab798.

 EMPA-HEART CardioLink-6 Randomized Clinical Trial
Effect of Empagliflozin on Left Ventricular Mass in T2DM & CAD

Aim To determine if empagliflozin causes a decrease in left ventricular (LV) mass in

people with type 2 diabetes mellitus and coronary artery disease.

Patients • 97 individuals ≥40 and ≤80 years old with HbA1c 6.5% to 10.0%, known CAD,
and eGFR ≥60mL/min/1.73m2

Interventio • Empagliflozin (10 mg/day,n=49) or placebo (n=48) for 6 months, in addition to

n standard of care.

Primary • 6-month change in LV mass indexed to body surface area from baseline as
outcome measured by cardiac magnetic resonance imaging

Other • 6-month changes in LV end-diastolic and -systolic volumes indexed to body

outcomes surface area, ejection fraction,
• 24-hour ambulatory blood pressure,
• Hematocrit
• NT-proBNP (N-terminal pro b-type natriuretic peptide).

Circulation. 2019;140:1693–1702. DOI: 10.1161/CIRCULATIONAHA.119.042375

 Empagliflozin exposure for 6 months is associated with a
decrease in LVMi as assessed by cardiac MRI
Mean LV mass indexed to body surface area
regression over 6 months was 2.6 g/m2 and
0.01 g/m2 for those assigned empagliflozin and
placebo, respectively

Empagliflozin

Overall ambulatory
Elevation of
SBP
hematocrit
DBP

Conclusion

• The EMPA-HEART CardioLink-6 trial has demonstrated that empagliflozin

leads to significant reduction in LVMi in patients with T2DM & CAD
• These benefits are observed in individuals who were well treated with
background therapies and appear to occur early (within 6 months).
 EMPA TROPISM

Randomized Trial of Empagliflozin in Nondiabetic Patients With Heart Failure and

Reduced Ejection Fraction
Aim To assess the effect of empagliflozin on left ventricular (LV) function
and volumes, functional capacity & QOL in nondiabetic HFrEF
patients.
Design Double-blind, placebo-controlled trial
Patients Nondiabetic HFrEF patients (n = 84) were randomized to
Empagliflozin 10 mg daily or placebo for 6 months.
Primary Change in LV end-diastolic and –systolic volume assessed by cardiac
endpoint magnetic resonance
Secondary Changes in LV mass, LV ejection fraction,
endpoints Peak oxygen consumption in the cardiopulmonary exercise test, 6-
min walk test, QOL

J Am Coll Cardiol 2021 Jan 26;77(3):243-255.

 Empagliflozin Improves Cardiac Structure and Function in
Patients with HFrEF, without T2DM (EMPA-TROPISM Study)

LV-ESV index LV-EDV index

0
-0.31
Change in LV Volumes from

-0.8
-3
Baseline (mL/m2)

-6

-9

-12
-12 P<0.001
-13.3
-15 P<0.001

Baseline Mean LV Volumes 72. 68. 110. 106.

(mL/m2) 4 1 6 7

LV-ESV-index: Left-ventricular End-systolic Volume Index. LE-EDV-index:

Left-ventricular End-diastolic volume index. Adapted: Santos-Gallego CG et al. J Am Coll Cardiol. 2021 Jan 26;77(3):243-55.
 Empagliflozin Improves Cardiac Structure and Function
in Patients with HFrEF, without T2DM (EMPA-TROPISM Study)

Maximum LA Minimum LA
Volume Volume
20
Change in LA Volume from

15 11.4
10 6.4
5
0
Baseline
(mL)

-5
-10
-15 -11.3 P<0.001
-20 -16.2 P<0.001
-25

Baseline Mean LA Volume (mL) 112. 101. 71.0 68.5

4 2
LA Volume: Left Atrial Volume
Adapted: Santos-Gallego CG et al. J Am Coll Cardiol. 2021 Jan 26;77(3):243-55.
 Empagliflozin Improves Cardiac Function
in Patients with HFrEF, without T2DM (EMPA-TROPISM Study)

LV-Ejection Fraction... Peak VO2 (CPET)

8 1.2 1.1
Change in LVEF from Baseline

Change in Peak VO2 from

P<0.001
6

Baseline (mL/min/Kg)
6 P<0.001 0.9

4 0.6

0.3
(%)

2
0
0
-0.1 -0.3
-2 -0.6 -0.5
Baseline 36.2 36.5 Baseline Mean 15.3 14.5
Mean LVEF % % Peak VO2
(%) (mL/min/kg)
Adapted: Santos-Gallego CG et al. J Am Coll Cardiol. 2021 Jan 26;77(3):243-55.
 Empagliflozin Improves Cardiac Structure and Function
in Patients with HFrEF, without T2DM (EMPA-TROPISM Study)

Empagliflozin is associated with greater reduction in both left ventricular end-

diastolic volume (LVEDV) (A) and left ventricular end-systolic volume (LVESV)
(B), more intense regression in left ventricular (LV) mass (C), and higher
improvement in left ventricular ejection fraction (LVEF) (D) between baseline and
6-month time points compared with placebo

Patients who received empagliflozin had significant improvements in peak O2

consumption , oxygen uptake efficiency slope, as well as in 6-min walk test quality
of life

Adapted: Santos-Gallego CG et al. J Am Coll Cardiol. 2021 Jan 26;77(3):243-55.

 Outline

Case presentation with HFrEF, HFmrEF, HFpEF

HF Burden and management guidelines

SGLT2i in HF

Clinical Evidence in Patients with Chronic HFrEF, HFmrEF,

HFpEF

Initiation in Stabilized Acute HF and Early Outcomes

Optimization of Place in Heart-Failure Therapy

 EMPA-RESPONSE-AHF

Aim To evaluate the safety and clinical efficacy of SGLT2 inhibitors in patients with
acute decompensated HF
Type of study • Randomized, placebo-controlled, double-blind, parallel group, multicenter pilot study

Patients • 80 acute HF patients with and without diabetes

Interventions • Empagliflozin 10 mg/day or placebo for 30 days.

Primary • Change in visual analogue scale (VAS) dyspnoea score

outcomes • Diuretic response (weight change per 40mg furosemide)
• Change in n-terminal pro brain natriuretic peptide (NT-proBNP)
• Length of stay.

Secondary • Worsening HF (defined as worsening signs and/or symptoms of HF that require an

outcomes intensification of intravenous therapy for HF or mechanical ventilatory, renal or
circulatory support),
• All-cause death and/or HF readmission through day 30 and through day 60 as part of
AE assessment
• Safety

K. Damman et al.European Journal of Heart Failure (2020) 22, 713–722

 Results
• No difference was observed in VAS dyspnoea score, diuretic response, length of
stay, or change in NT-proBNP between empagliflozin and placebo

Empagliflozin reduced a combined endpoint of in-hospital

worsening HF, rehospitalization for HF or death at 60 days
compared with placebo
 Summary of Studies in Recent Heart-Failure Event

SOLOIST-WHF1,2 GALACTIC-HF3 VICTORIA4 PIONEER-HF5 EMPULSE6

HFrEF

HFpEF

Diabetes

Non-diabetes

In-hospital treatment
49% 25% 11% 100% 100%
initiation

HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction.
1. Bhatt DL et al. N Engl J Med. 2021;384:117; 2. Bhatt DL et al. AHA 2020;LBS.07; 3. Teerlink JR et al. N Engl J Med. 2021;384:105; 4. Lam CSP et al. JAMA Cardiol. 2021;6:706; 5.
Velazquez EJ et al. N Engl J Med. 2019;380:539; 6. Voors AA. Presented at American Heart Association Virtual Annual Scientific Sessions (AHA 2021). Nov 14, 2021.
 Outline

Case presentation with HFrEF, HFmrEF, HFpEF

HF Burden and management guidelines

SGLT2i in HF

Clinical Evidence in Patients with Chronic HFrEF, HFmrEF,

HFpEF

Initiation in Stabilized Acute HF and Early Outcomes

Optimization of Place in Heart-Failure Therapy

 Foundational Four Therapies for Patients with HFrEF

Foundational
Therapies in HFrEF2 

 ACEi / ARB
Beta blocker SGLT2-i MRA
or ARNi

“Based on large randomized trials for HFrEF;

ARNI, evidence-based beta-blockers,
aldosterone antagonists, and SGLT2-i are
first-line medications for all populations.”
- ACC Expert Consensus Decision Pathway for HFrEF (2021)
 Rapid Sequencing Algorithm For Introduction of
Foundational Therapies in Patients with Stable HFrEF

Step 1. Simultaneous initiation of β-blocker + SGLT2-i

• β-blockers arguably most effective for risk of sudden death
• SGLT2-i have striking early benefit for hospitalization for
HF, may mitigate short-term risk of worsening HF with β-
blocker

Step 2. Addition of ARNi, within 1-2 weeks of Step 1

• If SBP <100 mmHg, evaluate tolerance in relation to
hypotension with ARB, before switching to ARNi
• Risk resolves with repeat dosing, or adjusting diuretic dose

Step 3. Addition of MRA, within 1-2 weeks of Step 2, if

serum K+ normal, Renal function not severely impaired
• Favorable effects of SGLT2-i and ARNi to improve renal
function and K+ homeostasis, may increase tolerability to
MRA
• MRAs may be Step 2 in a patient with troublesome
hypotension

1.Adapted: Packer M, McMurray JJV. Eur J Heart Fail. 2021 Mar 11. doi: 10.1002/ejhf.2149.
2.Adapted: McMurray JJV, Packer M. Circulation. 2021 Mar 2;143(9):875-7.
Summary: Empagliflozin For Heart Failure

First SGLT2i to be approved for all patients with

symptomatic CHF, irrespective of LVEF.

Significantly reduces the risk of CV death/HHF,

regardless of T2DM status and background HF therapy.

Significantly improves HRQOL.

Generally well tolerated