talks about f you

3. Journal club presentation
Presenter:- Dr Abdirisak Jacda
Moderator:- Dr Zamir internist

5. FDA-Approved SGLT2 Inhibitors for T2DM
Brand name Active ingredient(s)
Invokana canagliflozin
Invokamet canagliflozin and metformin
Farxiga dapagliflozin
Xigduo XR dapagliflozin and metformin
extended-release
Jardiance empagliflozin
Glyxambi empagliflozin and linagliptin
Synjardy empagliflozin and metformin
List of fda-approved sglt2 inhibitors for type 2 diabetes. Available from http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm3

6. Previous trials IN HEART FAILURE
• EMPA REDUCED
• EMPA REG
• Yeilded reduction in mortality, hospitalization and
adverse cardiovascular events

7. OUT LINE
• Hypothesis
• Introduction
• Objectives
• Methodology
• Statistical analysis
• Result and discussion
• Critical appraisal
• Local applicability
4/24/2023 7
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8. Background
• Sodium–glucose cotransporter 2 inhibitors reduce the
risk of hospitalization for heart failure in patients with
heart failure and a reduced ejection fraction,
• But their effects in patients with heart failure and a
preserved ejection fraction are uncertain.

9. Hypothesis:
• to demonstrate noninferiority for the primary
outcome with empagliflozin versus placebo
• superiority of placebo in outcome for pateints with
HFpEF

10. • The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure
with Preserved Ejection Fraction (EMPEROR-Preserved)
• was carried out to evaluate the effects of SGLT2 inhibition with
empagliflozin on major heart failure outcomes in patients with heart
failure and a preserved ejection fraction

11. • Data from prospective, RCTs enrolling patients with HFrEF has provided a
rich evidence base that supports the efficacy of stepped pharmacologic therapy
with neurohormonal antagonists.
• By contrast, treatment of patients with HFpEF has remained heavily
symptom-focused owing to the lack of evidence to support specific
pharmacologic therapies to modify disease progression
Introduction

12. • was a randomized, double blind, parallel-group, placebo-controlled
• multicenter, international, randomized, double-blind, placebo-
controlled trial.
• Enrollment; Between March 27, 2017, and April 13, 2020
• The final date of follow-up for data collection was April 26, 2021
Trial Design and Oversight
EMPEROR-Preserved

13. Trial Design
• Multicenter, double-blind, parallel-group, randomized, controlled trial
• N=5988
• Empagliflozin (n=2997)
• Standard (n=2991)
• Setting: 622 centers in 23 countries
• Enrollment: 2017-2020
• Median follow-up: 26.2 months
• Analysis: Intention-to-treat
• Primary outcome: Death from cardiovascular causes or hospitalization for
heart failure

14. Inclusion criteria
• All of the following criteria needed to be met:
• ≥ 18 years of age.
• Written informed consent prior to admission to the trial.
• Women of child‐bearing potential must agree to use birth control
measures with a failure rate of < 1% per year during the treatment
period of the study.
• Heart failure diagnosed ≥ 3 months before screening, and currently in
New York Heart Association class II–IV.

15. • Presence of ≥ 1 of the following:
• – Structural heart disease (left atrial enlargement and/or left ventricular hypertrophy)
documented by echocardiogram at screening
• – Hospitalisation for heart failure within previous 12 months prior to screening.
• Preserved ejection fraction, defined as left ventricular ejection fraction (LVEF)
> 40% (echocardiography) at screening per local reading and no prior
measurement of LVEF ≤ 40% under stable conditions.
• Elevated N‐terminal pro‐brain natriuretic peptide (> 300 pg/mL for patients without
atrial fibrillation; > 600 pg/mL for patients with atrial fibrillation).
• If oral diuretics are prescribed to control symptoms, the dose must have been
stable for ≥ 2 weeks prior to study entry.
• Clinically stable at randomisation with no signs of heart failure decompensation
(investigator's judgement).
Inclusion criteria

16. Exclusion criteria
• Myocardial infarction (increase in cardiac enzymes in combination with symptoms of
ischaemia or newly developed ischaemic echocardiogram changes), coronary artery
bypass graft, or other major cardiovascular surgery, stroke, or transient ischaemic
attack within 90 days prior to screening.
• Acute decompensated heart failure requiring i.v. diuretics, i.v. inotropes or i.v.
vasodilators, or left ventricular assist device within 4 weeks prior to screening and up
to baseline.
• Previous or current randomisation in another empagliflozin heart failure trial.
• Estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology creatinine
equation) < 20 mL/min/1.73 m2 or requiring dialysis.
• Type 1 diabetes.

17. • Symptomatic hypotension or systolic blood pressure (SBP)
< 100 mmHg at screening or baseline.
• SBP ≥ 180 mmHg at screening or baseline, or SBP > 160 mmHg at
both screening and baseline.
• Atrial fibrillation or atrial flutter with a resting heart rate > 110 b.p.m.
documented by echocardiogram at screening.
• Unstable angina within 30 days prior to screening.
• Largest 6MWT distance at baseline < 100 m.
• Conditions that preclude exercise testing.

18. • Patients in a structured (investigator's judgement) exercise training programme within
1 month prior to screening or planned to start one during the course of this trial.
• Heart transplant recipient or listed for heart transplant.
• Cardioverter‐defibrillator implantation within 1 month prior to screening or planned during
the course of the trial.
• Implanted cardiac resynchronisation therapy.
• Cardiomyopathy based on infiltrative diseases (e.g. amyloidosis), accumulation diseases
(e.g. haemochromatosis, Fabry disease), muscular dystrophies, cardiomyopathy with
reversible causes (e.g. stress cardiomyopathy), hypertrophic obstructive cardiomyopathy,
or known pericardial constriction.
• Any severe (obstructive or regurgitant) valvular heart disease that either represents a risk
for the conduct of the 6MWT or is expected to lead to surgery during the trial
(investigator's opinion).

19. • Chronic pulmonary disease (i.e. with known forced expiratory volume in 1 s < 50%
requiring home oxygen, or oral steroid therapy or hospitalisation for exacerbation
within 12 months, or significant chronic pulmonary disease (investigator's opinion), or
primary pulmonary arterial hypertension).
• Indication of liver disease, defined by serum levels of either alanine aminotransferase
(SGPT), aspartate aminotransferase (SGOT), or alkaline phosphatase above 3 x
upper limit of normal as determined at screening.
• Haemoglobin < 9 g/dL at screening.
• History of ketoacidosis.
• Major surgery (major according to investigator's opinion) performed within 90 days
prior to screening, or scheduled major elective surgery (e.g. hip or knee replacement)
during the course of the trial.

20. • Gastrointestinal surgery/disorder that could interfere with trial medication
absorption in the investigator's opinion.
• Any documented active or suspected malignancy or history of malignancy
within 2 years prior to screening, except appropriately treated basal cell
carcinoma of the skin or in situ carcinoma of uterine cervix or low‐risk
prostate cancer.
• Patients who must or wish to continue the intake of restricted medications or
any drug considered likely to interfere with the safe conduct of the trial.
• Current use or prior use of a sodium–glucose co‐transporter 2 (SGLT2)
inhibitor or combined SGLT1 and 2 inhibitor within 12 weeks prior to
screening or during screening period until randomisation. Discontinuation of
an SGLT2 inhibitor or combined SGLT1 and 2 inhibitor for the purposes of
study enrolment is not permitted.

21. • Treatment with i.v. iron therapy or erythropoietin within 3 months prior to screening.
• Currently enrolled in another investigational device or drug trial, or less than 30 days
since ending another investigational device or drug trial(s), or receiving other
investigational treatment(s). Patients participating in a purely observational trial will not be
excluded.
• Known allergy or hypersensitivity to empagliflozin or other SGLT2 inhibitors.
• Chronic alcohol or drug abuse or any condition that, in the investigator's opinion, makes
them an unreliable trial patient or unlikely to complete the trial.
• Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
• Any other clinical condition that would jeopardise patients safety while participating in this
trial, or may prevent the subject from adhering to the trial protocol.

22. Summary of exclusion criteria
• patients were excluded if they had a disorder that
could change their clinical course, independent of
heart failure, or if they had any condition that might
jeopardize patient safety or limit their participation in
the trial

24. Baseline Characteristic
• From the empagliflozin group.
• Demographics: Age 72 years, 45% female sex,
• 76% white race, 4% Black race, 14% Asian
• Geographical region: N America 12% , Latin America 25%, Europe 45%,
Asia 11%, other 6%
• NYHA class: I <1%, II 81%, III 18%, IV <1%
• Measurements: BMI 30 kg/m2, HR 70 BPM, SBP 132 mm Hg

25. Baseline Characteristic
• Echo details: LVEF 54%
• HFmrEF (LVEF 41 to <50%): 33%
• HFpEF, LVEF ≥50 to <60%: 34%
• HFpEF, LVEF ≥60%: 32%
• Median NT-proBNP: 994 (IQR 501-1740)
• HF type: Ischemic 36%, nonischemic 64%
• CV history: HF hospitalization in prior year 23%, AF 52%, diabetes 49%,
hypertension 91%
• eGFR: 61 mL/min/1.73 m2
• eGFR <60: 50%

28. Trial Visits and Follow-Up
• Randomized to empagliflozin 10 mg daily or placebo
• In addition to their usual optimal GDMT
• Stratified by geographic region, diabetes status, eGFR of 50, and LVEF
50%

29. Trial Visits and Follow-Up
• Patients Were Evaluated Periodically At Trial Visits For
• Symptoms,
• Health Status
• Adverse Events.
• Vital Signs,
• Body Weight,
• Glycated Hemoglobin Level,
• NT-PROBNP Level,
• eGFR,
• Uric Acid Level Were Also Assessed.

30. Primary outcome

32. Discussion
• In patients with heart failure and a preserved ejection fraction, SGLT2
inhibition with empagliflozin led to a 21% lower relative risk in the
composite of cardiovascular death or hospitalization for heart
failure, which was mainly related to a 29% lower risk of hospitalization
for heart failure with empagliflozin.
• The effects on the incidence of primary outcome events were generally
seen consistently across all prespecified subgroups, including patients
with or without diabetes.

33. Conclusion
• Empagliflozin reduced the combined risk of
cardiovascular death or hospitalization for heart
failure in patients with heart failure and a preserved
ejection fraction,
• regardless of the presence or absence of
diabetes.

34. Adverse Events
• Patients with any serious adverse event
• 47.9% vs.51.6%
• Genital infections
• 2.2 vs.0.7%
• Hypotension
• 10.4 vs.8.6%
• Symptomatic Hypotension
• 6.6% vs.5.2%
• No significant difference in rates of urinary tract infections, hypoglycemic
events, ketoacidosis, acute renal failure, or lower limb amputation between trial
arms.

35. Critical appraisal

36. Strengths/Weaknesses
⚫Strengths
 Sample size
 Study design
 Appropriate statistical analysis
 Baseline characteristics are similar
among all patients.
 Similar use of medications to
manage other health conditions
⚫Weaknesses
 Study duration,
 Africa and Asia representation
 Boehringer Ingelheim designed the
protocol and statistical analysis plan as well
as supervised the analysis of the data.
 Combined HFpEF and HFmreEF.

37. limitation
• Results cannot be extrapolated to patient populations
with other clinical characteristics.