Journal Club During Internal Medicine Rotation

1. Anna Sandler, PharmD Candidate ‘23
09.22.2022
1
BACKGROUND
Title  Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in Heart Failure
with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. Published
online August 27, 2022:NEJMoa2206286. doi:10.1056/NEJMoa2206286
Background  Heart failure (HF) is a progressive condition in which the heart is unable to
pump blood efficiently to the rest of the body.
 HF can stem from impaired cardiac contraction, or impaired ventricular
relaxation and compliance, the latter of which is typically associated with a
preserved the left ventricular ejection fraction (LVEF).
 Approximately 6 million Americans adults ≥ 20 years old have HF, and
roughly 50% have HFpEF.1
 While the incidence of HF with a reduced ejection fraction (HFrEF) has
decreased, there has been an increased incidence of HFpEF.2,3
 HFpEF leads to increased morbidity and mortality; five-year mortality may
be as high as 50%.3,4
 There are currently no mortality-benefiting therapies in HFpEF.
 With newer studies and proposed benefits5,6
, the 2022 American Heart
Association (AHA) HF guidelines2
list sodium-glucose cotransporter-2
(SGLT2) inhibitors as reasonable agents in symptomatic HFpEF (Class of
recommendation, 2a).
 Definitions by LVEF:
o HFrEF: LVEF ≤ 40%
o Heart failure with mildly reduced EF (HFmEF): LVEF 41-49%
o HFpEF: LVEF ≥ 50%
 SGLT2 inhibitor: Empagliflozin (Jardiance ® )7
o Indications: Diabetes mellitus type II (T2DM), HF
o Dosing in HF: 10 mg by mouth (PO) once daily
o Adverse effects (AEs): Hypovolemia, genitourinary (GU) fungal
infections, urinary tract infections, pyelonephritis, euglycemic
ketoacidosis, dyslipidemia
o Contraindications (CIs)/Warnings: Lower limb amputation? ,
dialysis patients, eGFR < 20 mL/min/1.73m2
o Pharmacokinetics/Pharmacodynamics (PK/PD):
 Volume of distribution (Vd): 73.8 L
 Time to peak: ~1.5 hours
 Metabolism: Mainly via glucuronidation
 Half-life elimination (t1/2): 12.4 hours
 Excretion: ~55% urine, ~41% feces
 SGLT2 inhibitor: Dapagliflozin (Farxiga ® )8
o Indications: T2DM, CKD (adjunct to first-line therapies), HFrEF,
HFpEF (off-label)
o Dosing in HF: 10 mg PO daily
o AEs: AKI, hypovolemia, GU infections, dyslipidemia,
o CIs/warnings: Dialysis patients, eGFR < 30 mL/min/1.73m2
o PK/PD:
 Bioavailability: 78%
 Time to peak: 2 hours
 Metabolism: Mainly via glucuronidation, minor CYP-
mediated metabolism

2.  t1/2: ~12.9 hours
 Excretion: ~75% urine, 21% feces
Previous trials 2019: Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction
(DAPA-HF trial9
)
 Phase three, randomized controlled trial assessing worsening HF or
cardiovascular (CV) death in patients with NYHA class II-IV HF and a
LVEF ≤ 40% treated with dapagliflozin or matching placebo.
 Primary outcome: dapagliflozin- 386 patients (16.3%); placebo-502
(21.2%); hazard ratio (HR), 0.74; 95% confidence interval (CI), 0.65-
0.85; P<0.001. Significant reductions in both hospitalizations and CV
death.
 Limitations: Exclusion of LVEF > 40%, low representation of existing
comorbidities
2021: Empagliflozin in Heart Failure with a Preserved Ejection Fraction
(EMPEROR-Preserved trial)10
 Double-blind randomized controlled trial evaluating the effect of
empagliflozin versus (vs.) matching placebo on CV death or hospitalization
for HF in patients with NYHA class II-IV HF and a LVEF >40%.
 Primary outcome: empagliflozin-415 patients (13.8%); placebo- 511
(17.1%); HR, 0.79; 95% CI, 0.69-0.90; P< 0.001.
 Limitations: Primary outcome driven by statistically significant reductions
in HF hospitalization, unknown whether benefits are consistent across
entire LVEF range11
, high discontinuation rates (23%)
Gap in Knowledge  Whether the benefits of SGLT2 inhibitors are consistent at higher LVEFs is
yet to be elucidated.
GENERAL STUDY OVERVIEW
Objective  Test whether dapagliflozin would reduce the risk of worsening HF or CV death
in patients with a mildly reduced or preserved ejection fraction
Trial design  Phase 3, international, multicenter, double-blind, randomized controlled trial
Null Hypothesis  Dapagliflozin does not reduce the risk of worsening HF and CV death among
patients with a LVEF of > 40%.
Funding Source  AstraZeneca
METHODS
Inclusion criteria  ≥ 40 years old
 NYHA class II-IV HF with symptoms ≥ 6 weeks before enrollment & at least an
intermittent need for diuretics
 LVEF > 40% and structural heart disease
 Ambulatory or hospitalized patients; off intravenous HF therapy for ≥ 12 hours
prior to enrollment
Exclusion criteria  Receipt of SGLT2 inhibitor within 4 weeks prior to randomization
 Prior intolerance to an SGLT2 inhibitor
 T1DM
 Systolic blood pressure (SBP) < 95 mmHg during first two visits
 SBP ≥ 180 mmHg
 eGFR < 25 mL/min/1.73 m2
 Myocardial infarction, unstable angina, coronary revascularization, atrial
fibrillation ablation or recent valve repair/replacement within 12 weeks prior to
enrollment
 Stroke or transient ischemic attack within 12 weeks prior to enrollment
 Severe pulmonary disease (e.g., COPD requiring home oxygen or a recent
exacerbation)
 Heart failure due to infiltrative cardiomyopathy, active myocarditis, genetic
hypertrophic cardiomyopathy
 Pregnant or breastfeeding individuals

3. Anna Sandler, PharmD Candidate ‘23
09.22.2022
3
Interventions + Control  Screening period: August 2018 – December 2020
 Patients randomized 1:1 to receive dapagliflozin 10 mg once daily or matching
placebo
 Randomization with stratification based on T2DM status
 Other medications could be continued
 Study visits: day 30, day 120, and every 120 days thereafter
 Median duration of follow-up (years): 2.3; interquartile range (IQR): 1.7-2.8
Primary + Secondary
Endpoints
Primary Endpoint:  Composite: Worsening HF or CV death
Statistical Test:  Cox proportional-hazards model stratified by
diabetes status
 Performed concurrently in the overall
population AND in patients with a LVEF <
60%
 Total significance alpha (α) split: α1= 0.038 for
LVEF < 60%; α2= 0.024 for overall population
Secondary
Endpoint(s):
 Change from baseline in total symptom score on
the Kansa City Cardiomyopathy Questionnaire
(KCCQ) at month 8
o Minimally clinically important difference:
5 points12
 CV death
 Death from any cause
Statistical Test:  KCCQ: Descriptive statistics
Safety Endpoint(s) Endpoint:  Amputations
 Diabetic ketoacidosis
 Hypoglycemic events
 Renal adverse events (AEs)
 Fourier’s Gangrene
Statistical Test:  Descriptive statistics
Additional Statistical
Analyses
 All efficacy analyses completed in the intention-to-treat (ITT) population
 Testing for significance was done in a hierarchical fashion from the primary
outcome to the secondary outcomes
 Power analysis: 6100 patients 1117 events & 93% power 20% risk
reduction in worsening HF or CV death
RESULTS
Total enrollment  Overall population: n= 6263; dapagliflozin: n=3131; placebo; n=3132
 LVEF < 60%: n=4372; dapagliflozin: n=2200; placebo: n=2172
 Total discontinuation rate: 14%
Baseline characteristics
(overall population)
 Groups well-balanced
 Mean age (years): ~72
 Female (%): ~43-44
 Asian (%): ~20
 Black (%): ~2
 White (%): ~71
 North America (%): ~14
 Latin America (%): ~19
 Europe or Saudi Arabia (%): ~48

4.  NYHA II (%): ~75
 NYHA III (%): ~25
 NYHA IV (%): 0.3
 LVEF ≤ 49: ~34%
 LVEF 50-59: ~36%
 LVEF ≥ 60: ~30%
 Prior LVEF ≤ 40: ~19%
 T2DM (%): ~45
 Hypertension (%): ~89%
 Prior hospitalization for HF (%) ~41%
 History and baseline ECG atrial fibrillation or flutter (%): ~56 and ~42
respectively
 Loop diuretic (%): ~77
 Beta-blocker (%): ~83
 Mineralocorticoid receptor antagonist (%): ~43
 ACE inhibitor (%): ~37
 Angiotensin receptor blocker (%): ~37
 Mean eGFR (mL/min/1.73 m2
) (+/- standard deviation): 61 +/- 19
Primary Outcome:
Worsening HF or CV death
no. events, (%)
 Overall population: Dapagliflozin: 512 (16.4); placebo: 610 (19.5); HR 0.82,
95% CI 0.73-0.92; P< 0.001 Number needed to treat (NNT) ~ 33
 LVEF < 60%: HR 0.83, 95% CI 0.73-0.95; P=0.009, NNT ~34
Secondary Outcome:
Worsening HF no. events,
(%)
 Overall population: Dapagliflozin: 368 (11.8); placebo: 455 (14.5); HR 0.79,
95% CI 0.69-0.91; NNT ~38
 LVEF < 60%: HR 0.77, 95% CI 0.66-0.91; NNT ~33
Secondary Outcome: CV
death no. events, (%)
 Overall population: Dapagliflozin: 231 (7.4); placebo: 261 (8.3); HR 0.88, 95%
CI 0.74-1.05
 LVEF < 60%: HR, 0.95; 95% CI 0.78-1.16
Secondary Outcome:
Change KCCQ total score
 Overall population: Mean score change at month 8: 2.4, 95% CI 1.5-3.4
Safety/AEs  Dapagliflozin: n- 3126; placebo: n=3127
 Adverse events (AEs) similar between two groups
 Any serious AE (%): ~44-46
 AEs leading to discontinuation (%): ~6
 AE leading to interruption of treatment (%): ~14-15
 Any amputation (%): 0.6-0.8
 Probable or definite diabetic ketoacidosis (%): dapagliflozin-0.1; placebo- 0
 Major hypoglycemic event (%): 0.2
AUTHORS’ CONCLUSIONS
Dapagliflozin resulted in a lower risk of worsening HF or CV death than placebo. There was no appreciable
difference in benefits between patients with a LVEF ≥ 60% and those with a LVEF of < 60%, or in other
subgroups. The incidence of AEs was similar to that observed in the placebo group. The trial was not powered to
assess the effect of dapagliflozin on CV death alone and had specific inclusion and exclusion criteria that limited
generalizability of the findings. Data support use of an SGLT2 inhibitor in patients with HF, regardless of LVEF.
CRITIQUE/DISCUSSION
Patient Population Strengths:  Large number
 International trial
 Inclusion of patients hospitalized for HF
 Inclusion of patients who previously had a LVEF <40%
 Larger representation of NYHA III patients

5. Anna Sandler, PharmD Candidate ‘23
09.22.2022
5
Limitations:  Less representations of lower eGFRs
 Exclusion of patients with recent (within 12 weeks) acute
coronary syndromes (e.g., coronary revascularization,
stroke) and those with higher BMIs
Intervention Strengths:  Quadruple-blinded
 Randomization with stratification by diabetes status
Limitations:  Did not stratify by region or eGFR, which the EMPEROR-
preserved trial did
Endpoints Strengths:  Clinically meaningful endpoints consistent with prior trials
Limitations:  Underpowered to detect mortality benefits
Statistics Strengths:  Analyses conducted in the ITT population
 Implementation of a dual primary analysis
 Use of hierarchical testing
 Sensitivity analysis to account for COVID-19 as a
competing risk for non-CV death
Limitations:  Did not analyze the primary outcome in those with a
LVEF ≥ 60% (Only subgroup analysis)
CONCLUSION AND RECOMMENDATIONS
Presenter’s Discussion and
Conclusion
The results in the DELIVER trial confirmed previous hospitalization and symptom
improvement benefits revealed in EMPEROR-preserved, and the benefits were
consistent in patients with an ejection fraction of less than 60%. The DELIVER trial
was a well-designed trial that had a more inclusive population, including
hospitalized patients and more patients with NYHA class III HF. Moreover, this
trial was unique in that it employed a dual primary analysis to compare treatment
effects between the overall population and patients with an ejection fraction less
than 60%. Noteworthy limitations include being underpowered to detect mortality
benefits and the fact that results were not analyzed in patients with an ejection
fraction of 60% or greater. Nevertheless, the benefits from this trial are clinically
important as hospitalization is a main driver of mortality in the disease. 13,14
Improvement in symptoms as noted by the KCCQ score results is equally
informative; poor quality of life has been linked to high hospitalization and
mortality rates.15
In the future it would be worth studying the long-term effects
SGLT2 inhibitors with longer follow-up times.
Application to Patient Care SGLT2 inhibitors may be appropriate to initiate in hospitalized patients with
HFmEF, or HFpEF, but may also be initiated after discharge. Hypotension is often a
limiting factor for initiating any blood pressure reduction therapies shortly after
admission for acute decompensated heart failure, and initiation with a less potent
agent such as an SGLT2 inhibitor may therefore be added inpatient for early
benefits.

6. References:
1. Virani SS, Alonso A, Aparicio HJ, et al. Heart Disease and Stroke Statistics—2021 Update: A Report From the
American Heart Association. Circulation. 2021;143(8). doi:10.1161/CIR.0000000000000950
2. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart
Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on
Clinical Practice Guidelines. Circulation. 2022;145(18). doi:10.1161/CIR.0000000000001063
3. Zhou L, Guo Z, Wang B, et al. Risk Prediction in Patients With Heart Failure With Preserved Ejection Fraction
Using Gene Expression Data and Machine Learning. Front Genet. 2021;12:652315.
doi:10.3389/fgene.2021.652315
4. Shah KS, Xu H, Matsouaka RA, et al. Heart Failure With Preserved, Borderline, and Reduced Ejection
Fraction. J Am Coll Cardiol. 2017;70(20):2476-2486. doi:10.1016/j.jacc.2017.08.074
5. Lopaschuk GD, Verma S. Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2
(SGLT2) Inhibitors: A State-of-the-Art Review. JACC Basic Transl Sci. 2020;5(6):632-644.
doi:10.1016/j.jacbts.2020.02.004
6. Joshi SS, Singh T, Newby DE, Singh J. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of
action in heart failure. Heart. 2021;107(13):1032-1038. doi:10.1136/heartjnl-2020-318060
7. Product Information: JARDIANCE(R) oral tablets, empagliflozin oral tablets. Published online 2022.
8. Product Information: FARXIGA(R) oral tablets, dapagliflozin oral tablets. Published online 2020.
9. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced
Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008. doi:10.1056/NEJMoa1911303
10. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N
Engl J Med. 2021;385(16):1451-1461. doi:10.1056/NEJMoa2107038
11. Butler J, Packer M, Filippatos G, et al. Effect of empagliflozin in patients with heart failure across the spectrum
of left ventricular ejection fraction. Eur Heart J. 2022;43(5):416-426. doi:10.1093/eurheartj/ehab798
12. Spertus JA, Jones PG, Sandhu AT, Arnold SV. Interpreting the Kansas City Cardiomyopathy Questionnaire in
Clinical Trials and Clinical Care. J Am Coll Cardiol. 2020;76(20):2379-2390. doi:10.1016/j.jacc.2020.09.542
13. Nanayakkara S, Patel HC, Kaye DM. Hospitalisation in Patients With Heart Failure With Preserved Ejection
Fraction. Clin Med Insights Cardiol. 2018;12:117954681775160. doi:10.1177/1179546817751609
14. Setoguchi S, Stevenson LW, Schneeweiss S. Repeated hospitalizations predict mortality in the community
population with heart failure. Am Heart J. 2007;154(2):260-266. doi:10.1016/j.ahj.2007.01.041
15. Heo S, Lennie TA, Okoli C, Moser DK. Quality of life in patients with heart failure: ask the patients. Heart
Lung J Crit Care. 2009;38(2):100-108. doi:10.1016/j.hrtlng.2008.04.002