JACC: HEART FAILURE VOL. -, NO.

-, 2023
ª 2023 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

SGLT2 Inhibitor Use and Risk of Clinical

Events in Patients With Cancer
Therapy–Related Cardiac Dysfunction
Vennela Avula, BSPH,a Garima Sharma, MD,b Mikhail N. Kosiborod, MD,c,d Muthiah Vaduganathan, MD,e
Tomas G. Neilan, MD,f Teresa Lopez, MD,g Susan Dent, MD,h Lauren Baldassarre, MD,i
Marielle Scherrer-Crosbie, MD,j Ana Barac, MD,k Jennifer Liu, MD,l Anita Deswal, MD, MPH,m Sumanth Khadke, MD,n
Eric H. Yang, MD,o Bonnie Ky, MD,j Daniel Lenihan, MD,p,q Anju Nohria, MD,r Sourbha S. Dani, MD, MSC,n
Sarju Ganatra, MDn

ABSTRACT

BACKGROUND Certain antineoplastic therapies are associated with an increased risk of cardiomyopathy and heart
failure (HF). Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in patients with HF.

OBJECTIVES This study aims to examine the efficacy of SGLT2 inhibitors in patients with cancer therapy–related cardiac
dysfunction (CTRCD) or HF.

METHODS The authors conducted a retrospective cohort analysis of deidentified, aggregate patient data from the
TriNetX research network. Patients aged $18 years with a history of type 2 diabetes mellitus, cancer, and exposure to
potentially cardiotoxic antineoplastic therapies, with a subsequent diagnosis of cardiomyopathy or HF between January 1,
2013, and April 30, 2020, were identified. Patients with ischemic heart disease were excluded. Patients receiving
guideline-directed medical therapy were divided into 2 groups based on SGLT2 inhibitor use. After propensity score
matching, odds ratios (ORs) and Cox proportional HRs were used to compare outcomes over a 2-year follow-up period.

RESULTS The study cohort included 1,280 patients with CTRCD/HF (n ¼ 640 per group; mean age: 67.6 years; 41.6%
female; 68% White). Patients on SGLT2 inhibitors in addition to conventional guideline-directed medical therapy had a
lower risk of acute HF exacerbation (OR: 0.483 [95% CI: 0.36-0.65]; P < 0.001) and all-cause mortality (OR: 0.296
[95% CI: 0.22-0.40]; P ¼ 0.001). All-cause hospitalizations or emergency department visits (OR: 0.479; 95% CI: 0.383-
0.599; P < 0.001), atrial fibrillation/flutter (OR: 0.397 [95% CI: 0.213-0.737]; P ¼ 0.003), acute kidney injury (OR:
0.486 [95% CI: 0.382-0.619]; P < 0.001), and need for renal replacement therapy (OR: 0.398 [95% CI: 0.189-0.839];
P ¼ 0.012) were also less frequent in patients on SGLT2 inhibitors.

CONCLUSIONS SGLT2 inhibitor use is associated with improved outcomes in patients with CTRCD/HF.
(J Am Coll Cardiol HF 2023;-:-–-) © 2023 by the American College of Cardiology Foundation.

From the aJohns Hopkins School of Medicine, Baltimore, Maryland, USA; bDivision of Cardiology, Johns Hopkins School of
Medicine, Baltimore, Maryland, USA; cSaint Luke’s Mid America Heart Institute, Kansas City, Missouri, USA; dUniversity of
Missouri, Kansas City, Missouri, USA; eBrigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School,
Boston, Massachusetts, USA; fCardio-Oncology Program, Division of Cardiology, Massachusetts General Hospital, Boston, Mas-
sachusetts, USA; gDepartment of Cardiology, La Paz University Hospital, Madrid, Spain; hDuke Cancer Institute, Department of
Medicine, Duke University, Durham, North Carolina, USA; iSection of Cardiovascular Medicine, Yale School of Medicine, New
Haven, Connecticut, USA; jDivision of Cardiology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsyl-
vania, USA; kCardio-Oncology Program, Division of Cardiology, MedStar Washington Hospital Center, Washington, DC, USA;
l
Cardio-Oncology Program, Memorial Sloan Kettering Cancer Center, New York City, New York, USA; mDepartment of Cardiology,
University of Texas MD Anderson Cancer Center, Houston, Texas, USA; nCardio-Oncology Program, Division of Cardiovascular
Medicine, Department of Medicine, Lahey Hospital and Medical Center, Beth Israel Lahey Health, Burlington, Massachusetts,
USA; oCardio-Oncology Program, Division of Cardiology, Department of Medicine, University of California at Los Angeles, Los
Angeles, California, USA; pInternational Cardio-Oncology Society, Tampa, Florida, USA; qSt. Francis Healthcare, Cape Girardeau,
Missouri, USA; and the rCardio-Oncology Program, Division of Cardiovascular Medicine, Department of Medicine, Brigham and
Women’s Hospital, Boston, Massachusetts, USA.
Deepak Bhatt, MD, served as Guest Associate Editor for this paper. Barry Greenberg, MD, served as Guest Editor-in-Chief for this
paper.

ISSN 2213-1779/$36.00 https://doi.org/10.1016/j.jchf.2023.08.026

2 Avula et al JACC: HEART FAILURE VOL. -, NO. -, 2023
SGLT2 Inhibitor for Cancer Therapy–Related Cardiac Dysfunction - 2023:-–-

S
ABBREVIATIONS odium-glucose cotransporter-2 Recent animal and in vitro studies have shown the
AND ACRONYMS (SGLT2) inhibitors have been shown cardioprotective effects of SGLT2 inhibitors in the
to be beneficial in patients with heart setting of cancer therapy–induced cardiotoxicity. For
CTRCD = cancer therapy–
related cardiac dysfunction
failure (HF), independent of diabetes status example, dapagliflozin significantly increased car-
and left ventricular ejection fraction diomyocyte viability in a study of HL-1 adult car-
CV = cardiovascular
(LVEF).1 Dapagliflozin and Prevention of diomyocytes exposed to subclinical concentrations of
ED = emergency department
Adverse Outcomes in Heart Failure (DAPA- doxorubicin and trastuzumab.12 In a nondiabetic
GDMT = guideline-directed
medical therapy
HF) and Empagliflozin Outcome Trial in mouse model, empagliflozin increased systolic and
Patients with Chroniic Heart Failure and a diastolic LV function and decreased myocardial
HF = heart failure
Reduced Ejection Fraction (EMPEROR- fibrosis by 50% in mice with doxorubicin cardiotox-
LV = left ventricular
Reduced) demonstrated that SGLT2 inhibi- icity.13 Empagliflozin was also shown to ameliorate
LVEF = left ventricular ejection
fraction
tors reduce the risk of cardiovascular (CV) sunitinib-induced cardiac dysfunction by reducing
death or hospitalization for HF in patients systolic blood pressure and improving LVEF via regu-
PSM = propensity score
matching with heart failure with reduced ejection frac- lation of adenosine 5 0 -monophosphate–activated pro-
2,3
SGLT2 = sodium-glucose tion (HFrEF). Subsequently, data from tein kinase–mammalian target of rapamycin (AMPK-
cotransporter-2 Empagliflozin Outcome Trial in Patients mTOR) signaling–mediated autophagy. 14,15 However,
T2DM = type 2 diabetes with Chronic Heart Failure with Preserved whether the benefits observed in animal and in vitro
mellitus Ejection Fraction (EMPEROR-Preserved) and studies are seen in clinical practice remains unclear.
Dapagliflozin Evaluation to Improve the Lives of Pa- This retrospective cohort study aimed to examine
tients with Preserved Ejection Fraction Heart Failure the efficacy of SGLT2 inhibitors in patients with
(DELIVER) have suggested that SGLT2 inhibitors CTRCD/HF.
are also beneficial in patients with heart failure
METHODS
with preserved ejection fraction (HFpEF).4,5 As a
result, the updated 2022 American College of Cardi-
STUDY OVERSIGHT. Data were analyzed and inter-
ology, American Heart Association, and
preted by the authors. All authors reviewed the
Heart Failure Society of America clinical practice
manuscript and affirmed the accuracy and complete-
guidelines and the 2021 European Society of Cardi-
ness of the data. Institutional Review Board approval
ology recommend the use of SGLT2 inhibitors as
was exempted by the Lahey Clinic Institutional Review
part of guideline-directed medical therapy (GDMT)
Board, given that aggregate deidentified data were
for HFrEF, heart failure with midrange ejection frac-
used from a research network database. These study
tion (HFmrEF), and HFpEF.6,7 In addition, SGLT2 in-
findings are reported per the Strengthening the
hibitors have also been shown to have significant
Reporting of Observational Studies in Epidemiology
renal protective effects, which may contribute to
(STROBE) guideline for cohort studies.
their efficacy in patients with HF. 8
HF is a significant and common cardiotoxicity DATA SOURCE. The data analyzed in this study were

among patients receiving certain antineoplastic obtained from the TriNetX research network, which
therapies. 9,10 For example, low-dose anthracyclines contains data from the electronic health records of
have been associated with a 2% to 4% incidence of approximately 90 million patients from 72 health care
clinical HF decompensation, 9% to 11% subclinical organizations, primarily in the United States. This
change identified on cardiac imaging, and 30% to 35% platform only has aggregate, deidentified data per the
for cardiac injury defined as biomarker increase.11 deidentification standard defined in section
Although SGLT2 inhibitors have demonstrated effi- x164.514(a) of the Health Insurance Portability and
cacy in the treatment of patients with ischemic and Accountability Act Privacy Rule.
nonischemic cardiomyopathy and HF, patients with STUDY POPULATION AND DESIGN. Patients
cancer are usually excluded from pivotal clinical tri- aged $18 years with type 2 diabetes mellitus (T2DM)
als. Hence, the efficacy of SGLT2 inhibitors remains with a history of cancer and exposure to potentially
understudied in patients with cancer therapy–related cardiotoxic antineoplastic therapies and with a sub-
cardiac dysfunction (CTRCD)/HF. sequent diagnosis of cardiomyopathy or HF between

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received November 29, 2022; revised manuscript received July 10, 2023, accepted August 28, 2023.
JACC: HEART FAILURE VOL. -, NO. -, 2023 Avula et al 3
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January 1, 2013, and April 30, 2020, were identified. chi-square test. Covariates were matched extensively
Patients on antineoplastic therapies consisting of by 1:1 PSM using the greedy nearest-neighbor algo-
either anthracyclines, alkylating agents, antimetabo- rithm with a caliper of 0.1 pooled standardized mean
lites, monoclonal antibodies, small-molecule tyrosine difference (SMD). The standardized mean difference
kinase inhibitors, or proteasome inhibitors were is a quantitative method used to represent the dif-
included (Supplemental Table 1). These medications ference between the means of 2 groups in terms of SD
were selected based on prior studies demonstrating units to assess the balance in measured variables in
their potential for cardiotoxicity.16 Patients with a the sample weighted by the inverse probability of
diagnosis of an acute coronary syndrome (acute treatment. Any characteristic with a between cohorts
myocardial infarction, ST-segment elevation lower than 0.1 was considered well matched. The
myocardial infarction, or non–ST-elevation myocar- measures of association included risk differences,
dial infarction), coronary artery bypass graft, or risk ratios, and odds ratios (ORs) on the matched
percutaneous coronary intervention after starting population for primary and secondary outcomes.
antineoplastic therapy were excluded. Identification Survival analyses were performed for each outcome
of a history of cancer was made using International by plotting Kaplan-Meier curves with log-rank tests;
Classification of Diseases-9th Revision (ICD-9) and additionally, Cox proportional hazard models were
International Classification of Diseases-10th Revision used to calculate the HR to compare the 2 groups.
(ICD-10) codes (Supplemental Methods). HF was Death was treated as a censoring event. Statistical
defined as an ICD-10 code of either HF or cardiomy- significance was set at a 2-sided value of P < 0.05. E
opathy or an LVEF of # 40%. Patients were further values were calculated for the primary and secondary
divided into 2 groups based on whether they were outcomes to address the unmeasured confounders.
prescribed SGLT2 inhibitors (dapagliflozin, empagli- Statistical analyses were completed using the TriNetX
flozin, or canagliflozin) or not. The non–SGLT2 in- online platform using R for statistical computing.
hibitor group was defined as those who received
RESULTS
contemporary HF medications, one from each class
of: 1) angiotensin-converting enzyme inhibitors,
STUDY POPULATION. We identified a total of 6,988
angiotensin receptor blockers, or angiotensin
patients who had developed cardiomyopathy or HF
receptor-neprilysin inhibitors; 2) beta-blockers; and
after receiving antineoplastic therapy for cancer; 654
3) mineralocorticoid receptor antagonists. The SGLT2
patients were on SGLT2 inhibitors, and 6,334 patients
inhibitor group was defined as those who received
were not on SGLT2 inhibitors (Figure 1). After PSM,
SGLT2 inhibitors in addition to other contemporary
640 matched patients remained in each cohort and
HF medications. Propensity score matching (PSM)
were included in this analysis (Figure 1).
was performed to reduce bias caused by unequal
distribution of baseline characteristics, treatment ef- PATIENT CHARACTERISTICS. Baseline patient char-

fect bias, and confounding. acteristics are summarized in Table 1. In the un-
matched cohort, patients treated with SGLT2
STUDY ENDPOINTS. Primary and secondary out-
inhibitors were more likely to be male (58.6 vs 53.2%;
comes were analyzed over a 2-year follow-up period. P < 0.05) and Hispanic (8.77 vs 5.1%; P < 0.05)
The primary outcomes of interest included HF exac- compared to those not on SGLT2 inhibitors. Further-
erbations (defined by ICD-10 codes or the need for more, patients on SGLT2 inhibitors had a higher
intravenous loop diuretics) and all-cause mortality. prevalence of hypertension, diabetes mellitus,
Other secondary outcomes included all-cause hospi- chronic kidney disease, and ischemic heart disease.
talizations or emergency department (ED) visits, However, after PSM, the baseline characteristics of
atrial fibrillation and flutter, acute kidney injury, and the 2 groups were similar. Additionally, we balanced
the need for renal replacement therapy. In addition, the population based on health care use, ie, all-cause
gastrointestinal bleeding was used as a falsifica- hospitalization and ED visits in the prior year of the
tion outcome. index event of HF/cardiomyopathy. We found no re-
STATISTICAL ANALYSIS. The patient population was sidual imbalance (standard difference: <0.1 for all
divided into 2 groups according to their use of SGLT2 covariates) (Figure 2).
inhibitors. Continuous variables are represented as Hematologic cancer was most common, followed
mean  SD and were compared between the groups by the gastrointestinal system and breast cancer. Of
using independent-samples Student’s t-tests. Cate- the total, 30% of patients had metastatic disease.
gorical variables are reported as count (percentage) Fluorouracil was the most commonly used antineo-
and were compared between the groups using the plastic therapy, followed by bevacizumab and
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F I G U R E 1 Study Consort Diagram

Consort diagram depicting inclusion and exclusion criteria. ACE ¼ angiotensin-converting enzyme; AMI ¼ acute myocardial infarction;
ARB ¼ angiotensin receptor blocker; ARNI ¼ angiotensin receptor-neprilysin inhibitor; BB ¼ beta-blocker; CABG ¼ coronary artery bypass
graft; DM ¼ diabetes mellitus; HF ¼ heart failure; LVEF ¼ left ventricular ejection fraction; MRA ¼ mineralocorticoid receptor antagonist;
NSTEMI ¼ non–ST-segment elevation myocardial infarction; PCI ¼ percutaneous coronary intervention; SGLT2 ¼ sodium-glucose cotrans-
porter-2; STEMI ¼ ST-segment elevation myocardial infarction.
JACC: HEART FAILURE VOL. -, NO. -, 2023 Avula et al 5
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T A B L E 1 Baseline Characteristics of the Study Cohort Before and After Propensity Score Matching Based on SGLT2 Inhibitor Treatment

Before Propensity Score Matching After Propensity Score Matching

SGLT2 Inhibitor SGLT2 Inhibitor

Yes No Standardized Yes No Standardized

(n ¼ 654) (n ¼ 6,334) Mean Difference (n ¼ 640) (n ¼ 640) Mean Difference

Demographics
Age, y 67.5  10.8 68.9  13.0 0.116 67.6  10.8 67.6  11.6 0.006
Female 271 (41.4) 2,966 (46.8) 0.109 266 (41.6) 266 (41.6) 0
White 448 (68.5) 4,469 (70.6) 0.045 438 (68.4) 432 (67.5) 0.020
Hispanic 57 (8.7) 320 (5.1) 0.145 57 (8.9) 67 (10.5) 0.053
Comorbidities
Hypertension 625 (95.6) 5,709 (90.1) 0.212 611 (95.5) 604 (94.4) 0.050
Hyperlipidemia 570 (87.2) 4,536 (71.6) 0.391 556 (86.9) 552 (86.3) 0.018
Atrial fibrillation/flutter 304 (46.5) 2,948 (46.5) 0.001 299 (46.7) 284 (44.4) 0.047
Chronic kidney disease 359 (54.9) 2,861 (45.2) 0.195 346 (54.1) 317 (49.5) 0.091
Medications
Antiarrhythmics 579 (88.5) 5,252 (82.9) 0.161 565 (88.3) 567 (88.6) 0.010
Antilipemic agents 574 (87.8) 4,612 (72.8) 0.383 560 (87.5) 551 (86.1) 0.042
Insulin 465 (71.1) 2,936 (46.4) 0.519 451 (70.5) 459 (71.7) 0.028
Exenatide 53 (8.1) 56 (0.9) 0.354 41 (6.6) 41 (6.4) 0.006
Metformin 384 (58.7) 1,526 (23.9) 0.755 370 (57.8) 370 (57.8) <0.001
Glipizide 148 (22.6) 592 (9.3) 0.369 140 (21.9) 153 (23.9) 0.048
Type of malignancy
Breast 100 (15.3) 1,027 (16.2) 0.025 96 (15) 103 (16.1) 0.30
Lymphomas 164 (24.3) 1,729 (27.3) 0.055 158 (24.7) 156 (24.4) 0.004
Myelodysplastic syndromes 256 (39.1) 2,351 (37.1) 0.042 254 (39.7) 220 (34.4) 0.110
Genitourinary 40 (6.1) 498 (7.9) 0.069 40 (6.3) 35 (5.5) 0.033
Gastrointestinal 117 (17.9) 1,365 (21.6) 0.092 114 (17.8) 139 (21.7) 0.098
Gynecologic 23 (3.5) 210 (3.3) 0.011 21 (3.3) 20 (3.1) 0.009
Respiratory and intrathoracic organs 35 (5.4) 364 (5.7) 0.017 35 (5.5) 31 (4.8) 0.028
Mesothelial and soft tissue 13 (2.0) 217 (3.4) 0.089 13 (2.0) 15 (2.3) 0.021
Neoplasms of unspecified behavior 139 (21.3) 1,249 (19.7) 0.038 138 (21.6) 141 (22.0) 0.011
Metastatic malignancy 197 (30.1) 2,228 (35.2) 0.108 192 (30) 190 (29.7) 0.007
Continued on the next page

cyclophosphamide. Anthracyclines were used in P ¼ 0.003), acute kidney injury (OR: 0.486 [95% CI:
w19% of patients. Radiation therapy was given to 11% 0.382-0.619]; P < 0.001), and renal replacement
of patients. Many patients may have received com- therapy (OR: 0.398 [95% CI: 0.189-0.839]; P ¼ 0.012)
bination therapies. The timeline of cancer diagnosis all occurred less frequently among patients on SGLT2
to cardiomyopathy or HF development and the cancer inhibitors (Table 2). There was also a decreased
status are poorly understood. instantaneous risk of adverse outcomes based on
MAIN OUTCOMES. A total of 85 patients in the SGLT2 time-to-event survival analysis (Table 3). Addition-
inhibitor group experienced an HF exacerbation ally, for safety outcomes, urinary tract infections
compared to 154 patients in the non-SGLT2 inhibitor were less frequent among patients on SGLT2 in-
group (OR: 0.483 [95% CI: 0.361-0.647]; P ¼ 0.001) hibitors (OR: 0.517 [95% CI: 0.368-0.727]; P < 0.001),
(Table 2, Figure 2). In addition, there were 73 deaths in and the frequency of lower extremity amputations
the SGLT2 inhibitor group compared to 194 deaths in was similar in both groups (OR: 1.000 [95% CI: 0.413-
the non-SGLT2 inhibitor group (OR: 0.296 [95% CI: 2.419]; P > 0.999) (Table 4).
0.220-0.398]; P < 0.001) (Table 2). The time-to-event FALSIFICATION OUTCOME AND SENSITIVITY ANALYSIS.
analysis also demonstrated the benefits of SGLT2 in- The incidence of gastrointestinal bleeding in patients
hibitor therapy in patients with CTRCD (Table 3, with an without SGLT2 inhibitors is 8 and 12,
Figure 3). respectively (OR: 0.527 [95% CI: 0.22-1.253]; P ¼ 0.15).
SECONDARY OUTCOMES. The secondary outcomes Furthermore, sensitivity analysis using the measure-
of all-cause hospitalizations or ED visits (OR: 0.479 ment of the E value for primary and secondary out-
[95% CI: 0.383-0.599]; P < 0.001), atrial fibrillation comes (Tables 2, 3, and 4) ruled out significant
and flutter (OR: 0.397 [95% CI: 0.213-0.737]; confounding.
6 Avula et al JACC: HEART FAILURE VOL. -, NO. -, 2023
SGLT2 Inhibitor for Cancer Therapy–Related Cardiac Dysfunction - 2023:-–-

T A B L E 1 Continued

Before Propensity Score Matching After Propensity Score Matching

SGLT2 Inhibitor SGLT2 Inhibitor

Yes No Standardized Yes No Standardized

(n ¼ 654) (n ¼ 6,334) Mean Difference (n ¼ 640) (n ¼ 640) Mean Difference

Antineoplastic therapy
Alkylating agents
Ifosfamide 10 (1.5) 35 (0.6) 0.096 10 (1.6) 10 (1.6) <0.001
Cyclophosphamide 142 (21.7) 1,470 (23.2) 0.036 135 (21.2) 143 (22.3) 0.030
Mitomycin 28 (4.3) 333 (5.3) 0.046 27 (4.2) 21 (3.3) 0.049
Carboplatin 20 (3.1) 273 (4.3) 0.066 20 (3.1) 13 (2.0) 0.069
Cisplatin 13 (2.0) 144 (2.3) 0.020 13 (2.0) 12 (1.9) 0.011
Anthracenediones
Mitoxantrone 10 (1.5) 35 (0.6) 0.096 10 (1.6) 10 (1.6) <0.001
Anthracyclines
Idarubicin 10 (1.5) 74 (1.2) 0.031 10 (1.6) 10 (1.6) <0.001
Doxorubicin 98 (15.0) 915 (14.4) 0.015 92 (14.4) 103 (16.1) 0.048
Doxorubicin liposomal 10 (1.5) 56 (0.9) 0.059 10 (1.6) 10 (1.6) <0.001
Daunorubicin 10 (1.5) 93 (1.5) 0.005 10 (1.6) 10 (1.6) <0.001
Antimetabolites
Fluorouracil 231 (35.3) 2,129 (33.6) 0.036 227 (35.5) 225 (35.2) 0.007
Capecitabine 36 (5.5) 200 (6.3) 0.034 36 (5.6) 28 (4.4) 0.057
Aromatase inhibitor
Anastrozole 46 (7.0) 292 (4.6) 0.104 44 (6.9) 48 (7.5) 0.024
Monoclonal antibodies
Pertuzumab 12 (1.8) 126 (2.0) 0.011 11 (1.7) 12 (1.9) 0.012
Trastuzumab 20 (3.1) 297 (4.7) 0.085 19 (3.0) 18 (2.8) 0.009
Bevacizumab 134 (20.5) 782 (12.3) 0.221 131 (20.5) 136 (21.3) 0.019
Rituximab 51 (7.8) 475 (7.5) 0.011 48 (7.5) 54 (8.4) 0.035
Alemtuzumab 10 (1.5) 22 (0.3) 0.123 10 (1.6) 10 (1.6) <0.001
Proteosome inhibitors
Carfilzomib 10 (1.5) 97 (1.5) <0.001 10 (1.6) 10 (1.6) <0.001
Bortezomib 34 (5.2) 508 (8.0) 0.114 34 (5.3) 31 (4.8) 0.021
Small-molecule TKIs
Cabozantinib 10 (1.5) 39 (0.6) 0.089 10 (1.6) 10 (1.6) <0.001
Nilotinib 10 (1.5) 56 (0.9) 0.059 10 (1.6) 11 (1.7) 0.012
Sorafenib 10 (1.5) 130 (2.1) 0.039 10 (1.6) 10 (1.6) <0.001
Imatinib 24 (3.7) 162 (2.6) 0.064 23 (3.6) 20 (3.1) 0.026
Osimertinib 10 (1.5) 26 (0.4) 0.114 10 (1.6) 10 (1.6) <0.001
Ibrutinib 15 (2.3) 187 (3.0) 0.041 15 (2.3) 16 (2.5) 0.010
Trametinib 10 (1.5) 52 (0.8) 0.066 10 (1.6) 10 (1.6) <0.001
Pazopanib 10 (1.5) 85 (1.3) 0.016 10 (1.6) 10 (1.6) <0.001
Ponatinib 10 (1.5) 22 (0.3) 0.123 10 (1.6) 10 (1.6) <0.001
Lapatinib 10 (1.5) 25 (0.4) 0.116 10 (1.6) 10 (1.6) <0.001
Radiation therapy 77 (11.8) 523 (8.3) 0.117 72 (11.3) 74 (11.6) 0.010
Laboratory data
Creatinine, mg/dL 1.4  3.7 1.4  1.9 0.009 1.4  3.7 1.4  1.6 0.012
BMI, kg/m2 32.9  7.6 30.1  7.1 0.385 32.7  7.5 32.0  7.5 0.099
LVEF # 40% 144 (22.0) 758 (12.0) 0.270 138 (21.6) 127 (19.8) 0.042
HbA1c $7% 244 (37.3) 950 (15) 0.525 226 (35.3) 229 (35.8) 0.011
Health care use in the prior year
Hospitalization 225 (34.4) 2,732 (43) 0.176 224 (35) 219 (34.3) 0.013
Emergency department visit 278 (42.5) 2,869 (45.3) 0.058 271 (42.3) 263 (41.1) 0.023

Values are n (%) or mean  SD.

BMI ¼ body mass index; HbA1c ¼ glycosylated hemoglobin; LVEF ¼ left ventricular ejection fraction; SGLT2 ¼ sodium-glucose cotransporter-2; TKI ¼ tyrosine kinase inhibitor.
JACC: HEART FAILURE VOL. -, NO. -, 2023 Avula et al 7
- 2023:-–- SGLT2 Inhibitor for Cancer Therapy–Related Cardiac Dysfunction

F I G U R E 2 Propensity Score Matching

This figure demonstrates the cohorts before and after propensity matching.

DISCUSSION The results of the present study built upon a recent

smaller study evaluating CV events in patients with
Our study demonstrates that in patients with T2DM diabetes and cancer who were on an SGLT2 inhibitor
and CTRCD, the use of SGLT2 inhibitors, in addition (n ¼ 32) while receiving anthracyclines compared to
to other contemporary GDMT, reduced HF exacer- control individuals (n ¼ 96).15 Gongora et al15 found
bations and all-cause mortality during a 2-year that the incidence of CV events, including new car-
follow-up period (Central Illustration). Supported diomyopathy, HF hospitalizations, and significant
by the recent guidelines recommending SGLT2 in- arrhythmias, was significantly reduced in patients
hibitors as GDMT for HF, this study demonstrates treated with SGLT2 inhibitors compared to those who
that SGLT2 inhibitors should be considered for pa- were not (3% vs 20%; P ¼ 0.025). These 2 studies
tients with CTRCD. 6 This study also demonstrates suggest that SGLT2 inhibitors may have a car-
that all-cause hospitalizations or ED visits, atrial dioprotective role in patients receiving potentially
fibrillation and flutter, acute kidney injury, and the cardiotoxic therapies and may also improve outcomes
need for renal replacement therapy occurred less in patients with established CTRCD and HF. Together,
frequently among patients with CTRCD treated with these results set the stage for larger randomized
SGLT2 inhibitors. clinical trials to investigate the efficacy of SGLT2

T A B L E 2 Comparison of Outcomes With and Without SGLT2 Inhibitors in Patients With Cancer Therapy–Related Cardiac Dysfunction/Heart Failure

SGLT2 Inhibitor E Value for

Risk OR E Value Lower Bound of
Yes No Difference (%) (95% CI) P Value for OR 95% CI of OR

Primary outcomes
Acute heart failure exacerbation 85 (13.3) 154 (24.1) –10.8 0.483 (0.361-0.647) <0.001 3.56 4.98
All-cause mortality 73 (11.4) 194 (30.3) –18.9 0.296 (0.220-0.398) <0.001 6.21 8.56
Secondary outcomes
All-cause hospitalizations or 279 (43.6) 395 (61.7) –18.1 0.479 (0.383-0.599) <0.001 2.25 2.61
emergency department visits
Atrial fibrillation/flutter 15 (4.5) 37 (10.6) –6.1 0.397 (0.213-0.737) 0.003 4.47 8.86
Acute kidney injury 152 (23.8) 250 (39.1) –15.3 0.486 (0.382-0.619) <0.001 2.22 2.62
Renal replacement therapy 10 (1.7) 24 (4.1) –2.4 0.398 (0.189-0.839) 0.012 4.46 10.06
Falsification outcome
Gastrointestinal bleeding 8 (1.3) 15 (2.4) –1.1 0.5274 (0.222-1.253) 0.148 3.2 8.48

Values are n (%) unless noted otherwise.

Abbreviation as in Table 1.
8 Avula et al JACC: HEART FAILURE VOL. -, NO. -, 2023
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T A B L E 3 Survival Analysis of Primary and Secondary Outcomes

Log-Rank Test

E Value for
E Value Lower Bound of
c2 HR 95% CI P Value for HR 95% CI of HR

Primary outcomes
Acute heart failure exacerbation 12.878 0.618 (0.474-0.806) <0.001 2.62 3.64
All-cause mortality 30.414 0.476 (0.363-0.623) <0.001 3.62 4.95
Secondary outcomes
All-cause hospitalizations or 17.703 0.720 (0.618-0.840) <0.001 1.82 2.14
emergency department visits
Atrial fibrillation and flutter 4.734 0.518 (0.284-0.947) 0.030 3.27 6.5
Acute kidney injury 17.156 0.654 (0.534-0.801) <0.001 2.02 2.46
Renal replacement therapy 2.537 0.552 (0.263-1.159) 0.111 3.02 7.07
Falsification outcome
Gastrointestinal bleeding 1.594 0.533 (0.225-1.267) 0.206 3.16 8.36

inhibitors in patients treated with potentially car- shown the efficacy of SGLT2 inhibitors in reducing the
diotoxic cancer therapies. risk of cardiac arrhythmias. For example, in a meta-
The reduction in atrial fibrillation and flutter after analysis of 34 randomized controlled trials in pa-
SGLT2 inhibitor use suggests that SGLT2 inhibitors tients with T2DM or HF, SGLT2 inhibitor therapy was
may effectively reduce the burden of arrhythmias in associated with a 0.81-fold reduction in the odds
this patient population. Clinically, this is important of incident atrial arrhythmias (95% CI: 0.69-0.95;
because arrhythmias may exacerbate HF symptoms P ¼ 0.008).20 Another meta-analysis reported similar
and progression and are commonly seen in patients results in patients with T2DM, HF, or chronic kidney
with CTRCD.17-19 Furthermore, several studies have disease; SGLT2 inhibitor therapy was associated with

F I G U R E 3 Acute HF Exacerbations in Patients Treated With and Without SGLT2 Inhibitors

Kaplan-Meier survival curves were used to depict acute heart failure exacerbations in patients with CTRCD/HF treated with or without SGLT2
inhibitors. Log-rank tests were used to compare outcomes between the 2 groups over a 2-year follow-up. CTRCD ¼ cancer therapy–related
cardiac dysfunction; other abbreviations as in Figure 1.
JACC: HEART FAILURE VOL. -, NO. -, 2023 Avula et al 9
- 2023:-–- SGLT2 Inhibitor for Cancer Therapy–Related Cardiac Dysfunction

T A B L E 4 Comparison of Safety Outcomes With and Without SGLT2 Inhibitors in Patients With Cancer Therapy–Related Cardiac Dysfunction

Risk
E Value for
On SGLT2 Not on SGLT2 Risk OR z E Value Lower Bound of
Adverse Outcomes Inhibitor Inhibitor Difference, % (95% CI) P Value for OR 95% CI for OR

Urinary tract infection 59 (9.2) 105 (16.4) –7.2 0.517 (0.368-0.727) <0.001 3.28 4.88
Lower extremity amputation 10 (1.6) 10 (1.6) 0.0 1.000 (0.413-2.419) >0.999 1 4.28

Values are n (%) unless noted otherwise.

Abbreviation as in Table 1.

C ENTR AL I LL U STRA T I O N Study Design and Key Results

Patient Population

6,988 patients with Type II DM and Cancer Therapy

Related Cardiac Dysfunction

654 patients on SGLT2i + GDMT 6,334 patients on GDMT only

1:1 Propensity score matching for demographics, comorbidities, medications

640 patients on SGLT2i + GDMT 640 patients on GDMT only

Primary Outcomes

Acute HF exacerbation

All-cause mortality

Secondary Outcomes

All-cause hospitalizations or ER visits

Atrial fibrillation/flutter

Acute kidney injury

Renal replacement therapy

Avula V, et al. J Am Coll Cardiol HF. 2023;-(-):-–-.

Diagram of the patient population and main findings. Propensity score matching was conducted to create 2 cohorts of patients with cancer
therapy–related cardiac dysfunction based on SGLT2 inhibitor use. Primary and secondary outcomes were demonstrated to be favorable in
the cohort on SGLT2 inhibitors using odds ratios and log-rank tests. DM ¼ diabetes mellitus; ER ¼ emergency room; GDMT ¼ guideline-
directed medical therapy; HF ¼ heart failure; SGLT2 ¼ sodium-glucose cotransporter-2.
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a lower risk of atrial fibrillation (relative risk [RR]: study, combined with in vitro and animal and human
0.93; 95% CI: 0.70-0.96) and ventricular tachycardia data, prompts further research and consideration of
(RR: 0.73; 95% CI: 0.53-0.99).21 The mechanisms of SGLT2 inhibitor use for CTRCD.
these effects are thought to be the cardioprotective STUDY LIMITATIONS. Data in this study were
mechanisms of SGLT2, such as increased natriuresis extracted from an aggregate electronic health record
and metabolic and pleiotropic effects. 22 database (TriNetX) and, therefore, may not contain
The observed reduction in acute kidney injury and accurately reported health conditions and do not
the need for renal replacement therapy suggests that capture outcomes occurring outside this database.
SGLT2 inhibitors may have significant renal protec- In addition, cardiotoxic drug exposures and their
tive effects in this patient population. Renal combinations were not well quantified, including
dysfunction is often associated with antineoplastic dose/durations of treatments. The database did not
therapy and may contribute to or be exacerbated by allow for the extraction of dosage information, so
HF.23 Previous studies have shown the benefit of we could not quantify how many patients in each
SGLT2 inhibitors (dapagliflozin, empagliflozin, and group achieved the target dose of GDMT. However,
canagliflozin) on renal function in patients with dia- these factors likely affect both cohorts equally. We
betes and increased CV risk.24-26 In the EMPA-REG selected patients based on a temporal association
OUTCOME (Cardiovascular Outcome Event Trial in between exposure to potentially cardiotoxic anti-
Type 2 Diabetes Mellitus Patients) trial, empagliflozin neoplastic therapies and the development of car-
improved renal outcomes, as defined by reduced risk diomyopathy/HF, but we cannot accurately attribute
of incident or worsening nephropathy, reduced pro- causation to antineoplastic therapies in all cases.
gression to macroalbuminuria, reduced incidence of The timeline of cancer diagnosis to cardiomyopathy
renal replacement therapies, and reduced occurrence or HF development, the status of cancer, and the
of doubling of serum creatinine in patients with exact timing of SGLT2 inhibitor use after cardio-
T2DM and an estimated glomerular filtration rate of myopathy or HF development are not well under-
30 mL/min/1.73 m 2, when compared to placebo.25 In stood in this database. However, we excluded any
the Canagliflozin and Renal Events in Diabetes with patients with acute coronary syndrome or revascu-
Established Nephropathy Clinical Evaluation larization after the cancer diagnosis, making it more
(CREDENCE) trial, canagliflozin reduced the primary likely that reported cardiomyopathy or HF is related
composite renal outcome of doubling serum creati- to antineoplastic therapy.
nine, end-stage kidney disease, renal death, or CV Furthermore, all patients in our study had T2DM;
death by 30% in patients with T2DM and albuminuric hence, the role of SGLT2 inhibitors in patients with
chronic kidney disease.26 Following this trial, regu- CTRCD without T2DM is not assessed. This study
lations for canagliflozin were modified to include the could not differentiate between the effects of the
use of this agent for renal protective therapy in different types of SGLT2 inhibitors (dapagliflozin,
appropriate patients. 27 The mechanisms behind the empagliflozin, canagliflozin, and ertugliflozin) or be-
renal protective effects of SGLT2 inhibitors are likely tween different durations and doses of SGLT2 inhib-
multifactorial. They are postulated to include vaso- itor use.
constriction of afferent arterioles via tubuloglo- Despite our best efforts, a significant limitation of
merular feedback, lowering of filtered albumin, renal this study is a potential selection bias attributable
transport work, and oxygen consumption, all of to unmeasured confounding factors despite robust
which help preserve the glomerular filtration rate and propensity matching at baseline. However, to over-
long-term kidney function. 8 come this limitation, we determined baseline health
From a safety perspective, SGLT2 inhibitors have care use in the form of all-cause hospitalizations
been associated with an increased risk of urinary tract and ED visits in the prior 12 months for better
infections, specifically fungal genital infections, and matching of the population. Additionally, we
canagliflozin has been associated with an increased assessed a falsification outcome in the form of
risk of lower extremity amputations. 28,29 These risks, gastrointestinal bleeding, which was similar be-
particularly urinary tract infections, are expected to be tween both the cohorts, and performed the E value
higher in patients with cancer undergoing antineo- calculation as a sensitivity analysis, a measure to
plastic therapy.30,31 However, this study shows that check for robustness against bias from unmeasured
SGLT2 inhibitor use is safe in patients with CTRCD. 32,33 confounding or omitted covariates in the observa-
Although evidence for SGLT2 inhibitor use in this tional studies for both primary and secondary out-
specific patient population is still emerging, this comes. A high E value implies that a stronger
JACC: HEART FAILURE VOL. -, NO. -, 2023 Avula et al 11
- 2023:-–- SGLT2 Inhibitor for Cancer Therapy–Related Cardiac Dysfunction

unmeasured confounder would be needed to negate

the covariate effect estimate and increase the like- ADDRESS FOR CORRESPONDENCE: Dr Sarju Ganatra,

lihood of causality. Division of Cardiology, Department of Medicine,

Lahey Hospital and Medical Center, Beth Israel Lahey
CONCLUSIONS Health, 41 Mall Road, Burlington, Massachusetts
01805, USA. E-mail: [email protected].
In summary, our data suggest that patients with @SarjuGanatraMD.
CTRCD and HF treated with SGLT2 inhibitors in
addition to other GDMTs, are associated with a lower PERSPECTIVES
rate of acute HF exacerbation, all-cause mortality,
hospitalizations or ED visits, atrial fibrillation or COMPETENCY IN MEDICAL KNOWLEDGE: In patients with
flutter, acute kidney injury, and renal replacement CTRCD or HF, treatment with SGLT2 inhibitors may reduce the
therapy when compared with patients on contempo- risk of mortality, acute HF exacerbation, atrial arrhythmias, and
rary GDMT except for SGLT2 inhibitors. However, adverse renal outcomes. SGLT2 inhibitors should be considered
larger prospective studies are needed to confirm for managing CTRCD/HF in addition to traditional HF
these findings. medications.

FUNDING SUPPORT AND AUTHOR DISCLOSURES

TRANSLATIONAL OUTLOOK: Further prospective studies are
Dr Deswal is supported in part by the Ting Tsung and Wei Fung needed to evaluate the efficacy of SGLT2 inhibitors in managing
Chao Distinguished Chair. All other authors have reported that they CTRCD or HF.
have no relationships relevant to the contents of this paper to
disclose.

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