Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2022 Nov 7.
Published in final edited form as: JACC Heart Fail. 2022 Jun 8;10(8):559–567. doi: 10.1016/j.jchf.2022.03.006

Sodium-Glucose Co-Transporter-2 Inhibitors and Cardiac Outcomes Among Patients Treated With Anthracyclines

Carlos A Gongora a,b, Zsofia D Drobni a,d, Thiago Quinaglia Araujo Costa Silva a, Amna Zafar a,b, Jingyi Gong e, Daniel A Zlotoff c, Hannah K Gilman a, Sarah E Hartmann a, Supraja Sama a, Sofia Nikolaidou a, Giselle Alexandra Suero-Abreu c, Eric Jacobsen f, Jeremy S Abramson g, Ephraim Hochberg g, Jeffrey Barnes g, Philippe Armand f, Paaladinesh Thavendiranathan h, Anju Nohria i, Tomas G Neilan a,c
PMCID: PMC9638993  NIHMSID: NIHMS1843269  PMID: 35902159

Abstract

BACKGROUND

Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve outcomes among patients with established heart failure. Despite supportive basic science studies, there are no data on the value of SGLT2 inhibitors among patients treated with anthracyclines.

OBJECTIVES

This study sought to test the cardiac efficacy and overall safety of SGLT2 inhibitors in patients treated with anthracyclines.

METHODS

This study identified 3,033 patients with diabetes mellitus (DM) and cancer who were treated with anthracyclines. Cases were patients with cancer and DM who were on SGLT2 inhibitor therapy during anthracycline treatment (n = 32). Control participants (n = 96) were patients with cancer and DM who were also treated with anthracyclines, but were not on an SGLT2 inhibitor. The primary cardiac outcome was a composite of cardiac events (heart failure incidence, heart failure admissions, new cardiomyopathy [>10% decline in ejection fraction to <53%], and clinically significant arrhythmias). The primary safety outcome was overall mortality.

RESULTS

Age, sex, ethnicity, cancer type, cancer stage, and other cardiac risk factors were similar between groups. There were 20 cardiac events over a median follow-up period of 1.5 years. The cardiac event incidence was lower among case patients in comparison to control participants (3% vs 20%; P = 0.025). Case patients also experienced lower overall mortality when compared with control participants (9% vs 43%; P < 0.001) and a lower composite of sepsis and neutropenic fever (16% vs 40%; P = 0.013).

CONCLUSIONS

SGLT2 inhibitors were associated with lower rate of cardiac events among patients with cancer and DM who were treated with anthracyclines. Additionally, SGLT2 inhibitors appeared to be safe. These data support the conducting of a randomized clinical trial testing SGLT2 inhibitors in patients at high cardiac risk treated with anthracyclines.

Keywords: anthracycline-induced cardiomyopathy, cardiotoxicity, cardiovascular outcomes, chemotherapy doxorubicin, heart failure, SGLT2 inhibitors

Anthracyclines are an effective and widely used chemotherapy agent in the treatment of multiple solid organ tumors and hematologic malignancies.1,2 The use of anthracyclines as a standard cancer therapy is limited by the potential for the development of cardiac dysfunction, arrhythmias, and clinical heart failure (HF).1–5 Beyond dose reduction, changing the formulation, and the infrequent use of chelation therapies (eg, dexrazoxane), there are no established and commonly applied therapies to reduce anthracycline-induced cardiotoxicity and HF.1,6–9

Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been shown to improve cardiac outcomes. This includes decreasing HF hospitalizations, arrhythmias, cardiac mortality, and all-cause mortality among patients with established HF independent of diabetes status.10–12 Although there are no clinical studies reporting the effect of SGLT2 inhibitors on cardiac events among patients treated with anthracycline, there are supportive basic science data. Specifically, in an animal model of anthracycline-associated cardiotoxicity, empagliflozin pretreatment was associated with preservation of cardiac function.13 Furthermore, in a second mouse model of anthracycline-associated cardiotoxicity, pretreatment with empagliflozin improved myocardial strain, reduced cardiac fibrosis, and decreased proinflammatory cytokines.14 Therefore, we hypothesized that SGLT2 inhibitors would be associated with improved cardiac outcomes in patients treated with anthracyclines.

METHODS

This was a retrospective cohort study of patients with diabetes mellitus (DM) and cancer treated with an anthracycline in the Massachusetts General Brigham system before September 2020. Patient selection parameters were derived from the RPDR (Research Patient Data Registry), a clinical database containing comprehensive clinical information obtained from patient electronic health records. The RPDR was queried for patients with DM who were treated with anthracyclines. This query identified 3,033 unique patients, of whom 1,131 were excluded because DM was coded after anthracycline initiation. This resulted in 1,902 patients with a diagnosis of DM prior to starting anthracycline treatment. Patients with prior HF were included in this cohort. Eighty-seven patients were treated with SGLT2 inhibitors and among those, 32 were on SGLT2 inhibitors during anthracycline therapy. Of the remaining 1,815 patients, 8 patients were excluded because they were <18 years of age at the anthracycline initiation date. From these 1,807 patients, a control group of patients not treated with SGLT2 inhibitors, matched by age, sex, and anthracycline start date was generated in a 3:1 ratio, creating a final cohort of 32 case patients and 96 control patients (Figure 1). The Institutional Review Board at Massachusetts General Hospital approved the study, and the requirement for written informed consent was waived.

FIGURE 1. Study Design.

FIGURE 1

Open in a new tab

In the initial search, we identified a total of 3,033 unique patients with diabetes mellitus treated with anthracyclines in a single large academic hospital network. Of these, 32 patients were treated with sodium-glucose co-transporter-2 (SGLT2) inhibitors prior to or during anthracyclines. Control patients were matched in a 3:1 ratio by age, sex, and anthracycline starting date.

COVARIATES OF INTEREST.

Data regarding demographics, baseline medical history, last known follow-up, date of death, clinical events, anthracycline dosing, and echocardiographic findings were collected by manual chart review from electronic medical records. Coronary artery disease was defined as documentation of coronary atherosclerosis, percutaneous coronary intervention, or coronary artery bypass graft. Baseline parameters and medications were identified from the oncology consultation note prior to anthracycline initiation.

STUDY END POINTS.

The primary efficacy outcome was a composite consisting of HF incidence, HF admissions, the development of cardiomyopathy (CM) (defined as a >10% decline in left ventricular ejection fraction to <53%) or clinically significant arrhythmias (Figure 2). These outcomes were chosen because they have been shown to increase with anthracyclines and are attenuated by SGLT2 inhibitors in patients with established HF.1,2,6,7,11,12,17–19 A complete list of definitions can be found in the Supplemental Appendix. All events were adjudicated using standard criteria by a cardiologist blinded to the group status. The original echocardiographic images were reviewed by 2 expert reviewers who were blinded to the group status. The primary safety outcome was all-cause mortality. Additional safety outcomes were a composite of sepsis and neutropenic fever. These safety outcomes were chosen as SGLT2 inhibitors have been linked to an increase in infections in some populations and patients receiving anthracyclines are at an increased risk of sepsis and neutropenic fever.15,16,20,21 Other safety outcomes of interest included urinary tract infection (UTI) and yeast infection.20,22

FIGURE 2. Study Timeline.

FIGURE 2

Open in a new tab

Pts = patients; SGLT2 = sodium-glucose co-transporter-2.

STATISTICAL ANALYSES.

Baseline characteristics of all patients are presented as continuous variables and summarized as mean ± SD for continuous variables and as count and percentage for categorical variables. Differences between continuous variables were assessed using Student’s t-test, whereas differences between categorical variables were assessed using the chi-square or Fisher exact test. All statistical tests were 2-sided and 5% was set as the level of significance. Overall mortality between the case patients and control patients was analyzed by comparing the overall survival, using Kaplan-Meier methods and the log-rank test. Statistical analysis was performed using RStudio (Version 1.4.1106, RStudio, Inc).23

RESULTS

BASELINE PATIENT CHARACTERISTICS.

Baseline demographic and clinical characteristics are summarized in Table 1, for all the patients with DM treated with anthracyclines and separated into those with and without SGLT2 inhibitors. There were 3 different types of SGLT2 inhibitors prescribed. The most common SGLT2 inhibitor was empagliflozin (50%, n = 16), followed by canagliflozin (34%, n = 11), and then dapagliflozin (16%, n = 5). The population was primarily White, and there was no significant difference between the proportions in each cohort with respect to race or ethnic groups (P = 0.60). Cancer types were similar between case patients and control patients. The most common cancer type in both groups was lymphoma, followed by breast cancer. There were no differences in the cancer types between the cohorts. Additionally, there was no significant difference in the stage of cancer between the 2 cohorts (Table 1).

TABLE 1.

Baseline Characteristics of Patients Treated With Anthracyclines by SGLT2 Inhibitors Status

SGLT2 Inhibitors (n = 32) Non-SGLT2 Inhibitors (n = 96) P Value
Demographics
 Female 16 (50) 41 (43) 0.50
 Age, y 60 ± 11 60 ± 10 0.80
Race or ethnic group 0.60
 White 29 (91) 75 (78)
 Black 2 (6) 9 (9)
 Other 0 (0) 7 (7)
 Asian 1 (3) 4 (4)
 Hispanic 0 (0) 1 (1)
Cancer types
 Lymphoma 11 (34) 33 (34) >0.90
 Breast 9 (28) 22 (23) 0.60
 Genitourinary 3 (9) 18 (19) 0.20
 Gastrointestinal 5 (16) 7 (7) 0.20
 Sarcoma 2 (6) 7 (7) >0.90
 Leukemia 1 (3) 3 (3) >0.90
 Other cancers 1 (3) 6 (6) 0.70
Cancer stages3
 I 3 (10) 11 (12) >0.90
 II 11 (35) 24 (27) 0.40
 III 8 (26) 25 (28) 0.80
 IV 9 (29) 30 (33) 0.70
Cardiovascular risk factors
 Hypertension 21 (66) 58 (60) 0.60
 Hyperlipidemia 19 (59) 53 (55) 0.70
 Obesity 17 (53) 36 (38) 0.12
 Former smoker 7 (22) 16 (17) 0.50
 Current smoker 4 (12) 13 (14) >0.90
 Body mass index, kg/m2 33 ± 5 32 ± 8 0.70
Other medical comorbidities
 Obstructive sleep apnea 11 (34) 17 (18) 0.048
 Coronary artery disease 2 (6) 10 (10) 0.70
 Prior heart failure 2 (6) 7 (7) >0.90
 Prior myocardial infarction 0 (0) 3 (3) 0.60
 Chronic kidney disease, eGFR <30 mL/min/1.73 m2 0 (0) 3 (3) 0.60
Cardiovascular medications
 Statin 20 (62) 53 (55) 0.50
 RAAS inhibitors 14 (44) 44 (46) 0.80
 Aspirin 12 (38) 27 (28) 0.30
 Beta-blocker 10 (31) 27 (28) 0.70
 Calcium channel blocker 6 (19) 13 (14) 0.60
 Diuretics, thiazides and loop diuretics 5 (16) 13 (14) 0.80
 Dyslipidemia medications, nonstatin 2 (6) 4 (4) 0.60
Doxorubicin dose equivalents
 Doxorubicin cumulative dosing, mg/m 189 ± 94 198 ±120 0.70
 Doxorubicin total dose, mg 369 ±188 377 ± 224 0.90
Baseline echocardiographic parameters
 Ejection fraction 62 ± 5 64 ± 7 0.20
 LVIDd, mm 46 ± 7 45 ± 6 0.70
 LVIDs, mm 31 ± 5 29 ± 5 0.20
Baseline laboratory parameters
 Hematocrit 38.3 ± 5.9 33.6 ± 5.7 <0.001
 Platelet, K/uL 229 ± 80 225 ± 122 0.90
 WBC, K/uL 7.5 ± 4.1 9.1 ± 10.9 0.50
 Creatinine, mg/dL 0.80 ± 0.17 0.91 ± 0.42 0.15
 Hemoglobin A1C 7.6 ± 1.4 6.9 ± 1.4 0.043
Open in a new tab

Values are n (%) or mean ± SD.

a

From available data.

eGFR = estimated glomerular filtration rate; LVIDd = left ventricular internal dimension in diastole; LVIDs = left ventricular internal dimension in systole; RAAS = renin-angiotensin-aldosterone system; SGLT2 = sodium-glucose co-transporter-2; WBC = white blood cell.

Both groups had a similar prevalence of cardiac risk factors such as hypertension, hyperlipidemia, and smoking history. There was no difference in the body mass index between both groups (SGLT2 inhibitor: 33 ± 5 kg/m2 vs non-SGLT2 inhibitor: 32 ± 8 kg/m2; P = 0.70). The proportion of patients with obstructive sleep apnea was higher in the SGLT2 inhibitor group (34%), than in the control group (18%; P = 0.048). There was no difference in the proportions with coronary artery disease (SGLT2 inhibitor: n = 2, 6% vs non-SGLT2 inhibitor: n = 10, 10%; P = 0.70) or prior HF (SGLT2 inhibitor: n = 2, 6% vs non-SGLT2 inhibitor: n = 7, 7%; P = 0.90). There was also no difference in the use of standard cardiac medications between both groups, including statins, aspirin, beta-blockers, calcium channel blockers, and renin-angiotensin-aldosterone system inhibitors.

Ninety-eight patients (77%) had an available echocardiogram at baseline, preanthracyclines. From the baseline transthoracic echocardiogram parameters, the mean ejection fraction was 62% ± 5% for the SGLT2 inhibitor group and 64% ± 7% for the control group. The mean left ventricular internal dimension in diastole (LVIDd) and left ventricular internal dimension in systole (LVIDs) were also similar among both groups (SGLT2 inhibitor: LVIDd 46 ± 7 mm, LVIDs 31 ± 5 mm vs non-SGLT2 inhibitor: LVIDd 45 ± 6 mm, LVIDs 29 ± 5 mm). Baseline hematocrit (SGLT2 inhibitor: 38.3 ± 5.9 vs non-SGLT2 inhibitor: 33.6 ± 5.7; P < 0.001) and glycosylated hemoglobin (SGLT2 inhibitor: 7.6 ± 1.4 vs non-SGLT2 inhibitor: 6.9 ± 1.4; P = 0.043) were higher in the SGLT2 inhibitor group compared with in the non-SGLT2 inhibitor group. The other baseline labs, including platelets, white blood cell count, and creatinine, were similar.

CHEMOTHERAPY DOSING.

The main anthracycline used in both groups was doxorubicin. There was no difference in the doxorubicin cumulative dosing between the SGLT2 inhibitor-treated group and the control group (189 ± 94 mg/m2 vs 198 ± 120 mg/m2; P = 0.70).

CARDIAC OUTCOMES.

There were a total of 20 cardiac events over a median follow-up period of 1.5 years. The incidence of cardiac events was lower in patients treated with SGLT2 inhibitors compared with in control patients (3% vs 20%; P = 0.025) (Central Illustration). The lower incidence of cardiac events was principally driven by a reduction in HF admissions and in new diagnoses of a CM (Table 2). Of the individual components, there was only 1 admission for HF in the SGLT2 inhibitor group as compared to 12 (12%) in the non-SGLT2 inhibitor group. A single patient in the SGLT2 inhibitor group was hospitalized with HF and had an admission N-terminal pro–B-type natriuretic peptide (NT-proBNP) level of 1,919 pg/mL and a peak NT-proBNP of 3,542 pg/mL. The mean admission NT-proBNP level from the 12 patients admitted with HF in the non-SLGT2 inhibitor group was 5,030 ± 3,294 pg/mL and the mean peak NT-proBNP was 5,769 ± 6,457 pg/mL. Overall, 47% of the patients in the SGLT2 inhibitor group and 55% of the control group had follow-up echocardiograms after anthracyclines. The median interval between the echocardiograms was similar between the SGLT2 inhibitor group and the non-SGLT2 inhibitor group (747; IQR: 513–1,340 days vs 372; IQR: 244–1,190 days; P = 0.20) (Supplemental Table 1). In the SGLT2 inhibitor group, there were no episodes of new cardiac dysfunction compared to 6 episodes (6%) in the non-SGLT2 inhibitor group. Similarly, there was no incident HF in the SGLT2 inhibitor arm, as compared to 7 (7%) in the non-SGLT2 inhibitor arm. Additionally, there were more cardiac arrhythmias in the non-SGLT2 inhibitor group (10%) compared with in the SGLT2 inhibitor group (3%).

CENTRAL ILLUSTRATION. Cardiovascular Outcomes of Cancer Patients With Diabetes Mellitus, Treated With Anthracyclines, Divided in Groups by Sodium-Glucose Co-Transporter-2 Inhibitors Status.

CENTRAL ILLUSTRATION

Open in a new tab

Composite was defined by heart failure admission, new cardiomyopathy, clinically significant arrhythmia, and heart failure incidence. (Composite events for each person were censored after they had a clinical event.) Cardiovascular risk factors and cardiovascular medications as defined in Table 1. *P value is significant. EF = ejection fraction; SGLT2 = sodium-glucose co-transporter-2.

TABLE 2.

Cardiac Outcomes of Patients Treated With Anthracyclines by SGLT2 Inhibitors Status

SGLT2 Inhibitors (n = 32) Non-SGLT2 Inhibitors (n = 96) P Value
Composite of cardiovascular outcomes 1 (3) 19 (20) 0.025
Heart failure admission 1 (3) 12 (12)
New cardiomyopathy, >10% difference and <53% EF 0 (0) 6 (6)
Clinically significant arrhythmia 1 (3) 10 (10)
Heart failure incidence 0 (0) 7 (7)
Heart failure exacerbation outpatient 0 (0) 2 (2) >0.90
Open in a new tab

Values are n (%). Composite was defined by heart failure admission, new cardiomyopathy, clinically significant arrhythmia, and heart failure incidence. (Composite events foreach person were censored afterthey had a clinical event.)

EF = ejection fraction; other abbreviation as in Table 1.

SURVIVAL AND SAFETY OUTCOMES.

In the entire cohort of 128 patients, there were 44 deaths over a median follow-up period of 1.5 years. There was an increased rate of overall mortality in the non-SGLT2 inhibitor group as compared to in the SGLT2 inhibitor group (HR: 4.7 [95% CI: 1.5–15.1]; P = 0.005) (Figure 3). Additionally, there was a higher rate of the composite of sepsis and neutropenic fever in patients not taking SGLT2 inhibitors (non-SGLT2 inhibitors: n = 38, 40% vs SGLT2 inhibitors: n = 5, 16%; P = 0.013) (Table 3). There were higher rates of UTI in the non-SGLT2 inhibitor group (SGLT2 inhibitors: n = 3, 9% vs non-SGLT2 inhibitors: n = 27, 28%; P = 0.03), but there were more genital yeast infections in the group taking SGLT2 inhibitor treatment. This difference in genital yeast infections was not significant (SGLT2 inhibitors: n = 3, 9% vs non-SGLT2 inhibitors: n = 3, 3%; P = 0.20). A full description of the genital yeast infections and management can be found in the Supplemental Appendix.

FIGURE 3. Kaplan-Meier Curve for Overall Mortality.

FIGURE 3

Open in a new tab

Kaplan-Meier curve showing higher survival in patients treated with sodium-glucose co-transporter-2 (SGLT2) inhibitors who received anthracyclines as compared to patients not on SGLT2 inhibitors who received anthracyclines.

TABLE 3.

Safety Outcomes of Patients Treated with Anthracyclines by SGLT2 Inhibitors Status

SGLT2 Inhibitors (n = 32) Non-SGLT2 Inhibitors (n = 96) P Value
Overall mortality 3 (9) 41 (43) <0.001
Composite of sepsis and neutropenic fever 5 (16) 38 (40) 0.013
Sepsis 4 (12) 26 (27)
Neutropenic fever 3 (9) 19 (20)
Urinary tract infection 3 (9) 27 (28) 0.030
Genital yeast 3 (9) 3 (3) 0.200
Open in a new tab

Values are n (%). Composite events for each person were censored after they had a clinical event.

Abbreviation as in Table 1.

DISCUSSION

In this retrospective study, we compared cardiac and noncardiac outcomes of patients with cancer and DM who were treated with anthracyclines and separated by the concomitant use of SGLT2 inhibitors. We report 3 novel clinical findings. 1) Patients who received SGLT2 inhibitors had fewer cardiac events, which generally accounted for lower HF admissions and a lower rate of cardiac dysfunction. 2) No cases of new doxorubicin-induced cardiac dysfunction were observed among the patients taking SGLT2 inhibitors. 3) SGLT2 inhibitors appear to be safe in this group of patients at high risk, with patients being treated with SGLT2 inhibitors experiencing a lower all-cause mortality, a reduced incidence of a composite of sepsis or neutropenic fever, and UTI; however, they did have a modest increase in the incidence of genital yeast infections. To our knowledge, these findings are the first data associating SGLT2 inhibitors with improved cardiac and noncardiovascular outcomes among patients treated with anthracyclines.

SGLT2 inhibitors were originally used as a medication to treat patients with DM,10 but accumulated data from multiple large, randomized trials have demonstrated that SGLT2 inhibitors reduce the risk of HF hospitalizations, all-cause death, and cardiovascular death in patients with HF with and without DM.12,16,24–26 Additionally, SGLT2 inhibitors appear to prevent the development of new CM in patients at high risk.26,29 Anthracyclines are a standard primary treatment for several malignancies and are associated with cardiovascular toxicity with an increased risk for HF, arrhythmias, and cardiac dysfunction.2,6,8,17,27 Translational studies in nondiabetic mice have shown that pretreatment with SGLT2 inhibitors prevented anthracycline-induced cardiotoxicity and the reduction in systolic function. These studies also have showed decreased myocardial fibrosis and less fiber disarray in mice with doxorubicin-induced CM that were pretreated with SGLT2 inhibitors.14,28,29 The cardioprotective effect in experimental models appears to be through up-regulation of SIRT1, proliferator-activated receptor gamma coactivator 1-α, and FGF21 in the heart.27,28–31 Our report is the first to examine the potential cardioprotective effects of SGLT2 inhibitors in patients with cancer who are receiving anthracycline chemotherapy. We found that this population of patients who are at high risk and treated with anthracyclines who were also on SGLT2 inhibitors had a lower risk of developing cardiac events. This high-risk population was 6× less likely to develop cardiac events if they were treated with SGLT2 inhibitors. The cardiac events in our cohort were driven by HF admissions and new CM.

In a large meta-analysis, SGLT2 inhibitors were safe when compared with placebo in patients with cardiac disease or malignancies.16,32 Evidence from randomized clinical trials has shown that SGLT2 inhibitors do not increase the risk of acute kidney injury, diabetic ketoacidosis, UTI, or fracture.16,20,33 Our data showed no increased signal for serious adverse events, including a composite of sepsis and neutropenic fever, and UTIs; a minor increase in the incidence of genital yeast infections was observed, similar to what has previously been reported about this drug class.22,34 We observed that the treatment with SGLT2 inhibitors was associated with improved overall mortality. These therapies can slow tumor growth in mouse models of breast and colon cancer by promoting a fasting-like state and mitigating hyperinsulinemia;35 similar antineoplastic effects have been seen in gastrointestinal cancers, lung cancer, and liver tumors.15,33,36–38 Although this may have been because of the reduced number of cardiovascular events, it is interesting to consider that SGLT2 inhibitor therapy may have had positive effects on the patients’ malignancies. However, further studies are clearly needed to investigate this possibility.

STUDY LIMITATIONS.

This study should be interpreted within the context of the study design. This was a retrospective study, and it is possible that several unmeasured residual confounders remain that may have influenced the associations among SGLT2 inhibitors, cardiac events, and mortality. This study also does not provide mechanistic insight into how SGLT2 inhibitors may reduce cardiovascular events in patients treated with anthracyclines. Additionally, this was a study of patients with DM. Therefore, whereas other data demonstrate that SGLT2 inhibitors have value among patients with HF but without DM, future studies may need to focus on patients who have cancer without DM. However, at the time of this study, the majority of the patients without DM treated with SGLT2 inhibitors already carried a diagnosis of HF, and therefore these patients were unlikely to be treated with anthracyclines.

CONCLUSIONS

The use of SGLT2 inhibitors was associated with a lower rate of cardiac events after anthracycline therapy in patients with cancer and DM. To our knowledge, these findings are the first data associating SGLT2 inhibitors with improved cardiac and noncardiac outcomes in this population. These findings support conducting randomized trials testing the effect of SGLT2 inhibitors on cardiac outcomes in patients treated with anthracyclines.

Supplementary Material

Supplement

PERSPECTIVES.

COMPETENCY IN MEDICAL KNOWLEDGE:

Our study showed that the use of SGLT2 inhibitors in patients with DM being treated with anthracyclines is associated with a lower cardiac event rate. Additionally, SGLT2 inhibitors appeared to be safe in patients with cancer who are being treated with anthracyclines.

TRANSLATIONAL OUTLOOK:

Our data support the performance of randomized clinical trials testing the value of SGLT2 inhibitors in preventing HF among patients at high risk who are being treated with anthracyclines.

FUNDING SUPPORT AND AUTHOR DISCLOSURES

This work was supported by National Institutes of Health/National Heart, Lung, Blood Institute (T32HL076136 to Drs Gongora and Zafar; R01HL137562, R01HL130539, and K24HL150238 to Dr Neilan). Dr Drobni has received support from the New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development, and Innovation Fund (ÚNKP-21-4-I-SE). Dr Zlotoff has received consulting fees from Bristol Myers Squibb and Freeline Therapeutics. Dr Armand has been a consultant for Merck, Bristol Myers Squibb, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Celgene, Morphosys, Daiichi Sankyo, Miltenyi, Tessa, GenMab, C4, Enterome, Regeneron, Epizyme, AstraZeneca, and Genentech; and has received honoraria form Merk and Bristol Myers Squibb. Dr Thavendiranathan has received support from the Canadian Institutes of Health Research New Investigator Award (147814) and a Canada Research Chair in Cardio-oncology; and has received speaker fees from Amgen, Boehringer Ingelheim, and Takeda. Dr Neilan has served as the Michael and Kathryn Park Chair in Cardiology; has received support from A. Curtis Greer and Pamela Kohlberg, Christina and Paul Kazilionis, and a Hassenfeld Scholar Award; has been a consultant to and received fees from Parexel Imaging, Intrinsic Imaging, H3-Biomedicine, AbbVie, C4-Therapeutics, Roche, and Genentech, outside of the current work; has received consulting fees from Bristol Myers Squibb for a Scientific Advisory Board and consultancy focused on myocarditis related to immune checkpoint inhibitors; and has received grant funding from AstraZeneca and Bristol Myers Squibb. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

ABBREVIATIONS AND ACRONYMS

CM

cardiomyopathy

DM

diabetes mellitus

HF

heart failure

LVIDd

left ventricular internal dimension in diastole

LVIDs

left ventricular internal dimension in systole

NT-proBNP

N-terminal pro–B-type natriuretic peptide

SGLT2

sodium-glucose co-transporter-2

UTI

urinary tract infection

Footnotes

APPENDIX For a list of definitions and a supplemental table, please see the online version of this paper.⨀2299

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.

REFERENCES

  • 1.Volkova M, Russell R 3rd. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr Cardiol Rev. 2011;7(4):214–220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Sawyer DB. Anthracyclines and heart failure. N Engl J Med. 2013;368(12):1154–1156. [DOI] [PubMed] [Google Scholar]
  • 3.Neilan TG, Coelho-Filho OR, Shah RV, et al. Myocardial extracellular volume by cardiac magnetic resonance imaging in patients treated with anthracycline-based chemotherapy. Am J Cardiol. 2013;111(5):717–722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Neilan TG, Coelho-Filho OR, Pena-Herrera D, et al. Left ventricular mass in patients with a cardiomyopathy after treatment with anthracyclines. Am J Cardiol. 2012;110:1679–1686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Suero-Abreu GA, Ganatra S, Neilan TG. Cardiotoxicity monitoring in patients with cancer: focus on safety and clinical relevance. JCO Oncol Pract. 2021;17(5):237–239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Favreau-Lessard AJ, Sawyer DB, Francis SA. Anthracycline cardiomyopathy. Circ Heart Fail. 2018;11(17):e005194. [DOI] [PubMed] [Google Scholar]
  • 7.Tan TC, Neilan TG, Francis S, Plana JC, Scherrer-Crosbie M. Anthracycline-induced cardiomyopathy in adults. Compr Physiol. 2015;5(3):1517–1540. [DOI] [PubMed] [Google Scholar]
  • 8.Vejpongsa P, Yeh ET. Prevention of anthracycline-induced cardiotoxicity: challenges and opportunities. J Am Coll Cardiol. 2014;64(9):938–945. [DOI] [PubMed] [Google Scholar]
  • 9.Ganatra S, Nohria A, Shah S, et al. Upfront dexrazoxane for the reduction of anthracycline-induced cardiotoxicity in adults with preexisting cardiomyopathy and cancer: a consecutive case series. Cardiooncology. 2019;5:1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Cowie MR, Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol. 2020;17(12):761–772. [DOI] [PubMed] [Google Scholar]
  • 11.McMurray JJV, Solomon SD, Inzucchi SE, et al. DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008. [DOI] [PubMed] [Google Scholar]
  • 12.Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396(10254):819–829. [DOI] [PubMed] [Google Scholar]
  • 13.Sabatino J, De Rosa S, Tammè L, et al. Empagliflozin prevents doxorubicin-induced myocardial dysfunction. Cardiovasc Diabetol. 2020;19(1):66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Oh CM, Cho S, Jang JY, et al. Cardioprotective potential of an SGLT2 inhibitor against doxorubicin-induced heart failure. Korean Circ J. 2019;49(12):1183–1195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Shiba K, Tsuchiya K, Komiya C, et al. Canagliflozin, an SGLT2 inhibitor, attenuates the development of hepatocellular carcinoma in a mouse model of human NASH. Sci Rep. 2018;8(1):2362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Donnan JR, Grandy CA, Chibrikov E, et al. Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis. BMJ Open. 2019;9(1):e022577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Jordan JH, Castellino SM, Meléndez GC, et al. Left ventricular mass change after anthracycline chemotherapy. Circ Heart Fail. 2018;11(7):e004560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Lam CSP, Chandramouli C, Ahooja V, Verma S. SGLT-2 inhibitors in heart failure: current management, unmet needs, and therapeutic prospects. J Am Heart Assoc. 2019;8(20):e013389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Komatsu S, Nomiyama T, Numata T, et al. SGLT2 inhibitor ipragliflozin attenuates breast cancer cell proliferation. Endocr J. 2020;67(1):99–106. [DOI] [PubMed] [Google Scholar]
  • 20.Dave CV, Schneeweiss S, Kim D, Fralick M, Tong A, Patorno E. Sodium-glucose cotransporter-2 inhibitors and the risk for severe urinary tract infections: a population-based cohort study. Ann Intern Med. 2019;171(4):248–256. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Minisini A, Spazzapan S, Crivellari D, Aapro M, Biganzoli L. Incidence of febrile neutropenia and neutropenic infections in elderly patients receiving anthracycline-based chemotherapy for breast cancer without primary prophylaxis with colony-stimulating factors. Crit Rev Oncol Hematol. 2005;53(2):125–131. [DOI] [PubMed] [Google Scholar]
  • 22.Unnikrishnan AG, Kalra S, Purandare V, Vasnawala H. Genital infections with sodium glucose cotransporter-2 inhibitors: occurrence and management in patients with type 2 diabetes mellitus. Indian J Endocrinol Metab. 2018;22(6):837–842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing; 2019. [Google Scholar]
  • 24.Rosano G, Quek D, Martínez F. Sodium-glucose co-transporter 2 inhibitors in heart failure: recent data and implications for practice. Card Fail Rev. 2020;6:e31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393(10166):31–39. [DOI] [PubMed] [Google Scholar]
  • 26.Vaduganathan M, Januzzi JL. Preventing and treating heart failure with sodium-glucose co-transporter 2 inhibitors. Am J Cardiol. 2019;124(suppl 1):S20–S27. [DOI] [PubMed] [Google Scholar]
  • 27.Wang J, Zhang J, Xiao M, et al. Molecular mechanisms of doxorubicin-induced cardiotoxicity: novel roles of sirtuin 1-mediated signaling pathways. Cell Mol Life Sci. 2021;78(7):3105–3125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Quagliariello V, De Laurentiis M, Rea D, et al. The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and proinflammatory cytokines in non-diabetic mice treated with doxorubicin. Cardiovasc Diabetol. 2021;20(1):150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Arow M, Waldman M, Yadin D, et al. Sodium-glucose cotransporter 2 inhibitor dapagliflozin attenuates diabetic cardiomyopathy. Cardiovasc Diabetol. 2020;19(1):7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Liu D, Ma Z, Di S, et al. AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis. Free Radic Biol Med. 2018;129:59–72. [DOI] [PubMed] [Google Scholar]
  • 31.Packer M Cardioprotective effects of sirtuin-1 and its downstream effectors. Circ Heart Fail. 2020;13(9):e007197. [DOI] [PubMed] [Google Scholar]
  • 32.Dicembrini I, Nreu B, Mannucci E, Monami M. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors and cancer: a meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2019;21(8):1871–1877. [DOI] [PubMed] [Google Scholar]
  • 33.Tang H, Dai Q, Shi W, Zhai S, Song Y, Han J. SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials. Diabetologia. 2017;60(10):1862–1872. [DOI] [PubMed] [Google Scholar]
  • 34.Engelhardt K, Ferguson M, Rosselli JL. Prevention and management of genital mycotic infections in the setting of sodium-glucose cotransporter 2 inhibitors. Ann Pharmacother. 2021;55(4):543–548. [DOI] [PubMed] [Google Scholar]
  • 35.Nasiri AR, Rodrigues MR, Li Z, Leitner BP, Perry RJ. SGLT2 inhibition slows tumor growth in mice by reversing hyperinsulinemia. Cancer Metab. 2019;7:10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Villani LA, Smith BK, Marcinko K, et al. The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration. Mol Metab. 2016;5(10):1048–1056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Scafoglio CR, Villegas B, Abdelhady G, et al. Sodium-glucose transporter 2 is a diagnostic and therapeutic target for early-stage lung adenocarcinoma. Sci Transl Med. 2018;10(467):eaat5933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Zhou J, Zhu J, Yu S-J, et al. Sodium-glucose co-transporter-2 (SGLT-2) inhibition reduces glucose uptake to induce breast cancer cell growth arrest through AMPK/mTOR pathway. Biomed Pharmacother. 2020;132:110821. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement
NIHMS1843269-supplement-Supplement.pdf (133KB, pdf)

RESOURCES