Beyond Hyperglycemia: The Role of Sodium-Glucose Cotransporter 2 Inhibitors in Cancer Treatment-related Cardiac Dysfunction.

With advances in cancer therapies and improved survival in cancer patients, attention must be paid to potential cardiotoxicity. Cancer therapy-related cardiac dysfunction (CTRCD) encapsulates a range of complications of cardiac injury, cardiomyopathy, and heart failure (HF) related to cancer therapy, and is termed ‘symptomatic’ CTRCD when HF symptoms are the predominant presentation. 1 Meta-analysis data estimate that incidence of CTRCD overall is 63.21 per 1,000 person-years, but variations exist between cancer types and anti-cancer therapies. 2 , 3 CTRCD appears to have a higher incidence in patients with breast cancer (72.97 per 1,000 person-years), leukemia (65.21 per 1,000 person-years), and lymphoma (55.43 per 1,000 person-years). Once CTRCD becomes symptomatic, prognosis for these patients worsens significantly. Severe symptomatic CTRCD is estimated to occur in 0.5–3% of patients. 1

CTRCD prevention has become a primary objective in cardio-oncology, with the early introduction of traditional guideline-directed medical therapy (GDMT) for HF alongside cardiovascular (CV) assessments prior to and during the initiation of cancer therapies as key strategies for prevention.

The purpose of this review is to explore the use of sodium–glucose cotransporter 2 inhibitors (SGLT2I), one of the fundamental pillars of HF GDMT, as a prevention and treatment modality for CTRCD. This review summarizes the major cancer therapies associated with CTRCD, with emphasis on therapies most relevant to current SGLT2I data; reviews current prevention strategies; and examines mechanistic, preclinical, and emerging clinical evidence supporting a potential role for SGLT2I.

Cancer Therapy-related Cardiac Dysfunction

Previously, CTRCD was classified based on the presence of structural abnormalities and the estimated degree of reversibility. Type 1 CTRCD referred to dose-dependent irreversible cardiac injury, while type 2 CTRCD was defined by reversible cardiac dysfunction with drug discontinuation. 4 However, this classification system is falling out of favor as the understanding of underlying mechanisms for ‘irreversible’ injury appears to have an element of reversibility and those with ‘reversible’ injury may have long-lasting effects on cardiac function. CTRCD can also be characterized by the timing of its onset. This includes acute, subacute, and late-term onset after completion of treatment. 5

Instead, the International Cardio-Oncology Society (IC-OS) has included CTRCD as part of five primary CV toxicities implicated in cancer treatment ( Figure 1 ). 6 These include myocarditis, vascular toxicity, hypertension, arrhythmia and QTc prolongation, and CTRCD presenting as cardiomyopathy and HF, further classified as asymptomatic or symptomatic. In this definition, CTRCD is diagnosed based on the presence of HF symptoms, abnormalities detected on cardiac imaging, such as changes in global longitudinal strain (decline by >15% from baseline) or left ventricular ejection fraction (LVEF, reduction by >10% to an LVEF of 40–49%) on echocardiography, and elevated cardiac biomarkers, including natriuretic peptides and troponin.

Overview of Cancer Therapies and Associated Cardiac Dysfunction

CTRCD can occur with any cancer treatment modality including chemotherapy, targeted agents, immunotherapies, and radiation therapy. However, the presentation, mechanisms, and timing may differ based on treatment regimen. Treatment with anthracyclines, anti-human epidermal growth factor receptor 2 (HER2) therapy, vascular endothelial growth factor (VEGF) inhibitors, and radiotherapy (RT) are most associated with the development of HF. 7 The following section will describe, for major treatments associated with CTRCD, the presentation of CTRCD, proposed mechanisms in developing CTRCD, and dose–response relationships and potential for reversibility of CTRCD ( Table 1 ).

Chemotherapy Agents

Anthracyclines are a well-recognized cause of CTRCD. The absolute risk depends on cumulative dose, concomitant therapies, and host factors. Historic series report symptomatic HF rates in the low single digits (commonly ~1.6–5% for late/chronic presentations) but estimates vary by cohort and definition. 8 Cardiotoxicity occurs on a continuum: subclinical (asymptomatic) declines in LVEF commonly appear during therapy or within the first year, while symptomatic cardiomyopathy can present acutely, within the first year, or many months to years later. 9

There are three main mechanisms that incite toxicity: DNA damage (specifically via type II topoisomerase poisoning); mitochondrial dysfunction; and oxidative stress (OS) of cardiomyocytes. 10 , 11 CTRCD in these patients is often dose-dependent, delayed in onset, and thought to be irreversible, though recovery of cardiac function has been reported with initiation of HF GDMT. 12 Overwhelmingly, combination chemotherapy regimens that include an anthracycline have an increased incidence of CTRCD. 13 , 14

Targeted Agents

HER2-targeting drugs, also called ErbB2-targeting drugs, can lead to CTRCD in 15–20% of patients undergoing treatment and have an increased risk of up to 28% in patients concomitantly treated with anthracyclines. 11 , 15 Trastuzumab is a monoclonal antibody against the HER2 membrane receptor that exerts cardiotoxic effects via maladaptation to cardiac stress. 10 Specifically, HER2 signaling under normal conditions mediates cardiomyocyte hypertrophy and sarcomere organization. 16 When this pathway is disrupted, the cardiac structural integrity and compensatory response to stress from catecholamines is compromised and may lead to the development of dilated cardiomyopathy. 17 , 18 Cardiomyocyte damage due to HER2-targeting therapies is thought to be reversible and is not reported to be dose-dependent, with concomitant risk factors and additional chemotherapy more significantly impacting CTRCD incidence. 19

Tyrosine kinase inhibitors (TKI) encompass several gene-targeting drugs. These drugs inhibit downstream pathways responsible for cell growth and tumor angiogenesis but may also cause a variety of on- and off-target effects. 20 Generally, CTRCD due to TKIs are thought to be late-onset, non-progressive, dose-dependent, and reversible with drug discontinuation. 20 , 21 In cancer therapy, specific gene-targeting TKIs that predispose to CTRCD often target angiogenesis and include drugs targeting HER2, VEGF (described below), BCR-ABL, EGFR, and BRAF/MEK. 16

VEGF pathway inhibitors, including monoclonal antibodies (e.g. bevacizumab) and small-molecule VEGF receptor TKIs, cause a spectrum of CV toxicities. Hypertension is the most common manifestation, and VEGF inhibitors have also been associated with left-ventricular (LV) systolic dysfunction/HF, QTc prolongation, and arterial and venous thrombotic events. 5 , 22 A pooled analysis of trials including 10,647 patients treated with VEGF receptor TKIs reported ≈2.4% incidence of asymptomatic LV systolic dysfunction and ≈1.2% incidence of symptomatic HF, with an increased relative risk versus control arms. 23 The mechanisms are multifactorial: VEGF inhibition produces microvascular rarefaction (reduced capillary density) and impaired myocardial perfusion; inhibition of platelet-derived growth factor receptors and loss of pericytes can further reduce myocardial microvascular support; and secondary effects such as sustained hypertension, ischemia, and thrombosis also contribute. 20 , 24 , 25 Together, these insults can lead to LV dysfunction and, in some patients, overt dilated cardiomyopathy and clinical HF.

Adoptive Cell Therapies

According to a meta-analysis by Maleki et al., chimeric antigen receptor T-cell (CAR T) therapy has been estimated to result in HF in up to 30% of patients undergoing treatment, though other reports have estimated lower rates ranging from 4% to 10%. 26 – 28 Cytokine release syndrome (CRS) is a common complication of chimeric antigen receptor T-cell therapy that occurs due to systemic immune activation and is characterized by increased inflammatory markers and cytokines. 29 The grade of CRS severity predicts HF in these patients. 30 , 31 Mechanistically, cardiotoxicity due to CAR T therapy is thought to be multifactorial: CRS with significant vascular leak leading to hypotension, tachycardia, and edema (on-target, on-tumor effect); direct T-cell mediated injury (on-target, off-tumor effect); and myocarditis-like damage of off-target, off-tumor tissues. 32 – 34 Dose-dependent effects of CAR T therapy on cardiomyopathy and its reversibility have not been well described. 35

Bispecific T-cell engagers (BTEs) are engineered antibodies that redirect T cells to tumor cells via dual binding to cluster of differentiation 3 and tumor-associated antigens. 36 Like CAR T therapy, they can precipitate CRS. Pharmacovigilance data from the Food and Drug Administration Adverse Event Reporting System showed that 747 of 3,668 BTE-related reports (20.4%) involved cardiovascular adverse events (CVAEs), and BTEs were associated with a signal for fatal CVAEs. 36 Real-world and trial-based estimates vary (some analyses report substantially lower proportions), and importantly, many CVAEs occur without documented CRS, although CRS clearly increases risk and severity of cardiac complications. 37 , 38

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors (ICIs), including CTLA-4, PD-1, and PD-L1 inhibitors, disinhibit T-cell responses and can produce immune-mediated injury to noncancer tissues, most notably myocarditis. 39 ICI-associated myocarditis is considered rare, but its most severe form can be fatal.

Incidence estimates vary by data set (reported ranges from <0.1% in early pharmacovigilance series to ~1% or higher in large real-world cohorts), and the condition typically occurs early with median onset around 3–5 weeks after ICI initiation (most cases present within the first 6–12 weeks). 40 – 43 Mortality for ICI myocarditis is substantial in severe/fulminant presentations (early reports and pooled analyses report short-term mortality in the range of ~17–50% for severe cases), though improved recognition and management have reduced mortality in contemporary series. 44 HF events and other cardiac immune-related adverse events are also reported (some registries report HF in the low single digits, e.g. ~3.5%), and combination ICI therapy markedly increases both the risk and severity of myocarditis compared with single-agent regimens. 45 , 46

Radiation Therapy

There is a clear link between radiation exposure and risk of cardiotoxicity, collectively termed ‘radiation-induced heart disease’. Radiation induces various degrees of coronary artery disease in up to 85% of patients, especially in those treated with mediastinal RT, but can also affect the pericardium, conduction system, and cardiac valves. 47 Radiation induces fibrosis throughout ventricular walls and can lead to a restrictive cardiomyopathy with diastolic dysfunction in up to 10% of patients. 47 The right ventricle is more often affected due to proximity to the radiation beam compared to the left ventricle. 48 Cardiac involvement is dose-dependent: higher total chest doses (commonly cited thresholds ≥30-35 Gy) and higher mean heart dose (MHD) increase risk, and guideline statements identify MHD >15 Gy as a level associated with meaningful long-term cardiac risk, particularly when combined with anthracyclines or other risk factors. 48 Radiation-related cardiac disease is typically late-onset, often emerging years to decades (commonly ~10–30 years) after exposure, although subclinical dysfunction can be detected earlier with sensitive imaging. 49 , 50

Current CTRCD Prevention Strategies and Guideline Recommendations

Risk Stratification Frameworks and Tools

Risk stratification is crucial for personalizing CV care for patients undergoing cancer therapy. The goal of pre-treatment risk assessment is to determine the patient’s individual risk for CV toxicity, inform appropriate cancer treatment selection, educate patients, and define an appropriate prevention and surveillance plan. 5

The Heart Failure Association (HFA) of the European Society of Cardiology (ESC), in collaboration with the IC-OS, developed risk assessment tools that should be considered to determine pre-treatment risk of cancer therapy-related CV toxicity (class IIa, level c recommendation). 51 The HFA-ICOS framework classifies patients into categories of low, moderate, high, and very high risk of CV complications before treatment initiation ( Table 2 ). The risk stratification tool covers several classes of cardiotoxic anti-cancer therapy, including anthracyclines, HER2-targeted therapies, VEGF inhibitors, BCR-ABL inhibitors, multiple myeloma therapies, and RAF/MEK inhibitors. For anthracycline therapy in particular, consideration of the total cumulative dose of therapy may be included as a high-risk factor for values ≥250 mg/m 2 of doxorubicin or equivalent anthracycline dosing. 51

Patients in the low-risk category generally are recommended to have routine oncology follow-up and should have a cardiology referral if CV toxicity or new CV risk factors develop. Moderate-risk patients may require closer cardiac monitoring, management of CV risk factors, and may benefit from cardio-oncology referral. Patients in the high/very high-risk category should have follow-up with cardio-oncology or a cardiologist familiar with managing CV disease in cancer patients, and a careful risk/benefit discussion should be conducted weighing in on the cardiotoxic effects and advantages of the anti-cancer treatment. 5

Specific timelines for routine surveillance by cancer therapy type vary greatly and can be complex. The 2022 ESC Guidelines contain treatment-specific timelines for routine surveillance.

Primary Prevention

Primary prevention of CTRCD starts with a baseline CV assessment for all patients prior to undergoing chemotherapy. This includes a careful history and physical examination, with a focus on lifestyle factors such as smoking, alcohol consumption, frailty, and pollution exposure. A baseline EKG (particularly when using agents that prolong the QTc interval; class I, level c recommendation), cardiac serum biomarkers (cardiac troponin and natriuretic peptides; class I, level c recommendation), and cardiac imaging tests (most often transthoracic echocardiography to assess global longitudinal strain and LVEF; class I, level c recommendation) can further characterize CV risk factors and stratification. Patients with a history of CV disease or symptomatic patients may require more intensive clinical evaluation including stress echocardiography, CV MRI, nuclear perfusion imaging, and coronary CT angiography. 5

After initial risk stratification, primary prevention involves consistent surveillance of CV risk factors based on risk category, cancer type and stage, and anti-cancer regimen. The 2022 ESC Guidelines describe primary prevention strategies in those undergoing treatment with anthracyclines and radiation. 5

GDMT in Primary Prevention

Li et al. conducted a comprehensive meta-analysis examining cardioprotective regimens in the prevention of LVEF decline for patients on a variety of anti-cancer regimens. 52 At the time of their analysis, GDMT included β-blockers, mineralocorticoid receptor antagonists, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARBs). They also included statin use in the analysis, and notably did not include SGLT2I, which were not guideline-directed for HF prevention at the time of the study (2020). Of these drug classes, mineralocorticoid receptor antagonists, and specifically spironolactone, were most efficacious in preventing LVEF changes compared to placebo (mean ejection fraction [EF] difference 12.77; 95% CI [1.76–23.79]), and there was an EF protective effect noted for ACEI, statins, and β-blockers. ARBs did not achieve a statistically significant preservation of EF compared to placebo. The compounding effect of multiple GDMT agents has not been well characterized.

Considerations for Primary Prevention with Anthracycline Therapy

Strategies related to the delivery of anthracycline itself, generally considered in the context of primary prevention or risk mitigation, include minimizing the dose of anthracycline administered or switching to liposomal anthracycline preparations, which have modified pharmacokinetics and tissue distribution (class IIa, level b recommendation). 53

Dexrazoxane is protective against CTRCD in patients treated with anthracyclines and is approved in patients with advanced or metastatic breast cancer after a minimum cumulative dose of 300 mg/m 2 of doxorubicin or equivalent (class IIa, level b recommendation). 5 Statins have also demonstrated cardioprotection in small randomized clinical trials (i.e. STOP-CA in patients with lymphoma), with larger confirmatory trials still accruing, and are a class IIa, level b recommendation according to ESC guidelines. 54

Considerations for Primary Prevention with Radiation Therapy

Primary prevention of radiation-induced damage to the CV system focuses heavily on technical and planning advances designed to improve the targeting of RT delivery while minimizing toxicity risk. Techniques to reduce the MHD of radiation include shaping of dose distribution, respiratory management with gaiting or breath hold, and proton therapy, although data are emerging on whether these strategies actually result in fewer therapy-related clinical events. 5 There are no medical therapies that have been proven to prevent radiation-induced heart disease.

Secondary Prevention

Elements of secondary prevention include optimal management of pre-existing CV disease and other comorbidities before and during cancer therapy, and regular surveillance and monitoring that includes 12-lead EKG, transthoracic echocardiogram, cardiac biomarkers, and in some cases CV MRI. Changes in these studies must be interpreted on an individual basis, as there are currently no established thresholds for concern for CTRCD by cancer treatment type or modality. 5 In general, new cardiac symptoms require cardiac imaging to evaluate for CTRCD.

Effects of SGLT2I on CTRCD

SGLT2I are established therapies across the HF spectrum, serving as one of the four pharmacologic ‘pillars’ of HF with reduced EF (HFrEF) management and are considered first-line therapy in managing patients with HF with preserved EF (HFpEF). In EMPEROR-Reduced, empagliflozin lowered the risk of CV death or HF hospitalization in patients with HF with reduced EF, and in EMPEROR-Preserved it similarly reduced the composite of CV death or HF hospitalization in patients with HFpEF. 55 , 56 These benefits, together with renal protection and consistent effects irrespective of diabetes status, provide an important rationale for exploring SGLT2I in CTRCD. Of note, the relationship between SGLT2I and CTRCD due to several key agents described previously is not well-described, namely VEGF inhibitors, CAR T therapy, BTE, ICI, and radiation therapy.

Mechanism of Action

SGLT2I act primarily by blocking sodium–glucose cotransporter 2 in the proximal renal tubules, thereby reducing glucose reabsorption, increasing urinary glucose excretion, and lowering blood glucose independently of insulin secretion. 57

Beyond glycemic control, SGLT2I induce natriuresis and osmotic diuresis, leading to reductions in blood pressure and interstitial fluid, which contribute to their CV and renal protective effects. 58 Mechanisms for CV protection, further described below, include metabolic shifts toward increased lipid oxidation and ketogenesis as well as reduction in inflammation, OS, and fibrosis.

Proposed Mechanisms in Managing CTRCD

SGLT2I are thought to provide cardioprotection through multiple complementary mechanisms that extend beyond glucose lowering ( Figure 2 ). More detailed explanations of the molecular mechanisms at play in SGLT2 inhibition can be found in the review by Dabour et al. 59

Anti-inflammatory Activity

SGLT2I may attenuate systemic inflammation by suppressing NLRP3 inflammasome activation and reducing pro-inflammatory cytokines such as interleukin 1, interleukin 6, tumor necrosis factor α and interferon γ. 60 This has been demonstrated consistently in the cardiac damage induced by doxorubicin in preclinical studies. 61 , 62

Decrease in Oxidative Stress

SGLT2I may help restore the balance between reactive oxygen species and antioxidant mechanisms via inhibition of enzymes leading to OS, including nicotinamide adenine dinucleotide phosphate oxidase 1 and 2 and oxidized protein. 63 SGLT2I may also salvage antioxidant enzymes and improve mitochondrial function. 59

Increased Ketogenesis and Improved Energy Metabolism

SGLT2I may induce a starvation-like state that shifts myocardial fuel use toward β-hydroxybutyrate, a more oxygen-efficient substrate than fatty acids. This promotes better mitochondrial work efficiency and enhances oxygen delivery to tissues. 64 Energy metabolism is improved by upregulating the expression of nutrient deprivation signaling pathways, including AMPK and sirtuin 1, to improve mitochondrial function, decrease apoptosis, regulate autophagy, and decrease fibrosis.

Ferroptosis Inhibition

Ferroptosis is an iron-dependent, nonapoptotic cell death that can lead to abnormal iron accumulation. 59 SGLT2I may decrease iron overload in cardiomyocytes caused by agents such as doxorubicin. 65

Endothelin-1 Inhibition

By downregulating endothelin-1, a potent vasoconstrictor linked to breast-cancer-related cardiac remodeling and therapy-induced injury, SGLT2I may reduce vascular stress, fibrosis and myocardial remodeling. 66

Direct Anti-tumor and Chemosensitizing Potential

Many cancers, including but not limited to lung adenocarcinoma, breast cancer, pancreatic, and prostate cancer, express SGLT2 transporters. 67 , 68 SGLT2I disrupt glucose uptake in tumor cells, which can result in apoptosis. Preclinical models show SGLT2 inhibition can slow tumor growth and enhance chemosensitivity, suggesting dual cardio-oncologic benefit when combined with cancer therapy. 69

Preclinical Evidence by Cancer Drug Type

Most preclinical studies have focused on cardiotoxicity mediated by anthracyclines and HER2-targeted therapies. While SGLT2I show promise in preclinical models of anthracycline-induced cardiotoxicity, there is a clear gap in the literature regarding their effects on CTRCD from alkylating agents, antimetabolites, RT, immunotherapy, and endocrine therapies.

Anthracyclines

Preclinical studies consistently demonstrate that SGLT2I, particularly dapagliflozin and empagliflozin, confer robust cardioprotection against anthracycline-induced cardiotoxicity through multiple complementary mechanisms. Across murine and large animal models, these agents preserve LV systolic and diastolic function, reduce circulating markers of myocardial injury (troponin T, heart-type fatty acid-binding protein), and attenuate oxidative and inflammatory responses. 70 , 71

Empagliflozin has shown additional benefits in cardiac energetics. In doxorubicin-treated pigs, empagliflozin improved mitochondrial structure and function, enhanced myocardial ketone usage, and preserved EF. 72 Similarly, Sabatino et al. reported preservation of LV systolic and diastolic function and reduced myocardial fibrosis in mice. 73 Oh et al. demonstrated improved cardiac performed and reduced fibrosis in vivo , potentially mediated by β-hydroxybutyrate driven ketone signaling. 74 Quagliariello et al. further showed that empagliflozin suppressed NLRP3 inflammasome and MyD88 signaling, reducing myocardial apoptosis and inflammation and preserving strain and function. 65

In vitro data corroborate these findings. Dapagliflozin protects H9c2 cardiomyocytes exposed to doxorubicin or trastuzumab by reducing apoptosis, calcium overload, lipid peroxidation, and pro-inflammatory cytokine expression. 75 , 76 Combination therapy with SGLT2I and angiotensin receptor-neprilysin inhibitors further augments survival and limits adverse ventricular remodeling in rodent models. 77

HER2-targeting Drugs

In preclinical mouse models, dapagliflozin preserved cardiac function and reduced biomarkers of myocardial injury, inflammation, and OS in animals treated with sequential doxorubicin and HER2-blocking antibody, compared with chemotherapy alone, suggesting attenuation of early cardiac dysfunction from combined anthracycline and HER2-targeted therapy. 78

In vitro , dapagliflozin improved cardiomyocyte viability and reduced apoptosis, calcium overload, lipid peroxidation, and pro-inflammatory cytokine expression while suppressing NLRP3 inflammasome activation in FL-1 cells exposed to doxorubicin and trastuzumab. 75 , 76 Data of their effects in HER2-only regimens remain sparse because most studies model combined anthracycline-HER2 exposure. 79

Tyrosine Kinase Inhibitors

Preclinical studies suggest that SGLT2I, particularly empagliflozin, may mitigate CTRCD induced by TKI, with the strongest evidence involving sunitinib. In a murine model, co-administration of empagliflozin significantly improved sunitinib-induced cardiac dysfunction, normalizing LV EF and attenuating systolic hypertension. 80

Mechanistically, empagliflozin restored AMPK-mTOR signaling and autophagy within cardiac tissue pathways essential for cardiomyocyte survival and energy homeostasis. These benefits were abolished by pharmacologic inhibition of AMPK or autophagy, confirming the pathway specificity. 80

Complementary in vitro studies using H9c2 cardiomyocytes demonstrated that empagliflozin prevented sunitinib-induced cell death and restored autophagic flux through similar AMPK-mTOR-mediated mechanisms, supporting a direct cellular cardioprotective effect of SGLT2I against TKI-related cardiotoxicity. 80

Retrospective and Clinical Trial Landscape

Clinical trials demonstrating the efficacy of SGLT2I in preventing CTRCD are sparse, and most of the data surrounding their use in CTRCD derive from retrospective, observational studies. Here we describe pivotal retrospective studies and clinical trials in exploring the impact of SGLT2I on CTRCD development ( Table 3 ).

Retrospective Studies Investigating Primary Prevention of CTRCD

Gongora et al. were among the first researchers to examine the use of SGLT2I in people with diabetes treated with anthracyclines. 81 In their cohort, patients treated with an SGLT2I (n=32) had a lower incidence of cardiac events (3% versus 20%, p=0.025) compared to controls (n=96). Included in this composite endpoint, the SGLT2I arm had no incident HF events and no new cardiomyopathy over a median follow-up of 1.5 years compared to controls.

Similarly, Abdel-Qadir et al. published a large retrospective cohort study evaluating 933 patients with type 2 diabetes and without HF prior to undergoing anthracycline treatment. 82 Patients treated with SGLT2I (n=99) were as likely to develop HF as controls (HR 0.55; 95% CI [0.23–1.31]); however, these patients were also less likely to require hospitalization for HF, though there was no significant difference in incident HF diagnosis. Several other retrospective studies examining the development of HF while on SGLT2I and anthracycline therapy have shown similarly favorable results. 83 , 84

Focusing on an ICI-treated population, Perelman et al. examined the effect of SGLT2I on the development of ICI-cardiotoxicity. 85 The study sample size was small, with 24 patients treated with an SGLT2I; however, the authors suggest that SGLT2I use prior to initiating ICI therapy resulted in fewer cases of myocarditis (0% versus 2%).

Bhatti et al. analyzed a propensity-matched cohort of 17,350 patients with diabetes and exposure to a variety of antineoplastic agents, stratified by SGLT2I use at the start of cancer treatment. 86 Antineoplastic therapies used in the cohort included anthracyclines, antimetabolites, monoclonal antibodies, small molecule TKIs, proteasome inhibitors, alkylating agents, and aromatase inhibitors. Overall, patients using SGLT2I were less likely to develop CTRCD compared to patients not on SGLT2I (HR 0.76; 95% CI [0.69–0.84]). This finding remained significant when stratifying by drug class for every antineoplastic agent used, except for proteasome inhibitors (HR 0.88; 95% CI [0.67–1.15]).

Meta-analyses have consistently demonstrated reductions in new HF diagnoses with a wide variety of cancer types and potential cardiotoxic cancer agents, but with more representation from anthracycline-based populations. Bhalraam et al. estimated a 71% decrease in HF diagnoses in patients prescribed SGLT2I (RR 0.29; 95% CI [0.10–0.87]; I 2 = 71%). 87 Similarly, Yan et al. demonstrated a risk reduction of 53% among patients treated with an SGLT2I (RR 0.47; 95% CI [0.33–0.68]; I 2 70%). 88 Finally, Vásquez-Tirado et al. demonstrated a 48% reduction in the risk of CTRCD development, including 10,460 patients receiving SGLT2I versus 12,815 controls (RR 0.52; 95% CI [0.30–0.90]; I 2 31%). 89

Retrospective Studies Investigating Secondary Prevention of CTRCD

Avula et al. specifically investigated secondary prevention of CTRCD and is the only study to do so to date. 90 The propensity-matched cohort included 1,280 patients with diabetes and CTRCD/HF. Patients on SGLT2I and GDMT had a lower risk of acute HF exacerbation (OR 0.48; 95% CI [0.36–0.65]) and all-cause mortality (OR 0.30; 95% CI [0.22–0.40]) compared to patients on GDMT alone. These patients also exhibited fewer episodes of acute kidney injury (AKI, OR 0.49; 05% CI [0.38–0.62]) and AF/flutter (OR 0.40; 95% CI [0.21–0.74]). Patients were exposed to a variety of antineoplastic therapies; however, the analysis of CTRCD attenuation by drug class was not performed and the doses and duration of drug regimens were not reported by the database used.

Clinical Trials

Anthracycline-induced cardiomyopathy is the primary focus of current clinical trials. The EMPACARD-PILOT trial (2024) represents one of the first prospective case-control investigations in this field. 91 Conducted in 76 high-risk breast cancer patients receiving anthracyclines, patients with diabetes or stable HFpEF were prescribed empagliflozin 10 mg daily 1 week before anthracycline treatment and for 6 months after treatment initiation. Patients in the empagliflozin group were also more likely to be prescribed a β-blocker compared to controls (58% versus 34%, p=0.038); however, all other GDMT were comparable. The use of empagliflozin significantly reduced the incidence of CTRCD at 6 months, with an 82% RR reduction compared with controls (RR 0.18; 95% CI [0.04–0.75]). LVEF was preserved in the empagliflozin group compared with controls (56.8% ± 5.8% versus 53.7% ± 6.7%, p=0.029), though the clinical relevance of this distinction is questionable.

There are several other anthracycline-based cohorts currently undergoing clinical trials. The EMPACT trial ( NCT05271162 ) is a double-blind, randomized, placebo-controlled study evaluating the use of empagliflozin for the primary prevention of anthracycline-induced cardiotoxicity/CTRCD. PROTECTAA ( NCT06304857 ) is a Phase II trial designed to test the efficacy of dapagliflozin in breast cancer patients undergoing anthracycline-based chemotherapy. The PROTECT trial ( NCT06341842 ) similarly explores dapagliflozin use and anthracycline exposure with and without trastuzumab. Of note, there are currently no clinical trials exploring secondary prevention of CTRCD using SGLT2I.

Evidence on Concurrent Use of SGLT2I with Other GDMTs

Randomized clinical trials testing SGLT2I specifically as an add-on to established GDMT to reduce CTRCD are not yet available; the human evidence to date comes primarily from retrospective cohort studies (e.g. Avula et al.), and meta-analyses have largely pooled observational data. Ongoing randomized trials are under way to test SGLT2I for anthracycline-related cardiotoxicity, but definitive trial evidence of additive benefit with GDMT is awaited. 90

Additional Considerations and Potential Side-effects

SGLT2Is have several potential complications that need to be considered prior to starting treatment. With suppression of the immune system from chemotherapy regimens, the risk of urinary tract infection when using SGLT2I should be assessed for each patient. SGLT2I have a mild diuretic effect, and so volume depletion and renal injury are possible using these medications.

Meta-analyses have reported sepsis, AKI, and urinary tract infections as the most common complications associated with SGLT2I use in cancer patients, with fewer reports of hypoglycemia, diabetic ketoacidosis, yeast infections, and amputations. 87 However, other meta-analyses suggest decreased risk of AKI in these patients, with Vasquez-Tirado reporting a decreased risk of AKI of 0.61 in patients treated with SGLT2I (RR 0.61; 95% CI [0.49–0.77]; I 2 0%). 89

Bhalraam et al. also reported a decreased incidence of atrial flutter/AF (RR 0.38; 95% CI [0.26–0.56]). 87 Avula et al., in their use of SGLT2I as secondary prevention of CTRCD, found that patients prescribed SGLT2I had lower chances of developing AF or flutter (OR 0.40; 95% CI [0.21–0.74]), AKI (OR 0.49; 95% CI [0.38–0.62]), and need for renal replacement therapy (OR 0.40; 95% CI [0.19–0.84]). 90

Best practices on the timing of SGLT2I initiation relative to chemotherapy have not been well described. While there exists no specific guidance regarding timing of SGLT2I initiation, a proactive strategy considering CV risk factors, biomarker elevations, and early signs of cardiac dysfunction should be used. 79

Future Directions

Future studies and clinical trials should aim to determine the efficacy of SGLT2I on CTRCD prevention and attenuation based on various cancer regimens that incite the initial CTRCD presentation. There is a specific need for clinical trials investigating the secondary prevention effectiveness of SGLT2I in patients who have already developed CTRCD. Several of the upcoming anthracycline-based clinical trials include patients who are not diagnosed with diabetes or HFpEF, which may improve generalizability of findings. There is an additional need to examine more frail populations, including the elderly and those with renal impairment. Future studies should examine the cost-effectiveness of SGLT2I use on the prevention of HF hospitalizations and major adverse CV events, as well as best combinations of GDMT to prevent and manage CTRCD. Finally, consideration of the patient experience with SGLT2I and antineoplastic therapies should be characterized, including patient quality of life, pill burden, and shared decision-making regarding the use of SGLT2I.

Conclusion

As strategies to prevent and manage CTRCD evolve alongside advances in HF GDMT, SGLT2I have emerged as a promising option for both prevention and treatment. Most available data are observational and derived largely from anthracycline exposure, but several randomized trials are now in progress. If these trials confirm benefit, SGLT2I may become a central strategy to prevent and treat CTRCD while allowing patients to continue life-saving cancer therapy more safely.

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