Cardioprotective Empagliflozin for Cancer Patients Receiving Doxorubicin

In cancer therapy, several cytotoxic drugs may cause cardiotoxicity which is associated with poor short- and long-term outcome. Anthracyclines (ANT) are natural products with topoisomerase-interacting activity. These compounds are broadly utilized in the treatment of lymphoma, sarcoma, breast cancer, and pediatric leukemia. ANT has long been demonstrated to improve survival in cancer patients. However, despite its broad effectiveness, ANT therapy is associated with irreversible dilated cardiomyopathy (CMP). Toxic effect may occur at any stage of ANT treatment. and it seems that females are affected more often than males. The incidence increases from 5% in patients receiving doses up to 400 mg/m2 to 48% in patients receiving more than 700 mg/m2 of doxorubicin (DOX). Although the risk of cardiac dysfunction is proportional to the cumulative ANT exposure, a substantial number of patients still develop severe cardiotoxicity at doses well below 550 mg/m2. In a study on the early detection and prediction of cardiotoxicity, 27.6% of patients developed chemotherapy-related cardiotoxicity. Another study found that DOX in doses of less than 300 mg/m2 could induce cardiotoxicity. Strategies that might prevent chemotherapy-induced CMP are receiving increased attention from oncologists and cardiologists. It is also well known that most doxorubicin-induced cardiotoxicity occurs within the first year (mainly within 6-months after chemotherapy). Acute toxicity is a reversible adverse effect that develops during or within days of ANT infusion, and its incidence has been significantly reduced by slowing the ANT infusion rates. Congestive heart failure due to chronic cardiotoxicity is the most common type of ANT damage, is irreversible, and peaks at 1-3 months but can occur even years after therapy. Free radical formation is generally accepted as the main mechanism. cardiomyocytes have poor antioxidant defense systems, and free oxygen radicals can damage various targets in the cell. This may result in impairment of cardiac contractility and the development of CMP. Compared with other more common forms of CMP, myocardial damage has been accompanied by a grave prognosis, has a 2-year mortality rate of up to 6 %, and seems to be refractory to therapy. The various approaches that can be employed in clinical practice include dosage restriction; encapsulating ANT in liposomes to reduce myocardial uptake; and simultaneous administration with iron chelator dexrazoxane to reduce the free iron-catalyzed reactive oxygen formation and the alteration of ANT configuration.

Nonetheless, ANT-induced heart failure has morbidity and mortality sequelae. The second evident problem of using DOX as a chemotherapeutic agent is the acquired tumor resistance against it "Multidrug resistance (MDR)". DOX drug resistance is developed as a result of increased expression of the ATP-dependent efflux pump ABCB1 (MDR1), which encodes the membrane drug transporter P-glycoprotein.

Empagliflozin (EMPA) exerts an antidiabetic effect by reducing glucose reabsorption from the renal proximal tubules using sodium-glucose cotransporter-2 (SGLT-2) inhibition. Dissecting the exact molecular mechanism of SGLT2 inhibitors is therefore hampered by the diabetic scenario. Moreover, current clinical trials indicate that SGLT2 inhibitors protect against heart failure outcomes even in patients without diabetes. Beyond its antidiabetic effects, it has been shown to reduce all-cause death, cardiovascular death, and hospitalizations due to heart failure in diabetic patients compared to placebo in the EMPA-REG OUTCOME clinical study. As well, EMPORER reduced clinical trial revealed EMPA reduced cardiovascular mortality and hospitalization for heart failure in patients with heart failure with or without diabetes. The SGLT2 inhibitors canagliflozin, dapagliflozin, empagliflozin, ertugliflozin and sotagliflozin were studied in patients with established CV disease in the EMPAREG OUTCOME and VERTIS-CV trials, with established CV disease or CV risk factors in the CANVAS and DECLARE-TIMI 58 trials, and with CKD and CV risk in the SCORED trial, respectively. EMPA and canagliflozin reduced the primary composite endpoint of major CV adverse events, including CV death or nonfatal MI or non-fatal stroke, and HF hospitalizations in EMPA-REG OUTCOME and CANVAS, respectively. EMPA also reduced all-cause death or CV death alone. The effects on the primary endpoint were driven by the reduction in HF-related events. Many different chemical agents have been examined to prevent ANT-induced CMP and some of them showed promising results. Recent animal studies and experimental observations showed that EMPA prevented the development of CMP, free radical release, and apoptosis in cardiomyocytes due to chemotherapeutics including; DOX. These cardiovascular outcome trials of SGLT2 inhibitors have led to numerous speculations and studies related to their potential protective mechanisms in patients with heart failure. Some of the proposed mechanisms are hemodynamic-related, including natriuresis, osmotic diuresis, blood pressure-lowering, and LV remodeling. Other mechanisms are related to more systemic effects, including the regulation of myocardial energetics, inhibition of sodium-hydrogen exchange, adipokines and myokines, uric acid homeostasis, elevation in erythropoietin levels, increases in endothelial progenitor cells, protection from DOX, and the regulation of autophagy. Despite this, little is currently known about the molecular mechanisms underlying the cardiac protection provided by SGLT2 inhibitors. According to ESC guidelines in Aug.2021, Dapagliflozin or EMPA is recommended for patients with chronic Heart failure with reduced ejection fraction (HFrEF) with or without diabetes to reduce the risk of HF hospitalization and death.

Evidence Class Ia Level Ab. The sodium-glucose co-transporter 2 (SGLT2) inhibitors dapagliflozin and EMPA added to therapy with ACE-I/ARNI/betablocker/MRA reduced the risk of CV death and worsening HF in patients with HFrEF. Unless contraindicated or not tolerated, dapagliflozin or EMPA are recommended for all patients with HFrEF already treated with an ACE-I/ARNI (angiotensin-converting enzyme inhibitor/ angiotensin receptor neprilysin inhibitor), a beta-blocker, and an MRA (mineralocorticoid receptor antagonist), regardless of whether they have diabetes or not. The SGLT2 inhibitor, EMPA, protects the heart from DOX associated CMP in mice, by acting through a novel Beclin 1-toll-like receptor (TLR) 9-sirtuin-(SIRT) 3 axis. EMPA increases the abundance of mitochondrial SIRT3. Also; it enhances the activation of TLR9 to bind with Beclin 1, triggering communication to the autophagic, immune system, and Inflammatory machinery. Further studies also showed that EMPA can protect DOX-induced heart failure in mice. This evidence clearly indicates that SGLT2 inhibitors have direct cardiac protection mechanisms other than glucose modulation. EMPA attenuates the cardiotoxic effects exerted by DOX on LV function and remodeling in nondiabetic mice, independently of glycemic control. EMPA prevents the reduction in cardiac systolic function induced by a cardiotoxic ANT in a model of non-diabetic mice. The protective impact of EMPA on systolic function was also associated with better systolic and diastolic blood pressures in mice treated with EMPA compared to those treated with DOX alone. Finally, histological examination showed a lower degree of myocardial fibrosis in mice treated with EMPA. Also the protective effect of EMPA against DOX cardiotoxicity can be explained by several mechanisms including;

1. EMPA upregulates mitochondrial PGC-1α, thereby increasing mitochondrial biogenesis and protecting mitochondria.
2. EMPA prevents cardiomyocyte apoptosis by reducing sarcoplasmic reticulum degeneration in a significant manner.

4- Prevents the deterioration of left ventricular systolic functions in echocardiography. 5- EMPA markedly attenuates DOX -induced prolongation of the QT and QTc intervals on the ECG through decreasing the amount of cytosolic calcium and decreasing late sodium channel activation in this way can shorten QT interval. 6- Oh et al. showed EMPA improved fractional shortening (FS) but not ejection fraction (EF) in MRI and reduced perivascular and interstitial fibrosis in histologic examination in DOX-induced chronic cardiotoxicity. 7- Protective effects of EMPA on cardiomyocytes originate from an increase in beta-hydroxybutyrate (βoh) (as an antioxidant) level. 8- Decrease in preload and afterload due to natriuresis or the antioxidant effect provided by the elevated levels of antioxidant βoh. EMPA exerts anti-inflammatory and cardioprotective effects in DOXO-induced cardiotoxicity as EMPA inhibits the activity of SGLT-2 thereby reducing intracellular glucose and sodium in cardiomyocytes, resulting in the inhibition of iROS, lipid peroxidation and NLRP3/MyD88-related pathways; the inhibition of NLRP3 and NF-kB reduces the pro-inflammatory cytokine storm in cardiomyocytes exposed to DOXO. Finally, EMPA has shown antitumor activity in different murine cancer models The anti-hyperglycemic drug, EMPA, was recently indicated to have in vitro anticancer potential together with its previously reported cardioprotective properties related to calmodulin inhibition.

• Recently, it was indicated that EMPA has an in vitro anticancer potential against both breast cancer cell lines MCF-7 and lung cancer cell lines (A549.21).
• EMPA has shown cardioprotective properties due to its role as an inhibitor of calmodulin.
• Calmodulin is a calcium-binding protein which is regulating many of the intracellular actions of calcium. It is proposed that calmodulin is responsible for the regulation of cellular proliferation and that its function may be altered in malignancy.
• Mustroph et al. proposed that EMP reduces Ca2+/calmodulin-dependent kinase (CaMKII) activity in isolated murine ventricular myocytes. Also, the diastolic function of heart failure was improved in a nondiabetic rodent model by using EMPA.
• Also; calmodulin antagonists are cytotoxic and can restore the sensitivity of resistant cells to drugs such as DOX and vincristine. Consequently, calmodulin has been suggested as an emerging target for anticancer therapeutic intervention.

The aim of this study is to:

• Evaluate the prophylactic effect of using Empagliflozin "a selective inhibitor of the sodium glucose co-transporter 2 (SGLT2)" against doxorubicin induced cardiotoxicity in patients receiving doxorubicin-based chemotherapy.
• Monitor the safety of adding empagliflozin to doxorubicin-based chemotherapy.