Metabolic syndrome represents a significant contemporary crisis on a global scale, creating a conducive ground for cardiovascular diseases (CVDs) and cancer development; in this context, the exploration of potential therapies aimed at correcting metabolic dysfunctions in the realm of preventive cardio-oncology appears to be particularly promising (–).
Cardio-oncology is an emerging specialty within the field of internal medicine. Despite an extensive history of research in this area, we face more questions than answers, as highlighted by the first consensus guidelines provided by the European Society of Cardiology (), in which only 3% of the guidelines hold an evidence level of “A.” Furthermore, the proposed algorithms for primary and secondary prevention primarily focus on suppressing neurohumoral activation, advocating for a combination of angiotensin-converting enzyme (ACE) inhibition or angiotensin receptor blockade (ARB) alongside β-blockers. There is also an ongoing discussion regarding the rationale behind prescribing statins and mineralocorticoid inhibitors.
The therapeutic landscape in cardiology shows that nearly all available treatment options are being utilized in cardio-oncology. It is noteworthy that, according to analyses of real clinical practice, the established combination of ACEi/ARB with β-blockers is linked to a 42% responders’ rate; conversely, non-responders in this group experience a decline in the clinical status among cardio-oncological patients (). This observation, alongside the challenges of prescribing this combination to normotensive cancer patients, raises questions about the true clinical effectiveness of this strategy, particularly in the fashion of statistically insignificant changes in heart failure incidence ().
Additionally, the only specific cardioprotective agent currently recognized is dexrazoxane, an iron chelator that modifies doxorubicin (DOX)-associated ferroptosis and oxidative damage in cardiomyocytes. Though its use is limited, and the drug has sparked considerable debate regarding its potential negative impact on oncological outcomes, it is worth noting that an increasing number of randomized clinical trials and meta-analyses are emerging that indicate no adverse effects of this medication on cancer prognosis, but this question is still open and debatable (–).
What accounts for the “failure” of studies conducted in cardio-oncology over the past seven decades? Two primary factors stand out: first, most foundational studies were performed predominantly on initially healthy male experimental subjects, utilizing a single chemotherapy drug without tumor modeling and with a wide spectra of experimental models; that is why the proposed studies have a significant number of limitations, which make it hard to compare. Second, all cardioprotective compounds investigated rely, one way or another, on the antioxidant AKT/PI3K/Sirt3/Nrf2 cascade activation. However, translating these findings into clinical practice has shown no clinically significant effects. Traditionally, oxidative stress has been viewed as the initiating factor in the pathogenesis of cancer therapy-related cardiovascular toxicity (CTR- CVT) and cancer therapy-related cardiac dysfunction (CTRCD) (). However, the modern scenario indicates that DOX-based chemotherapy is associated with a range of cardiometabolic disorders (–):
DOX treatment correlates with elevated glucose levels. Hyperglycemia, insulin resistance, and heightened free fatty acid levels emerge in both acute and chronic models of cardiotoxicity, typically due to disturbances in glucose metabolism within striated muscles. As part of our clinical investigation into the issues of hyperglycemia, prediabetes, and type 2 diabetes mellitus (T2DM) in cardio-oncology, our research team is examining metabolic disorders in the Cardiovascular Events in Breast and Colorectal Cancer (CIBC) cohort, headed by Prof. Nizal Sarrafzadegan, focusing on the effects of chemotherapy on cancer patients with or without T2DM.
Furthermore, treatment with DOX is associated with reduced activity of GLUT-1 and GLUT-4, a dose- and time-dependent decline in PPARγ expression, and an increase in miR-130a levels. DOX-based chemotherapy leads to glucose metabolism disturbances not only in the endothelium but also in the myocardium. Additionally, DOX provides versatile toxic impairment on pancreatic B cells.
Despite an overall reduction in body weight, DOX treatment leads to the development of atherogenic dyslipidemia with augmented serum triglyceride levels, characterized by elevated non-HDL cholesterol, a high triglyceride/glucose index, and increased atherogenicity.
Upon analyzing the information above, it is important to highlight the increasing interest in the study of relatively new antidiabetic drugs within the field of cardio-oncology, particularly sodium glucose co-transporter-2 inhibitors (SGLT2i) such as dapagliflozin and empagliflozin, and glucagon-like peptide-1 (GLP-1) receptor agonists like semaglutide and tirzepatide. While the emerging evidence underscores the substantial cardioprotective potential of semaglutide and tirzepatide in cardiology, their widespread use among cancer patients presents significant challenges due to their pancreatotoxic effects and the frequent occurrence of severe gastrointestinal complications.
In this context, SGLT2i appears especially relevant. Current research indicates that gliflozins, in addition to their primary metaboprotective effects, possess a range of pleiotropic mechanisms, such as antioxidant, energy stabilization, endothelium protection, and anti-inflammatory effects, that not only positively influence the heart, kidneys, nervous system, and liver but also serve some anti-cancer properties (–).
The advantages of SGLT2i, coupled with their endorsement as an initial therapeutic agent for heart failure beyond the entire spectrum of left ventricular ejection fraction, underscore the relevance of assessing SGLT2i in cardio-oncology. In light of this, our research group aims to not only evaluate the incidence of chemotherapy-related glucose metabolism disturbances at the population level (CIBC cohort); we also aimed to investigate the rationale for dapagliflozin prescription to prevent metabolic disorders and cardiovascular complications of chemotherapy-related cardiotoxicity. Our preclinical studies will be conducted on our experimental model (Avagimyan et al. ()) in female rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer. Preliminary evaluation suggests that dapagliflozin enhances the structural and functional parameters of CVD without any pathomorphological (immunohistochemical) data exacerbating the oncological process.
In analyzing these findings, it is essential to emphasize the need for future assessments of chemotherapy-related metabolic disturbances. This should involve the integration of cardiometabolic screening strategies into clinical practice for both primary and secondary prevention of cardiovascular events, along with cardiac rehabilitation for cancer patients. Therefore, further investigation into the effects of SGLT2i for the cardiometabolic toxicity prevention in undertreated and post-treatment cancer patients is needed.
Statements
Author contributions
AA: Conceptualization, Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing. NP: Conceptualization, Investigation, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. MR: Investigation, Methodology, Supervision, Validation, Writing – original draft, Writing – review & editing. NS: Conceptualization, Investigation, Supervision, Validation, Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
RizviAStoianARizzoM. Metabolic syndrome: from molecular mechanisms to novel therapies. Int. J. Mol. Sci. (2021) 22:10038. doi: 10.3390/ijms221810038
2
RizzoMRizviAA. New advances in metabolic syndrome. Int. J. Mol. Sci. (2024) 25:8311. doi: 10.3390/ijms25158311
3
PatouliasDKoufakisTRužaIEl-TananiMRizzoM. Therapeutic advances in obesity: how real-world evidence impacts affordability beyond standard of care. Pragmat Obs Res. (2024) 15:139–49. doi: 10.2147/POR.S471476
4
LyonARLópez-FernándezTCouchLSAsteggianoRAznarMBergler-KleinJet al. ESC Scientific Document Group. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur. Heart J. (2022) 43:4229–361. doi: 10.1093/eurheartj/ehac244
5
CardinaleDColomboALamantiaGColomboNCivelliMGiacomiGet al. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J. Am. Coll. Cardiol. (2010) 55:213–20. doi: 10.1016/j.jacc.2009.03.095
6
CaspaniFTralongoACampiottiLAsteggianoRGuastiLSquizzatoA. Prevention of anthracycline-induced cardiotoxicity: a systematic review and meta-analysis. Intern. Emerg. Med. (2021) 16:477–86. doi: 10.1007/s11739-020-02508-8
7
de BaatECMulderRLArmenianSFeijenEGrotenhuisHHudsonMet al. Dexrazoxane for preventing or reducing cardiotoxicity in adults and children with cancer receiving anthracyclines. Cochrane Database System Rev. (2022) 9:CD014638. doi: 10.1002/14651858.CD014638.pub2
8
ChowEJAplencRVroomanLMDoodyDHuangYAggarwalSet al. Late health outcomes after dexrazoxane treatment: A report from the Children’s Oncology Group. Cancer. (2022) 128:788–96. doi: 10.1002/cncr.33974
9
UpshawJNParsonSKBuchsbaumRJSchlamIRuddyKDuraniUet al. Dexrazoxane to prevent cardiotoxicity in adults treated with anthracyclines: JACC: cardioOncology controversies in cardio-oncology. JACC CardioOncol. (2024) 6:322–4. doi: 10.1016/j.jaccao.2024.02.004
10
AvagimyanAPogosovaNKakturskiyLSheibaniMChallaAKoganEet al. Doxorubicin-related cardiotoxicity: review of fundamental pathways of cardiovascular system injury. Cardiovasc. Pathol. (2024) 73:107683. doi: 10.1016/j.carpath
11
de Lima JuniorEAYamashitaASPimentelGDDe SousaLSantosRGoncalvesCet al. Doxorubicin caused severe hyperglycaemia and insulin resistance, mediated by inhibition in AMPk signalling in skeletal muscle. J. Cachexia Sarcopenia Muscle. (2016) 7:615–25. doi: 10.1002/jcsm.12104
12
ArunachalamSTirupathi PichiahPBAchiramanS. Doxorubicin treatment inhibits PPARγ and may induce lipotoxicity by mimicking a type 2 diabetes-like condition in rodent models. FEBS Lett. (2013) 587:105–10. doi: 10.1016/j.febslet.2012.11.019
13
SupriyaRTamBTPeiXMWlaiCChanLYungBet al. Doxorubicin induces inflammatory modulation and metabolic dysregulation in diabetic skeletal muscle. Front. Physiol. (2016) 7:323. doi: 10.3389/fphys.2016.00323
14
RussoMDella SalaATocchettiCPorporatoPChigoA. Metabolic aspects of anthracycline cardiotoxicity. Curr. Treat Opt Oncol. (2021) 22:18. doi: 10.1007/s11864-020-00812-1
15
HeartEAKarandreaSLiangXBalkeMBeringerPBobczynskiEet al. Mechanisms of doxorubicin toxicity in pancreatic β-cells. Toxicol. Sci. (2016) 152:395–405. doi: 10.1093/toxsci/kfw096
16
DabourMSGeorgeMYDanielMRBleasAZordokyB. The cardioprotective and anticancer effects of SGLT2 inhibitors: JACC: cardioOncology state-of-the-art review. JACC CardioOncol. (2024) 6:159–82. doi: 10.1016/j.jaccao.2024.01.007
17
BasakDGamezDDebS. SGLT2 inhibitors as potential anticancer agents. Biomedicines. (2023) 11:1867. doi: 10.3390/biomedicines11071867
18
SunMSunJSunWLiXWangZSunLet al. Unveiling the anticancer effects of SGLT-2i: mechanisms and therapeutic potential. Front. Pharmacol. (2024) 15:1369352. doi: 10.3389/fphar.2024.1369352
19
AvagimyanASheibaniMPogosovaNMkrtchyanLYeranosyanHAznauryanAet al. Possibilities of dapagliflozin-induced cardioprotection on doxorubicin + cyclophosphamide mode of chemotherapy-induced cardiomyopathy. Int. J. Cardiol. (2023) 391:131331. doi: 10.1016/j.ijcard.2023.131331
Summary
Keywords
doxorubicin, chemotherapy, metabolism, cardiometabolic, myocardium, glucose, GLUT, insulin resistance
Citation
Avagimyan A, Pogosova N, Rizzo M and Sarrafzadegan N (2025) Doxorubicin-induced cardiometabolic disturbances: what can we do?. Front. Clin. Diabetes Healthc. 6:1537699. doi: 10.3389/fcdhc.2025.1537699
Received
01 December 2024
Accepted
22 January 2025
Published
14 February 2025
Volume
6 - 2025
Edited by
Belma Pojskic, University of Zenica, Bosnia and Herzegovina
Reviewed by
Lamija Ferhatbegovic (Pojskic), University of Zenica, Bosnia and Herzegovina
Updates
Copyright
© 2025 Avagimyan, Pogosova, Rizzo and Sarrafzadegan.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ashot Avagimyan, dr.ashotavagimyan@gmail.com
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.