Influence of sodium-glucose cotransporter-2 inhibitors on cardiovascular outcomes during lung cancer chemotherapy
Background. Chronic heart failure with preserved ejection fraction (CHFpEF) in patients with type 2 diabetes mellitus (T2DM) and lung cancer receiving polychemotherapy (PCT) is a serious clinical problem. Objective: To evaluate the influence of sodium-glucose cotransporter 2 (SGLT2) inhibitors on clinical, laboratory, and echocardiographic parameters and the incidence of “hard” cardiovascular outcomes in patients with CHFpEF, T2DM, and lung cancer receiving PCT. Material and methods. A single-center, prospective, randomized study was performed in 196 patients with lung cancer, type 2 diabetes mellitus, and CHFpEF scheduled for PCT. The study group (n = 98) received standard CHF therapy in combination with an SGLT2 inhibitor (dapagliflozin/empagliflozin 10 mg/day), while the control group (n = 98) received standard CHF therapy alone. The follow-up period was 24 months. Participants were assessed for biomarker levels (NT-proBNP, high-sensitivity troponin I, high-sensitivity C-reactive protein, galectin-3), echocardiographic parameters (GLS), exercise tolerance, and life quality. Results. After 24 months in the SGLT2 inhibitors group, there was a statistically significant decrease in NT-proBNP, high-sensitivity troponin I, high-sensitivity C-reactive protein, and galectin-3 (p <0.001 for all parameters). They also had improved GLS (from -15.6 ± 2.7 to -19.8 ± 1.9; p <0.001), diastolic function, and 6-minute walk test distance (an increase of 126 m; p <0.001). The incidence of hospitalizations for cardiovascular diseases in the study group consisted 3.1% versus 14.3% in the control group (odds ratio 0.19; 95% confidence interval: 0.05–0.67; p = 0.004). The risk of cardiac dysfunction in the groups was 2.0% and 12.2%, respectively (odds ratio 0.15; 95% confidence interval: 0.03–0.69; p = 0.006). Between-group differences in cardiovascular and cancer mortality did not reach statistical significance (p = 0.110 and p = 0.480, respectively), but a trend toward a reduction in cardiovascular mortality was observed in patients receiving SGLT-2 inhibitors. Conclusion. 24-month therapy with SGLT-2 inhibitors in patients with CHFpEF, T2DM, and lung cancer receiving chemotherapy has a cardioprotective effect, reducing the incidence of cardiovascular hospitalizations and the risk of cardiac dysfunction without negatively impacting cancer outcomes.L.L. Sarkisyan, S.V. Kruchinova, E.D. Kosmacheva
Keywords
sodium-glucose cotransporter-2 inhibitors
chronic heart failure with preserved ejection fraction
type 2 diabetes mellitus
lung cancer
cardio-oncology
cardioprotection
dapagliflozin
empagliflozin
polychemotherapy
References
1. Smolarz B, Lukasiewicz H, Samulak D, Piekarska E, Kołacinski R, Romanowicz H. Lung cancer – epidemiology, pathogenesis, treatment and molecular aspect (review of literature). Int J Mol Sci. 2025;26(5):2049.
PMID: 40076671. PMCID: PMC11900952. https://doi.org/10.3390/ijms26052049
2. Lyon AR, Lopez-Fernández T, Couch LS, Asteggiano R, Aznar MC, Bergler-Klein J, et al.; ESC Scientific Document Group. 2022 ESC guidelines on cardio-oncology developed in collaboration with the EHA, the ESTRO and the IC-OS. Eur Heart J. 2022;43(41):E333–E465.
PMID: 36017568. https://doi.org/10.1093/eurheartj/ehac244. Erratum in: Eur Heart J. 2023;44(18):1621.
https://doi.org/10.1093/eurheartj/ehad196
3. Чазова И.Е., Агеев Ф.Т., Аксенова А.В., Виценя М.В., Гиляров М.Ю., Мартынюк Т.В. с соавт. Евразийские клинические рекомендации по диагностике, профилактике и лечению сердечно-сосудистых осложнений при противоопухолевой терапии (2022). Евразийский кардиологический журнал. 2022;(1):6–79. [Chazova IE, Ageev FT, Aksenova AV, Vicenya MV, Gilyarov MYu, Martynyuk TV, et al. Eurasian clinical guidelines for cardiovascular complications of cancer treatments: Diagnosis, prevention and treatment (2022). Yevraziyskiy kardiologicheskiy zhurnal = Eurasian Heart Journal. 2022; (1):6–79 (In Russ.)].
EDN: SIVDQT. https://doi.org/10.38109/2225-1685-2022-1-6-79
4. Бойцов С.А., Погосова Н.В., Аншелес А.А., Бадтиева В.А., Балахонова Т.В., Барбараш О.Л. с соавт. Кардиоваскулярная профилактика 2022. Российские национальные рекомендации. Российский кардиологический журнал. 2023;28(5):119–249. [Boytsov SA, Pogosova NV, Ansheles AA, Badtieva VA, Balakhonova TV, Barbarash OL, et al. Cardiovascular prevention 2022. Russian national guidelines. Rossiyskiy kardiologicheskiy zhurnal = Russian Journal of Cardiology. 2023;28(5):119–249 (In Russ.)].
EDN: EUDWYG. https://doi.org/10.15829/1560-4071-2023-5452
5. Avagimyan A, Madonna R, Sheibani M, Pogosova N, Trofimenko A, Urazova O, et al. Translational aspects of doxorubicin-induced cardiotoxicity: What we have omitted for the past decades? Vascul Pharmacol. 2025;160:107526.
PMID: 40714257. https://doi.org/10.1016/j.vph.2025.107526
6. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.
PMID: 26378978. https://doi.org/10.1056/NEJMoa1504720
7. McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, 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.
PMID: 31535829. https://doi.org/10.1056/NEJMoa1911303
8. Kuo HH, Wang KT, Chen HH, Lai ZY, Lin PL, Chuang YJ, Liu LY. Cardiovascular outcomes associated with SGLT2 inhibitor therapy in patients with type 2 diabetes mellitus and cancer: A systematic review and meta-analysis. Diabetol Metab Syndr. 2024;16(1):108.
PMID: 38773486. PMCID: PMC11110336. https://doi.org/10.1186/s13098-024-01354-4
9. Bhalraam U, Veerni RB, Paddock S, Meng J, Piepoli M, Lopez-Fernandez T, et al. Impact of sodium-glucose cotransporter-2 inhibitors on heart failure outcomes in cancer patients and survivors: A systematic review and meta-analysis. Eur J Prev Cardiol. 2026;33(2):214–26.
PMID: 40044419. https://doi.org/10.1093/eurjpc/zwaf026
10. Avagimyan A, Pogosova N, Kakturskiy L, Sheibani M, Challa A, Kogan E, et al. Doxorubicin-related cardiotoxicity: Review of fundamental pathways of cardiovascular system injury. Cardiovasc Pathol. 2024;73:107683.
PMID: 39111556. https://doi.org/10.1016/j.carpath.2024.107683
11. Lu Y, An L, Taylor MRG, Chen QM. Nrf2 signaling in heart failure: Expression of Nrf2, keap1, antioxidant, and detoxification genes in dilated or ischemic cardiomyopathy. hysiol Genomics. 2022;54(3):115–27.
PMID: 35073209. PMCID: PMC8897001. https://doi.org/10.1152/physiolgenomics.00079.2021
12. Chen YY, Wu TT, Ho CY, Yeh TC, Sun GC, Tseng CJ, Cheng PW. Blocking of SGLT2 to eliminate NADPH-induced oxidative stress in lenses of animals with fructose-induced diabetes mellitus. Int J Mol Sci. 2022;23(13):7142.
PMID: 35806147. PMCID: PMC9266761. https://doi.org/10.3390/ijms23137142
13. Massague J, Sheppard D. TGF-β signaling in health and disease. Cell. 2023;186(19):4007–37.
PMID: 37714133. PMCID: PMC10772989. https://doi.org/10.1016/j.cell.2023.07.036
14. Hata A, Chen YG. TGF-β signaling from receptors to Smads. Cold Spring Harb Perspect Biol. 2016;8(9):a022061.
PMID: 27449815. PMCID: PMC5008074. https://doi.org/10.1101/cshperspect.a022061
15. Fatehi Hassanabad A, Zarzycki A, Fedak PWM. Cellular and molecular mechanisms driving cardiac tissue fibrosis: On the precipice of personalized and precision medicine. Cardiovasc Pathol. 2024;71:107635.
PMID: 38508436. https://doi.org/10.1016/j.carpath.2024.107635
16. Giordano C, Francone M, Cundari G, Pisano A, d’Amati G. Myocardial fibrosis: Morphologic patterns and role of imaging in diagnosis and prognostication. Cardiovasc Pathol. 2022;56:107391.
PMID: 34601072. https://doi.org/10.1016/j.carpath.2021.107391
17. Gager GM, von Lewinski D, Sourij H, Jilma B, Eyileten C, Filipiak K, et al. Effects of SGLT2 inhibitors on ion homeostasis and oxidative stress associated mechanisms in heart failure. Biomed Pharmacother. 2021;143:112169.
PMID: 34560555. https://doi.org/10.1016/j.biopha.2021.112169
18. Kume S, Packer M. SGLT2 inhibitors act as metabolic transducers to restore healthy nutrient deprivation and surplus signaling in the kidney. Kidney Int. 2024;105(6):1172–76.
PMID: 38777403. https://doi.org/10.1016/j.kint.2024.01.044
19. Packer M. Critical reanalysis of the mechanisms underlying the cardiorenal benefits of SGLT2 inhibitors and reaffirmation of the nutrient deprivation signaling/autophagy hypothesis. Circulation. 2022;146(18):1383–405.
PMID: 36315602. PMCID: PMC9624240. https://doi.org/10.1161/CIRCULATIONAHA.122.061732
20. Stachteas P, Karakasis P, Patoulias D, Clemenza F, Fragakis N, Rizzo M. The effect of sodium-glucose co-transporter-2 inhibitors on markers of subclinical atherosclerosis. Ann Med. 2023;55(2):2304667.
PMID: 38233735. PMCID: PMC10798275. https://doi.org/10.1080/07853890.2024.2304667
21. Gaspari T, Spizzo I, Liu H, Hu Y, Simpson RW, Widdop RE, Dear AE. Dapagliflozin attenuates human vascular endothelial cell activation and induces vasorelaxation: A potential mechanism for inhibition of atherogenesis. Diab Vasc Dis Res. 2018;15(1):64–73.
PMID: 28976221. https://doi.org/10.1177/1479164117733626. Erratum in: Diab Vasc Dis Res. 2018;15(4):364.
https://doi.org/10.1177/1479164118775894
22. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al.; EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451–61.
PMID: 34449189. https://doi.org/10.1056/NEJMoa2107038
23. Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, et al.; DELIVER Trial Committees and Investigators. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387(12):1089–98.
PMID: 36027570. https://doi.org/10.1056/NEJMoa2206286
24. Gongora CA, Drobni ZD, Quinaglia Araujo Costa Silva T, Zafar A, Gong J, Zlotoff DA, et al. Sodium-glucose co-transporter-2 inhibitors and cardiac outcomes among patients treated with anthracyclines. JACC Heart Fail. 2022;10(8):559–67.
PMID: 35902159. PMCID: PMC9638993. https://doi.org/10.1016/j.jchf.2022.03.006
25. Avula V, Sharma G, Kosiborod MN, Vaduganathan M, Neilan TG, Lopez T, et al. SGLT2 inhibitor use and risk of clinical events in patients with cancer therapy-related cardiac dysfunction. JACC Heart Fail. 2024;12(1):67–78.
PMID: 37897456. https://doi.org/10.1016/j.jchf.2023.08.026
26. Huang YM, Chen WM, Jao AT, Chen M, Shia BC, Wu SY. Effects of SGLT2 inhibitors on clinical cancer survival in patients with type 2 diabetes. Diabetes Metab. 2024;50(1):101500.
PMID: 38036054. https://doi.org/10.1016/j.diabet.2023.101500
27. Chiang CH, Chiang CH, Chiang CH, Ma KS, Peng CY, Hsia YP, et al. Impact of sodium-glucose cotransporter-2 inhibitors on heart failure and mortality in patients with cancer. Heart. 2023;109(6):470–77.
PMID: 36351793. PMCID: PMC10037540. https://doi.org/10.1136/heartjnl-2022-321545
28. Abdel-Qadir H, Carrasco R, Austin PC, Chen Y, Zhou L, Fang J, et al. The association of sodium-glucose cotransporter 2 inhibitors with cardiovascular outcomes in anthracycline-treated patients with cancer. JACC CardioOncol. 2023;5(3):318–28.
PMID: 37397088. PMCID: PMC10308059. https://doi.org/10.1016/j.jaccao.2023.03.011
29. Perelman MG, Brzezinski RY, Waissengrin B, Leshem Y, Bainhoren O, Rubinstein TA, et al. Sodium-glucose co-transporter-2 inhibitors in patients treated with immune checkpoint inhibitors. Cardiooncology. 2024;10(1):2.
PMID: 38212825. PMCID: PMC10782769. https://doi.org/10.1186/s40959-023-00199-6
30. Fath AR, Aglan M, Aglan A, Chilton RJ, Trakhtenbroit A, Al-Shammary OA, et al. Cardioprotective potential of sodium-glucose cotransporter-2 inhibitors in patients with cancer treated with anthracyclines: An observational study. Am J Cardiol. 2024;222:175–82.
PMID: 38692401. https://doi.org/10.1016/j.amjcard.2024.04.032
31. Hwang HJ, Kim M, Jun JE, Yon DK. Sodium-glucose cotransporter-2 inhibitors improve clinical outcomes in patients with type 2 diabetes mellitus undergoing anthracycline-containing chemotherapy: An emulated target trial using nationwide cohort data in South Korea. Sci Rep. 2023;13(1):21756.
PMID: 38066029. PMCID: PMC10709414. https://doi.org/10.1038/s41598-023-48678-1
About the Authors
Lucine L. Sarkisyan, MD, postgraduate student, assistant at the Department of therapy No. 1, Kuban State Medical University, Krasnodar, Russian Federation.E-mail: lsarkisan2@gmail.com
ORCID: https://orcid.org/0009-0001-2019-387X
Sofiya V. Kruchinova, MD, PhD (Medicine), cardiologist at the Department of cardiology No. 2 for patients with myocardial infarction, Professor S.V. Ochapovsky Research Institute – Regional Clinical Hospital No. 1 (Krasnodar region); associate professor of the Department of therapy No. 1, Kuban State Medical University, Krasnodar, Russian Federation.
E-mail: skruchinova@mail.ru
ORCID: https://orcid.org/0000-0002-7538-0437
Elena D. Kosmacheva, MD, Dr. Sci. (Medicine), professor, head of the Department of therapy No. 1, Kuban State Medical University; deputy chief physician for clinical work, Professor S.V. Ochapovsky Research Institute – Regional Clinical Hospital No. 1 (Krasnodar region); chief external expert-cardiologist of the Krasnodar region and Southern Federal District, Krasnodar, Russian Federation.
E-mail: kosmachova_h@mail.ru
ORCID: https://orcid.org/0000-0001-8600-0199
Similar Articles
