Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) significantly improve cancer prognosis but are associated with the risk of immune checkpoint inhibitor-related cardiotoxicity (iRCs), a life-threatening complication. Type 2 Diabetes Mellitus (T2DM) further increases the risk of iRCs and worsens outcomes in these patients. Although sodium-glucose cotransporter-2 inhibitors (SGLT2i) confer cardioprotective and potential antitumor effects, their prognostic value in cancer patients with T2DM and established iRCs remains unknown. OBJECTIVE: To investigate the association of SGLT2i use with all-cause mortality, iRCs severity, and major adverse cardiovascular events (MACE) in cancer patients with T2DM who developed iRCs during ICI therapy. METHODS: In this retrospective study, we analyzed 98 cancer patients with T2DM and established iRCs between January 2019 and June 2025. Participants were categorized into an SGLT2i group (n = 26) and a non-SGLT2i group (n = 72). The primary endpoint was all-cause mortality; secondary endpoints included 40-day MACE and iRCs severity. Survival analyses were performed using Kaplan-Meier curves with the log-rank test. Independent associations were assessed via Cox proportional hazards regression. RESULTS: Median follow-up was 950.5 days. SGLT2i use was independently associated with reduced all-cause mortality (adjusted HR = 0.520, 95% CI: 0.285-0.947, p = 0.033). The SGLT2i group exhibited a longer median survival time (743 days vs. 494 days) and consistently higher 1-, 2-, and 3-year survival rates (73.1% vs. 60.6%; 51.5% vs. 26.4%; 31.2% vs. 8.8%) compared to the non-SGLT2i group. Additionally, the SGLT2i group had a significantly lower proportion of high-grade iRCs (19.2% vs. 45.8%, p = 0.031). Although the incidence of MACE did not differ significantly between groups (19.2% vs. 33.3%, p = 0.271), univariate Cox regression indicated a 47% lower risk of MACE in the SGLT2i group (HR = 0.531, 95% CI: 0.202-1.391, p = 0.198), with numerical reductions observed for both overall MACE and its individual components. CONCLUSION: SGLT2i use in cancer patients with T2DM and established iRCs was independently associated with lower all-cause mortality and linked to a reduced incidence of high-grade iRCs and favorable MACE trends. These findings warrant prospective validation to confirm cardioprotective and potential oncologic benefits of SGLT2i in this high-risk population.