The present study is a single-center retrospective observational study whose study population selected form the institutional database, and conducted in conformity of the Declaration of Helsinki. The study protocol was approved by Shanghai Chest Hospital Ethics Committee, and written consent was waived. Briefly, the medical records of consecutive patients diagnosed with advanced lung cancer and diabetes between July 2020 and July 2024 were reviewed. Inclusion criteria were as follows. 1) The patients were diagnosed Stage III-IV NSCLC according to World Health Organization (WHO) histological classification and the UICC/AJCC TNM Classification; 2) the advanced lung cancer patients with concurrent diabetes; 3) patients with a score of 0–2 assessed by Eastern Cooperative Oncology Group’s performance status (ECOG PS); Exclusion criteria included: 1) age <18 or ≥80 years old; 2) Survival period shorter than 3 months; 3) incomplete medical records.

The primary endpoint was all-cause mortality. The secondary endpoint was a composite of major adverse cardiovascular events (MACE), including new-onset atrial fibrillation/flutter, acute coronary syndrome, myocarditis, heart failure and third-degree atrioventricular block or other malignant arrhythmias (sustained ventricular tachycardia or ventricular fibrillation).

For normally distributed variables, continuous variables are expressed as mean± standard deviation (SD), and compared by independent t-test. For variables with non-normal distributions, continuous variables were expressed as median (interquartile range, IQR) and compared by Mann-Whitney U test. Categorical variables are expressed as percentage and compared by Chi-square test. A 1:1 propensity score matching was performed to balance the differences between SGLT2i group and control group in baseline characteristics, including age, sex, TNM stage and the pathological types of lung cancer. Matching was based on propensity scores yielded by logistic regression model. The cut-off value of the matching tolerance was set at 0.02 to obtain satisfactory matching. The overall survival of the two groups was compared via Kaplan-Meier methods and log-rank test. Cox proportional hazard models were applied to assess the risk of all-cause mortality between SGLT2i group and control group. A two-tailed P value<0.05 was considered statistically significant. All statistical analyses were performed with the SPSS (IBM SPSS 26.0 IBM Corp, Armonk, NY, USA) and R statistical package 3.3.1 (R Foundation for Statistical Computing, Vienna, Austria).

Among 581 advanced lung cancer with diabetes under chemotherapy, immunotherapy, targeted therapy, and/or radiotherapy, 94 patients under concomitant SGLT2i were included in the SGLT2i group and their matched 94 patients without SGLT2i treatment were included in the control group. The detailed selection process is illustrated in Figure 1. Among the 94 patients receiving SGLT2i therapy, the majority received a dosage of 10 mg once daily, and the median duration of treatment was 13 months (Supplementary Table S1).

Baseline clinical characteristics are summarized in Table 1. The groups were well matched at baseline. There were no significant differences in age, gender, cancer types, stages and therapy between the two groups. In cardiovascular risk factors, coronary artery disease was more prevalent in SGLT2i group than non- SGLT2i group (35.1% [33/94] vs. 17.0% [16/94]; P = 0.005). A similar trend was observed for insulin use (60.6% [57/94] vs. 44.7% [42/94]; P = 0.028). Hemoglobin A1C levels was higher in the SGLT2i group (7.5 ± 1.2% vs. 7.1 ± 1.3%; P = 0.040). No other statistically significant differences were observed in the remaining baseline variables (P>0.05 for all comparisons).

The specific cancer therapy protocol was chosen by oncologists according to current guidelines (11, 12). There was no statistically significant difference in the proportion of chemotherapy and targeted therapy between SGLT2i group and non-SGLT2i group. SGLT2i group had a higher proportion of patients receiving immunotherapy and radiotherapy, but without statistical significance.

Over a median follow-up of 16 months, 79 (42.0%) patients died, including 32 patients in SGLT2i group (32/94, 34.0%) and 47 in non-SGLT2i group (47/94, 50.0%). The all-cause mortality rate is significantly lower in SGLT2i group than in non-SGLT2i group (34.0% vs. 50.0%, P = 0.027, Table 2). Compared with non-SGLT2i group, SGLT2i group had a significantly improved outcome (HR = 0.56; 95% CI 0.35– 0.87, P = 0.009, Figure 2), with higher estimated survival rates at 12 months [77.3% (95% CI 69.00–86.60)vs. 64.6% (95% CI 55.10–75.70)] and 24 months [59.7% (95% CI 49.60–72.00) vs. 40.2% (95% CI 30.40–53.20)], as yielded by Kaplan-Meier analysis. During follow-up, patients with MACE had a lower survival rate at 12 months [60.1% (95% CI 42.80–84.20) vs. 72.8% (95% CI 66.00–80.30)] and 24 months [32.3% (95% CI 17.60–59.30) vs. 53.0% (95% CI 44.90–62.50)], compared with patients without MACE. However, the mortality risk was similar. (HR 1.69; 95% CI 0.96–2.97, P = 0.067, Figure 3). Univariate cox regression included age, sex, cancer types, stages, smoking, BMI, anticancer therapy, cardiovascular risk factors, medications, baseline laboratory parameters and SGLT2i. Variables with a P value < 0.05 including SGLT2i, ACEI/ARB/ARNI, smoking, and male were adjusted in the multivariable cox regression analysis (Table 3). After adjusting for confounding factors including HbA1c, history of coronary artery disease, and insulin use, multivariable cox regression analysis yielded that SGLT2i was an independent significant predictor for lower all-cause mortality (HR = 0.618; 95% CI 0.390–0.979, P = 0.041). After adjusting for confounding factors including HbA1c and history of coronary, multivariable cox regression analysis yielded that SGLT2i was an independent significant predictor for lower all-cause mortality (HR = 0.576; 95% CI 0.366–0.907, P = 0.017).

Overall, a total of 24 cardiovascular adverse events occurred, including 11 events in the SGLT2i group and 13 events in the control group, of which new-onset atrial fibrillation or atrial flutter occurred most frequently (n=12). In SGLT2i group, cardiovascular adverse events included atrial fibrillation/flutter in 4 patients, HF in 4 patients, myocarditis in 2 patients, ACS in 1 patient, and third-degree AV block in 1 patient. While in control group, there were atrial fibrillation/flutter in 8 patients, HF in 4 patients, myocarditis in 2 patients, ACS in 2 patients. No events of sustained ventricular tachycardia or ventricular fibrillation were recorded in either group. (Table 2). The MACE incidence rate was insignificant between the two groups (11.7% vs 13.8%; P = 0.662).

Overall, the incidence of diabetes treatment-related adverse events was similar between SGLT2i group and non-SGLT2i group. The most frequent adverse event was acute kidney injury, which occurred in 6 patients in SGLT2i group and 12 patients in non-SGLT2i group (6.4% [6/94] vs. 12.8% [12/94]; P = 0.137). Urinary tract infection is the second most common adverse, which was observed in 3 patients in SGLT2i group and 2 patients in non-SGLT2i group. (3.2% [3/94] vs. 2.1% [2/94]; P = 0.650). Other adverse events included hypoglycemia in 2 patients in non-SGLT2i group and diabetic ketoacidosis in 1 patient in SGLT2i group.

Similar to the multiple roles of selenoproteins in diabetes (13), SGLT2i is also closely associated with both diabetes and heart disease. Although it remains undetermined about the detailed mechanism of the improved outcome associated with SGLT2i, it seems plausible that the cardioprotective effect of SGLT2i played a critical role in alleviating the cardiotoxicity of anti-cancer treatments. SGLT2i target the SGLT2 protein, which is located on the luminal border of the epithelial cells of the proximal convoluted tubules in the kidney. This cotransporter ordinarily reabsorbs 90–97% of the glucose filtered at the glomerulus (14). SGLT2i effectively treat type 2 diabetes by improving glucose levels, which are associated with reductions in body mass and blood pressure. Beyond diabetes, they also protect against heart and kidney complications, decreasing heart failure hospitalization and effect seen even in non-diabetic patients with reduced ejection fraction heart failure (15). In previous studies, SGLT2i could potentially mitigate the adverse effects, especially cardiotoxicity of cancer treatments (16, 17). The incidence of MACE was insignificant in the present study, which is consistent with previous studies (10). However, a trend toward fewer MACE was observed in SGLT2i group. The total number of cardiovascular events was relatively low, and our study may have been underpowered to detect a statistically significant difference in MACE rates, representing a potential type II error. Definitive evaluation of the cardioprotective effects of SGLT2i in this specific population requires future investigation with larger sample sizes and longer follow-up durations to adequately capture cardiovascular endpoints.

Other than cardioprotective effect, SGLT2i may also exert potential anti-tumor effect via multiple mechanisms, including metabolic modulation, disruption of oncogenic signaling pathways, and synergism with conventional therapies. 1) Reduction of glucose uptake in tumor cells. The Warburg effect, marked by elevated glucose consumption and lactate fermentation, is a prevalent characteristic of lung cancer (18). SGLT2 is one of the transporters for active glucose uptake into cancer cell, which has been detected in lung cancer (6, 7). SGLT2i reduces glucose uptake in cancer cells, thereby impairing their metabolic adaptability and proliferation. 2) Interference with tumor cell signaling pathways. Beyond metabolic effects, SGLT2i may disrupt critical oncogenic signaling cascades. Dapagliflozin has also been demonstrated to suppress tumor growth and clonogenic survival by targeting the AMPK/mTOR pathway in breast cancer (19). The AMPK/mTOR Pathway as a critical driver of lung cancer growth, potential modulation by dapagliflozin to suppress tumor progression and improve survival. It is noteworthy that these pathways also serve as core regulatory hubs in the development of diabetic complications, such as diabetic cardiomyopathy. Previous study indicates that dysregulation of signaling pathways including TGF-β/Smad, NF-κB, PI3K/AKT, Nrf2, and AMPK is a key mechanism underlying myocardial injury, and that multi-targeted interventions on these pathways can offer therapeutic benefits (20). 3) Synergistic effects with cancer therapy. The combination of SGLT2i with conventional anticancer therapies presents a promising therapeutic strategy. Current clinical evidence suggested that the addition of SGLT2i can enhance the efficacy of standard chemotherapy, radiotherapy targeted or immunotherapy in cancer patients (10, 21–23).

Beyond the direct antitumor effects of SGLT2i, indirect mechanisms may also confer potential survival benefits. 1) Ameliorating metabolic derangements. The relationship between type 2 diabetes and cancer is shaped by several metabolic abnormalities, including hyperinsulinemia, elevated insulin-like growth factor I (IGF-I), hyperglycemia, and inflammatory cytokines (24). In addition, malignancies can disrupt glucose metabolism by inducing peripheral insulin resistance and sequestering glucose from skeletal muscle and adipose tissue to fuel tumor proliferation (25). Therefore the use of SGLT2i may offer significant benefits in improving survival outcomes by potentially ameliorate metabolic derangements. 2) Weight and blood pressure management. SGLT2i effectively manage body weight and blood pressure (26), with obesity and hypertension having been demonstrated in previous studies to contribute to disease progression in cancer patients (24). 3) Cardiorenal protective effects. SGLT2i exhibit potential cardiorenal protective effects while also mitigating cancer-therapy-induced cardiotoxicity (27).

In patients with advanced lung cancer receiving medical therapy, acute kidney injury was not an uncommon complication. Although there was no significant difference in baseline creatinine levels between the two groups and the difference in the incidence of acute kidney injury did not reach statistical significance, we observed a numerically lower incidence of acute kidney injury in the SGLT2i group compared with the control group. This trend may be related to the known reno-protective mechanisms of SGLT2i. Through multiple pathways—such as reducing intraglomerular pressure, improving tubular hypoxia, attenuating inflammation and fibrosis, direct cellular protection and systemic benefits with indirect renal effects (28). In this study, patients with advanced lung cancer are often at high risk of acute kidney injury due to factors such as the tumor itself, dehydration, or nephrotoxic agents. The potential reno-protective effects of SGLT2i may have partially mitigated the impact of these factors on renal function. However, it must be emphasized that, given the limited sample size and retrospective design of this study, this observation should be interpreted as preliminary and may be influenced by unmeasured confounding factors. Future larger-scale prospective studies are warranted to specifically evaluate the renal safety and protective effects of SGLT2i in cancer patients, particularly those receiving nephrotoxic anticancer therapies. Interestingly, the SGLT2i group showed a numerically lower incidence compared with the control group, although the difference did not reach statistical significance. This observation may reflect potential renal protective effects of SGLT2i, consistent with their known mechanisms of action (29). SGLT2i promote urinary glucose excretion, a mechanism that has been associated with an increased risk of urinary tract infections (30). In prior studies, urinary tract infection was the most frequently reported adverse effect of SGLT2i, with an incidence of approximately 3.6-5.7% (29). In our study, the incidence of urinary tract infections was 3.2% in patients with SGLT2i was similar to previous reports (29). In addition, compared with the control group, SGLT2i did not significantly increase the risk of urinary tract infections. The incidence of hypoglycemia and ketoacidosis was low in both the SGLT2i and control groups without significant difference. Our findings suggest that the use of SGLT2i did not increase the risk of these adverse events.

The demonstrated efficacy of SGLT2i in improving survival rates among patients with advanced lung cancer and diabetes, without increasing additional risks, could support their integration into treatment protocols for this vulnerable population. Current standard cancer therapies, including chemotherapy and immunotherapy, may benefit from the adjunctive use of SGLT2i to optimize diabetic patient outcomes. However, whether SGLT2i confer survival benefits in non-diabetic patients with advanced lung cancer remains uncertain and warrants further investigation.