Weight change and Impact on prognosis in patients with Advanced Non-small Cell Lung Cancer with Concomitant diabetes mellitus treated with SGLT2 inhibitors

Weight change and Impact on prognosis in patients with Advanced Non-small Cell Lung Cancer with Concomitant diabetes mellitus treated with SGLT2 inhibitors | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Weight change and Impact on prognosis in patients with Advanced Non-small Cell Lung Cancer with Concomitant diabetes mellitus treated with SGLT2 inhibitors Noboru Morikawa, Tateaki Naito, Yuta Okawa, Suguru Matsuda, Meiko Morita, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8406171/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Apr, 2026 Read the published version in Supportive Care in Cancer → Version 1 posted 9 You are reading this latest preprint version Abstract Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are commonly used to manage diabetes and are known to cause weight loss. This study aimed to clarify whether SGLT2i-induced weight loss influences survival or toxicity during chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and comorbid diabetes. Methods: We conducted a retrospective analysis of patients with advanced NSCLC and diabetes who received first-line chemotherapy. Patients with an Eastern Cooperative Oncology Group performance status (PS) ≥ 3 or higher, driver mutations, interstitial lung disease, untreated diabetes, or missing data were excluded. We compared weight changes, progression-free survival (PFS), overall survival (OS), and adverse events between patients with and without SGLT2i. We defined cachexia as either 5% or more body-weight loss within six months prior to the initiation of lung cancer treatment or weight loss greater than 2% and a body-mass index (BMI) of less than 20 kg/m². Results: Eighteen patients (21.9%) out of 82 received SGLT2i for diabetes. There was no difference in the incidence of cachexia between the two groups (66.7% vs. 46.9%, p = 0.184), despite significant weight loss in the SGLT2 group compared to the non-SGLT2 group (median − 5.8% vs. −3.4%, p = 0.039). No significant differences were observed in progression-free survival (PFS) (median 6.2 vs. 4.1 months, p = 0.512) or overall survival (OS) (median 11.9 vs. 14.6 months, p = 0.583). Grade ≥ 3 adverse events occurred in 11.1% of patients in the SGLT2i group and 31.2% of patients in the non-SGLT2i group (P = 0.132). There were no cases of diabetic ketoacidosis or urinary tract infections. Conclusion: SGLT2 inhibitors were associated with weight loss and were not associated with worse survival or increased toxicity in this retrospective cohort. NSCLC Diabetes mellitus SGLT2i Cachexia Weight loss Figures Figure 1 Figure 2 Figure 3 Introduction Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a class of oral antidiabetic agents that promote urinary glucose excretion by inhibiting glucose reabsorption in the renal proximal tubules.[ 1 ] Beyond their glucose-lowering effects, SGLT2is are associated with weight loss, diuresis, and potential cardiovascular and renal benefits. Consequently, they are being prescribed to a growing number of patients with chronic heart failure, chronic kidney disease, and type 2 diabetes mellitus. [ 2 – 5 ] In patients with advanced non-small cell lung cancer (NSCLC), unintentional weight loss is a well-recognized poor prognostic factor. [ 6 , 7 ] Cancer cachexia, which is characterized by involuntary weight loss and metabolic dysfunction, negatively impacts physical function, tolerance to anticancer therapy, and survival outcomes. [ 8 – 10 ] Since the diagnostic criteria for cachexia are largely based on body weight and BMI, [ 11 ] medications that cause weight loss may complicate the interpretation of clinical deterioration in cancer patients. Despite the growing use of SGLT2is, few studies have evaluated their impact on cancer-related outcomes, particularly in patients with lung cancer. [ 12 ] It remains unclear whether SGLT2i-induced weight loss exacerbates cancer cachexia or affects the efficacy and safety of chemotherapy. Thus, we investigated whether SGLT2i use was associated with body weight loss, survival outcomes, and treatment-related toxicity in patients with advanced NSCLC and comorbid diabetes receiving first-line chemotherapy. Materials and Methods Study Design and Patient Selection: This retrospective study was conducted at the Shizuoka Cancer Center. We reviewed the medical records. The inclusion criteria were: 1) pathologically confirmed advanced or recurrent NSCLC; 2) comorbid type 2 diabetes requiring treatment; 3) ECOG (Eastern Cooperative Oncology Group) performance status (PS) of 0–2; and 4) received at least first-line chemotherapy between January 2017 and December 2022. Patients were excluded if they had driver mutations (EGFR, ALK, or ROS1), interstitial lung disease, untreated diabetes, missing clinical data, or had received unapproved agents through clinical trials. (Fig. 1 ) We defined cachexia as either 1) a loss of at least 5% of body weight within six months prior to the initiation of lung cancer treatment or 2) weight loss of more than 2% and a body mass index (BMI) of less than 20 kg/m². Data collection and group definition: Patient characteristics, including age, sex, ECOG performance status (PS), histology, body mass index (BMI), laboratory data, and treatment regimens, were obtained from electronic medical records. Patients were categorized into two groups based on SGLT2i use at the start of chemotherapy. Diabetes medications include SGLT2 inhibitors, biguanides, dipeptidyl peptidase-4 inhibitors (DPP4i), thiazolidinediones, sulfonylureas, glinides, α-glucosidase inhibitors, and GLP-1 receptor agonists. The first-line chemotherapy regimen included chemotherapy alone (CDDP/CBDCA + PEM, CBDCA + nab-PTX, CDGP + DTX, or VNR) or chemotherapy plus immune checkpoint inhibitors (CDDP/CBDCA + PEM + pembrolizumab, CBDCA + nab-PTX + pembrolizumab, CBDCA + PEM, PTX + nivolumab + ipilimumab, CBDCA + PTX + atezolizumab + bevacizumab), or immune checkpoint inhibitors alone (pembrolizumab or atezolizumab). Endpoints The primary endpoint was the rate of weight loss and incidence of cachexia within six months of initiating lung cancer chemotherapy. The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and the frequency of grade ≥ 3 adverse events. PFS and OS were defined from the date of chemotherapy initiation to the date of disease progression or death, respectively. Statistical Analysis: PFS and OS were estimated using the Kaplan–Meier method. PFS and OS were calculated from the initiation of chemotherapy. OS was censored at the date of the last visit for patients whose deaths could not be confirmed. Chi-square tests or Fisher's exact tests were used to compare categorical variables, and the Wilcoxon rank-sum test was used to compare continuous measures between groups. Two-sided P-values less than 0.05 were considered statistically significant. We used Cox proportional hazards regression models to evaluate potential predictive and prognostic factors for OS. Significant factors from the initial analysis and known prognostic factors, including PD-L1 tumor proportion score (TPS), were included in the multivariable analysis. Analyses were performed using EZR version 1.60 (Saitama Medical Center, Jichi Medical University, Saitama, Japan). [ 13 ] Ethical Considerations This study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was reviewed and approved by the Institutional Review Board of Shizuoka cancer center (Approval No. J2023-165-2023-2), which waived the requirement for informed consent since patient information was collected via an opt-out method. Details of the study were made publicly available to allow patients to opt out of participating. Results Patient Characteristics Of the 183 consecutive patients, those with driver mutations, interstitial pneumonia, untreated diabetes, missing data, or participation in a clinical trial were excluded. A total of 82 patients were included in this study. The median age was 71 years (range, 44–88 years). Seventy-four patients (90.2%) had an ECOG PS of 0 or 1, 69 patients (84.1%) were male, and 74 patients (90.2%) were smokers. NSCLC was observed in 65 patients (79.2%). Twenty-eight patients (34.1%) received only chemotherapy, 31 patients (37.8%) received immune checkpoint inhibitor (ICI) monotherapy, and 23 patients (28.0%) received ICI + chemotherapy. SGLT2i were administered to 18 patients (21.9%). The median age was significantly lower in the SGLT2i group than in the non-SGLT2i group (68.5 years [range: 44–80] vs. 73.0 years [range: 51–88]; P = 0.014). Additionally, the SGLT2i group required a higher number of diabetes medications (median: 3 [range: 1–5]) than the non-SGLT2i group (median: 2 [range: 1–4]). Twenty-seven patients (32.9%) had a PD-L1 TPS ≥ 50%. All patients received first-line chemotherapy, with 28 patients (34.1%) receiving chemotherapy alone, 31 patients (37.8%) receiving a PD-1/PD-L1 inhibitor monotherapy, and 23 patients (28.0%) receiving a PD-1/PD-L1 inhibitor and platinum-based chemotherapy (Table 1 ). Table 1 Patient characteristics Patients background All (n = 82) SGLT2 (n = 18) non-SGLT2 (n = 64) P-value Median age (range) yr median 71.0 (44–88) 68.5 (44–80) 73.0 (51–88) 0.014 ECOG-PS:0–1, n (%) 74 (90.2) 17 (94.4) 56 (87.5) 0.676 Gender, n (%) male 69 (84.1) 16 (88.9) 53 (82.8) 0.723 Smoking-status, n (%) smoker 74 (90.2) 57 (89.1) 17 (94.4) 0.678 Histology, n (%) non-Sq 65 (79.2) 15 (83.3) 49 (76.6) 0.75 Body mass index median 22.8 (14.4–40.5) 24.1(17.6–40.5) 22.7 (14.4–29.6) 0.203 Cachexia, n (%) 42 (51.2) 12 (66.7) 30 (46.9) 0.184 HbA1c (range) % 7.0 (4.2–9.5) 7.3 (4.2–9.3) 6.8 (5.5–9.5) 0.223 PD-L1 TPS, n (%) ≧ 50% 27 (32.9) 2 (11.1) 25 (39.1) 0.044 Albumine (range) g/dl 3.8 (1.8–5.2) 3.8 (3.3–5.2) 3.8 (1.8–4.6) 0.36 Hemoglobin (range) g/dl 13.1 (7.7–17.1) 13.4 (11.4–17.7) 13.0 (7.1–16.6) 0.082 CRP (range) mg/dl 1.04 (0.04–23.9) 1.05 (0.2–12.9) 1.04 (0.04–23.9) 0.801 Number of medications for DM 2 (1–5) 3 (1–5) 2 (1–4) 0.026 First-line regimen Chemocherapy only % 28 (34.1) 4 (22.2) 24 (37.5) 0.27 ICI only % 31 (37.8) 2 (11.1) 29 (45.3) 0.012 ICI + Chemocherapy % 23 (28.0) 12 (66.7) 11 (11.2) < 0.001 Abbreviations: ECOG-PS: eastern cooperative oncology group-performance status, TPS: Tumor Proportion Score, CRP: C-reactive protein, DM: Diabetes Mellitus, ICI: immune check inhibitor. No significant differences were observed between the two groups regarding ECOG PS, gender, BMI, histological subtype, smoking status, or frequency of ICI use. Similarly, there were no significant differences in HbA1c, hemoglobin, or albumin levels between the groups. The most prescribed antidiabetic medication was DPP4i, used by 59 patients (71.9%), followed by metformin in 31 patients (37.8%). SGLT2i was the third most common medication. Body weight changes and cachexia In the SGLT2i group, there was a significant reduction in body weight at the start of lung cancer treatment compared to six months prior. The reduction was − 5.8% (range: −16.5% to − 1.2%) vs. −3.4% (range: −16.1% to + 7.1%) ( P = 0.039). While not statistically significant, there was a trend towards a higher incidence of cachexia in the SGLT2i group compared to the non-SGLT2i group (66.7% vs. 46.9%; P = 0.184). In contrast, no significant weight reduction was observed with other antidiabetic agents, including DPP4i, biguanides, α-glucosidase inhibitors, thiazolidinediones, insulin, sulfonylureas, glinides, and glucagon-like peptide-1 receptor agonists. (Fig. 2 ). Outcomes of Chemotherapy The median follow-up duration from the initiation of chemotherapy was 13.7 months. The ORR was 32.9% across the cohort, with 44.4% in the SGLT2i group and 29.7% in the non-SGLT2i group. There was no significant difference between the two groups. ( P = 0.266). The median PFS was 6.2 months (95% confidence interval [CI]: 4.5–18.3 months) in the SGLT2i group and 4.1 months (95% CI: 3.2–7.5 months) in the non-SGLT2i group. There was no significant difference between the groups (hazard ratio [HR]: 0.82; 95% CI: 0.45–1.48; P = 0.512) (Fig. 3 a). The median OS was 11.9 months (95% CI: 6.9–28.1 months) in the SGLT2i group and 14.6 months (95% CI: 10.8–20.5 months) in the non-SGLT2i group. Again, no significant difference was observed between the groups (HR: 1.18; 95% CI: 0.64–2.12; P = 0.583) (Fig. 3 B). Multivariate analysis, adjusted for age and ECOG-PS, showed that the use of SGLT2i and PD-L1 (TPS ≥ 50% vs. <50%) were not significantly associated with overall survival (Table 2 ). Table 2 Multivariate analysis for OS Variants HR 95% CI P value SGLT2i (yes vs. no) 1.15 0.58–2.29 0.685 ECOG-PS (0–1 vs. 2) 1.13 0.46–2.80 0.866 Age (under 75 vs. over 75years) 1.13 0.67–1.91 0.647 TPS ( ≧ 50% vs. <50%) 0.69 0.36–1.34 0.281 ICI (yes vs. no) 0.37 0.18–0.77 0.007 Abbreviations: OS overall survival, HR hazard ratio, CI: confidence interval, SGLT2i: sodium-glucose cotransporter 2 inhibitor, ECOG-PS: eastern cooperative oncology group-performance status, TPS: tumor proportion score, ICI: immune check inhibitor. Adverse Event There was no significant difference in the incidence of Grade ≥ 3 adverse events between the groups: 2 patients (11.1%) in the SGLT2i group and 20 patients (31.2%) in the non-SGLT2i group ( P = 0.132). The incidence of gastrointestinal toxicity was comparable between the SGLT2i group (seven patients, 38.9%) and the non-SGLT2i group (23 patients, 35.9%) ( P = 1.00). There were also no significant differences in the incidence of anorexia, nausea, constipation, or other gastrointestinal symptoms between the two groups ( P > 0.05). Additionally, no SGLT2i-specific adverse events, such as urinary tract infections or diabetic ketoacidosis, were observed in either group during chemotherapy (Table 3 ). Table 3 Adverse event Adverse event SGLT2 Non-SGLT2 p-value n 18 64 Any grade ≧ 3 (%) 2 (11.1) 20 (31.2) 0.132 Gastrointestinal toxicity (%) 7 (38.9) 23 (35.9) 1 Anorexia (%) 1 (5.6) 12 (18.8) 0.279 Nausea (%) 1 (5.6) 6 (9.3) 1 Constipation (%) 4 (22.2) 7 (10.9) 0.246 Diabetic ketoacidosis (%) 0 (0) 0 (0) Urinary tract infection (%) 0 (0) 0 (0) Discussion This study is among the first to investigate whether SGLT2i induces weight loss and affect survival outcomes in patients with advanced NSCLC and comorbid diabetes. Use of SGLT2i was associated with significant weight loss at the initiation of first-line therapy for NSCLC, compared with six months prior. However, no significant differences in objective response rate or survival outcomes were observed between patients treated with and without SGLT2i. Among patients with advanced NSCLC and diabetes who received SGLT2i during chemotherapy, there were no cases of diabetic ketoacidosis or urinary tract infections. Furthermore, SGLT2i use was not associated with an increased incidence of adverse events, such as anorexia, nausea, or vomiting, which may also be symptoms of ketoacidosis. In patients with advanced NSCLC undergoing chemotherapy, the use of SGLT2i was associated with significant weight loss. Previous studies have reported that SGLT2i induce weight loss. Although weight reduction varied across studies, rates of approximately 2.5% to 4.7% have been reported in patients with diabetes. SGLT2i promote weight loss by exerting a diuretic effect through the inhibition of glucose reabsorption in the proximal renal tubules and by enhancing catabolism, which leads to reductions in skeletal muscle mass and adipose tissue [ 15 ]. A multicenter, prospective study of advanced NSCLC patients without treatment and with a good performance status demonstrated that greater weight loss over a 52-week period was significantly associated with shorter overall survival [ 17 ]. While no significant differences in weight loss were observed with antidiabetic agents other than SGLT2i, this study clearly demonstrated that SGLT2i use was associated with significant weight loss in patients with NSCLC and comorbid diabetes. Weight loss is a known poor prognostic factor for patients with NSCLC [ 18 ]. In the present study, significant weight loss was associated with SGLT2i use. However, despite the observed weight loss, there were no significant differences in PFS and OS between the SGLT2i and non-SGLT2i groups. This suggests that the impact of weight loss on survival may be limited. Two possible reasons for this can be proposed. First, although SGLT2i induced weight loss, it may not have met the criteria for cancer cachexia, which is associated with severe weight loss. Cancer cachexia is a well-established poor prognostic factor, as shown in some studies. [ 6 , 19 ] Cancer cachexia is mainly defined by weight loss. In the present study, cachexia was defined as either a reduction in body weight of at least 5% or a BMI of less than 20 with a weight loss of at least 2%. There was a trend toward more patients in the SGLT2i group having cachexia, though it was not statistically significant. In cancer cachexia, weight loss is induced by the release of inflammatory cytokines as a biological response to cancer [ 20 ]. Both cancer cachexia and SGLT2i use result in weight loss; however, the mechanisms differ. Weight loss caused by SGLT2i does not involve inflammatory cytokines, unlike weight loss associated with cancer cachexia. This distinction may explain why no significant impact on survival outcomes was seen despite the weight loss observed with SGLT2i. A second possible reason is that the weight loss induced by SGLT2i is different from that seen in cancer cachexia. It primarily involves a reduction in body fluid volume rather than a substantial decrease in skeletal muscle mass. SGLT2 inhibitors are known to have a diuretic effect by inhibiting glucose reabsorption in the renal proximal tubules [ 21 ]. A prospective study using bioimpedance spectroscopy tracked changes in body composition and fluid status over six months in 27 patients with type 2 diabetes who were treated with either empagliflozin or dapagliflozin. The primary cause of weight loss was a reduction in fat mass. Lean body mass (including skeletal muscle) showed a temporary decrease in the early stages, followed by stabilization. A transient reduction in extracellular fluid was observed immediately after treatment initiation, but by three months, it had returned to baseline. These findings suggest that weight loss induced by SGLT2 inhibitors is mainly due to reductions in fat and body fluid with limited impact on skeletal muscle mass. This mechanism differs from that of cancer cachexia. Fluid retention, such as edema or pleural/peritoneal effusions, is a strong negative prognostic factor in cancer patients. Therefore, a reduction in body fluid volume may promote survival. [ 22 ] Therefore, the mild weight loss induced by SGLT2 inhibitors, which occurs via a mechanism different from that of cancer cachexia, likely has little impact on prognosis. Previous studies have demonstrated the effects of SGLT2i on reducing blood glucose, reducing cardiovascular risk, and protecting the kidneys.[ 21 , 23 ] However, they have also been associated with adverse events, such as ketoacidosis and urinary tract infections.[ 24 ] In the case of ketoacidosis, gastrointestinal symptoms such as nausea, vomiting, loss of appetite, and abdominal pain have been reported. [ 25 ] These symptoms also occur as side effects of chemotherapy. Furthermore, since SGLT2i-induced euglycemic diabetic ketoacidosis has been reported, [ 26 ] it may be difficult to distinguish whether nausea and loss of appetite are caused by ketosis or are adverse events. Reports exist of ketoacidosis being induced during fasting periods, such as the perioperative phase, despite continued SGLT2i use.[ 27 ] Therefore, although chemotherapy-related adverse events like nausea and anorexia may occur, the continuation of SGLT2i therapy could induce ketoacidosis. Given normal blood glucose levels, ketoacidosis may not be easily recognized, and its gastrointestinal symptoms may be misinterpreted as adverse effects of chemotherapy. In the present study, however, no cases of ketoacidosis occurred during chemotherapy, and there were no significant differences in the incidence of gastrointestinal symptoms, such as nausea and vomiting, between the SGLT2i and non-SGLT2i groups. With appropriate supportive care, chemotherapy can be safely administered even while taking SGLT2 inhibitors. Therefore, there is little evidence to suggest discontinuing SGLT2i at the start of chemotherapy for lung cancer patients. However, if chemotherapy causes fasting due to gastrointestinal toxicity, suspending SGLT2i use might be advisable. Limitations of This Study Our study has several limitations. First, it is a single-center, retrospective study with a small sample size, which may introduce selection bias and prevent the findings from being generalized. Second, the SGLT2i analyzed in this study was prescribed by the patients' primary care physicians. Therefore, the exact timing of SGLT2i initiation is unclear, which makes it difficult to determine if the weight loss was due to the cancer itself or the initiation of SGLT2i therapy. Third, since we did not measure serum ketone levels, it is unclear whether SGLT2i use during chemotherapy for non-small cell lung cancer contributes to an increase in ketosis. In our cohort, patients in the SGLT2i group had a higher percentage of tumors with PD-L1 expression below 50%, and they were more likely to receive chemoimmunotherapy as a primary treatment. Meanwhile, immune checkpoint inhibitor (ICI) monotherapy was more prevalent in the non-SGLT2i group. These imbalances may reflect physician preferences to avoid ICI monotherapy in diabetic patients, or they may have arisen by chance given the limited sample size. A significantly higher rate of patients in the SGLT2i group received combination therapy with ICIs (immune checkpoint inhibitors) and chemotherapy. This could potentially introduce an additional confounding factor when evaluating the impact of SGLT2i on prognosis. Future Perspectives SGLT2 inhibitors have demonstrated efficacy in patients with diabetes, chronic heart failure, and chronic kidney disease. As such, their use is expected to increase in the coming years. Additionally, one report indicates that SGLT2 inhibitors may improve chemotherapy-related edema.[ 28 ] In the future, prospective studies will be needed to evaluate whether SGLT2i impact survival outcomes or reduce adverse events in patients with advanced NSCLC receiving chemotherapy. These studies should include patients with diabetes, chronic heart failure, and chronic kidney disease. Furthermore, the potential for increased ketosis must be investigated, especially in patients who experience gastrointestinal toxicity during chemotherapy, by measuring serum ketone levels prospectively. As the indications for SGLT2i expand, the number of lung cancer patients receiving these agents will likely grow. Therefore, it will become increasingly relevant to determine whether SGLT2i uses prognosis or contributes to weight loss in patients with lung cancer. Conclusion In patients with advanced NSCLC and comorbid diabetes, SGLT2i use was associated with significant weight loss compared to six months prior to lung cancer treatment. There were no significant differences in response rate or survival outcomes; however, the incidence of adverse events was not increased in the SGLT2i group. The weight loss associated with SGLT2i use in patients with advanced NSCLC and diabetes was statistically significant but did not meet the criteria for cachexia. Its impact on prognosis was also considered limited. Declarations Conflict of Interest None of the authors has any financial or personal relationship with other individuals or organizations that could inappropriately influence this study. Author Contribution Conceptualization: Noboru Morikawa, Tateaki Naito, Yuta Okawa.Data collection: Noboru Morikawa.Formal analysis: Noboru Morikawa, Tateaki Naito.Manuscript draft: Noboru Morikawa, Tateaki Naito.Manuscript editing and review: all authors.All authors approved the final published version. Acknowledgments None. Data Availability The datasets generated and/or analyzed during the current study are not publicly available due to ethical restrictions but are available from the corresponding author on reasonable request. References Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128. doi: 10.1056/NEJMoa1504720 . Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323–334. doi: 10.1056/NEJMoa1515920 . Girardi ACC, Polidoro JZ, Castro PC, et al. 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Euglycemic diabetic ketoacidosis in the era of SGLT-2 inhibitors. BMJ Open Diabetes Res Care. 2023;11(5):e003666. doi: 10.1136/bmjdrc-2023-003666 . Thiruvenkatarajan V, Meyer EJ, Nanjappa N, et al. Perioperative diabetic ketoacidosis associated with sodium-glucose cotransporter-2 inhibitors: a systematic review. Br J Anaesth. 2019;123(1):27–36. doi: 10.1016/j.bja.2019.03.028 . Oyakawa T, Miura K, Muraoka N, et al. Sodium-glucose cotransporter 2 inhibitors for mesenchymal-epithelial transition inhibitor-induced edema. Thorac Cancer. 2025;16(2):e15509. doi: 10.1111/1759-7714.15509 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 28 Apr, 2026 Read the published version in Supportive Care in Cancer → Version 1 posted Editorial decision: Revision requested 20 Feb, 2026 Reviews received at journal 18 Feb, 2026 Reviewers agreed at journal 08 Feb, 2026 Reviews received at journal 26 Jan, 2026 Reviewers agreed at journal 22 Jan, 2026 Reviewers invited by journal 21 Jan, 2026 Editor assigned by journal 15 Jan, 2026 Submission checks completed at journal 05 Jan, 2026 First submitted to journal 19 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8406171","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":579003416,"identity":"eb738b3d-1372-4142-94ac-61f92bd7f4d8","order_by":0,"name":"Noboru Morikawa","email":"","orcid":"","institution":"Division of Thoracic Oncology, Shizuoka Cancer Center","correspondingAuthor":false,"prefix":"","firstName":"Noboru","middleName":"","lastName":"Morikawa","suffix":""},{"id":579003417,"identity":"df222ae2-9f0b-49ae-b5c2-b46510122ba1","order_by":1,"name":"Tateaki 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09:43:28","extension":"xml","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":91020,"visible":true,"origin":"","legend":"","description":"","filename":"8c60052891f94715a150f6ca4b8971921structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8406171/v1/f40347d1658c4cbc43ce756f.xml"},{"id":101019160,"identity":"dbf80062-e61e-4a21-8d76-42c7af907863","added_by":"auto","created_at":"2026-01-24 00:37:32","extension":"html","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":102629,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8406171/v1/cd0a0fce23dcc64c2fe2f717.html"},{"id":101019157,"identity":"ff888f81-efd1-4f25-ba6c-d8c68985376d","added_by":"auto","created_at":"2026-01-24 00:37:32","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":102202,"visible":true,"origin":"","legend":"\u003cp\u003ePatients flow diagram\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8406171/v1/5ae6a6ee56dd538bc6c0df42.jpg"},{"id":101019142,"identity":"7cc9901a-815b-49cc-93e4-c704535f9878","added_by":"auto","created_at":"2026-01-24 00:37:32","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":124507,"visible":true,"origin":"","legend":"\u003cp\u003eWeight rate change\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8406171/v1/9312c39b06398c07c704d20e.jpg"},{"id":101019161,"identity":"a46486dd-1692-484b-aa95-9bac5182e5d2","added_by":"auto","created_at":"2026-01-24 00:37:33","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":72984,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Kaplan–Meier estimates of progression-free survival among patients with or without SGLT2i. (b) Kaplan–Meier estimates of overall survival among patients with or without SGLT2i.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8406171/v1/50658325aca63faa2189efec.jpg"},{"id":108437873,"identity":"11de5361-c090-4445-9cc7-35ea09663117","added_by":"auto","created_at":"2026-05-04 16:04:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":607809,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8406171/v1/3baa3fe5-e0a6-4da1-801f-999c209599ab.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eWeight change and Impact on prognosis in patients with Advanced Non-small Cell Lung Cancer with Concomitant diabetes mellitus treated with SGLT2 inhibitors\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSodium-glucose cotransporter 2 inhibitors (SGLT2i) are a class of oral antidiabetic agents that promote urinary glucose excretion by inhibiting glucose reabsorption in the renal proximal tubules.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] Beyond their glucose-lowering effects, SGLT2is are associated with weight loss, diuresis, and potential cardiovascular and renal benefits. Consequently, they are being prescribed to a growing number of patients with chronic heart failure, chronic kidney disease, and type 2 diabetes mellitus. [\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eIn patients with advanced non-small cell lung cancer (NSCLC), unintentional weight loss is a well-recognized poor prognostic factor. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] Cancer cachexia, which is characterized by involuntary weight loss and metabolic dysfunction, negatively impacts physical function, tolerance to anticancer therapy, and survival outcomes. [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Since the diagnostic criteria for cachexia are largely based on body weight and BMI, [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] medications that cause weight loss may complicate the interpretation of clinical deterioration in cancer patients. Despite the growing use of SGLT2is, few studies have evaluated their impact on cancer-related outcomes, particularly in patients with lung cancer. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] It remains unclear whether SGLT2i-induced weight loss exacerbates cancer cachexia or affects the efficacy and safety of chemotherapy.\u003c/p\u003e \u003cp\u003eThus, we investigated whether SGLT2i use was associated with body weight loss, survival outcomes, and treatment-related toxicity in patients with advanced NSCLC and comorbid diabetes receiving first-line chemotherapy.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003eStudy Design and Patient Selection:\u003c/p\u003e \u003cp\u003eThis retrospective study was conducted at the Shizuoka Cancer Center. We reviewed the medical records. The inclusion criteria were: 1) pathologically confirmed advanced or recurrent NSCLC; 2) comorbid type 2 diabetes requiring treatment; 3) ECOG (Eastern Cooperative Oncology Group) performance status (PS) of 0\u0026ndash;2; and 4) received at least first-line chemotherapy between January 2017 and December 2022. Patients were excluded if they had driver mutations (EGFR, ALK, or ROS1), interstitial lung disease, untreated diabetes, missing clinical data, or had received unapproved agents through clinical trials. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) We defined cachexia as either 1) a loss of at least 5% of body weight within six months prior to the initiation of lung cancer treatment or 2) weight loss of more than 2% and a body mass index (BMI) of less than 20 kg/m\u0026sup2;.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eData collection and group definition:\u003c/p\u003e \u003cp\u003ePatient characteristics, including age, sex, ECOG performance status (PS), histology, body mass index (BMI), laboratory data, and treatment regimens, were obtained from electronic medical records. Patients were categorized into two groups based on SGLT2i use at the start of chemotherapy. Diabetes medications include SGLT2 inhibitors, biguanides, dipeptidyl peptidase-4 inhibitors (DPP4i), thiazolidinediones, sulfonylureas, glinides, α-glucosidase inhibitors, and GLP-1 receptor agonists. The first-line chemotherapy regimen included chemotherapy alone (CDDP/CBDCA\u0026thinsp;+\u0026thinsp;PEM, CBDCA\u0026thinsp;+\u0026thinsp;nab-PTX, CDGP\u0026thinsp;+\u0026thinsp;DTX, or VNR) or chemotherapy plus immune checkpoint inhibitors (CDDP/CBDCA\u0026thinsp;+\u0026thinsp;PEM\u0026thinsp;+\u0026thinsp;pembrolizumab, CBDCA\u0026thinsp;+\u0026thinsp;nab-PTX\u0026thinsp;+\u0026thinsp;pembrolizumab, CBDCA\u0026thinsp;+\u0026thinsp;PEM, PTX\u0026thinsp;+\u0026thinsp;nivolumab\u0026thinsp;+\u0026thinsp;ipilimumab, CBDCA\u0026thinsp;+\u0026thinsp;PTX\u0026thinsp;+\u0026thinsp;atezolizumab\u0026thinsp;+\u0026thinsp;bevacizumab), or immune checkpoint inhibitors alone (pembrolizumab or atezolizumab).\u003c/p\u003e \u003cp\u003eEndpoints\u003c/p\u003e \u003cp\u003eThe primary endpoint was the rate of weight loss and incidence of cachexia within six months of initiating lung cancer chemotherapy. The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and the frequency of grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events. PFS and OS were defined from the date of chemotherapy initiation to the date of disease progression or death, respectively.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis:\u003c/h2\u003e \u003cp\u003ePFS and OS were estimated using the Kaplan\u0026ndash;Meier method. PFS and OS were calculated from the initiation of chemotherapy. OS was censored at the date of the last visit for patients whose deaths could not be confirmed. Chi-square tests or Fisher's exact tests were used to compare categorical variables, and the Wilcoxon rank-sum test was used to compare continuous measures between groups. Two-sided P-values less than 0.05 were considered statistically significant. We used Cox proportional hazards regression models to evaluate potential predictive and prognostic factors for OS. Significant factors from the initial analysis and known prognostic factors, including PD-L1 tumor proportion score (TPS), were included in the multivariable analysis. Analyses were performed using EZR version 1.60 (Saitama Medical Center, Jichi Medical University, Saitama, Japan). [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eEthical Considerations\u003c/p\u003e \u003cp\u003e This study was conducted in accordance with the principles of the Declaration of Helsinki.\u003c/p\u003e \u003cp\u003e The study protocol was reviewed and approved by the Institutional Review Board of Shizuoka cancer center (Approval No. J2023-165-2023-2), which waived the requirement for informed consent since patient information was collected via an opt-out method. Details of the study were made publicly available to allow patients to opt out of participating.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003ePatient Characteristics\u003c/p\u003e \u003cp\u003eOf the 183 consecutive patients, those with driver mutations, interstitial pneumonia, untreated diabetes, missing data, or participation in a clinical trial were excluded. A total of 82 patients were included in this study. The median age was 71 years (range, 44\u0026ndash;88 years). Seventy-four patients (90.2%) had an ECOG PS of 0 or 1, 69 patients (84.1%) were male, and 74 patients (90.2%) were smokers. NSCLC was observed in 65 patients (79.2%). Twenty-eight patients (34.1%) received only chemotherapy, 31 patients (37.8%) received immune checkpoint inhibitor (ICI) monotherapy, and 23 patients (28.0%) received ICI\u0026thinsp;+\u0026thinsp;chemotherapy. SGLT2i were administered to 18 patients (21.9%). The median age was significantly lower in the SGLT2i group than in the non-SGLT2i group (68.5 years [range: 44\u0026ndash;80] vs. 73.0 years [range: 51\u0026ndash;88]; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014). Additionally, the SGLT2i group required a higher number of diabetes medications (median: 3 [range: 1\u0026ndash;5]) than the non-SGLT2i group (median: 2 [range: 1\u0026ndash;4]). Twenty-seven patients (32.9%) had a PD-L1 TPS\u0026thinsp;\u0026ge;\u0026thinsp;50%. All patients received first-line chemotherapy, with 28 patients (34.1%) receiving chemotherapy alone, 31 patients (37.8%) receiving a PD-1/PD-L1 inhibitor monotherapy, and 23 patients (28.0%) receiving a PD-1/PD-L1 inhibitor and platinum-based chemotherapy (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e Patient characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients background\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAll (n\u0026thinsp;=\u0026thinsp;82)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSGLT2 (n\u0026thinsp;=\u0026thinsp;18)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003enon-SGLT2 (n\u0026thinsp;=\u0026thinsp;64)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age (range) yr\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71.0 (44\u0026ndash;88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68.5 (44\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e73.0 (51\u0026ndash;88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.014\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG-PS:0\u0026ndash;1, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74 (90.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (94.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e56 (87.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.676\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69 (84.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (88.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e53 (82.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.723\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking-status, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003esmoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74 (90.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e57 (89.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17 (94.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.678\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistology, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003enon-Sq\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65 (79.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49 (76.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emedian\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.8 (14.4\u0026ndash;40.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e24.1(17.6\u0026ndash;40.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e22.7 (14.4\u0026ndash;29.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.203\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCachexia, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (51.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e30 (46.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.184\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHbA1c (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.0 (4.2\u0026ndash;9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.3 (4.2\u0026ndash;9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.8 (5.5\u0026ndash;9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.223\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePD-L1 TPS, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e≧\u0026thinsp;50%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (32.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e25 (39.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.044\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlbumine (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eg/dl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.8 (1.8\u0026ndash;5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.8 (3.3\u0026ndash;5.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.8 (1.8\u0026ndash;4.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eg/dl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.1 (7.7\u0026ndash;17.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13.4 (11.4\u0026ndash;17.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.0 (7.1\u0026ndash;16.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.082\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003emg/dl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.04 (0.04\u0026ndash;23.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.05 (0.2\u0026ndash;12.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.04 (0.04\u0026ndash;23.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.801\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of medications for DM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (1\u0026ndash;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (1\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.026\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst-line regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemocherapy only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (34.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24 (37.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.27\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICI only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (37.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e29 (45.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e0.012\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICI\u0026thinsp;+\u0026thinsp;Chemocherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (28.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11 (11.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eAbbreviations: ECOG-PS: eastern cooperative oncology group-performance status, TPS: Tumor Proportion Score, CRP: C-reactive protein, DM: Diabetes Mellitus, ICI: immune check inhibitor.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNo significant differences were observed between the two groups regarding ECOG PS, gender, BMI, histological subtype, smoking status, or frequency of ICI use. Similarly, there were no significant differences in HbA1c, hemoglobin, or albumin levels between the groups.\u003c/p\u003e \u003cp\u003eThe most prescribed antidiabetic medication was DPP4i, used by 59 patients (71.9%), followed by metformin in 31 patients (37.8%). SGLT2i was the third most common medication.\u003c/p\u003e \u003cp\u003eBody weight changes and cachexia\u003c/p\u003e \u003cp\u003eIn the SGLT2i group, there was a significant reduction in body weight at the start of lung cancer treatment compared to six months prior. The reduction was \u0026minus;\u0026thinsp;5.8% (range: \u0026minus;16.5% to \u0026minus;\u0026thinsp;1.2%) vs. \u0026minus;3.4% (range: \u0026minus;16.1% to +\u0026thinsp;7.1%) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.039). While not statistically significant, there was a trend towards a higher incidence of cachexia in the SGLT2i group compared to the non-SGLT2i group (66.7% vs. 46.9%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.184).\u003c/p\u003e \u003cp\u003eIn contrast, no significant weight reduction was observed with other antidiabetic agents, including DPP4i, biguanides, α-glucosidase inhibitors, thiazolidinediones, insulin, sulfonylureas, glinides, and glucagon-like peptide-1 receptor agonists. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOutcomes of Chemotherapy\u003c/p\u003e \u003cp\u003eThe median follow-up duration from the initiation of chemotherapy was 13.7 months. The ORR was 32.9% across the cohort, with 44.4% in the SGLT2i group and 29.7% in the non-SGLT2i group. There was no significant difference between the two groups. (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.266). The median PFS was 6.2 months (95% confidence interval [CI]: 4.5\u0026ndash;18.3 months) in the SGLT2i group and 4.1 months (95% CI: 3.2\u0026ndash;7.5 months) in the non-SGLT2i group. There was no significant difference between the groups (hazard ratio [HR]: 0.82; 95% CI: 0.45\u0026ndash;1.48; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.512) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea). The median OS was 11.9 months (95% CI: 6.9\u0026ndash;28.1 months) in the SGLT2i group and 14.6 months (95% CI: 10.8\u0026ndash;20.5 months) in the non-SGLT2i group. Again, no significant difference was observed between the groups (HR: 1.18; 95% CI: 0.64\u0026ndash;2.12; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.583) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Multivariate analysis, adjusted for age and ECOG-PS, showed that the use of SGLT2i and PD-L1 (TPS\u0026thinsp;\u0026ge;\u0026thinsp;50% vs. \u0026lt;50%) were not significantly associated with overall survival (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate analysis for OS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariants\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSGLT2i (yes vs. no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.58\u0026ndash;2.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.685\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG-PS (0\u0026ndash;1 vs. 2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.46\u0026ndash;2.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.866\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (under 75 vs. over 75years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.67\u0026ndash;1.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.647\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTPS (\u0026thinsp;≧\u0026thinsp;50% vs. \u0026lt;50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.36\u0026ndash;1.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.281\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICI (yes vs. no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.18\u0026ndash;0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.007\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: OS overall survival, HR hazard ratio, CI: confidence interval, SGLT2i: sodium-glucose cotransporter 2 inhibitor, ECOG-PS: eastern cooperative oncology group-performance status, TPS: tumor proportion score, ICI: immune check inhibitor.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAdverse Event\u003c/p\u003e \u003cp\u003eThere was no significant difference in the incidence of Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events between the groups: 2 patients (11.1%) in the SGLT2i group and 20 patients (31.2%) in the non-SGLT2i group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.132).\u003c/p\u003e \u003cp\u003eThe incidence of gastrointestinal toxicity was comparable between the SGLT2i group (seven patients, 38.9%) and the non-SGLT2i group (23 patients, 35.9%) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.00). There were also no significant differences in the incidence of anorexia, nausea, constipation, or other gastrointestinal symptoms between the two groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003eAdditionally, no SGLT2i-specific adverse events, such as urinary tract infections or diabetic ketoacidosis, were observed in either group during chemotherapy (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse event\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse event\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSGLT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-SGLT2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAny grade\u0026thinsp;≧\u0026thinsp;3 (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20 (31.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.132\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal toxicity (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (38.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (35.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnorexia (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (18.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.279\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (5.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (9.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConstipation (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (10.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.246\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetic ketoacidosis (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrinary tract infection (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study is among the first to investigate whether SGLT2i induces weight loss and affect survival outcomes in patients with advanced NSCLC and comorbid diabetes. Use of SGLT2i was associated with significant weight loss at the initiation of first-line therapy for NSCLC, compared with six months prior. However, no significant differences in objective response rate or survival outcomes were observed between patients treated with and without SGLT2i. Among patients with advanced NSCLC and diabetes who received SGLT2i during chemotherapy, there were no cases of diabetic ketoacidosis or urinary tract infections. Furthermore, SGLT2i use was not associated with an increased incidence of adverse events, such as anorexia, nausea, or vomiting, which may also be symptoms of ketoacidosis.\u003c/p\u003e \u003cp\u003eIn patients with advanced NSCLC undergoing chemotherapy, the use of SGLT2i was associated with significant weight loss. Previous studies have reported that SGLT2i induce weight loss. Although weight reduction varied across studies, rates of approximately 2.5% to 4.7% have been reported in patients with diabetes. SGLT2i promote weight loss by exerting a diuretic effect through the inhibition of glucose reabsorption in the proximal renal tubules and by enhancing catabolism, which leads to reductions in skeletal muscle mass and adipose tissue [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A multicenter, prospective study of advanced NSCLC patients without treatment and with a good performance status demonstrated that greater weight loss over a 52-week period was significantly associated with shorter overall survival [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. While no significant differences in weight loss were observed with antidiabetic agents other than SGLT2i, this study clearly demonstrated that SGLT2i use was associated with significant weight loss in patients with NSCLC and comorbid diabetes.\u003c/p\u003e \u003cp\u003eWeight loss is a known poor prognostic factor for patients with NSCLC [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In the present study, significant weight loss was associated with SGLT2i use. However, despite the observed weight loss, there were no significant differences in PFS and OS between the SGLT2i and non-SGLT2i groups. This suggests that the impact of weight loss on survival may be limited. Two possible reasons for this can be proposed. First, although SGLT2i induced weight loss, it may not have met the criteria for cancer cachexia, which is associated with severe weight loss. Cancer cachexia is a well-established poor prognostic factor, as shown in some studies. [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] Cancer cachexia is mainly defined by weight loss. In the present study, cachexia was defined as either a reduction in body weight of at least 5% or a BMI of less than 20 with a weight loss of at least 2%. There was a trend toward more patients in the SGLT2i group having cachexia, though it was not statistically significant. In cancer cachexia, weight loss is induced by the release of inflammatory cytokines as a biological response to cancer [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Both cancer cachexia and SGLT2i use result in weight loss; however, the mechanisms differ. Weight loss caused by SGLT2i does not involve inflammatory cytokines, unlike weight loss associated with cancer cachexia. This distinction may explain why no significant impact on survival outcomes was seen despite the weight loss observed with SGLT2i.\u003c/p\u003e \u003cp\u003eA second possible reason is that the weight loss induced by SGLT2i is different from that seen in cancer cachexia. It primarily involves a reduction in body fluid volume rather than a substantial decrease in skeletal muscle mass. SGLT2 inhibitors are known to have a diuretic effect by inhibiting glucose reabsorption in the renal proximal tubules [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. A prospective study using bioimpedance spectroscopy tracked changes in body composition and fluid status over six months in 27 patients with type 2 diabetes who were treated with either empagliflozin or dapagliflozin. The primary cause of weight loss was a reduction in fat mass. Lean body mass (including skeletal muscle) showed a temporary decrease in the early stages, followed by stabilization. A transient reduction in extracellular fluid was observed immediately after treatment initiation, but by three months, it had returned to baseline. These findings suggest that weight loss induced by SGLT2 inhibitors is mainly due to reductions in fat and body fluid with limited impact on skeletal muscle mass. This mechanism differs from that of cancer cachexia. Fluid retention, such as edema or pleural/peritoneal effusions, is a strong negative prognostic factor in cancer patients. Therefore, a reduction in body fluid volume may promote survival. [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] Therefore, the mild weight loss induced by SGLT2 inhibitors, which occurs via a mechanism different from that of cancer cachexia, likely has little impact on prognosis.\u003c/p\u003e \u003cp\u003ePrevious studies have demonstrated the effects of SGLT2i on reducing blood glucose, reducing cardiovascular risk, and protecting the kidneys.[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] However, they have also been associated with adverse events, such as ketoacidosis and urinary tract infections.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] In the case of ketoacidosis, gastrointestinal symptoms such as nausea, vomiting, loss of appetite, and abdominal pain have been reported. [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] These symptoms also occur as side effects of chemotherapy. Furthermore, since SGLT2i-induced euglycemic diabetic ketoacidosis has been reported, [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] it may be difficult to distinguish whether nausea and loss of appetite are caused by ketosis or are adverse events. Reports exist of ketoacidosis being induced during fasting periods, such as the perioperative phase, despite continued SGLT2i use.[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] Therefore, although chemotherapy-related adverse events like nausea and anorexia may occur, the continuation of SGLT2i therapy could induce ketoacidosis. Given normal blood glucose levels, ketoacidosis may not be easily recognized, and its gastrointestinal symptoms may be misinterpreted as adverse effects of chemotherapy. In the present study, however, no cases of ketoacidosis occurred during chemotherapy, and there were no significant differences in the incidence of gastrointestinal symptoms, such as nausea and vomiting, between the SGLT2i and non-SGLT2i groups. With appropriate supportive care, chemotherapy can be safely administered even while taking SGLT2 inhibitors. Therefore, there is little evidence to suggest discontinuing SGLT2i at the start of chemotherapy for lung cancer patients. However, if chemotherapy causes fasting due to gastrointestinal toxicity, suspending SGLT2i use might be advisable.\u003c/p\u003e\n\u003ch3\u003eLimitations of This Study\u003c/h3\u003e\n\u003cp\u003eOur study has several limitations. First, it is a single-center, retrospective study with a small sample size, which may introduce selection bias and prevent the findings from being generalized. Second, the SGLT2i analyzed in this study was prescribed by the patients' primary care physicians. Therefore, the exact timing of SGLT2i initiation is unclear, which makes it difficult to determine if the weight loss was due to the cancer itself or the initiation of SGLT2i therapy. Third, since we did not measure serum ketone levels, it is unclear whether SGLT2i use during chemotherapy for non-small cell lung cancer contributes to an increase in ketosis.\u003c/p\u003e \u003cp\u003eIn our cohort, patients in the SGLT2i group had a higher percentage of tumors with PD-L1 expression below 50%, and they were more likely to receive chemoimmunotherapy as a primary treatment. Meanwhile, immune checkpoint inhibitor (ICI) monotherapy was more prevalent in the non-SGLT2i group. These imbalances may reflect physician preferences to avoid ICI monotherapy in diabetic patients, or they may have arisen by chance given the limited sample size. A significantly higher rate of patients in the SGLT2i group received combination therapy with ICIs (immune checkpoint inhibitors) and chemotherapy. This could potentially introduce an additional confounding factor when evaluating the impact of SGLT2i on prognosis.\u003c/p\u003e \u003cp\u003eFuture Perspectives\u003c/p\u003e \u003cp\u003eSGLT2 inhibitors have demonstrated efficacy in patients with diabetes, chronic heart failure, and chronic kidney disease. As such, their use is expected to increase in the coming years. Additionally, one report indicates that SGLT2 inhibitors may improve chemotherapy-related edema.[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] In the future, prospective studies will be needed to evaluate whether SGLT2i impact survival outcomes or reduce adverse events in patients with advanced NSCLC receiving chemotherapy. These studies should include patients with diabetes, chronic heart failure, and chronic kidney disease. Furthermore, the potential for increased ketosis must be investigated, especially in patients who experience gastrointestinal toxicity during chemotherapy, by measuring serum ketone levels prospectively. As the indications for SGLT2i expand, the number of lung cancer patients receiving these agents will likely grow. Therefore, it will become increasingly relevant to determine whether SGLT2i uses prognosis or contributes to weight loss in patients with lung cancer.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn patients with advanced NSCLC and comorbid diabetes, SGLT2i use was associated with significant weight loss compared to six months prior to lung cancer treatment. There were no significant differences in response rate or survival outcomes; however, the incidence of adverse events was not increased in the SGLT2i group. The weight loss associated with SGLT2i use in patients with advanced NSCLC and diabetes was statistically significant but did not meet the criteria for cachexia. Its impact on prognosis was also considered limited.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eNone of the authors has any financial or personal relationship with other individuals or organizations that could inappropriately influence this study.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConceptualization: Noboru Morikawa, Tateaki Naito, Yuta Okawa.Data collection: Noboru Morikawa.Formal analysis: Noboru Morikawa, Tateaki Naito.Manuscript draft: Noboru Morikawa, Tateaki Naito.Manuscript editing and review: all authors.All authors approved the final published version.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eNone.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to ethical restrictions but are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZinman B, Wanner C, Lachin JM, et al. 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Thorac Cancer. 2025;16(2):e15509. doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/1759-7714.15509\u003c/span\u003e\u003cspan address=\"10.1111/1759-7714.15509\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"NSCLC, Diabetes mellitus, SGLT2i, Cachexia, Weight loss","lastPublishedDoi":"10.21203/rs.3.rs-8406171/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8406171/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eSodium-glucose cotransporter 2 inhibitors (SGLT2i) are commonly used to manage diabetes and are known to cause weight loss. This study aimed to clarify whether SGLT2i-induced weight loss influences survival or toxicity during chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and comorbid diabetes.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective analysis of patients with advanced NSCLC and diabetes who received first-line chemotherapy. Patients with an Eastern Cooperative Oncology Group performance status (PS)\u0026thinsp;\u0026ge;\u0026thinsp;3 or higher, driver mutations, interstitial lung disease, untreated diabetes, or missing data were excluded. We compared weight changes, progression-free survival (PFS), overall survival (OS), and adverse events between patients with and without SGLT2i. We defined cachexia as either 5% or more body-weight loss within six months prior to the initiation of lung cancer treatment or weight loss greater than 2% and a body-mass index (BMI) of less than 20 kg/m\u0026sup2;.\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eEighteen patients (21.9%) out of 82 received SGLT2i for diabetes. There was no difference in the incidence of cachexia between the two groups (66.7% vs. 46.9%, p\u0026thinsp;=\u0026thinsp;0.184), despite significant weight loss in the SGLT2 group compared to the non-SGLT2 group (median \u0026minus;\u0026thinsp;5.8% vs. \u0026minus;3.4%, p\u0026thinsp;=\u0026thinsp;0.039). No significant differences were observed in progression-free survival (PFS) (median 6.2 vs. 4.1 months, p\u0026thinsp;=\u0026thinsp;0.512) or overall survival (OS) (median 11.9 vs. 14.6 months, p\u0026thinsp;=\u0026thinsp;0.583). Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events occurred in 11.1% of patients in the SGLT2i group and 31.2% of patients in the non-SGLT2i group (P\u0026thinsp;=\u0026thinsp;0.132). There were no cases of diabetic ketoacidosis or urinary tract infections.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eSGLT2 inhibitors were associated with weight loss and were not associated with worse survival or increased toxicity in this retrospective cohort.\u003c/p\u003e","manuscriptTitle":"Weight change and Impact on prognosis in patients with Advanced Non-small Cell Lung Cancer with Concomitant diabetes mellitus treated with SGLT2 inhibitors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-24 00:37:27","doi":"10.21203/rs.3.rs-8406171/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-20T12:29:21+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-18T17:33:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"233503794713320894786799646615112257718","date":"2026-02-09T01:20:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-26T22:56:58+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"57333181099709909433470810119595147937","date":"2026-01-22T23:09:08+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-21T12:46:38+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-01-15T18:18:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-01-06T00:25:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"Supportive Care in Cancer","date":"2025-12-19T14:53:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"supportive-care-in-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jscc","sideBox":"Learn more about [Supportive Care in Cancer](https://www.springer.com/journal/520)","snPcode":"520","submissionUrl":"https://submission.nature.com/new-submission/520/3","title":"Supportive Care in Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3376cc57-245a-4033-94e8-01cf35b6258f","owner":[],"postedDate":"January 24th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T16:03:04+00:00","versionOfRecord":{"articleIdentity":"rs-8406171","link":"https://doi.org/10.1007/s00520-026-10709-8","journal":{"identity":"supportive-care-in-cancer","isVorOnly":false,"title":"Supportive Care in Cancer"},"publishedOn":"2026-04-28 15:58:16","publishedOnDateReadable":"April 28th, 2026"},"versionCreatedAt":"2026-01-24 00:37:27","video":"","vorDoi":"10.1007/s00520-026-10709-8","vorDoiUrl":"https://doi.org/10.1007/s00520-026-10709-8","workflowStages":[]},"version":"v1","identity":"rs-8406171","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8406171","identity":"rs-8406171","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}