POS1323 SGLT2 INHIBITORS DO NOT INCREASE THE RISK OF URINARY TRACT INFECTIONS REGARDLESS OF IMMUNOSUPPRESSIVE THERAPY: AN ACTIVE COMPARATOR NEW USER DESIGN USING A REAL-WORLD HOSPITAL-BASED DATABASE IN JAPAN

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Background: Sodium-glucose cotransporters inhibitors (SGLT2i) are anti-diabetic drugs by blocking the major transporter involved in glucose reabsorption [1]. In recent years, the organ-protective effects of SGLT2i have attracted attention, particularly with respect to their cardio-renal protective effects [2, 3]. Moreover, therapeutic interventions related to autoimmune diseases for SGLT2i have been reported and are expected to be widely used in the near future [4]. On the other hand, FDA has revised the labels of SGLT2i, highlighting their potential to induce serious urinary tract infections (UTIs), and since then, there has been extensive discussion regarding the risk of UTIs associated with SGLT2i [5, 6]. However, detailed studies on the safety of SGLT2i in patients with autoimmune diseases are still scarce. Objectives: This study aims to evaluate the safety of SGLT2i compared to metformin as an active comparator in patients with autoimmune diseases, focusing on the risk of UTIs based on a real-world database. Methods: This retrospective cohort study and an active comparator new user design used the JMDC hospital-based claims database (JMDC Inc., Tokyo, Japan) between April 1, 2014, and January 31, 2024. Patients with autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, coexisting with diabetes were identified using ICD-10 codes, and only those actively receiving immunosuppressive agents or immunomodulators were included. UTIs were defined as having diagnosis codes accompanied by antibiotic prescriptions within 1 month of the diagnosis during the observation period. The primary exposure was new use of SGLT2i, with initiation of metformin as an active comparator. The primary outcome was the occurrence of UTIs with or without the use of SGLT2i, assessed over a follow-up period of 1096 days. Propensity score matching was performed using potential covariates, including age, sex, laboratory data, comorbidities, and medication history in the ratio of 1:1, using the nearest neighbor matching algorithm. To estimate whether there was a difference in UTI-free survival between the two groups, Kaplan-Meier survival curves were constructed. The Cox proportional hazards model was used to calculate the hazard ratios (HRs) for both groups and in the subgroup analyses. Furthermore, subgroup analyses were conducted stratified by age, sex, immunosuppressive agents, and types of autoimmune diseases. Statistical analysis was performed using R version 4.4.1, including the EZR package. Results: From the database, 787,737 cases with autoimmune diseases codes were identified, and among them, 3,547 patients who were concurrently receiving SGLT2i or metformin along with autoimmune diseases treatment were extracted. After propensity score matching, 2,370 patients with a mean age of 71.1 years (IQR: 64.9-79.6) and 44.1% female were included in the analysis. All baseline covariates were balanced between the groups, achieving a standardized mean difference (SMD) of less than 0.1. The primary outcome showed that SGLT2i did not increase the UTI risk compared to metformin (Figure 1). The hazard ratio for the SGLT2i group was 0.97 (95% CI: 0.70–1.34) indicating that there was no statistically significant difference in UTI risk between the two groups. For the subgroup analysis, UTI risk was not increased across subgroups stratified by age, sex, glucocorticoid dosage, or the presence of underlying diseases (Table 1). Conclusion: In patients being treated for autoimmune diseases, SGLT2i did not increase the risk of UTIs compared to metformin. Clinicians managing patients with autoimmune diseases can confidently prescribe SGLT2i without an increased concern for UTIs, even in those receiving immunosuppressive therapy, potentially broadening the use of SGLT2i in this population for their cardio-renal protective effects. Further research is warranted to explore the broader safety and organ-protective effects of SGLT2i in patients with autoimmune diseases, particularly in specific subgroups or rare autoimmune conditions not thoroughly assessed in this study. This result was consistent regardless of the patients' characteristics or treatment details. REFERENCES: [1] Komoroski B, Vachharajani N, Boulton D, Kornhauser D, Geraldes M, Li L, et al. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther. 2009;85(5):520-6. [2] Bauersachs J. Heart failure drug treatment: the fantastic four. Eur Heart J. 2021;42(6):681-3. [3] Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-46. [4] Wang H, Li T, Sun F, Liu Z, Zhang D, Teng X, et al. Safety and efficacy of the SGLT2 inhibitor dapagliflozin in patients with systemic lupus erythematosus: a phase I/II trial. RMD Open. 2022;8(2). [5] Liu J, Li L, Li S, Jia P, Deng K, Chen W, et al. Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis. Sci Rep. 2017;7(1):2824. [6] Dave CV, Schneeweiss S, Kim D, Fralick M, Tong A, Patorno E. Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Severe Urinary Tract Infections: A Population-Based Cohort Study. Ann Intern Med. 2019;171(4):248-56. Figure 1Kaplan-Meier curves for UTI in patients treated with SGLT2i versus metformin. Table 1. Subgroup analysis; The hazard ratio for UTI incidence among patients with autoimmune diseases using SGLT2i compared to those using metformin. Acknowledgements: NIL . Disclosure of Interests: Hiroshi Tsushima Nippon Shinyaku Co., Ltd., Janssen Pharmaceutical Companies of Johnson & Johnson, Asahi Kasei Pharma Corporation, Ayumi Pharmaceutical Corporation, Taisho Pharmaceutical Co., Ltd., AstraZeneca, Kissei Pharmaceutical Co., Ltd., GlaxoSmithKline, Astellas Pharma Inc., Eli Lilly Japan K.K., Mitsubishi Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd., AbbVie Inc., Eisai Co., Ltd., Bristol-Myers Squibb Company, Boehringer Ingelheim International GmbH, Nobuyuki Yajima: None declared, Ryoko Sakai Mitsubishi Tanabe Pharma, Chugai Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Japan Inc., Akira Katagiri Taisho Pharmaceutical Co., Ltd., AbbVie Inc., Eli Lilly Japan K.K., Asahi Kasei Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Naoto Tamura Asahi Kasei Pharma, Asahi Kasei Pharma, AbbVie, Eli Lilly Japan, GlaxoSmithKline, Chugai, Novartis, Bristol Myers Squibb, Janssen, Asahi Kasei Medical, Ayumi, AbbVie, Eisai, Nippon Boehringer Ingelheim, Taisho, Tanabe Mitsubishi, Chugai. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.

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