(A-088) Sodium-Glucose Cotransporter-2 Inhibitors and Risk of Autoimmune Rheumatic Diseases: A Population-based Cohort Study

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are now also considered one of the drug repurposing candidates for autoimmune diseases due to their immunomodulatory properties. However, whether the inhibitory effects of SGLT2 inhibitors on critical cells and molecules which are implicated in autoimmune pathogenesis is clinically meaningful, remains unclear.

Objectives: To evaluate the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors and risk of autoimmune rheumatic diseases (AIRDs) in patients with type 2 diabetes (T2D).

Methods: Using the nationwide healthcare data of South Korea between 2010 and 2022, we conducted an active comparator, new user cohort study in patients aged over 40 with T2D initiating SGLT2 inhibitors versus sulfonylureas. The primary outcome was AIRD, defined using established diagnostic criteria as well as physicians’ clinical judgement. Genital infections and herpes zoster were employed as positive and negative control outcomes, respectively, to evaluate residual confounding. Patients were followed from the date of drug initiation to the earliest of outcome occurrence, discontinuation (60-day grace period) or switching of study drugs, death, or the study end date (31 December 2022). Hazard ratios (HRs) and rate differences (RDs) per 10 000 person-years were estimated after normalized inverse probability treatment weighting (IPTW) based on propensity score. Subgroup analyses stratified by age, sex, individual drug of SGLT2 inhibitors, baseline use of insulin, history of cardiovascular disease, and body mass index category were performed.

Results: 444 197 individuals initiated an SGLT2 inhibitor (mean age 57.8 years; 57.7% male) and 1 339 666 individuals initiated a sulfonylurea (mean age 61.8 years; 60.1% male). The weighted incidence rate per 10 000 person-years was 5.61 and 6.44 in individuals initiating SGLT2 inhibitors and sulfonylureas, respectively. Over a 0.89-year median follow-up, SGLT2 inhibitors were associated with a 13% lower risk of incident dementia compared with sulfonylureas (HR 0.87, 95% CI 0.79 to 0.95; RD -0.83, -1.42 to -0.24). Findings were highly consistent among all predefined subgroups. In addition, a positive association between SGLT2 inhibitors and the risk of genital infections was observed compared to sulfonylureas (HR 2.81, 2.75 to 2.88), while no association was observed for risk of herpes zoster, as we expected (HR 1.03, 1.00 to 1.05).

Conclusions: In this large cohort of individuals with T2D, SGLT2 inhibitors were associated with a 13% lower risk of AIRD compared with sulfonylureas. These results may provide evidence for the repurposing SGLT2 inhibitors in the treatment of autoimmune diseases.