Association of Sodium-Glucose Cotransporter-2 Inhibitors With Incident Gout Risk: A Population-Based Comparative Cohort Study With Genetic Evidence From Mendelian Randomisation

Abstract

Aim: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are known to reduce serum urate levels, yet their specific impact on gout incidence in the Korean population remains underexplored. We investigated the association between SGLT2i use and incident gout using real-world data and Mendelian randomisation (MR) analysis. Materials and Methods: We conducted a population-based cohort study using the Korean National Health Insurance Service database (2015–2020). New users of SGLT2i were compared to dipeptidyl peptidase-4 inhibitor (DPP4i) users. After 1:1 propensity score matching (PSM), 20 866 pairs were analysed using Cox proportional hazards models. The primary outcome was incident gout. Additionally, a two-sample MR analysis utilised genetic variants in SLC5A2 as proxies for SGLT2 inhibition and gout summary statistics from the FinnGen consortium. Results: In the cohort study, SGLT2i use was associated with a significantly lower risk of gout compared to DPP4i (incidence rate: 2792.6 vs. 3346.7 per 100 000 person-years). The hazard ratio in the PSM model was 0.80 (95% confidence interval [CI] 0.76–0.84, p value < 0.001). This finding was robust across multiple sensitivity analyses, including landmark and time-varying exposure models. In the MR analysis, genetically proxied SGLT2 inhibition was associated with a reduced risk of gout (odds ratio 0.10 per 1-standard deviation decrease in HbA1c; 95% CI: 0.017–0.463; p value < 0.001), with consistent results across robust MR methods. Conclusion: SGLT2i therapy is associated with a lower risk of incident gout compared to DPP4i in patients with type 2 diabetes. While these findings suggest potential pleiotropic effects of SGLT2i beyond glucose control, they should be interpreted with caution given the limitations of observational study designs.