Highlight
- A large retrospective cohort study from South Korea evaluates SGLT-2 inhibitors versus sulfonylureas on autoimmune rheumatic disease risk in adults with type 2 diabetes.
- SGLT-2 inhibitor initiation was associated with an 11% reduced risk of autoimmune rheumatic diseases over a median follow-up of nine months.
- The risk reduction was consistent across subgroups stratified by age, sex, baseline cardiovascular disease, obesity, and SGLT-2 inhibitor type.
- Positive and negative control outcomes (genital infections and herpes zoster) confirmed expected safety profiles and methodological robustness.
Study Background
Autoimmune rheumatic diseases (ARDs) encompass a heterogeneous group of disorders characterized by aberrant immune activation leading to chronic inflammation affecting joints, connective tissue, and other organs. Common diseases include rheumatoid arthritis, systemic lupus erythematosus, and other connective tissue diseases. Such conditions pose significant morbidity and healthcare burden worldwide. Patients with type 2 diabetes mellitus, a prevalent metabolic disease, have a heightened risk of immune dysregulation and inflammation, potentially increasing susceptibility to ARDs. However, the interplay between antidiabetic therapies and the risk of developing autoimmune conditions remains inadequately understood.
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a class of oral antidiabetic agents that reduce renal glucose reabsorption, improving glycemic control. Beyond their metabolic effects, accumulating evidence indicates possible immunomodulatory and anti-inflammatory properties of SGLT-2 inhibitors, suggesting potential benefits in autoimmune and inflammatory conditions. Conversely, sulfonylureas, another widely used class of glucose-lowering drugs, have a different mechanism without documented immunomodulatory effects.
Given the extensive use of SGLT-2 inhibitors and the clinical significance of ARDs, understanding whether SGLT-2 inhibitors influence autoimmune risk has important implications for patient care and drug selection in diabetes management.
Study Design
This retrospective population-based cohort study utilized a nationwide healthcare database from South Korea covering the years 2012 to 2022. It included 2,032,157 adults aged 18 years and older with type 2 diabetes initiating either SGLT-2 inhibitors (n=552,065) or sulfonylureas (n=1,480,092) as antidiabetic treatment.
The primary endpoint was incident autoimmune rheumatic disease, identified via a validated algorithm integrating diagnostic codes and enrollment in a disease-specific nationwide program. Secondary endpoints analyzed risks for specific autoimmune rheumatic disease categories, including inflammatory arthritis and connective tissue diseases.
The study employed a propensity score approach with inverse probability of treatment weighting to adjust for baseline confounding variables, balancing covariates between SGLT-2 inhibitor and sulfonylurea initiators. Positive and negative control outcomes were used for validation: genital infections (known side effect of SGLT-2 inhibitors) as positive control, and herpes zoster incidence as negative control.
Follow-up time median was nine months post drug initiation, during which hazard ratios (HRs) and incidence rate differences were calculated per 100,000 person-years.
Key Findings
After matching and weighting, study cohorts were well balanced with mean age approximately 58.5 years and about 60% male in both groups. The weighted incidence rates of autoimmune rheumatic diseases were 51.90 and 58.41 per 100,000 person-years for SGLT-2 inhibitor and sulfonylurea groups, respectively.
The main result demonstrated that initiation of SGLT-2 inhibitors was associated with an 11% relative reduction in risk of developing autoimmune rheumatic diseases compared with sulfonylureas (HR 0.89, 95% confidence interval [CI] 0.81 to 0.98). The absolute risk reduction was 6.5 fewer cases per 100,000 person-years (95% CI -11.86 to -1.14).
Subgroup analyses showed no meaningful heterogeneity by age, sex, baseline cardiovascular disease status, obesity, or specific SGLT-2 inhibitor molecule, indicating consistent benefit across these patient subsets.
Regarding the controls, there was a substantially increased risk of genital infections with SGLT-2 inhibitors (HR 2.78, 95% CI 2.72 to 2.83), confirming the expected safety signal. Herpes zoster incidence did not differ significantly (HR 1.03, 95% CI 1.01 to 1.05), supporting minimal residual confounding.
These findings collectively support a potentially protective effect of SGLT-2 inhibitors against the development of autoimmune rheumatic diseases in adults with type 2 diabetes, while validating the study’s methodology and safety profile.
Expert Commentary
This landmark study from Hong et al. leverages a large, well-characterized population with rigorous methodology to address an important, previously underexplored clinical question: Can SGLT-2 inhibitors modulate autoimmune risk in diabetes?
The plausible biological rationale includes SGLT-2 inhibitors’ roles in reducing inflammation, oxidative stress, and improving metabolic parameters that influence immune cell function. The relatively early median follow-up suggests that the immunomodulatory effects may manifest within months of therapy initiation.
However, limitations inherent to retrospective observational studies remain. Despite advanced propensity score methods, potential residual confounding by disease severity or unmeasured factors could influence results. The relatively short follow-up may underestimate long-term autoimmune risks and benefits. The study population predominantly of Korean ethnicity also warrants caution when generalizing to other ethnic groups.
Furthermore, the study does not address the effect of SGLT-2 inhibitors in patients with established autoimmune rheumatic diseases, an important area for future research regarding disease activity and management.
These findings align with emerging literature suggesting anti-inflammatory effects of SGLT-2 inhibitors beyond glucose lowering, prompting reconsideration of their broader therapeutic value and risk-benefit profile in diabetes management.
Conclusion
In a large South Korean cohort of adults with type 2 diabetes, initiation of SGLT-2 inhibitors was associated with an 11% lower risk of incident autoimmune rheumatic diseases compared to sulfonylureas over a median of nine months. This novel evidence points toward potential immunoprotective effects of SGLT-2 inhibitors, expanding their clinical implications beyond glycemic control.
While encouraging, these findings require replication in diverse populations and clinical settings. Prospective studies and trials assessing the impact of SGLT-2 inhibitors on immune function and outcomes in patients with existing autoimmune rheumatic diseases are needed to clarify causality and therapeutic potential.
Clinicians should balance possible autoimmune risk reduction against known adverse events of SGLT-2 inhibitors, such as increased genital infections, when selecting antidiabetic therapies.
Funding and ClinicalTrials.gov
The study was supported by governmental healthcare databases in South Korea. No specific clinical trial registration applies as this was an observational cohort study.
References
- Hong B, Lee H, Jung K, Rhee SY, Yon DK, Shin JY. Sodium-glucose cotransporter-2 inhibitors and risk of autoimmune rheumatic diseases: population based cohort study. BMJ. 2025 Oct 15;391:e085196. doi: 10.1136/bmj-2025-085196. PMID: 41093607; PMCID: PMC12522398.
- Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61(10):2108-2117.
- Neuen BL, Young T, Heerspink HJL, et al. Cardiovascular and renal outcomes with SGLT2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis. Circulation. 2019;139(17):1984-1997.
- Kohsaka S, Shalev V. Immune quiescence in type 2 diabetes: could SGLT2 inhibitors be beneficial? Trends Endocrinol Metab. 2023;34(3):187-197.