SGLT2 Inhibitors Linked to Lower RA Risk Versus Sulfonylureas in T2D

As the global prevalence of rheumatoid arthritis (RA) continues to rise, researchers are examining whether commonly used medications may influence the likelihood of developing the disease. A large multicenter analysis suggests that among patients with type 2 diabetes (T2D), use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) is associated with a modestly lower risk of incident RA compared with sulfonylureas.

How the Analysis Was Designed

Researchers conducted emulated target trials using the TriNetX network, identifying 4,991,988 patients with T2D between January 1, 2016 and June 30, 2023. The analysis compared SGLT2i treatment with three other glucose-lowering treatment options: sulfonylureas, dipeptidyl peptidase-4 inhibitors (DPP-4i), and pioglitazone.

After propensity score matching, the comparisons included:

• 310,507 pairs for SGLT2i versus sulfonylureas
• 206,069 pairs for SGLT2i versus DPP-4 inhibitors
• 80,846 pairs for SGLT2i versus pioglitazone

A Difference in Risk Emerged Specifically Against Sulfonylureas

SGLT2i use was associated with a significantly lower risk of developing RA compared with sulfonylurea use, with a hazard ratio (HR) of 0.899 (95% CI, 0.835–0.968). Kaplan-Meier analysis similarly showed a significantly lower likelihood of incident RA among SGLT2i users compared with sulfonylurea users (log-rank p=0.004).

The same statistically significant difference was not observed with the other two treatments, however. Compared with DPP-4 inhibitors, the HR for RA among SGLT2i users was 0.914 (95% CI, 0.831–1.005), and compared with pioglitazone, the HR was 0.922 (95% CI, 0.796–1.068).

Subgroup analyses examined the findings according to sex, age, race, obesity status, HbA1C levels, and estimated glomerular filtration rate (eGFR). The overall association generally favored SGLT2i use in several subgroups, with significantly lower RA risk observed among males, adults aged 65 years or older, individuals with obesity, and those with an eGFR of 60–90 mL/min/1.73 m².

Sensitivity analyses generally supported the findings from the primary SGLT2i-versus-sulfonylurea comparison, although the association was not statistically significant in the per-protocol analysis.

What the Findings Mean

The large study population support the observed association between SGLT2i use and lower incident RA risk relative to sulfonylureas.

However, it’s important to note that the findings do not establish that SGLT2 inhibitors prevent RA. And because the study was observational, the investigators emphasize that the results should be interpreted as associations rather than evidence of causality.

But for clinicians caring for patients with T2D, the study adds a potentially relevant observation about RA risk across glucose-lowering treatment groups, while leaving the clinical and causal significance of that association unresolved.

Reference:

Yen FS, Wang SI, Hsu CC, Tsai SHL, Hwu CM, Wei JC. The association between SGLT2 inhibitors and rheumatoid arthritis risk in type 2 diabetes: findings from large-scale emulated target trials. Front Immunol. 2026;17:1867117. Published 2026 Aug 4. doi:10.3389/fimmu.2026.1867117