Background/Purpose: Treatment with dipeptidyl peptidase-4 inhibitors (DPP4i) have been shown to reduce the risk of systemic autoimmune rheumatic diseases (SARD) in patients with type 2 diabetes (T2D). This study aimed to evaluate the effect of treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) on the risk of new-onset SARD.

Methods: This emulated target trial used electronic health records of adults with T2D who initiated either an SGLT2i (canagliflozin, dapagliflozin, empagliflozin, or ertugliflozin) or a DPP4i (alogliptin, saxagliptin, linagliptin, or sitagliptin) between 2016 and 2024 from 101 U.S. healthcare organizations. Propensity score matching was used to balance baseline characteristics. Outcomes included new-onset rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), systemic sclerosis (SSc), Sjögren’s syndrome (SjS), mixed connective tissue disease (MCTD), Behcet’s disease, polymyalgia rheumatica (PMR), and vasculitis. Patients were followed from initial prescription through incident SARD, end of prescription or switch to the other drug class, death or end of follow-up. Cox proportional hazards models and the log-rank test were used to evaluate the effect of SGLT2i on SARD over time.

Results: A total of 699,1977 pairs of SGLT2i and matched-DPP4i initiators were included. SGLT2i initiators had a significantly lower risk of RA (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.54-0.58), SLE (HR=0.85, 95% CI 0.79-0.92), SSc (HR 0.80, 95% CI=0.66-0.96), MCTD (HR=0.83, 95% CI=0.80-0.87), PMR (HR=0.67, 95% CI=0.62-0.72), and vasculitis (HR=0.79, 95% CI=0.70-0.89). Risks of Sjögren’s and AS were not significantly reduced. Overall risk of any SARD was HR (95%CI). Among the SGLT2i studied, dapagliflozin and empagliflozin showed the most pronounced reductions in the risk of new-onset SARD. Canagliflozin was associated with a reduced risk of new-onset RA and vasculitis.

Conclusion: Treatment with SGLT2i, especially dapagliflozin and empagliflozin, was associated with reduced risks of developing various SARD compared to DPP4i. These findings provide evidence for the broader immunomodulatory effects of SGLT2i. Prospective studies on the roles of SGLT2i in attenuating inflammation and autoimmunity are warranted to validate the finding.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sodium-glucose-cotransporter-2-inhibitors-for-the-primary-prevention-of-systemic-autoimmune-rheumatic-diseases-in-patients-with-type-2-diabetes-a-population-based-target-trial-emulation/