DPP-4 inhibitors may have a distinct autoimmune safety profile

Clinical takeaway: DPP-4 inhibitors may differ from GLP-1 receptor agonists and SGLT2 inhibitors in autoimmune disease risk, adding a potential future consideration when selecting glucose-lowering therapy.

GLP-1 receptor agonists, SGLT2 inhibitors, and DPP-4 inhibitors are widely prescribed for type 2 diabetes, yet little has been known about how they compare with respect to autoimmune disease risk. This large target trial emulation provides new comparative safety data that may help inform future prescribing decisions.

Researchers analyzed electronic health record data from more than 150 million individuals, comparing matched cohorts of adults with type 2 diabetes who newly initiated DPP-4 inhibitors, GLP-1 receptor agonists, or SGLT2 inhibitors and had no prior autoimmune disease.

Compared with GLP-1 receptor agonists, DPP-4 inhibitor use was associated with a 21% lower risk of psoriasis, a 35% lower risk of psoriatic arthritis, and a 32% lower risk of autoimmune thyroiditis. However, DPP-4 inhibitors were associated with more than twice the risk of dermatomyositis and nearly twice the risk of bullous pemphigoid. Similar patterns emerged when DPP-4 inhibitors were compared with SGLT2 inhibitors, including higher risks of dermatomyositis, bullous pemphigoid, and giant cell arteritis, alongside lower risks of psoriasis and autoimmune thyroiditis.

In contrast, no statistically significant differences in autoimmune disease risk were observed between GLP-1 receptor agonists and SGLT2 inhibitors after adjustment for multiple comparisons.

Although the absolute risks of these autoimmune diseases were low, the findings suggest that DPP-4 inhibitors may have distinct immunologic effects compared with the newer drug classes. The authors emphasized that these results should be viewed as hypothesis-generating and should not outweigh established cardiovascular, kidney, glycemic, or weight-loss benefits when selecting diabetes therapy.

"These findings provide novel safety signals and may inform antidiabetic drug selection while guiding future mechanistic and prospective research," said study authors.

Source: Mahajan A, et al. (2026 July 7) ACR Open Rheumatol. Autoimmune Disease Risk With GLP-1RA, DPP-4i, and SGLT2i Treatment in Patients With Diabetes