Key safety outcomes of SGLT2 inhibitors versus DPP ‐4 inhibitors in general and vulnerable participants with T2DM : A target trial emulation study

Aims Sodium–glucose cotransporter‐2 inhibitors (SGLT2i), a class of oral hypoglycaemic agents (OHAs), have demonstrated cardiovascular and renal benefits. However, safety concerns may hinder their broader adoption, particularly among frail populations. We evaluated key safety outcomes associated with SGLT2i compared with dipeptidyl peptidase‐4 inhibitors (DPP4i), an OHA class with low risks of complications. Methods We conducted a target trial emulation (TTE) study using Taiwan's National Health Insurance Research Database (NHIRD) and enrolled participants with type 2 diabetes mellitus (T2DM). Eligible participants were categorized according to newly initiated SGLT2i ( n = 224,510) or newly initiated DPP4i ( n = 698,012) with continuous use for at least 30 days. Propensity score overlap weighting (PSOW) was used to balance baseline characteristics. Results In the intention‐to‐treat analysis, the SGLT2i group showed significantly lower incidence rate (per person‐years) of several safety outcomes than the DPP4i group, including urinary tract infection (UTI) (23.84‰ vs. 27.88‰; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.84–0.87), fractures or falls (16.55‰ vs. 17.79‰; HR, 0.93; 95% CI, 0.91–0.95), acute kidney injury (AKI) (1.06‰ vs. 1.91‰; HR, 0.55; 95% CI, 0.51–0.59), bullous pemphigoid (0.02‰ vs. 0.07‰; HR, 0.35; 95% CI, 0.23–0.54), and all‐cause mortality (13.05‰ vs. 19.72‰; HR, 0.66; 95% CI, 0.65–0.67). Conversely, the risk of genital infection was higher in the SGLT2i group (2.96‰ vs. 2.05‰; HR, 1.44; 95% CI, 1.38–1.51). These findings remained consistent in the per‐protocol analysis, across most vulnerable subgroups and individual SGLT2i and DPP4i agents. Conclusions SGLT2i, compared with DPP4i, demonstrated a favourable safety profile across most evaluated outcomes, except for genital infections.