Safety of SGLT2 inhibitors versus DPP-4 inhibitors in super-elderly patients (≥ 80 years) with type 2 diabetes: a propensity score-matched cohort study

Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) provide cardiovascular and renal benefits in type 2 diabetes, yet safety data in super-elderly patients (≥ 80 years) remain limited. We compared the safety of SGLT2i versus dipeptidyl peptidase-4 inhibitors (DPP-4i) in this vulnerable population. Methods We conducted a retrospective, new-user, active-comparator cohort study using the TriNetX Global Collaborative Network (176 healthcare organizations). Patients aged ≥ 80 years at treatment initiation with type 2 diabetes newly prescribed SGLT2i or DPP-4i were matched 1:1 using propensity scores incorporating demographics, comorbidities, frailty proxies, and concomitant medications. Primary safety outcomes included falls, hip fracture, acute kidney injury, urinary tract infection, genital candidiasis, hypoglycemia, volume depletion, hypotension, and syncope. Secondary outcomes included stroke, myocardial infarction, heart failure hospitalization, and all-cause mortality. Subgroup analyses assessed falls risk among insulin, benzodiazepine, and loop diuretic users. Results After matching, 65,119 patients remained in each cohort (mean age 82.2 ± 2.3 years; 48.7% female). Over a mean follow-up of 269 days, SGLT2i was associated with significantly lower risks of falls (HR 0.90; 95% CI 0.85–0.95), hip fracture (HR 0.78; 0.69–0.89), acute kidney injury (HR 0.82; 0.78–0.85), urinary tract infection (HR 0.79; 0.75–0.83), hypoglycemia (HR 0.74; 0.67–0.82), volume depletion (HR 0.91; 0.86–0.97), stroke (HR 0.88; 0.82–0.95), and all-cause mortality (HR 0.73; 0.70–0.76; all p < 0.05). Genital candidiasis risk was higher with SGLT2i (HR 1.70; 1.50–1.93; p < 0.001), as was heart failure hospitalization (HR 1.07; 1.02–1.12; p = 0.007). Hypotension, syncope, and myocardial infarction did not differ significantly. The falls reduction was consistent across subgroups using insulin, benzodiazepines, and loop diuretics. Sensitivity analysis with fixed 250-day follow-up confirmed all primary findings. Conclusions In super-elderly patients with type 2 diabetes, SGLT2i demonstrated a favorable safety profile compared to DPP-4i, with significantly lower risks of falls (10%), hip fracture (22%), acute kidney injury (18%), hypoglycemia (26%), and mortality (27%). Safety concerns included increased genital candidiasis (70%) and modestly higher heart failure hospitalization (7%). These findings support SGLT2i use in appropriately selected super-elderly patients. Clinical trial number Not applicable.