Predictors of diabetic ketoacidosis in patients with insulin-deficient diabetes phenotype initiating SGLT2 inhibitors

Aims: To identify predictors of diabetic ketoacidosis (DKA) in patients with an insulin-deficient phenotype initiating sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy. Materials and Methods: This retrospective cohort study analysed data from 31 900 patients with diabetes aged 18–70 identified as having an insulin-deficient phenotype. After applying inclusion and exclusion criteria, patients were matched and divided into SGLT2i users (n = 6572) and non-users (n = 6382). The primary endpoint was the first DKA event in patients with no prior history of DKA. Independent risk factors for DKA were assessed using Cox regression. Results: Over a median follow-up of 4.4 years, 239 patients experienced DKA (143 [2.22%] SGLT2i users vs. 96 [1.54%] non-users; HR [95% confidence interval, CI] 1.39 [1.07–1.79]; p = 0.014). The adjusted model confirmed an increased DKA risk with SGLT2i use (adjusted hazard ratio, aHR [95% CI] 1.50 [1.15–1.95]; p = 0.003). Baseline HbA1c >9% was associated with a 53% higher risk (aHR [95% CI] 1.53 [1.18–1.99]; p = 0.0016), while body mass index (BMI) ≤25 kg/m² was linked to a 61% increased risk (aHR [95% CI] 1.61 [1.24–2.09]; p = 0.0003). Insulin use further heightened risk (aHR [95% CI] 2.35 [1.71–3.23]; p < 0.0001). Conclusions: SGLT2i use in patients with an insulin-deficient phenotype is associated with increased DKA risk, particularly in those with HbA1c >9% and BMI ≤25 kg/m². Clinicians should exercise caution in these patients, carefully assessing risks and implementing mitigation strategies to ensure safe use.