Predicting the occurrence of DKA following sodium glucose co-transporter-2 inhibitors: An international cohort study

Background: Sodium glucose co-transporter 2 inhibitors (SGLT2i) are associated with a small-magnitude but higher risk of diabetic ketoacidosis (DKA). However, objectively identifying patients at lowest and highest risk of DKA is challenging. Methods: We developed a prediction model using outpatient prescription data from Ontario, Canada and externally validated it using data from Denmark. We included adults with type 2 diabetes mellitus who were newly prescribed an SGLT2i. Our candidate predictors in the model were based on prior work and included the following: Sex, insulin use, prior DKA, dementia, hemoglobin A1C, and creatinine. Our outcome was 1-year risk of hospitalization with DKA. We calculated a risk score using an adaptation of penalized regression for each patient reported test characteristics in Ontario (derivation cohort) and Denmark (external validation cohort). Results: We identified 322,135 in Ontario and 43,377 adults in Denmark who had type 2 diabetes mellitus and received an SGLT2i. The absolute risk of DKA within 1-year was 0.28 % (N = 916) in Ontario and 0.23 % (N = 101) in Denmark. Using data from Ontario, the risk score for each variable were as follows: Insulin use = 4 points, A1C > 9 % = 4 points and prior DKA = 19 points. All other variables received zero points. The overall model AUC was 63 % in Ontario and 66 % in Denmark (external validation set). Within Ontario, at a score threshold of zero, the risk of DKA was 0.19 % and the PPV was 0.3 % and the sensitivity was 100 % and similar results were observed in Denmark. For adults with a score of 19 or higher, the risk of DKA was 35-fold higher but false positives were common yielding a PPV of 6.7 % and sensitivity was lower at 3 %. In Denmark, adults with a score of 19 or higher had a risk of 11 % and the PPV was 10.2 % and sensitivity was 5 %. Conclusion: Adults with a score of 0 (that is, simply a lack of DKA history, lack of insulin therapy, and A1c < 9 %) can be reassured that 99.8 % will not experience DKA in the subsequent year. In contrast, for adults with a score of 19 or higher the one-year risk of DKA is approximately 9 %, but false positives and false negatives are common and thus more work is needed to improve the predictive performance of the model.