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Sotagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor. Data from the Zynquista (sotagliflozin) clinical studies reported an increased risk of diabetic ketoacidosis (DKA) in patients with type I diabetes mellitus (T1DM) exposed to sotagliflozin compared to the placebo arm. In 2018, to support the review of Zynquista (sotagliflozin), proposed for T1DM, the U.S. Food and Drug Administration (FDA) initiated a study using the FDA Sentinel System to describe the characteristics and risk of DKA among patients with T1DM who received SGLT2 inhibitors from 2013 to 2018. The 2018 study found that the observed rates of DKA among patients with T1DM exceeded the expectation based on the Zynquista clinical trials. These findings were presented in the January 17, 2019 Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) meeting, and informed the discussion on the benefit-risk assessment of Zynquista.
In 2024, to support the review of Zynquista (sotagliflozin), proposed for T1DM with chronic kidney disease (CKD), FDA investigated the occurrence of DKA (1) in patients with T1DM who initiated SGLT2 inhibitors to inform the DKA risk over time and (2) in patients with T1DM by CKD stages to describe risk of DKA in patients with T1DM at different stages of CKD, using the Sentinel Distributed Database. Findings from these descriptive analyses observed that crude incidence rates of DKA in patients with T1DM who initiated SGLT2 inhibitors did not appear to have declined from 2013 to 2024 and that there is an increase in incidence rate of DKA with advancing CKD stage in patients with T1DM, regardless of SGLT2 inhibitor use. These findings were presented in the October 31, 2024 EMDAC meeting, where the benefits and risks of sotagliflozin as an adjunct to insulin therapy to improve glycemic control in adult patients with T1DM with CKD were discussed.
FDA also conducted a comparative analysis to assess the risk of DKA by CKD stage in patients with T1DM. Compared to patients with T1DM and CKD stage 1 or 2, the crude incidence rates of DKA were significantly higher in patients with T1DM and CKD stage 3 or CKD stage 4 or 5. Though FDA conducted an additional analysis using 1:1 propensity score matching to balance the baseline characteristics of patients with T1DM at different stages of CKD, there were limitations in interpretation of findings with covariate adjustments. There was limited overlap in propensity score for the respective comparison groups (i.e., 56% of subjects with advanced CKD were excluded from analyses because of non-overlapping propensity score), and comparative analyses results were applicable to a subset of patients with T1DM with advanced CKD. Furthermore, given that CKD is strongly associated with increased patient age, duration of diabetes, and comorbidities that contribute to progression of CKD, such as hypertension, it may not be clinically meaningful to estimate the risk of DKA under the assumption that patients with and without advanced CKD had similar characteristics in terms of age and certain comorbidities (e.g., hypertension). The results of the descriptive analyses (i.e., the crude incidence rates) helped inform FDA’s understanding of DKA in patients with T1DM and CKD.