SGLT2 Inhibitors: A Systematic Review of Diabetic Ketoacidosis and Related Risk Factors in the Primary Literature

Study objective: Currently only minimal information is available regarding risk factors for the development of sodium glucose cotransporter-2 inhibitor (SGLT2i)-related diabetic ketoacidosis (DKA). We aim to identify individual patient characteristics associated with cases of SGLT2i-related DKA to better describe potential risk factors.

Design: Systematic review of primary literature.

Patients: Thirty-four case reports of patients with type 1 and type 2 diabetes mellitus who developed DKA while receiving an SGLT2i.

Methods and main results: This systematic review investigated the relationship between SGLT2i and DKA in patients with diabetes. The existing literature was reviewed with a primary outcome to identify patient-specific factors contributing to the incidence of ketoacidosis in patients with diabetes who were treated with a SGLT2i. Numerous databases were searched to identify appropriate primary literature. Search terms included canagliflozin, dapagliflozin, empagliflozin, SGLT2, sodium glucose cotransporter-2 inhibitor, diabetic ketoacidosis, ketoacidosis, metabolic acidosis, and acidosis. Primary literature was analyzed via descriptive statistics. Thirty-four individual case reports were identified via the primary literature search. Two-thirds (25 cases) involved patients with a diagnosis of type 2 diabetes mellitus (T2DM). The average blood glucose on presentation for SGLT2i-induced DKA was 265.6 ± 140.7 mg/dl (14.7 ± 7.8 mmol/L), with common symptoms including nausea, vomiting, and abdominal pain. Common precipitating factors included patients who were diagnosed with T2DM and were subsequently found to have latent autoimmune diabetes of adulthood, patients who had recently undergone major surgery, or patients who had decreased or discontinued insulin. No cases were fatal.

Conclusion: In this review, episodes of DKA with SGLT2i use were characterized by lower blood glucose levels and were often caused by a precipitating factor. Understanding precipitating factors for SGLT2i-related DKA may help providers better identify patients at risk for development of DKA.