Comparison of Protocols to Reduce Diabetic Ketoacidosis in Patients With Type 1 Diabetes Prescribed a Sodium–Glucose Cotransporter 2 Inhibitor

Abstract

OBJECTIVE | Sodium–glucose cotransporter 2 (SGLT2) inhibitors are approved for type 1 diabetes in Europe and Japan, with off-label use in type 1 diabetes in the United States. Although there were no consistent approaches to risk mitigation in clinical trials of these agents, protocols have been developed to try to reduce the risk of diabetic ketoacidosis (DKA). However, a validated risk mitigation strategy does not exist. We reviewed available DKA risk mitigation protocols to better understand the various strategies currently in use. METHODS | We conducted a search of the published medical literature and other medical information sources, including conference presentations, for protocols. We then categorized the information provided into guidance on patient selection, initiation of SGLT2 inhibitors, ketone monitoring, necessary patient action in the event of ketosis or DKA, and inpatient treatment of ketosis or DKA. RESULTS | Patient selection is generally similar among the protocols, although some require a minimum BMI and insulin dose. All protocols advocate routine measurement of ketones, although some insist on blood ketone tests. Although action steps for ketosis varies, all protocols advocate rapid patient intervention. The importance of evaluating ketones and acid-base balance even in the absence of hyperglycemia is emphasized by all protocols, as is the need to continue administering insulin until ketosis has resolved. CONCLUSION | DKA risk mitigation must be pursued systematically in individuals with type 1 diabetes, although the best strategy remains to be determined. Given the ongoing need for adjunctive therapies in type 1 diabetes and current use of SGLT2 inhibitors for this purpose, additional education and research are crucial, especially in the hospital environment, where DKA may not be diagnosed promptly and treated appropriately.

Off‐label use of sodium glucose co‐transporter inhibitors among adults in type 1 diabetes exchange registry

“…3 However, while clinical trials showed improved glycaemic endpoints, [4][5][6] reviewed elsewhere, 7 concerns about side effects, particularly diabetic ketoacidosis (DKA), remain a major limitation. Risk-mitigation strategies have been proposed 8 ; yet, regulatory judgement of these strategies' sufficiency has differed. Whereas SGLTi use in T1D is approved in Japan and for adults with body mass index (BMI) >27 kg/m 2 in Europe, the US Food and Drug Administration (FDA) rejected similar approval requests.…”

Sick day management in children and adolescents with diabetes

“…The greatest concern stems from the DKA risk, which can occur without extreme hyperglycemia (euglycemic DKA), especially in the setting of "low carb" diets or low carbohydrate intake or associated with dehydration. 63,64 Any person receiving SGLT1/2 inhibitors must receive rigorous sick day management education and strategies for mitigating DKA risk need to be discussed to avoid progression to DKA. This includes training on the use of blood ketone monitoring and counseling patients that DKA may occur without severe hyperglycemia if SGLT1/2 inhibitors are being taken.…”

“…Adjunctive use of the new class of oral agents called SGLT2 (or SGLT1/2) inhibitors have been reported to increase risk for DKA in persons with T1D or type 2 diabetes. The greatest concern stems from the DKA risk, which can occur without extreme hyperglycemia (euglycemic DKA), especially in the setting of “low carb” diets or low carbohydrate intake or associated with dehydration 63,64 . Any person receiving SGLT1/2 inhibitors must receive rigorous sick day management education and strategies for mitigating DKA risk need to be discussed to avoid progression to DKA.…”