Study of glucagon response and its association with glycemic control and variability after administration of ipragliflozin as an adjunctive to insulin treatment in patients with type 1 diabetes (Suglat-AID)

Abstract

Abstract Background: Despite advances in insulin preparation, insulin delivery systems and glucose monitoring, it is extremely difficult to maintain glucose levels within the non-diabetic range in patients with type 1 diabetes (T1D). Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently raised the prospect of improving glucometabolic outcomes in an insulin-independent manner. SGLT2 inhibitors adjunctive to insulin treatment have been shown in T1D clinical trials to improve glycemic variability without increasing hypoglycemia. Conversely, some meta-analyses raised valid concerns regarding increased risk of euglycemic ketoacidosis after treatment of SGLT2 inhibitors in T1D. Increased hepatic ketogenesis caused by elevated glucagon secretion in patients receiving SGLT2 inhibitors has been discussed as a potential mechanism for euglycemic ketoacidosis in insulinopenic T1D, but the mechanism has not been fully elucidated. In this study, we investigate 1) whether glucagon secretions are altered by treatment with the SGLT2 inhibitor ipragliflozin as an adjunctive to insulin therapy in T1D patients, and 2) whether the glucagon responses are associated with amelioration/deterioration in glycemic control and serum ketone levels. Methods/design: This is a single-arm, multicenter, open-label, prospective exploratory trial designated Suglat-AID. Eligible participants are absolute-insulin-deficient T1D patients with glycated hemoglobin levels over 7.5%, who are receiving intensive insulin therapy using intermittently scanned continuous glucose monitoring. Thirty patients will be recruited and will take orally administered ipragliflozin as an add-on to insulin therapy. The primary endpoint is the change in glucagon levels during a mixed meal tolerance test between before and 12 weeks after initiation of ipragliflozin. Secondary endpoints include the changes in insulin and glucose levels during mixed meal tolerance test, the change in the patients’ glycemic control, change in the intermittently scanned continuous glucose monitoring-based profile and others. Discussion: To the best of our knowledge, this will be the first study assessing changes in glucagon response to an SGLT2 inhibitor in patients with T1D in a clinical setting. This study may help to clarify the pathophysiological role of glucagon in glycemia and ketogenesis in patients with T1D receiving SGLT2 inhibitors. Trial registration: This study was registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (https://umin.ac.jp) on 24 March, 2020 under registration no. UMIN000039635.