SGLT2 inhibitor therapy in islet transplantation

About This Grant

PROJECT SUMMARY Islet transplantation is a promising treatment for insulin-dependent forms of diabetes, including type 1 diabetes and surgical diabetes induced by total pancreatectomy. In the U.S., total pancreatectomy with islet autotransplantation (TPIAT)—which is performed to relieve pain in patients with chronic pancreatitis-- has been the most prevalent form of islet transplant to date. At the same time, islet allotransplantation for type 1 diabetes is growing, and will continue to grow with the success of stem-cell derived islets and future approaches to reduce immunosuppression risks via technological advancements, genetic editing, or newer immunomodulation. Islet autotransplant is a useful research model to study adjunctive therapies for glycemic control and islet graft survival because it is free of the confounding factors of alloimmune rejection and recurrent type 1 diabetes. In TPIAT, about 70% of patients require exogenous insulin despite having some endogenous islet function, and attrition of islet function over time occurs in both auto and allografts. This attrition appears to be at least in part driven by metabolic stress on the transplanted beta cells. This pilot clinical trial, submitted in response to PAS-25-102, is designed to gather preliminary data on the efficacy and safety of SGLT2 inhibitor therapy (SGLT2i) in islet autotransplant recipients who have partial islet function. Our rationale for studying SGLT2i in this population is: (1) SGLT2i reduces blood glucose levels through increased glucosuria and do not directly stimulate islets (avoiding extra metabolic stress), nor does the benefit depend on presence of insulin resistance, which is often absent in islet transplant; (2) in both T1D and total pancreatectomy, there is evidence of reduced prandial glucose excursions with SGLT2i, which in turn may reduce metabolic beta-cell stress on transplanted islets in TPIAT; (3) SGLT2i are acceptable to patients as a once-daily oral medication. However, safety of these agents is unknown in TPIAT, and in theory they may increase risk for diabetic ketoacidosis in this population of patients who have partial insulin deficiency. We will enroll 30 patients with partial islet function >1 year after TPIAT, randomized to a standard care control arm (n=10) or one of 2 doses of empagliflozin (n=10 on 10 mg; n=10 on 25 mg) for 3 months, followed by a 3 month extension during which all patients will receive empagliflozin (25 mg daily). Specific Aim 1 will determine if empagliflozin improves glycemic control and reduces beta-cell specific endoplasmic reticulum stress after islet autotransplant. Specific Aim 2 will assess safety and feasibility of empagliflozin in islet autotransplant recipients. If results from this pilot study are promising, we will conduct a larger randomized blinded study. PI Bellin has led two multicenter TPIAT studies and has relationships with other centers to build a larger randomized trial. Importantly, we expect that results from this study will also inform the field of islet allotransplant for type 1 diabetes.