Exenatide Use in Islet Transplantation: Words of Caution

Exenatide is an analog of the hormone glucagon-like peptide-1 (GLP-1) that normally functions to enhance glucose-dependent insulin secretion and may be trophic for islet β cells, and so is receiving considerable attention as a possible adjuvant therapy in islet transplantation. In the July 15 issue, Froud et al. (1) concluded “the overall effect of exenatide administration in islet transplant recipients with graft dysfunction has been a positive one resulting in a reduction in insulin requirements” based on their experience with 12 subjects during a 6-month uncontrolled trial. However, one subject resumed insulin and four received additional islet infusions during exenatide therapy (1), suggesting that the effect of exenatide therapy may not be durable and only temporarily mask anticipated deterioration in islet graft function. Indeed, the reduction in insulin requirements decreased from 40% between 1 and 4 months of exenatide to 20% between 5 and 6 months of exenatide (1). The series by Al Ghofaili et al. (2) previously reported that 3 months of exenatide administration to 10 islet recipients with graft dysfunction similarly resulted in a maximal 40% reduction in insulin requirements, and also noted an “increase in insulin requirements in some patients during the study.” In both series, overall glycemic control was not different after starting exenatide, with the HbA1c remaining 6.3% (1) and 6.7% (2), respectively. Moreover, despite reduced insulin requirements and no change in HbA1c, Froud et al. (1) reported an increased incidence of moderate hypoglycemia (blood glucose <54 mg/dL) on exenatide, a concerning finding given the selection of candidates for islet transplantation is based on the presence of hypoglycemia unawareness. Since the reduced insulin requirement on exenatide is not associated with less hypoglycemia or an improvement in HbA1c, it does not seem that exenatide therapy should substitute for either a sufficient islet mass or appropriate insulin therapy to maintain normoglycemia. Froud et al. (1) suggest the increased hypoglycemia seen on exenatide might be due to an inability of intrahepatic islets to turn off insulin secretion; however, it has been demonstrated using hyperinsulinemic-hypoglycemic clamps in islet recipients that intrahepatic islets respond appropriately to hypoglycemia by suppressing endogenous insulin secretion (3). Rather, exenatide is likely producing reactive hypoglycemia mediated by excessive insulin secretion in response to nutrient ingestion as may occur by increased endogenous GLP-1 in subjects postgastrectomy (4), after gastric bypass (5), and with GLP-1 secreting neuroendocrine tumors (6). This mechanism is supported by the majority of the hypoglycemic events in islet recipients on exenatide occurring after meals (1, 2). Finally, Froud et al. (1) contend that “the use of exenatide is better indicated from the time of initial islet transplantation” to promote successful (insulin independent) results using a single islet donor, an approach that has been piloted in a series of six islet recipients, two of whom went on to require second islet infusions (7). Because single donor insulin independence has also been reported in the absence of exenatide (8, 9), randomized-controlled trials remain necessary to determine whether exenatide use may be associated with long-term beneficial effects on islet graft function or survival. Michael R. Rickels Ali Naji Type 1 Diabetes Unit Institute for Diabetes, Obesity & Metabolism University of Pennsylvania School of Medicine Philadelphia, PA