Chronic Liraglutide Administration Fails to Suppress Postprandial Glucagon Levels in Type 1 Diabetic Islet Allograft Recipients With Graft Dysfunction

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To the Editor:
The initial success of islet transplantation for patients with type 1 diabetes is often followed by a decline of islet function.1 We previously showed that treatment with exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, improves islet graft function up to 12 months after occurrence of graft dysfunction requiring the reintroduction of insulin therapy.2 Exenatide treatment required two daily injections and was associated with gastrointestinal side effects.2 Liraglutide, an acylated GLP-1 receptor agonist, represents a viable therapeutic option because it is administrated once daily and has better tolerability. However, the recent LIBRA trial in patients with type 2 diabetes suggests that liraglutide chronic administration is associated with postprandial hyperglucagonemia.3 To investigate the use of liraglutide as adjuvant agent for islet transplantation in relation to its effect on glucagon secretion, we retrospectively analyzed five cases of islet transplant recipients with graft dysfunction who were switched from exenatide to liraglutide treatment to simplify their diabetic regimen and improve gastrointestinal side effects. Patients were part of the cohort study previously described (Figure 1A).2 After being treated with exenatide (10–30 μg SQ daily divided in two doses) for a total of 60 months, patients were started on liraglutide (titrated from 0.6 to 1.2 mg SQ once daily) and treated for 12 months. Islet function was assessed by 5 h mixed meal tolerance test (MMTT). Initial data analysis limited to glucagon secretion revealed that for the entire duration of exenatide treatment, glucagon levels were consistently suppressed, returned to baseline after exenatide discontinuation but surprisingly remained elevated despite starting liraglutide (P = 0.0005 by Friedman test) (Figure 1B). This finding was further investigated by comparing equivalent lengths of time for each medication after adjusting for baseline values. Exenatide consistently suppressed glucagon secretion, but liraglutide failed to do so both at 6 and 12 months (P = 0.0313 by Wilcoxon test) (Figure 1C). Assessment of beta cell secretion showed that there were no significant differences in glucose and insulin profiles (Figure 1D, E). C-peptide levels were comparable under exenatide and liraglutide treatments at 12 months, but there was a discrepancy between pro-insulin and c-peptide levels indicative of graft dysfunction (Figure 1F, G). Liraglutide medical adherence was confirmed by the increase in GLP-1 levels (P = 0.0239 by Friedman test) (Figure 1H). HbA1c, insulin doses, and body weight were not significantly different under the two treatments. Gastrointestinal side effects, which occurred in two subjects with exenatide treatment, were not observed with liraglutide. We recognize the limitations of this study, which include the small sample size and lack of a control group. Our data suggest that the chronic administration of liraglutide may result in a lack of suppression of postchallenge glucagon levels. More studies are needed to investigate the clinical implication of these findings and their impact on islet transplantation.
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