The use of exenatide in islet transplant recipients with chronic allograft dysfunction: safety, efficacy, and metabolic effects

Abstract

Background: A current limitation of islet transplantation is reduced long-term graft function. The glucagon-like peptide-1 receptor agonist, exenatide (Byetta, Amylin Pharmaceuticals, CA) has properties that could improve existing islet function, prevent further loss of islet mass and possibly even stimulate islet regeneration.

Methods: This prospective study evaluated the safety, efficacy, and metabolic effects of exenatide in subjects with type 1 diabetes mellitus and islet allograft dysfunction requiring exogenous insulin.

Results: Sixteen subjects commenced exenatide, 12 continue (follow-up 214+/-57 days; range 108-287), four (25%) discontinued medication because of side effects. At 6 months, exogenous insulin was significantly reduced with stable glycemic control (0.15+/-0.02 vs. 0.11+/-0.025 U/kg per day; P<0.0001); three subjects discontinued insulin from 4, 5, and 9 U/day, respectively, two sustained insulin independence with A1c reduction below graft dysfunction criteria. Postprandial capillary blood glucose was significantly decreased (129.4+/-3.8 vs. 118.7+/-4.6 mg/dL; P<0.001), C-peptide and C-peptide-to-glucose ratio increased significantly by 5th and 6th months of treatment (ratio, 1.09+/-0.15 vs. 1.52+/-0.18; P<0.05). Weight loss more than 3 kg occurred in 8 of 12 (67%) subjects. Stimulation testing demonstrated improved glucose disposal and C-peptide secretion (glucose area under the curve 52,332+/-3,219 vs. 42,072+/-1,965; P=0.002 mg x min x dL, mixed meal stimulation index 0.50+/-0.06 vs. 0.66+/-0.09; P=0.03 pmol x mL), with marked suppression of glucagon secretion and progressive increase in amylin secretion. Side effects were more frequent and severe compared with published reports in type 2 diabetes, tolerated doses were lower.

Conclusions: Exenatide was tolerated in this patient population after appropriate dose titration and there appeared to be gradual but sustained positive effects on glycemic control and islet graft function.

Figure 1

Panel A. Weight changes in exenatide subjects. Single measure in each subject at follow up visits demonstrates weight loss during initial 3 months with some stabilization thereafter (mean pre: 65.5±3.1 (n=16 range 48.2-92.3), 3 months: 64.0±3.4 (n=14 range 48.2-91.8) [diff=1.5, p=0.052], 6 months: 62.8±3.43 (n=14 range 44.1-92.3) [diff=2.75, p=0.024*] kg Panel B. Monthly Mean±SEM insulin requirements (ins/Day) demonstrate a significant reduction at all time points. Initially reduction is iatrogenic but at the end of 5/6 months of treatment, insulin requirements remain significantly decreased (pre: 0.15±0.03, 5-6 months: 0.12±0.03 [diff=0.04, p<0.0001]). By comparison, insulin requirements tend to increase over the 6 months prior to exenatide. Panel C/ D. Exenatide subjects demonstrated a significant increase in C-peptide levels by 5-6 months post treatment compared to baseline (pre: 1.13±0.14, 1-4 months: 1.22±0.15 [NS], 5-6 months: 1.58±0.17 [diff=0.46, p=0.001] mg/dL) and CPGR (pre 1.08±0.15, 1-4 months: 1.17±0.16 [NS], 5-6 months: 1.36±0.18 [diff=0.43, p=0.001]).

Figure 2

Panel A. In exenatide subjects fasting CBG levels increase significantly at all time points, although values are approaching baseline by 5-6 months (pre: 110.0±2.9, 1-4 months: 120.8±3.0 [p<0.001], 5-6 months: 113.2±3.1 [p<0.001] mg/dL). Panel B. In exenatide subjects reduction in postprandial CBG levels is immediate and significant by 6 months (pre: 129.4±3.8, months 1-4: 125.5±3.8 [p=0.06], months 5-6: 120.6±4.0 [p=0.0004] mg/dL). Panel C. Sub-analysis of meal excursions demonstrates more clearly the acute effects of exenatide. During months 5-6 of treatment, meal excursions are markedly diminished when exenatide is administered; when exenatide is not administered, excursions are greater than baseline likely secondary to a reduction in TDD insulin. Post meal CBG values (mean±SEM): meals without exenatide 152.8±7.8; meals with exenatide: 119.3±2.1 [diff=16.2 p<0.001] mg/dL. Panel D. In exenatide-treated subject only, chronological changes in preprandial and postprandial CBG levels are shown (mean±SEM) during the follow-up period and compared to stable levels prior to initiation of exenatide.

Figure 3

Panel A. In exenatide subjects levels of glucose during MMTT (without exenatide administration) demonstrated a progressive decrease over time, significant at 6 months (Glucose AUC pre: 52,332±3,219, 3 months: 44,732±2,418 [diff=7601, p=0.052], 6 months: 42,072±1,965 [diff=10,261, p=0.002] mg·min·dL^-1). Panel B. In exenatide subjects CPGR during MMTT (without exenatide administration) demonstrated a progressive increase over time, significant at 6 months (CPGR AUC pre: 469±56, 3 months: 502±64 [diff=36, p=0.40], 6 months: 616±85 [diff=149, p=0.03]). Panel C. In exenatide subjects levels of Amylin during MMTT (without exenatide administration) demonstrated a progressive increase over time, significant at both 3 and 6 months (Amylin AUC pre: 3,718±781, 3 months: 6,787±942 [diff=3,069, p=0.004], 6 months: 7,777±1,504 [diff=4,060, p=0.02] mg·min·dL^-1). Panel D. In exenatide subjects levels of glucose during MMTT (with and without exenatide administration) at 3 months post treatment demonstrated near complete abrogation of the glucose peak following meal ingestion resulting in significant reduction in glucose AUC (Glucose AUC pre: 52,332±3,219, 3 months exenatide negative: 44,732±2,418, 3 months exenatide positive: 36,635±1,522 [diff=8,097, p=0.002] mg·min·dL^-1). Panel E. In exenatide subjects levels of glucagon during MMTT without exenatide administration demonstrated abnormal elevation of glucagon levels following meal ingestion, while during MMTT with exenatide administration, glucagon secretion was completely inhibited resulting in significant reduction in glucagon AUC (Glucagon AUC pre: 23,865±3,077, 3 months exenatide negative: 25,681±2,802, 3 months exenatide positive: 18,522±1,835 [diff=7,159, p=0.0001] mg·min·dL^-1). Panel F. In exenatide subjects levels of C-peptide during MMTT with exenatide administration were lower compared to levels during MMTT without exenatide administration although when comparing C-peptide AUC during MMTT with exenatide administration at 3 and 6 months post treatment there was a progressive rise (C-peptide AUC pre: 761±71, 3 months exenatide positive: 659±111, 6 months exenatide positive: 771±86 ng·min·mL^-1).