Effect of exenatide on gastric emptying and graft survival in islet allograft recipients

Abstract

Objective: To evaluate the effect of exenatide on gastric emptying and long-term metabolic control.

Methods: Ten islet allograft recipients treated with exenatide up to 4 years. Data from a mixed meal test with (MMT+) versus without (MMT-) administration of exenatide before boost ingestion were analyzed at 6, 12, 24, 36, or 48 months after initiation of exenatide treatment. None of the subjects were symptomatic for gastroparesis before or during the study. The c-peptide, acetaminophen absorption and glucose responses to MMT were analyzed by Student t test and analysis of variance.

Results: Average exenatide dose was 12.75 ± 9.46 μg/dL. The MMT subjects included two groups those with acetaminophen peak ≤120 minutes ("good gastric emptying; n = 4") versus those with an acetaminophen peak ≥180 minutes ("delayed gastric emptying"). Among the MMT+, acetaminophen absorption was the same in both groups (P = .27). Up to 48 months exenatide delayed time to peak of glucose, c-peptide, and acetaminophen as well as suppressed the glucagon response to MMT mean peak: 70.89 ± 12.45 versus 43.24 ± 4.67. The mean values of c-peptide and glucose responses to MMT were not significantly different.

Conclusions: Long-term exenatide administration up to 4 years was safe in islet transplant recipients, even in the presence of delayed gastric emptying. The effects of exenatide were acute and reversible when the agent was withdrawn. The main difficulty with the use of exenatide in islet transplant subjects is their poor tolerability, although the physiological effects are clearly evident even at low doses. Approximately 63% of total subjects under exenatide treatment discontinued the drug due to nausea and vomiting. The use of new GLP1 analogs with longer half lives and fewer side effects may help to attain higher GLP1 levels, therefore improving islet function and survival.

Fig 1

On the left, acetaminophen levels were measured during MMT exenatide negative at different times. Two groups were identified: the GGE and DGE. The GGE group (circles) has a peak of acetaminophen absorption at 120 minutes, and the DGE group (squares) has a peak of absorption at 180 minutes. On the right, acetaminophen absorption is delayed to a similar degree in both groups. MMT, mixed meal tolerance test; GGE, good gastric emptying; DGE, delayed gastric emptying.

Fig 2

Glucose and c-peptide curves during MMT exenatide negative (left) and positive (right). Exenatide (right) delayed time to peak of glucose and c-peptide as compared to MMT without exenatide (left). The means of c-peptide and glucose at different time points were not statistically different. MMT, mixed meal tolerance test.

Fig 3

Exenatide (Exn) suppressed the abnormal glucagon increase after hyperglycemia observed in our subjects at all study times up to 48 months of follow-up.