Dual-Hormone Closed-Loop System Using a Liquid Stable Glucagon Formulation Versus Insulin-Only Closed-Loop System Compared With a Predictive Low Glucose Suspend System: An Open-Label, Outpatient, Single-Center, Crossover, Randomized Controlled Trial

Abstract

OBJECTIVE To assess the efficacy and feasibility of a dual-hormone (DH) closed-loop system with insulin and a novel liquid stable glucagon formulation compared with an insulin-only closed-loop system and a predictive low glucose suspend (PLGS) system. RESEARCH DESIGN AND METHODS In a 76-h, randomized, crossover, outpatient study, 23 participants with type 1 diabetes used three modes of the Oregon Artificial Pancreas system: 1) dual-hormone (DH) closed-loop control, 2) insulin-only single-hormone (SH) closed-loop control, and 3) PLGS system. The primary end point was percentage time in hypoglycemia (<70 mg/dL) from the start of in-clinic aerobic exercise (45 min at 60% VO2max) to 4 h after. RESULTS DH reduced hypoglycemia compared with SH during and after exercise (DH 0.0% [interquartile range 0.0–4.2], SH 8.3% [0.0–12.5], P = 0.025). There was an increased time in hyperglycemia (>180 mg/dL) during and after exercise for DH versus SH (20.8% DH vs. 6.3% SH, P = 0.038). Mean glucose during the entire study duration was DH, 159.2; SH, 151.6; and PLGS, 163.6 mg/dL. Across the entire study duration, DH resulted in 7.5% more time in target range (70–180 mg/dL) compared with the PLGS system (71.0% vs. 63.4%, P = 0.044). For the entire study duration, DH had 28.2% time in hyperglycemia vs. 25.1% for SH (P = 0.044) and 34.7% for PLGS (P = 0.140). Four participants experienced nausea related to glucagon, leading three to withdraw from the study. CONCLUSIONS The glucagon formulation demonstrated feasibility in a closed-loop system. The DH system reduced hypoglycemia during and after exercise, with some increase in hyperglycemia.

Adjunctive Therapies to Optimize Closed-loop Glucose Control

“…The Oregon University CL group used stable glucagon (XeriSol glucagon:Xeris Pharmaceuticals, Chicago, IL) in their 76 hour, randomized, crossover, outpatient study that showed an increase in the TIR during the bihormonal CL system use compared to Predictive Low Glucose Suspend (PLGS) (7.5%) with some increase in hyperglycemia compared to a single hormone CL system (28.2 vs. 25.1%). 27 Insulin TDD was not different among groups. 27 The most common side effect of glucagon has been nausea that resulted in 4 out of 23 study participants withdrawing from the study.…”

Dual‐hormone artificial pancreas for management of type 1 diabetes: Recent progress and future directions

“…Since native glucagon is a highly unstable peptide, which tends to form β‐pleated sheets of amyloid‐like fibrils in aqueous solution, 110,111 glucagon cartridges for pump use need to be replaced every 8‐24 hours with freshly reconstituted glucagon. To overcome the issue of chemical and physical stability of glucagon, in recent years, several pharmaceutical companies have been focusing on the development of novel alternative and stable liquid glucagon (or glucagon analog) formulations, 109,112 which will potentially be available for continuous pump use in dual‐hormone artificial pancreas systems in the near future 111 …”

Fault Tolerant Strategies for Automated Insulin Delivery Considering the Human Component: Current and Future Perspectives

“…The iLet system 80,81 delivers both insulin and glucagon, but the first commercial version will likely administer only insulin. Wilson et al 82 present results for the Oregon Artificial pancreas, with and without glucagon, in a 76-hour outpatient study with 23 participants. Wilson et al 83 provides a comprehensive review of the potential benefits of using dual hormone systems, concluding that the use of glucagon contributes in lowering hypoglycemia.…”