Efficacy determinants of subcutaneous microdose glucagon during closed-loop control

Abstract

Background: During a previous clinical trial of a closed-loop blood glucose (BG) control system that administered insulin and microdose glucagon subcutaneously, glucagon was not uniformly effective in preventing hypoglycemia (BG<70 mg/dl). After a global adjustment of control algorithm parameters used to model insulin absorption and clearance to more closely match insulin pharmacokinetic (PK) parameters observed in the study cohort, administration of glucagon by the control system was more effective in preventing hypoglycemia. We evaluated the role of plasma insulin and plasma glucagon levels in determining whether glucagon was effective in preventing hypoglycemia.

Methods: We identified and analyzed 36 episodes during which glucagon was given and categorized them as either successful or unsuccessful in preventing hypoglycemia.

Results: In 20 of the 36 episodes, glucagon administration prevented hypoglycemia. In the remaining 16, BG fell below 70 mg/dl (12 of the 16 occurred during experiments performed before PK parameters were adjusted). The (dimensionless) levels of plasma insulin (normalized relative to each subject's baseline insulin level) were significantly higher during episodes ending in hypoglycemia (5.2 versus 3.7 times the baseline insulin level, p=.01). The relative error in the control algorithm's online estimate of the instantaneous plasma insulin level was also higher during episodes ending in hypoglycemia (50 versus 30%, p=.003), as were the peak plasma glucagon levels (183 versus 116 pg/ml, p=.007, normal range 50-150 pg/ml) and mean plasma glucagon levels (142 versus 75 pg/ml, p=.02). Relative to mean plasma insulin levels, mean plasma glucagon levels tended to be 59% higher during episodes ending in hypoglycemia, although this result was not found to be statistically significant (p=.14). The rate of BG descent was also significantly greater during episodes ending in hypoglycemia (1.5 versus 1.0 mg/dl/min, p=.02).

Conclusions: Microdose glucagon administration was relatively ineffective in preventing hypoglycemia when plasma insulin levels exceeded the controller's online estimate by >60%. After the algorithm PK parameters were globally adjusted, insulin dosing was more conservative and microdose glucagon administration was very effective in reducing hypoglycemia while maintaining normal plasma glucagon levels. Improvements in the accuracy of the controller's online estimate of plasma insulin levels could be achieved if ultrarapid-acting insulin formulations could be developed with faster absorption and less intra- and intersubject variability than the current insulin analogs available today.

Figure 1

Two representative episodes are shown, one for a case when glucagon dosing was effective in preventing hypoglycemia (A, C, and E) and another for a case when glucagon dosing failed to prevent hypoglycemia (B, D, and F). Shown in both cases are the BG data segment and corresponding glucagon doses (A and B, respectively), the corresponding measured plasma-glucagon levels (C and D, respectively), and the corresponding measured and controller-predicted plasma-insulin levels (E and F, respectively). Note the strong agreement between the measured and controller-predicted plasma-insulin levels in E. In contrast, there was a substantial disparity between the measured and predicted insulin levels in F, which was arguably the leading cause of hypoglycemia in that case, despite the larger glucagon doses (red bars) in B relative to A and the significantly higher plasma-glucagon levels in D relative to C. The position of the triangle in B corresponds to the location along the timeline of a 15-g carbohydrate intervention for hypoglycemia. The episode shown in B, D, and F occurred during an experiment in which the control algorithm assumed fast PK parameter settings. Blood glucose was measured every 5 minutes.

Figure A1

Blood-glucose traces around individual glucagon episodes (successes) from closed-loop control experiment #108-1 (A), #110-2 (B and C),and #117-1 (D and E). Corresponding glucagon doses are shown at the bottom of each panel. The episodes shown in A, D, and E occurred during an experiment in which the control algorithm was configured with fast PK parameter settings. Blood glucose was measured every 5 minutes.

Figure A2

Blood-glucose traces around individual glucagon episodes (successes) from closed-loop control experiment #126-1 (A–D) and #128-1 (E and F). Corresponding glucagon doses are shown at the bottom of each panel. The episodes shown in A–F occurred during an experiment in which the control algorithm was configured with fast PK parameter settings. Blood glucose was measured every 5 minutes.

Figure A3

Blood-glucose traces around individual glucagon episodes (successes) from closed-loop control experiment #110-3 (A), #115-2 (B and C), and #117-2 (D). Corresponding glucagon doses are shown at the bottom of each panel. The episodes shown in B and C occurred during an experiment in which the control algorithm was configured with fast PK parameter settings. Blood glucose was measured every 5 minutes.

Figure A4

Blood-glucose traces around individual glucagon episodes (successes) from closed-loop control experiment #122-2 (A), #126-2 (B), #129-2 (C), and #132-2 (D and E). Corresponding glucagon doses are shown at the bottom of each panel. Blood glucose was measured every 5 minutes.

Figure A5

Blood-glucose traces around individual glucagon episodes (failures) from closed-loop control experiment #115-2 (A), #117-1 (B), #121-1 (C) and #121-2 (D). The locations along the timeline of the triangles in A and C correspond to 15-g carbohydrate interventions for hypoglycemia. Corresponding glucagon doses are shown at the bottom of each panel. The episodes shown in A–C occurred during experiments in which the control algorithm was configured with fast PK parameter settings. Blood glucose was measured every 5 minutes.

Figure A6

Blood-glucose traces around four individual glucagon episodes (failures) from closed-loop control experiment #122-1 (A–D). The locations along the timeline of the triangles in A–D correspond to 15-g carbohydrate interventions for hypoglycemia. Corresponding glucagon doses are shown at the bottom of each panel. The episodes shown in A–D occurred during an experiment in which the control algorithm was configured with fast PK parameter settings. Blood glucose was measured every 5 minutes.

Figure A7

Blood-glucose traces around three individual glucagon episodes (failures) from closed-loop control experiment #129-1 (A–C). The locations along the timeline of the triangles in A and C correspond to 15-g carbohydrate interventions for hypoglycemia. Corresponding glucagon doses are shown at the bottom of each panel. The episodes shown in A–C occurred during an experiment in which the control algorithm was configured with fast PK parameter settings. Blood glucose was measured every 5 minutes.

Figure A8

Blood-glucose traces around five individual glucagon episodes (failures) from closed-loop control experiment #132-1 (A–D). The locations along the timeline of the triangles in A, C, and D correspond to 15-g carbohydrate interventions for hypoglycemia. Corresponding glucagon doses are shown at the bottom of each panel. The episodes shown in A–D occurred during an experiment in which the control algorithm was configured with fast PK parameter settings. Blood glucose was measured every 5 minutes.