A Randomized, Placebo-Controlled Double-Blind Trial of a Closed-Loop Glucagon System for Postbariatric Hypoglycemia

Abstract

Background Postbariatric hypoglycemia (PBH) can threaten safety and reduce quality of life. Current therapies are incompletely effective. Methods Patients with PBH were enrolled in a double-blind, placebo-controlled, crossover trial to evaluate a closed-loop glucose-responsive automated glucagon delivery system designed to reduce severe hypoglycemia. A hypoglycemia detection and mitigation algorithm was embedded in the artificial pancreas system connected to a continuous glucose monitor (CGM, Dexcom) driving a patch infusion pump (Insulet) filled with liquid investigational glucagon (Xeris) or placebo (vehicle). Sensor/plasma glucose responses to mixed meal were assessed during 2 study visits. The system delivered up to 2 doses of study drug (300/150 μg glucagon or equal-volume vehicle) if triggered by the algorithm. Rescue dextrose was given for plasma glucose <55 mg/dL or neuroglycopenia. Results Twelve participants (11 females/1 male, age 52 ± 2, 8 ± 1 years postsurgery, mean ± SEM) completed all visits. Predictive hypoglycemia alerts prompted automated drug delivery postmeal, when sensor glucose was 114 ± 7 vs 121 ± 5 mg/dL (P = .39). Seven participants required rescue glucose after vehicle but not glucagon (P = .008). Five participants had severe hypoglycemia (<55 mg/dL) after vehicle but not glucagon (P = .03). Nadir plasma glucose was higher with glucagon vs vehicle (67 ± 3 vs 59 ± 2 mg/dL, P = .004). Plasma glucagon rose after glucagon delivery (1231 ± 187 vs 16 ± 1 pg/mL at 30 minutes, P = .001). No rebound hyperglycemia occurred. Transient infusion site discomfort was reported with both glucagon (n = 11/12) and vehicle (n = 10/12). No other adverse events were observed. Conclusion A CGM-guided closed-loop rescue system can detect imminent hypoglycemia and deliver glucagon, reducing severe hypoglycemia in PBH. Clinical Trials Registration NCT03255629

A Potential Role for Endogenous Glucagon in Preventing Post-Bariatric Hypoglycemia

“…However, PBH is usually associated with weight regain (45). Nevertheless, the potential use of glucagon for treating patients with PBH was tested using low-dose closedloop infusion pumps that demonstrated to reduce the rates of hypoglycemia and prevent rebound hyperglycemia (16).…”

“…The fact that PBH frequency can be mitigated by dietary interventions (2,13,14) and pharmacological interventions that reduce carbohydrate digestion or absorption, delay gastro-intestinal transit time, limit insulin secretion or suppress incretin effects (10,15,16), suggests a role for entero-pancreatic hormone dynamics in this condition.…”

Roux-en-Y Gastric Bypass Increases Glycemic Variability and Time in Hypoglycemia in Patients With Obesity and Prediabetes or Type 2 Diabetes: A Prospective Cohort Study

“…Our data support the hypothesis that PBH is associated with excessive GLP-1 secretion and additionally a possible association with reduced glucagon secretion during the MMT. Consistent with this, both the GLP-1 receptor antagonist exendin(9-39) (16) and glucagon itself (17) are being investigated as potential therapies for PBH.…”

<p>Hypoglycemia After Upper Gastrointestinal Surgery: Clinical Approach to Assessment, Diagnosis, and Treatment</p>

“…Another approach under investigation is the use of a closed-loop glucose-responsive automated glucagon delivery (AGD) system. 105 Automation was achieved by development of a hypoglycemia algorithm, 106 which was embedded in an artificial pancreas system, guided by CGM. The AGD system delivered a mini-dose of stable liquid glucagon via a patch pump when glucose levels were dropping rapidly, or submit your manuscript | www.dovepress.com…”