Automated Event-Based System for the Prevention of Post-Bariatric Hypoglycemia Using a Mini-Dose of a Stable Glucagon Formulation

Presentation Number: OR14-5
Date of Presentation: April 3rd, 2017

Christopher M. Mulla*1, Alejandro Laguna2, Kristen M. Fowler1, Emilie Cloutier1, Allison B. Goldfine1, Brett Newswanger3, Martin Cummins3, Sunil Deshpande2, Steven J. Prestrelski3, Howard Zisser4, Francis J. Doyle III2, Eyal Dassau2 and Mary Elizabeth Patti1
1Research Division, Joslin Diabetes Center, Boston, MA, 2Harvard John A. Paulson School of Engineering and Applied Sciences, 3Xeris Pharmaceuticals, 4University of California Santa Barbara, Santa Barbara, CA

Abstract

Patients with post-bariatric hypoglycemia (PBH) experience severe hypoglycemia and neuroglycopenia. Current nutritional and medication therapies are incompletely effective for hypoglycemia prevention. However, severe hypoglycemia in PBH can be treated successfully with rescue glucagon. We hypothesized that small doses of an investigational stable liquid glucagon delivered via subcutaneous infusion pump, guided by alerts from a continuous glucose monitor (CGM)-triggered low glucose prediction algorithm, could prevent severe hypoglycemia without rebound hyperglycemia. We performed a proof-of-concept study employing a novel open-loop glucagon system, utilizing (1) a Dexcom® CGM connected to (2) a Windows® tablet running a hypoglycemia prediction algorithm, and (3) an Omnipod® pump filled with Xeris glucagon.

Patients with PBH and neuroglycopenia were recruited. After screening, two sensors were placed. Participants returned 1-2 days later after an overnight fast; the sensor most concordant with plasma glucose was utilized to guide the system. Participants consumed a liquid mixed meal (Ensure Compact: 64 g of CHO, 18 g protein, 236 ml). Sensor and plasma glucose (YSI), insulin, and glucagon were measured. The low glucose prediction algorithm uses CGM data to estimate future trends and time to impending hypoglycemia. Two distinct alarms were implemented in parallel to ensure reliable detection: 1) PBH postprandial alarm, issued after a meal when sensor glucose was rapidly dropping; and 2) hypoglycemia proximity alarm, issued when sensor glucose was close to the hypoglycemia threshold. Xeris glucagon (150 μg) was administered in response to the predicted hypoglycemia alert; blood sampling was continued for 2 hours.

Four females and one male, age (mean ± SD) 47 ± 7 years, BMI 32 ± 5 kg/m2, and 100 ± 51 months postoperative, were studied. Peak post-meal glucose was 205 ± 22 mg/dl, occurring at 38 ± 8 minutes, with plasma insulin 234 ± 20 µU/ml. Glucose fell rapidly thereafter, with max rate of change -8 ± 3 mg/dl/min. Predictive hypoglycemia alerts were triggered at 105 ± 40 minutes after mixed meal, prompting physician glucagon delivery via pump 6 ± 3 minutes later. Mean CGM and YSI glucose at alert were 92 ± 15 and 78 ± 9 mg/dl respectively, with insulin 31 ± 30 µU/ml. Glucagon levels were undetectable at alert but peaked at 387 ± 141 pg/ml 20 minutes after bolus. Minimum glucose during the study was 59 ± 7 mg/dl. Two patients required oral glucose following glucagon. No rebound hyperglycemia was observed.

In conclusion, we report the first use of an event-based glucagon rescue system, which successfully predicted and helped prevent severe hypoglycemic episodes. Two of five participants avoided severe hypoglycemia (<60 mg/dl). Higher doses of glucagon may be required to fully reverse rapid postprandial falls in glucose in the setting of very high peak postprandial insulin levels in patients with PBH.

 

Disclosure: CMM: Coinvestigator, Xeris Pharmaceuticals. BN: Employee, Xeris Pharmaceuticals, Employee, Xeris Pharmaceuticals. MC: Employee, Xeris Pharmaceuticals. SJP: Founder, Xeris Pharmaceuticals. MEP: Ad Hoc Consultant, Eiger Pharmaceuticals, Recipient Award, Astra Zeneca, Recipient Award, Jansen Pharmaceuticals, Recipient Award, Medimmune, Collaborator, Xeris Pharmaceuticals. Nothing to Disclose: AL, KMF, EC, ABG, SD, HZ, FJD III, ED