Comparison of a ready-to-use liquid glucagon injection administered by autoinjector to glucagon emergency kit for the symptomatic relief of severe hypoglycemia: two randomized crossover non-inferiority studies

Abstract

Introduction: To prevent medical sequelae of severe hypoglycemic emergencies, prompt and reliable rescue intervention is critically important. A ready-to-use, liquid stable glucagon, administered subcutaneously by glucagon autoinjector (GAI), Gvoke HypoPen (glucagon injection; Xeris Pharmaceuticals), was evaluated for rescue treatment of severe hypoglycemia.

Research design and methods: Two phase III, randomized, controlled, blinded, non-inferiority crossover studies were conducted in 161 adults with type 1 diabetes to compare 1 mg doses of GAI versus glucagon emergency kit (GEK) for treating insulin-induced severe hypoglycemia. Efficacy was evaluated as either a return of plasma glucose to >70 mg/dL (3.9 mmol/L) or increase ≥20 mg/dL (1.1 mmol/L) from a baseline glucose of <50 mg/dL (2.9 mmol/L), within 30 min of dosing.

Results: For successful plasma glucose recovery within 30 min, treatment with GAI was non-inferior to GEK. Treatment with GAI was non-inferior to GEK for a plasma glucose >70 mg/dL (3.9 mmol/L) or neuroglycopenic symptom relief within 30 min. From administration of glucagon, the mean time to achieve plasma glucose >70 mg/dL (3.9 mmol/L) or increase ≥20 mg/dL (1.1 mmol/L) was 13.8±5.6 min for GAI and 10.0±3.6 min for GEK. This mean time does not account for the significantly shorter (p<0.0001) drug preparation and administration time for GAI (27.3±19.7 s) versus GEK (97.2±45.1 s). The incidence of treatment emergent adverse events was comparable in both groups.

Conclusions: A ready-to-use GAI was non-inferior to GEK, with a similar tolerability profile. GAI is an effective, safe, and well-tolerated rescue treatment for severe hypoglycemia and is a viable alternative to GEK.

Trial registration numbers: NCT02656069 and NCT03439072.

Keywords: adult; diabetes mellitus; glucagon; hypoglycemia; type 1.

Conflict of interest statement

Competing interests: MPC is employed by Diablo Clinical Research, Walnut Creek, California, and served as a study investigator to Xeris Pharmaceuticals for both XSGP-301 and XSGP-303. As an employee of Diablo Clinical Research, MPC also receives research funding from Abbott Diabetes Care, Biolinq, Dexcom, Medtronic, Novo Nordisk, Eli Lilly, Helixmith, Pfizer, Novabio, GraphWear, Ascensia, Abbott Point of Care. MC was employed by Xeris Pharmaceuticals, Inc at the time of study conduct and analysis and currently serves as a consultant to Xeris Pharmaceuticals, Inc. SP and KJ are employees of Xeris Pharmaceuticals, Inc. AN is a former employee of Xeris Pharmaceuticals, Inc. NCC is employed by Empiristat, Inc and served as a consultant to Xeris Pharmaceuticals during the conduct of the study, study analysis, and manuscript development.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

XSGP-303 – ITT population. (A) Number of participants with an average neuroglycopenic score >1 by nominal time from injection and treatment group; (B) mean neuroglycopenic symptom score and mean plasma glucose (mg/dL) by nominal time from injection and treatment group; and (C) mean hypoglycemia symptom score and mean plasma glucose (mg/dL) by nominal time from injection and treatment group. GAI, glucagon autoinjector; GEK, glucagon emergency kit; ITT, intent-to-treat.