Is there any literature or recommendations available to support the use of a glucagon infusion for treatment of hypoglycemia?

Comment by InpharmD Researcher

Although guidelines consistently highlight glucagon as an essential rescue therapy for severe hypoglycemia, available recommendations focus on single or limited parenteral or intranasal doses rather than continuous infusion. Evidence assessing glucagon infusion for hypoglycemia management is sparse and primarily derived from small observational reports in neonates and infants with refractory hypoglycemia, where results suggest potential benefit (see Tables 1-2). However, the relevance of these findings to older children and adults with hypoglycemia remains uncertain.

Background

The 2025 Standard of Diabetes Care outlines comprehensive components for diabetes management, including general treatment goals, guidelines, and quality evaluation tools. Glucagon prescriptions are given consideration for individuals hospitalized due to severe hypoglycemia, those with impaired awareness of hypoglycemia, or patients at high risk for future hypoglycemic events (e.g., end-stage kidney disease, intensive insulin management, frailty), specifically for managing any future severe episodes. Chapter 6 of the Standard of Diabetes Care, which addresses glycemic goals and hypoglycemia management, explicitly recommends that glucagon be prescribed for all individuals taking insulin or at high risk for hypoglycemia, indicating its use for people unable or unwilling to orally consume carbohydrates during a hypoglycemic event. This ensures that essential rescue medication (injection, nasal spray, autoinjector) is available for at-risk patients to manage severe hypoglycemic episodes effectively outside of direct hospital intervention. [1], [2]

A 2012 guideline published by The Endocrine Society outlined comprehensive strategies for managing hyperglycemia in hospitalized patients within non-critical care settings. As the suggested nurse-initiated strategies for treating hypoglycemia, for patients with an altered level of consciousness and no available intravenous (IV) access, glucagon 1 mg is given intramuscularly, limited to two times. The updated 2022 Endocrine Society Clinical Practice guidelines provide no updates regarding the use of glucagon for the treatment of hypoglycemia. [3], [4]

Glucagon is an important therapeutic option for treating severe hypoglycemia, defined as a blood glucose level under 3.0 mmol/L for adults and events requiring external assistance for children. The primary use of glucagon appears to be in outpatient settings for emergency episodes of hypoglycemia. Within hospital settings, the standard practice is administering a 1 mg IV dose of glucagon (limit two times). However, there is a lack of details regarding glucagon use for specific scenarios, such as patients who are NPO or fluid-restricted. Another review highlights its role as an essential, yet underutilized, emergency therapy. The article discusses the efficacy of glucagon as a rapid response treatment for severe hypoglycemia, which is available in emergency kits and can be administered by non-medical personnel in non-hospital settings, thereby offering a critical advantage in emergency scenarios. The article's insights are supported by data showing the high incidence of severe hypoglycemic episodes among patients with type 1 diabetes and, to a lesser extent, in type 2 diabetes when insulin therapy is employed. It emphasizes the need for better education on glucagon use among patients and their caregivers to overcome the fear of hypoglycemia and encourage more frequent use of glucagon in emergencies. [5], [6], [7]

A recent retrospective, single-center study conducted as part of the EPI-GLUREDIA study evaluated the management and direct medical costs of severe hypoglycemia (SH) in children and adolescents with type 1 diabetes (T1D) at a Belgian tertiary pediatric care center. The study included 358 eligible patients aged 2-20 years. A total of 208 SH episodes were recorded in 113 patients, with a mean age of 13.6 years and an average duration of T1D of 6.2 years. The estimated frequency of SH was 0.08 episodes per patient per year. SH events and their management were documented using EPIC® medical records software, with clinical information recorded at each follow-up consultation. The study identified six treatment categories: no treatment, oral glucose (sugary food or drink), glucagon (administered intramuscularly or intranasally), emergency medical intervention, emergency care following the failure of oral glucose, and hospitalization for at least 24 hours. Oral glucose was the most frequently used treatment (47.4%), followed by glucagon (25.4%), which was used more often in boys (30.8%) than in girls (18.7%). Only 43% of SH episodes were treated in accordance with international guidelines. A significant increase in glucagon use occurred after reimbursement of the intranasal formulation in January 2022. After this policy change, glucagon use increased from 25 of 129 episodes (19.4%) to 28 of 81 episodes (34.6%) (p = 0.013), with a particularly greater uptake among teachers and educators (18/49 vs. 10/78; p = 0.002). These findings underscore the ongoing challenges in SH management, including low adherence to guideline-based treatment. However, the availability and reimbursement of intranasal glucagon appear to have improved access and uptake of appropriate therapy. [8], [9]

References:

[1] American Diabetes Association Professional Practice Committee. 6. Glycemic Goals and Hypoglycemia: Standards of Care in Diabetes-2025. Diabetes Care. 2025;48(1 Suppl 1):S128-S145. doi:10.2337/dc25-S006
[2] American Diabetes Association Professional Practice Committee. 16. Diabetes Care in the Hospital: Standards of Care in Diabetes-2025. Diabetes Care. 2025;48(1 Suppl 1):S321-S334. doi:10.2337/dc25-S016
[3] Umpierrez GE, Hellman R, Korytkowski MT, et al. Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(1):16-38. doi:10.1210/jc.2011-2098
[4] Korytkowski MT, Muniyappa R, Antinori-Lent K, et al. Management of Hyperglycemia in Hospitalized Adult Patients in Non-Critical Care Settings: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2022;107(8):2101-2128. doi:10.1210/clinem/dgac278
[5] Hulkower RD, Pollack RM, Zonszein J. Understanding hypoglycemia in hospitalized patients. Diabetes Manag (Lond). 2014;4(2):165-176. doi:10.2217/DMT.13.73
[6] Thieu VT, Mitchell BD, Varnado OJ, Frier BM. Treatment and prevention of severe hypoglycaemia in people with diabetes: Current and new formulations of glucagon. Diabetes Obes Metab. 2020;22(4):469-479. doi:10.1111/dom.13941
[7] Kedia N. Treatment of severe diabetic hypoglycemia with glucagon: an underutilized therapeutic approach. Diabetes Metab Syndr Obes. 2011;4:337-346. doi:10.2147/DMSO.S20633
[8] Harvengt A, Maure A, Beckers M, et al. Evaluation of severe hypoglycemia management in children and adolescents with type 1 diabetes in a Belgian tertiary pediatric care center: impact of intranasal glucagon and cost analysis. Eur J Pediatr. 2025;184(2):162. Published 2025 Jan 30. doi:10.1007/s00431-025-05992-2
[9] Harvengt A, Beckers M, Boutsen L, Costenoble E, Brunelle C, Lysy P. Deep Analysis of Clinical Parameters and Temporal Evolution of Glycemic Parameters Based on CGM Data for the Characterization of Severe Hypoglycemia in a Cohort of Children and Adolescents with Type 1 Diabetes. Nutrients. 2023;15(13):2957. Published 2023 Jun 29. doi:10.3390/nu15132957
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Is there any literature or recommendations available to support the use of a glucagon infusion for treatment of hypoglycemia?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

 

Experience With Intravenous Glucagon Infusions as a Treatment for Resistant Neonatal Hypoglycemia
Design

Retrospective observational study

N=55
Objective To evaluate the short-term response of blood glucose levels to an intravenous infusion of glucagon
Study Groups All newborns (n=55)
Inclusion Criteria Newborns admitted to the NICU who received a glucagon infusion for hypoglycemia during a 5-year period (1994-1998) and had at least one laboratory-determined blood glucose level before and after glucagon infusion
Exclusion Criteria Not explicitly stated
Methods Newborns received glucagon infusions at a usual dose of 0.5-1 mg/day. Blood glucose levels were measured 24 hours before and 72 hours after glucagon infusion. Effects on sodium and platelet levels were also examined
Duration 5-year period (1994-1998)
Outcome Measures Rise in blood glucose concentration 
Baseline Characteristics   All patients (n= 55)
Gestational age, weeks  36 ± 7.1
Birth weight, kg 2.35 ± 0.99
Male 37
Female 18
Results   All patients (n= 55)
Mean rise in blood glucose, mg/dL (mmol/L) 52.6 (2.92)

Glucagon infusion was associated with a reduction in hypoglycemic episodes, with no further cases of severe hypoglycemia (≤20 mg/dL [≤1.1 mmol/L]) reported. Five newborns, four of whom were preterm with intrauterine growth restriction, required additional glycemic treatment. Before starting glucagon, 75% of newborns were thrombocytopenic, and platelet counts decreased in nine newborns during therapy. There were no cases of hyponatremia attributed to glucagon.
Adverse Events Seventy-five percent of newborns were thrombocytopenic before starting glucagon infusion, and in 9 newborns platelet counts decreased following glucagon infusion. No hyponatremia attributable to glucagon.
Study Author Conclusions Glucagon infusions appear to be beneficial for problematic neonatal hypoglycemia of different causes.
Critique The study's retrospective nature limits control over timing of blood glucose measurements and lacks plasma insulin or other metabolic studies for most newborns. The wide variation in glucagon dosage per kilogram may affect results. Despite these limitations, the study provides valuable insights into the use of glucagon for resistant neonatal hypoglycemia.
References:

Miralles RE, Lodha A, Perlman M, Moore AM. Experience with intravenous glucagon infusions as a treatment for resistant neonatal hypoglycemia. Arch Pediatr Adolesc Med. 2002;156(10):999-1004. doi:10.1001/archpedi.156.10.999
Efficacy of Dose-Titrated Glucagon Infusions in the Management of Congenital Hyperinsulinism: A Case Series
Design

Case series

N= 33
Objective To assess the potential clinical utility of dose-titrated glucagon infusions in stabilizing glycemic status in pediatric patients with CHI, who were managed by medical and/or surgical approaches
Study Groups All patients (n= 33)
Inclusion Criteria Patients with CHI requiring glucagon by dose titration in addition to intravenous dextrose and medical therapy with diazoxide/octreotide to achieve glycemic stability
Exclusion Criteria Patients suspected to have genetic syndromes with prior risk of hypoglycemia; patients likely to have mild transient CHI
Methods Patients received glucagon infusion starting at 5 mcg/kg/h, titrated as needed. Glucagon solutions were changed every 12 h. Plasma glucose was monitored hourly. The goal was to maintain plasma glucose ≥3.5 mmol/L and total fluid volume ≤150 mL/kg/day. Dextrose infusion rate was reduced over a 24-h period after achieving glycemic stability
Duration 2007 to 2015
Outcome Measures Achievement of glycemic stability and reduction in glucose infusion rate (GIR)
Baseline Characteristics   All patients (n= 33)
Gender - Male 24 (72.7%)
Birthweight, kg  3.29 ± 0.93
Age at diagnosis, days (range) 1 (1-366)
Convulsions - Yes 6 (18.2%)
Mutation status - Any mutation 10 (30.3%)
Glucose at diagnosis, mmol/L  1.39 ± 0.82
Insulin concentration at diagnosis, pmol/L  17.8 ± 15.9
Results   All patients (n= 32) p-value
GIR1, mg/kg/min  15.6 ± 4.5 -
GIR2, mg/kg/min  13.4 ± 4.5 -
Mean difference in GIR 2.2 0.000019

All patients achieved glycemic stability with glucagon infusion, demonstrating clinical benefit.
Adverse Events Adverse events were infrequent with diarrhea possibly attributed to glucagon treatment in 1 patient. Necrolytic migratory erythema was observed in another patient with long-term treatment.
Study Author Conclusions These data suggest that dose-titrated glucagon infusion therapy aids hypoglycemia prevention and reduction in GIR in the clinical management of patients with CHI.
Critique The study demonstrates the efficacy of glucagon in stabilizing glucose levels and reducing GIR in CHI patients. However, the absence of a control group and the modest sample size limit the ability to attribute GIR reduction solely to glucagon. The observational design and lack of uniform dosing for diazoxide and octreotide are additional limitations. 
References:

Salomon-Estebanez M, Yau D, Dunne MJ, et al. Efficacy of Dose-Titrated Glucagon Infusions in the Management of Congenital Hyperinsulinism: A Case Series. Front Endocrinol (Lausanne). 2020;11:441. Published 2020 Sep 3. doi:10.3389/fendo.2020.00441