Intranasal Glucagon for Treatment of Insulin-Induced Hypoglycemia in Adults With Type 1 Diabetes: A Randomized Crossover Noninferiority Study

Abstract

OBJECTIVETreatment of severe hypoglycemia with loss of consciousness or seizure outside of the hospital setting is presently limited to intramuscular glucagon requiring reconstitution immediately prior to injection, a process prone to error or omission. A needle-free intranasal glucagon preparation was compared with intramuscular glucagon for treatment of insulin-induced hypoglycemia.RESEARCH DESIGN AND METHODSAt eight clinical centers, a randomized crossover noninferiority trial was conducted involving 75 adults with type 1 diabetes (mean age, 33 ± 12 years; median diabetes duration, 18 years) to compare intranasal (3 mg) versus intramuscular (1 mg) glucagon for treatment of hypoglycemia induced by intravenous insulin. Success was defined as an increase in plasma glucose to ≥70 mg/dL or ≥20 mg/dL from the glucose nadir within 30 min after receiving glucagon.RESULTSMean plasma glucose at time of glucagon administration was 48 ± 8 and 49 ± 8 mg/dL at the intranasal and intramuscular visits, respectively. Success criteria were met at all but one intranasal visit and at all intramuscular visits (98.7% vs. 100%; difference 1.3%, upper end of 1-sided 97.5% CI 4.0%). Mean time to success was 16 min for intranasal and 13 min for intramuscular (P < 0.001). Head/facial discomfort was reported during 25% of intranasal and 9% of intramuscular dosing visits; nausea (with or without vomiting) occurred with 35% and 38% of visits, respectively.CONCLUSIONSIntranasal glucagon was highly effective in treating insulin-induced hypoglycemia in adults with type 1 diabetes. Although the trial was conducted in a controlled setting, the results are applicable to real-world management of severe hypoglycemia, which occurs owing to excessive therapeutic insulin relative to the impaired or absent endogenous glucagon response.

Prospective study evaluating the use of nasal glucagon for the treatment of moderate to severe hypoglycaemia in adults with type 1 diabetes in a real‐world setting

“…A previous randomized study in adults with T1D showed that 3‐mg NG was non‐inferior to 1‐mg intramuscular glucagon in treating insulin‐induced hypoglycaemia in a hospital setting 5. Another study in young people with T1D found that NG and injectable glucagon demonstrated similar glycaemic responses 8.…”

“…Nasal glucagon (NG), a needle‐free, single‐use, compact, portable, drug‐device combination consisting of 3 mg dry glucagon powder that does not require reconstitution, is currently under development as a rescue medication for severe hypoglycaemia 1. NG (3 mg) produced a rapid increase in blood glucose (BG) levels and was non‐inferior to intramuscular glucagon (1 mg) in a previous study in adults with insulin‐induced hypoglycaemia 5. The aim of the present study was to evaluate the real‐world effectiveness, tolerability and ease of use of NG (3 mg nasal glucagon; Eli Lilly and Company) in the treatment of moderate and severe HEs in adults with T1D.…”

Comment on Rickels et al. Intranasal Glucagon for Treatment of Insulin-Induced Hypoglycemia in Adults With Type 1 Diabetes: A Randomized Crossover Noninferiority Study. Diabetes Care 2016;39:264–270

“…In Fig. 2 of the study (1), it is clear that before 30 min, the probability of success was lower for intranasal glucagon. As per the data in that figure, the probability for success at minute 15 for intramuscular glucagon was 86% as compared with 71% for the nasal glucagon.…”

“…Diabetes Care 2016;39:e192 | DOI: 10.2337/dc16-0955 Rickels et al (1) report the results of a randomized crossover noninferiority study, making the firm assertion that intranasal glucagon was highly effective in treating insulin-induced hypoglycemia in type 1 diabetes. Unfortunately, the methods described in their article fail to support such a strong claim.…”

Letter to the Editor: Intranasal Glucagon for Hypoglycemia

“…The data reported by the authors under ref. 41 [6] are the result of the efforts of that company together with the T1D registry in adults, while evidence of a positive effect of intranasal glucagon on children and adolescents had been published earlier [2]. Due to its simple use, if intranasal glucagon could be brought to the market and to regular use, it might represent a universal remedy for hypoglycemia in children, adolescents, and adults with type 1 diabetes and in all insulin-treated patients with diabetes.…”