We thank Munoz et al. (1) for the opportunity to provide additional rationale for the study design and interpretation of the data supporting the noninferiority of intranasal glucagon for treatment of insulin-induced hypoglycemia. Our study (2) was not designed to test recovery from severe hypoglycemia but rather recovery from insulin-induced hypoglycemia that ethically may only be produced under the controlled conditions available in a clinical research center. Intranasal glucagon was effective in correcting insulin-induced hypoglycemia, and when considering only those subjects with nadir glucose concentrations <50 mg/dL, the average time to achieving a glucose concentration of 70 mg/dL or a 20 mg/dL increase was 16 min compared with 13 min with intramuscular glucagon (2). We make no claims that intranasal glucagon and intramuscular glucagon are “equally” effective. The noninferiority margin of 10% was chosen on the basis of the data for glucagon injection in a simulated emergency study where 10% of participants (parents of children and adolescents with type 1 diabetes) entirely failed to administer the injectable glucagon product (3). Despite the preplanned noninferiority margin of 10%, the one-sided 97.5% CI was 4%, with only 1 of 75 participants failing to achieve a glucose concentration of 70 mg/dL or a 20 mg/dL increase by 30 min with intranasal glucagon (2). Although there is always a certain degree of arbitrariness in selecting a noninferiority margin as well as statistical power in planning a study, once the study has concluded, it is the CI that provides the precision of the point estimate that is important for interpreting the results. We believe that physicians will accept a possible 4% less efficacy for the ease of bystander administration of the intranasal glucagon preparation. In a more recent simulated emergency study, 94% of trained caregivers of insulin-using persons administered intranasal glucagon correctly, compared with only 50% for intramuscular glucagon, and, more importantly, 93% of untrained acquaintances administered intranasal glucagon correctly, compared with a mere 20% for intramuscular glucagon (4). An outpatient study of the use of intranasal versus intramuscular glucagon for treatment of severe hypoglycemia in patients with type 1 diabetes is ongoing (ClinicalTrials.gov: NCT02171130). The appropriate use of glucagon in the treatment of severe hypoglycemia is to raise the glucose concentration sufficiently to restore cognition to the point where oral carbohydrate can be ingested. At 15 min following administration, the mean ± SD glucose had increased from a nadir 44 ± 8 to 71 ± 15 mg/dL with intranasal glucagon, and from 47 ± 8 to 82 ± 19 mg/dL with intramuscular glucagon; at 20 min following intranasal glucagon the glucose was 85 ± 18 mg/dL. The average 3-min pharmacodynamic lag with intranasal versus intramuscular glucagon seen in our adult cohort (2) would be offset clinically by the 2-min preparation lag with intramuscular versus intranasal glucagon assuming both products are successfully administered (4). Importantly, this pharmacodynamic delay was not seen in a parallel study of intranasal versus intramuscular glucagon in children aged 4–16 years with type 1 diabetes where all 24 intramuscular and 58 of 59 intranasal glucagon administrations produced a ≥25 mg/dL increase in glucose from nadir within 20 min of dosing (5). Because use of intramuscular glucagon is error prone and often omitted in practice, intranasal glucagon can be expected to have a substantial beneficial impact on the treatment of severe hypoglycemia.
Funding. This work was funded by a grant from the Leona M. and Harry B. Helmsley Charitable Trust; by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through grants UL1TR000003 (University of Pennsylvania), UL1TR000064 (University of Florida), and UL1TR001108 (Indiana University); and by Locemia Solutions ULC. Studies at the Barbara Davis Center for Childhood Diabetes were performed in their infusion center and not the hospital Clinical Translational Research Center. Locemia Solutions provided the intranasal glucagon product.
Duality of Interest. All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. M.R.R. has received consultancy payments from Longevity Biotech, Janssen Research & Development, and Semma Therapeutics and research support from Merck. C.A.P. is an employee and member of the board for Locemia Solutions, one of the entities that provided financial support for the conduct of this study. H.D. is an employee for Locemia Solutions, one of the entities that provided financial support for the conduct of this study. J.L.S.’s nonprofit employer has received grants for support of supplies for investigator-initiated studies from Medtronic. W.V.T.’s nonprofit employer has received consulting fees from Novo Nordisk and Locemia Solutions (Locemia consultancy for protocol development). R.P.W. reports receiving research support from Novo Nordisk and serves as a consultant for Novo Nordisk and Medtronic. E.R. and L.M. received payment for pharmacokinetic/pharmacodynamic analysis. R.W.B.’s nonprofit employer has received consultant payments on his behalf from Sanofi and Animas and a research grant from Novo Nordisk with no personal compensation to R.W.B. No other potential conflicts of interest relevant to this article were reported.