Intranasal Glucagon Research Articles

Fear of hypoglycemia in parents of children with type 1 diabetes trained for intranasal glucagon use

ObjectiveTo investigate fear of hypoglycemia (FoH) in parents of children with type 1 diabetes (T1D) before and after undergoing training to learn intranasal (IN) glucagon administration. MethodIn this pre-test/post-test uncontrolled study 364 caregivers of patients with T1D (6–18 years) completed questionnaires measuring sociodemographic characteristics, diabetes-related factors (e.g., type of insulin therapy, glycemic control), and parents' trait anxiety. Parents' FoH was assessed at baseline (T0, training) and after nine months (T1). Two repeated-measure mixed analyses of covariance (ANCOVA) compared the FoH at T0 and at T1 and analyzed the moderating roles of anxiety proneness and type of insulin therapy, as well as of anxiety proneness and use of sensor. Age, T1D duration, HbA1c values, and SES were included as covariates. ResultsParental FoH at T1 (M = 1.72; SE = 0.06/M = 1.57; SE = 0.09) was significantly lower than parental FoH at T0 (M = 1.89; SE = 0.06/M = 1.77; SE = 0.09). The group with high trait-anxiety had a higher level of FoH (M = 2.05; SE = 0.08/M = 1.89; SE = 0.12) than the group with low trait-anxiety (M = 1.57; SE = 0.08/M = 1.46; SE = 0.09) at both time points. SES was negatively associated with FoH at T0 (t = −2.87; p = .004/t = −2.87; p = .005). No other significant effects were found. ConclusionsTraining and educating parents on IN glucagon use can help them effectively manage hypoglycemic episodes and alleviate the fear that generally accompany such events.

Glucagon fill rates and cost among children and adolescents with type 1 diabetes in the United States, 2011–2021

AimsTo characterize glucagon fill rates and costs among youth with type 1 diabetes mellitus (T1DM). MethodsClaims-based analysis of commercially-insured youth with T1DM included in OptumLabs® Data Warehouse between 2011 and 2021. Glucagon fill rates and costs were calculated overall and by formulation (injectable, intranasal, autoinjector, and pre-filled syringe). Sociodemographic and clinical factors associated with glucagon fills were examined using Cox regression. ResultsWe identified 13,267 children with T1DM (76.4% non-Hispanic White). Over mean follow-up of 2.81 years (SD 2.62), 70.0% filled glucagon, with stable fill rates from 2011 to 2021. Intranasal glucagon had rapid uptake following initial approval, and it accounted for almost half (46.6%) of all glucagon fills by 2021. Family income was positively associated with glucagon fills in a stepwise fashion (HR 1.39 [95% CI 1.27–1.52] for annual household income ≥$200,000 vs. <$40,000), while Black race was negatively associated with fills (HR 0.83 [95% CI 0.76–0.91]) compared to White race). Annual mean out-of-pocket costs ranged from $21-$68 (IQR $29-$44). ConclusionRoughly 30% of commercially-insured youth with T1DM may lack access to unexpired glucagon, with significant disparities among Black and low-income patients. Health systems, clinicians, schools, and caregivers should work together to ensure children have reliable access to this critical medication.

382-P: Comparison of Intranasal and Injectable Glucagon Administration among Pediatric Population Responders

Context: Intranasal glucagon (INg) might improve the management of severe hypoglycemia (SH) at school in children with type 1 diabetes (T1D), which is a major concern of our patient partners. Objectives: We compared the performance of parents of children with T1D &amp; school workers (SW) for INg and injectable glucagon (IJg) administration. We also assessed the enablers and barriers associated with each glucagon and preferred teaching methods. Methods: After watching a video on glucagon administration, Patients and SW (30/group) administered both glucagon in random order in 2 simulated scenarios, followed by an individual interview. Performance was rated by a direct observer: completion time, successful execution of predefined key steps and critical steps. Results: Both groups had a better performance with INg than IJg (Fig 1). The majority preferred INg for its ease of use, safety in the pediatric context and better acceptability by SW. Some participants thought that IJg is more effective and useful for off-label smaller doses to prevent SH. Preferred teaching methods were videos and workshops, but only videos could be sufficient for INg. Conclusions: INg is faster and more likely to be successfully administered than IJg by. Implementing mandatory video-based trainings for SW could improve SH management and the involvement of SW. Disclosure Y.Wang: None. A.Brazeau: Other Relationship; Dexcom, Inc., Diabète québec, Ordre des diététistes nutritionnistes du Québec, Research Support; Canadian Institutes of Health Research, Fonds de recherche du Québec en Santé. R.Rabasa-lhoret: Consultant; Dexcom, Inc., Abbott, Janssen Pharmaceuticals, Inc., Novo Nordisk Canada Inc., Sanofi, Lilly, Tandem Diabetes Care, Inc., Insulet Corporation. C.Gagnon: Advisory Panel; Novo Nordisk, Other Relationship; Ascendis Pharma A/S, Research Support; Novo Nordisk. F.Bernatchez: None. S.Chouinard-castonguay: None. M.Tremblay: None. A.Vanasse: None. M.Megalli: None. M.Millette: Advisory Panel; Novo Nordisk Canada Inc., Pfizer Inc. G.Boulet: Other Relationship; Dexcom, Inc. M.Henderson: None. Funding Canadian Institutes of Health Research (157204); JDRF (2018651)

Adrenocortical, somatotropic, and antidiuretic response to nasal glucagon in healthy subjects.

The glucagon stimulation test involves the peptide intramuscular or subcutaneous administration for the diagnosis of hypopituitarism. To date, no data are available regarding its intranasal formulation. Our study intended to investigate the role of intranasal glucagon as a potential stimulus test for the evaluation of the corticotropic, somatotropic, and antidiuretic axes. Non-randomized, single-blinded, cross-over study including 10 healthy subjects (50% women). All participants underwent 2 days of testing, and intranasal glucagon or placebo was administered. At baseline, every 15' up to +90', and then every 30' up to +180', a blood sample was taken for adrenocorticotropic hormone (ACTH), cortisol, growth hormone (GH), copeptin, glucose, insulin, sodium, potassium, and plasma osmolarity. At baseline and at the end of the test, urinary osmolarity was evaluated as well. After administration of both glucagon and placebo, ACTH and cortisol values decreased progressively (P < 0.001), but in the drug group, the reduction in cortisol was less accentuated up to +90' (P < 0.05). Growth hormone values decreased after placebo administration (P < 0.001); on the other hand, after glucagon, an increasing, yet non-significant trend was observed (P = 0.096) with the difference between the two groups evident starting from +120' onwards (P < 0.005). The placebo administration led to a reduction of copeptin, while its stability was observed after glucagon administration. Six subjects developed hypokalemia (ie, potassium <3.5 mmol/L) post-glucagon, with the nadir at 45' (3.6 [3.2-3.8] mmol/L) significantly correlated with the immediate post-glycemic rise insulin peak (Spearman's rho -0.719; P = 0.019). No significant differences were observed compared to the other analytes tested. Intranasal glucagon administration is not an effective stimulus for hypophyseal secretion. Hypokalemia secondary to hyperinsulinemic rebound appears to be a frequent complication of its acute administration.

Not only for caregivers: intranasal glucagon for severe hypoglycaemia in a simulation study.

To evaluate: (i) the propensity of paediatrics and emergency medicine residents to select different therapeutic options and (ii) the speed and administration success in a high-fidelity simulation of severe hypoglycaemia in a child with type 1 diabetes (T1DM). In this single-centre high-fidelity simulation study, 51 paediatrics or emergency medicine residents were exposed to a scenario of severe hypoglycaemia in a T1DM child attending an ambulatory setting, before and after a training on the preparation and administration of both injectable and IN glucagon. Time for drug delivery and its effectiveness were collected. Before training, 45.1% of participants chose to administer injectable glucagon, 43.1% intravenous glucose solution, 5.9% intranasal (IN) glucagon, and 5.9% took no action. Administration was successful in 74% of injectable glucagon, 33.3% intravenous glucose solution, and 22.7% IN glucagon. After training, 58.8% of participants chose IN and 41.2% injectable glucagon, with 100% of successful administrations for IN glucagon and 90.5% for injectable glucagon. Time to successful administration was shorter for IN than injectable glucagon (23 ± 10 vs. 38 ± 7s, p < 0.0001). IN glucagon is an easy and effective option for severe hypoglycaemia treatment, with an almost zero possibility of failure provided that adequate training is imparted.

New Developments in Glucagon Treatment for Hypoglycemia.

Glucagon is essential for endogenous glucose regulation along with the paired hormone, insulin. Unlike insulin, pharmaceutical use of glucagon has been limited due to the unstable nature of the peptide. Glucagon has the potential to address hypoglycemia as a major limiting factor in the treatment of diabetes, which remains very common in the type 1 and type 2 diabetes. Recent developments are poised to change this paradigm and expand the use of glucagon for people with diabetes. Glucagon emergency kits have major limitations for their use in treating severe hypoglycemia. A complicated reconstitution and injection process often results in incomplete or aborted administration. New preparations include intranasal glucagon with an easy-to-use and needle-free nasal applicator as well as two stable liquid formulations in pre-filled injection devices. These may ease the burden of severe hypoglycemia treatment. The liquid preparations may also have a role in the treatment of non-severe hypoglycemia. Despite potential benefits of expanded use of glucagon, undesirable side effects (nausea, vomiting), cost, and complexity of adding another medication may limit real-world use. Additionally, more long-term safety and outcome data are needed before widespread, frequent use of glucagon is recommended by providers.

Intranasal Glucagon for the Treatment of Hypoglycemia

&#x0D; Intranasal glucagon was equally effective compared with glucagon given by intramuscular or subcutaneous injection to treat experimentally insulin-induced hypoglycemia in both adults and children with type 1 diabetes.&#x0D; The overall rates of adverse events were similar between groups treated with intranasal glucagon or intramuscular or subcutaneous glucagon. Nausea and vomiting were more frequent in the groups treated with intramuscular or subcutaneous glucagon, whereas eye and nose symptoms occurred more frequently in the intranasal glucagon group.&#x0D; There was no evidence identified that compared the clinical effectiveness of intranasal glucagon with placebo or no treatment in people treated with insulin who received treatment for hypoglycemia.&#x0D; No evidence was found about the cost-effectiveness of intranasal glucagon and no evidence-based guidelines were found about the use of intranasal glucagon for the treatment of hypoglycemia in people who receive treatment with insulin.&#x0D;

904-P: Trends in Out-of-Pocket Cost for Glucagon 2010–2020

The ADA Standards of Care recommend that all patients with diabetes at risk of hypoglycemia have glucagon available for emergency use. However, glucagon prescriptions are filled by only a small minority of patients with type 1 and type 2 diabetes in the United States each year. While there are multiple barriers to glucagon use, the extent to which out-of-pocket medication costs contributes to low uptake is not clear. Using administrative claims from Optum’s de-identified Clinformatics® Data Mart Database (2007-2019) for adults with commercial or Medicaid insurance from 2010-2020, we sought to describe the trends in out-of-pocket costs for glucagon over time. Analyzed claims included all fills of glucagon, based on National Drug Codes, from 20through 9/30/2020. Our primary outcome was total out-of-pocket costs defined as the sum of copays and deductibles. Costs were adjusted for inflation based on 2020 dollars and scaled per single-use kit. Insurance type was based on the primary payor at the time of the glucagon fill. The median (IQR) out-of-pocket cost of unmixed glucagon was $27.42 (15.09-37.98) in 2010, $33.58 (5.60-41.97) in 2015, and $30.42 (15.21-40.56) in 2020 for commercially insured beneficiaries. For Medicare beneficiaries, cost for unmixed glucagon was $0 (0-25.35) in 2010, $0 (0-33.58) in 2015, and $0 (0-40.56) in 2020. After introduction in 2019, the 2020 out-of-pocket cost of intranasal glucagon was $15.21 (7.60-35.49) for commercially insured beneficiaries and $10.14 (0.99-23.83) for Medicare beneficiaries. Out-of-pocket costs for unmixed glucagon was stable for most commercially insured patients, and $0 for most Medicare beneficiaries from 20through 2020; therefore, cost should not serve as the primary barrier to accessing glucagon for most patients. However, for the subset of patients (4th quartile) with the highest out-of-pocket costs in both insurance groups, the cost of unmixed glucagon has increased over time. Novel intranasal glucagon had lower out-of-pocket cost compared to unmixed glucagon for most commercially insured patients immediately after introduction. Disclosure M.Zupa: None. R.Feldman: None. J.Luo: None. Funding NCATS KL2 (TR001856)

Prehospital Intranasal Glucagon for Hypoglycemia

Background Prehospital hypoglycemia is usually treated with oral or intravenous (IV) dextrose in a variety of concentrations. In the absence of vascular access, intramuscular (IM) glucagon is commonly administered. Occupational needle-stick injury remains a significant risk while attempting to obtain vascular access or administer medications intramuscularly in the prehospital setting. We sought to determine if intranasal (IN) glucagon is effective in the prehospital treatment of hypoglycemia. Methods We performed a retrospective analysis of all consecutive cases where recombinant glucagon was administered IN by paramedics from January 1, 2015 through December 31, 2020. Excluded were cases without pre or post administration blood glucose documentation, and cases where another form of treatment for hypoglycemia was administered at any time during the EMS encounter. The primary outcome was clinical response to IN glucagon documented by paramedics; secondary outcomes included pre and post administration blood glucose values. Results Out of 44 cases that met study inclusion criteria, 14 patients (32%) had substantial improvement, 13 patients (30%) had slight improvement, and 17 patients (38%) had no improvement in mental status after administration of IN glucagon. In cases with substantial improvement (n = 14), the mean pre administration blood glucose was 33.8 mg/dl and the mean post administration blood glucose was 87.1 mg/dl (mean increase 53.3 mg/dl, 95% CI: 21.5 to 85.1). In cases with slight improvement (n = 13), the mean pre administration blood glucose was 23.9 mg/dl and the mean post administration blood glucose was 53.8 mg/dl (mean increase 29.9 mg/dl, 95% CI = 2.9 to 56.9). In case with no improvement (n = 17) the mean pre administration blood glucose was 30.1 mg/dl and the mean post administration glucose was 33.1 mg/dl (mean difference 3.1 mg/dl, 95% CI: −10.1 to 3.9). Conclusion Intranasal administration of recombinant glucagon for hypoglycemia resulted in a clinically significant improvement in mental status and a corresponding increase in blood glucose levels in select cases in the prehospital setting.

New Fast Acting Glucagon for Recovery from Hypoglycemia, a Life-Threatening Situation: Nasal Powder and Injected Stable Solutions.

The goal of diabetes care is to achieve and maintain good glycemic control over time, so as to prevent or delay the development of micro- and macrovascular complications in type 1 (T1D) and type 2 diabetes (T2D). However, numerous barriers hinder the achievement of this goal, first of all the frequent episodes of hypoglycemia typical in patients treated with insulin as T1D patients, or sulphonylureas as T2D patients. The prevention strategy and treatment of hypoglycemia are important for the well-being of patients with diabetes. Hypoglycemia is strongly associated with an increased risk of cardiovascular disease in diabetic patients, due probably to the release of inflammatory markers and prothrombotic effects triggered by hypoglycemia. Treatment of hypoglycemia is traditionally based on administration of carbohydrates or of glucagon via intramuscular (IM) or subcutaneous injection (SC). The injection of traditional glucagon is cumbersome, such that glucagon is an under-utilized drug. In 1983, it was shown for the first time that intranasal (IN) glucagon increases blood glucose levels in healthy volunteers, and in 1989–1992 that IN glucagon is similar to IM glucagon in resolving hypoglycemia in normal volunteers and in patients with diabetes, both adults and children. IN glucagon was developed in 2010 and continued in 2015; in 2019 IN glucagon obtained approval in the US, Canada, and Europe for severe hypoglycemia in children and adults. In the 2010s, two ready-to-use injectable formulations, a stable non-aqueous glucagon solution and the glucagon analog dasiglucagon, were developed, showing an efficacy similar to traditional glucagon, and approved in the US in 2020 and in 2021, respectively, for severe hypoglycemia in adults and in children. Fast-acting glucagon (nasal administration and injected solutions) appears to represent a major breakthrough in the treatment of severe hypoglycemia in insulin-treated patients with diabetes, both adults and children. It is anticipated that the availability of fast-acting glucagon will expand the use of glucagon, improve overall metabolic control, and prevent hypoglycemia-related complications, in particular cardiovascular complications and cognitive impairment.

Inhaled Glucagon

Until now injectable glucagon was the only available treatment used in the management of severe hypoglycemia wherein glucagon had to be prepared in several steps before administration. This method of delivery of injectable glucagon being cumbersome and unappealing for a wide majority of the patients had led to a search for an alternative route of drug delivery. Intranasal (IN) glucagon now serves an efficient, safe, easy to administer, and a favorable substitute to glucagon injections. This ready-to-use device stands in clear contrast to overcome the limitations associated with the currently available glucagon preparations, which has emerged a key advancement in the management of severe hypoglycemia in adolescents and children with type 1 diabetes. IN glucagon is now being developed and studied in other countries as well to meet the unmet need for an easy and convenient glucagon administration. This review covers the basic information of nasal glucagon, trials on nasal glucagon in children's and adults, and its potential uses, limitations, and future scope in practice.

Nasal glucagon - a new way to treat severe hypoglycemia in patients with diabetes.

Hypoglycaemia is the most frequent acute complication of diabetes in patients treated with insulin. Severe hypoglycaemia can lead to life-threatening disorders. In addition, fear of hypoglycaemia remains a major obstacle to achieving therapeutic goals in diabetics, espe-cially with type 1. As such, both the prevention and treatment of hypoglycemia are so important in diabetes care. Treatment of hypoglycemia is still based on administration of glucose (oral or parenteral depending on the level of consciousness) or of glucagon injected intramuscularly or subcutaneously. In 1983, it was shown for the first time that intranasal glucagon drops increase blood glucose levels in healthy volunteers. In subsequent years, a new powder formulation of glucagon was developed, which is applied intranasally and passively absorbed through the nasal mucosa and it is not necessary to take a deep breath to take it. Intranasal glucagon is as effective as injectable glucagon and devoid of most of the technical problems associated with injectable glucagon. No serious adverse effects of the new preparation have been de-scribed so far. In December 2019 under the name Baqsimi TM (Eli Lilly, USA) has been approved by EMA for the treatment of severe hypoglycemia in patients since 4 years of age. Intranasal glucagon appears to be a breakthrough in the treatment of severe hypoglycemia in diabetic patients treated with insulin in both children and adults.

Intranasal Glucagon: A New Way to Treat Hypoglycemic Emergencies.

Objective: To review the safety, efficacy, and administration of intranasal (IN) glucagon for the management of hypoglycemia. Data Source: A literature search of PubMed/MEDLINE (1995 to November 2019) using the terms intranasal glucagon, nasal glucagon, glucagon, hypoglycemia treatment, and hypoglycemia management was completed. Study Selection and Data Extraction: English-language studies evaluating IN glucagon were evaluated. Data Synthesis: IN glucagon is a newly approved product for the treatment of hypoglycemia in patients with diabetes, 4 years and older. Administered as a 3-mg dose, it was shown to be noninferior to intramuscular (IM) glucagon. In comparison trials, more than 98% of hypoglycemic events were treated successfully with IN glucagon in both pediatric and adult patients. In simulated and real-world studies, IN glucagon was administered in less than a minute for the majority of scenarios. IM glucagon took longer to administer, ranging from 1 to 4 minutes, and often, patients did not receive the intended full dose. Nausea and vomiting, known adverse events for glucagon, as well as local adverse events were most commonly reported with IN glucagon. Relevance to Patient Care and Clinical Practice: IN glucagon is safe, effective, easy to use, and does not require reconstitution prior to use, which can lead to faster delivery in a severe hypoglycemic event. It does not require age- or weight-based dosing. This delivery method offers an option for someone who fears needles or is uncomfortable with injections. Conclusion: IN glucagon is a safe, effective, easy to use, needle-free treatment option for severe hypoglycemia.

Intranasal versus injectable glucagon for hypoglycemia in type 1 diabetes: systematic review and meta-analysis.

Glucagon is used to resolve severe hypoglycemia in unconscious patients with diabetes, requiring third-party assistance. A few studies have shown that intranasal (IN) glucagon causes resolution of hypoglycemia in insulin-treated patients with type 1 (T1DM) diabetes. This systematic review and meta-analysis updates the comparison of the effectiveness of IN glucagon with injected intramuscular/subcutaneous (IM/SC) glucagon in treatment of hypoglycemia in T1DM. Controlled randomized studies were considered; eight studies, published in English, were included in a meta-analysis (random-effects model). Intervention effect (resolution of hypoglycemia) was expressed as odds ratio (OR), with 95% confidence intervals. Meta-regression was employed to correlate the effect with size of studies, age of patients, basal blood glucose levels. In a total of 467 treatments in 269 patients with IN and IM/SC glucagon, the OR IN versus IM/SC was 0.61 (CI 0.13-2.82); since four of eight studies showed 100% effectiveness, a simulation was made with 1 failure for each treatment; in this simulation analysis, the OR was 0.80 (95% CI 0.28-2.32). Heterogeneity was low and not statistically significant. Publication bias was absent, and quality of papers was high. At meta-regression, no correlation was found between the effect and number of patients in each study, age of patients, basal blood glucose levels. No study formally compared IN versus IM/SC in unconscious patients. This meta-analysis indicates that in conscious T1DM patients IN glucagon and IM/SC glucagon are equally effective in resolution of hypoglycemia.

Novel Preparations of Glucagon for the Prevention and Treatment of Hypoglycemia

New more stable formulations of glucagon have recently become available, and these provide an opportunity to expand the clinical roles of this hormone in the prevention and management of insulin-induced hypoglycemia. This is applicable in type 1 diabetes, hyperinsulinism, and alimentary hypoglycemia. The aim of this review is to describe these new formulations of glucagon and to provide an overview of current and future therapeutic opportunities that these may provide. Four main categories of glucagon formulation have been studied: intranasal glucagon, biochaperone glucagon, dasiglucagon, and non-aqueous soluble glucagon. All four have demonstrated similar glycemic responses to standard glucagon formulations when administered during hypoglycemia. In addition, potential roles of these formulations in the management of congenital hyperinsulinism, alimentary hypoglycemia, and exercise-induced hypoglycemia in type 1 diabetes have been described. As our experience with newer glucagon preparations increases, the role of glucagon is likely to expand beyond the emergency use that this medication has been limited to in the past. The innovations described in this review likely represent early examples of a pending large repertoire of indications for stable glucagon.

Therapeutic Use of Intranasal Glucagon: Resolution of Hypoglycemia.

Episodes of hypoglycemia are frequent in patients with diabetes treated with insulin or sulphonylureas. Hypoglycemia can lead to severe acute complications, and, as such, both prevention and treatment of hypoglycemia are important for the well-being of patients with diabetes. The experience of hypoglycemia also leads to fear of hypoglycemia, that in turn can limit optimal glycemic control in patients, especially with type 1 diabetes. Treatment of hypoglycemia is still based on administration of carbohydrates (oral or parenteral according to the level of consciousness) or of glucagon (intramuscular or subcutaneous injection). In 1983, it was shown for the first time that intranasal (IN) glucagon drops (with sodium glycocholate as a promoter) increase blood glucose levels in healthy volunteers. During the following decade, several authors showed the efficacy of IN glucagon (drops, powders, and sprays) to resolve hypoglycemia in normal volunteers and in patients with diabetes, both adults and children. Only in 2010, based on evaluation of patients’ beliefs and patients’ expectations, a canadian pharmaceutical company (Locemia Solutions, Montreal, Canada) reinitiated efforts to develop glucagon for IN administration. The project has been continued by Eli Lilly, that is seeking to obtain registration in order to make IN glucagon available to insulin users (children and adolescents) worldwide. IN glucagon is as effective as injectable glucagon, and devoid of most of the technical difficulties associated with administration of injectable glucagon. IN glucagon appears to represent a major breakthrough in the treatment of severe hypoglycemia in insulin-treated patients with diabetes, both children and adults.

Evaluation of the Acute Effects of Intranasal Glucagon on Energy Balance in Overweight/Obese Adults

Background: Obesity is a major driver of type 2 diabetes. Weight loss improves glycemia but is seldom sustained. This is partly due to a weight loss-associated decrease in energy expenditure (EE). Current weight loss medications do not target EE. Intravenous glucagon acutely increases EE and reduces food intake (FI) in humans, but hyperglycemia precludes its use for weight loss. We have previously shown that intranasal glucagon (ING) paradoxically attenuates hyperglycemia. Here, we report the acute effects of ING on EE and FI.

Intranasal glucagon for hypoglycaemia in diabetic patients. An old dream is becoming reality?

In 1983 it was shown that glucagon administered intranasally (IN) was absorbed through the nasal mucosa and increased blood glucose in healthy subjects. Shortly thereafter, it was shown that IN glucagon counteracts with hypoglycaemia in insulin-treated diabetic patients. In spite of this evidence, IN glucagon was not developed by any pharmaceutical company before 2010, when renewed interest led to intensive evaluation of a possible remedy for hypoglycaemia in insulin-treated diabetic adults and children. IN glucagon is now being developed as a needle-free device that delivers glucagon powder for treatment of severe hypoglycaemia; the ease of using this device stands in stark contrast to the difficulties encountered in use of the current intramuscular glucagon emergency kits. Studies have demonstrated the efficacy, safety and ease-of-use of this IN glucagon preparation, and suggest IN glucagon as a promising alternative to injectable glucagon for treating severe hypoglycaemia in children and adults who use insulin. This would meet the unmet medical need for an easily administered glucagon preparation.

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

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. We have several concerns about their ambitious conclusion. First, because of the controlled and artificial environment, this was not an effectiveness but an efficacy trial. Testing effectiveness requires carrying out the comparison in a “real-world setting” of severe hypoglycemia. Second, the design of the study does not seem appropriate considering that the intention was to prove intranasal glucagon was clinically equivalent to …

Glucagon Nasal Powder: A Promising Alternative to Intramuscular Glucagon in Youth With Type 1 Diabetes.

OBJECTIVETreatment of severe hypoglycemia outside of the hospital setting is limited to intramuscular glucagon requiring reconstitution prior to injection. The current study examined the safety and dose-response relationships of a needle-free intranasal glucagon preparation in youth aged 4 to <17 years.RESEARCH DESIGN AND METHODSA total of 48 youth with type 1 diabetes completed the study at seven clinical centers. Participants in the two youngest cohorts (4 to <8 and 8 to <12 years old) were randomly assigned to receive either 2 or 3 mg intranasal glucagon in two separate sessions or to receive a single, weight-based dose of intramuscular glucagon. Participants aged 12 to <17 years received 1 mg intramuscular glucagon in one session and 3 mg intranasal glucagon in the other session. Glucagon was given after glucose was lowered to <80 mg/dL (mean nadir ranged between 67 and 75 mg/dL).RESULTSAll 24 intramuscular and 58 of the 59 intranasal doses produced a ≥25 mg/dL rise in glucose from nadir within 20 min of dosing. Times to peak plasma glucose and glucagon levels were similar under both intramuscular and intranasal conditions. Transient nausea occurred in 67% of intramuscular sessions versus 42% of intranasal sessions (P = 0.05); the efficacy and safety of the 2- and 3-mg intranasal doses were similar in the youngest cohorts.CONCLUSIONSResults of this phase 1, pharmacokinetic, and pharmacodynamic study support the potential efficacy of a needle-free glucagon nasal powder delivery system for treatment of hypoglycemia in youth with type 1 diabetes. Given the similar frequency and transient nature of adverse effects of the 2- and 3-mg intranasal doses in the two youngest cohorts, a single 3-mg intranasal dose appears to be appropriate for use across the entire 4- to <17-year age range.