OBJECTIVE: To 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.
METHODS: In 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.
RESULTS: Parental 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.
CONCLUSIONS: Training and educating parents on IN glucagon use can help them effectively manage hypoglycemic episodes and alleviate the fear that generally accompany such events.

UNASSIGNED: Rebound hyperglycemia may occur following glucagon treatment for severe hypoglycemia. We assessed rebound hyperglycemia occurrence after nasal glucagon (NG) or injectable glucagon (IG) administration in patients with type 1 diabetes (T1D) and type 2 diabetes (T2D).
UNASSIGNED: This was a pooled analysis of 3 multicenter, randomized, open-label studies (NCT03339453, NCT03421379, NCT01994746) in patients ≥18 years with T1D or T2D with induced hypoglycemia. Proportions of patients achieving treatment success [blood glucose (BG) increase to ≥70 mg/dL or increase of ≥20 mg/dL from nadir within 15 and 30 minutes]; BG ≥70 mg/dL within 15 minutes; in-range BG (70-180 mg/dL) 1 to 2 and 1 to 4 hours postdose; and BG >180 mg/dL 1 to 2 and 1 to 4 hours postdose were compared. Incremental area under curve (iAUC) of BG >180 mg/dL and area under curve (AUC) of observed BG values postdose were analyzed. Safety was assessed in all studies.
UNASSIGNED: Higher proportions of patients had in-range BG with NG vs IG (1-2 hours: P = .0047; 1-4 hours: P = .0034). Lower proportions of patients had at least 1 BG value >180 mg/dL with NG vs IG (1-2 hours: P = .0034; 1-4 hours: P = .0068). iAUC and AUC were lower with NG vs IG (P = .025 and P < .0001). As expected, similar proportions of patients receiving NG or IG achieved treatment success at 15 and 30 minutes (97-100%). Most patients had BG ≥70 mg/dL within 15 minutes (93-96%). The safety profile was consistent with previous studies.
UNASSIGNED: This study demonstrated lower rebound hyperglycemia risk after NG treatment compared with IG.
UNASSIGNED: NCT03421379, NCT03339453, NCT01994746.

As the 100th anniversary of glucagon\'s discovery approaches, we reflect on the remarkable journey of understanding its pivotal role in glucose regulation. Advancements in glucagon delivery systems for managing hypoglycemia are unfolding with promise, albeit accompanied by formulation and implementation challenges. Recent developments include non-injectable methods like BAQSIMI® (Nasal glucagon) offers a user-friendly option, but stability, bioavailability, and rapid onset remain formulation hurdles. Closed-loop systems, combining glucagon with insulin, aim to automate glucose control, demanding stable and precise formulations compatible with complex algorithms. However, achieving co-delivery harmony and effective dual-hormone responses poses substantial challenges. Ogluo® and Gvoke HypoPen® are auto-injector pens, a ready-to-use solution that can rapidly control hypoglycemia and eliminate the need for mixing powder and liquid. GlucaGen® Hypokit® and Glucagon Emergency Kits are traditional deliveries that possess complexity during administration and are still widely used in clinical practice. In addition to this advancement, we have covered the recent patents and clinical trials of glucagon delivery. The synergy of patent innovation and clinical validation offers a glimpse into the transformative potential of glucagon delivery yet underscores the intricate path toward widespread adoption and improved diabetes care. Finally, this review will help the formulation scientist, clinicians, healthcare providers, and patient to manage hypoglycemia using glucagon.

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Aims: Ease of use and acceptability of nasal versus injectable glucagon (IG) among pediatric responders have been little investigated. This study compared the performance of administering nasal and IG in parents of youth with type 1 diabetes (T1D) and in school workers. Enablers and barriers associated with each glucagon and preferred glucagon administration learning modality were also evaluated. Methods: Three months after watching short pedagogical videos, 30 parents and 30 school workers performed simulated scenarios where they administered both glucagon. Completion time and successful execution of critical steps were collected. Interviews assessed preferred learning modalities, barriers, and enablers associated with each glucagon. Results: Both groups administered nasal glucagon faster than IG (median [interquartile range]: parents 19 [12-29] vs. 97 [71-117] s, P < 0.001; school workers 24 [16-33] vs. 129 [105-165] s, P < 0.001). A lower proportion of participants successfully executed all critical steps for injectable versus nasal glucagon (significant difference for school workers [53% vs. 90%; P = 0.007] but not for parents [68% vs. 83%; P = 0.227]). Nasal glucagon was preferred for ease of use and acceptability. Preferred learning modalities were a combination of videos and workshops, but videos alone could suffice for nasal glucagon. Conclusions: Nasal glucagon is faster to use, more likely to be successfully administered, and more acceptable than IG for parents of children with T1D and school workers. Nasal glucagon training with videos could improve school workers\' involvement in severe hypoglycemia management. Clinical Trial number, URL to the registration: NCT05395000, https://clinicaltrials.gov/ct2/show/NCT05395000.

BACKGROUND: Severe hypoglycemic events are distressing. Although past studies have shown that young adulthood is a potentially distressing time, few studies have explored distress about severe hypoglycemia in this age group. The real-world psychosocial experiences of potential severe hypoglycemic events and the perceived impact of glucagon treatments like nasal glucagon are currently unknown. We explored perceptions of severe hypoglycemic events and impact of nasal glucagon on psychosocial experiences with these events in emerging adults with type 1 diabetes and caregivers of emerging adults and children/teens. Further, we compared perceptions of preparedness and protection in handling severe hypoglycemic events with nasal glucagon versus the emergency glucagon kit that requires reconstitution (e-kit).
METHODS: This observational, cross-sectional study enrolled emerging adults (aged 18-26; N = 364) with type 1 diabetes, caregivers of emerging adults (aged 18-26; N = 138) with type 1 diabetes, and caregivers of children/teens (aged 4-17; N = 315) with type 1 diabetes. Participants completed an online survey about their experiences with severe hypoglycemia, perceptions of nasal glucagon impact on psychosocial experiences, and perceptions of feeling prepared and protected with nasal glucagon and the e-kit.
RESULTS: Many emerging adults (63.7%) agreed that the experience of severe hypoglycemic events was distressing; 33.3% and 46.7% of caregivers of emerging adults and children/teens, respectively, reported distress. Participants reported positive perceptions of nasal glucagon impact, particularly improved confidence in other people\'s ability to help during severe hypoglycemic events: emerging adults, 81.4%; caregivers of emerging adults, 77.6%; caregivers of children/teens, 75.5%. Participants demonstrated higher perceptions of preparedness and protection for nasal glucagon than for the e-kit (p < 0.001).
CONCLUSIONS: Participants reported improved confidence in other people\'s ability to help during severe hypoglycemic events since having nasal glucagon available. This suggests that nasal glucagon may help broaden the support network for young people with type 1 diabetes and their caregivers.

Glucagon (traditional kits for intramuscular administration, Glucagon and Glucagen), although recommended as a remedy for severe hypoglycemia (SH), has been reported to be under-utilized, likely because of technical problems. The aims of this study were to evaluate the use of glucagon in persons with type 1 diabetes in several countries, and to investigate if the availability of new ready-to-use glucagons (Baqsimi, Gvoke, Zegalogue, years 2019 to 2021) has expanded the overall use of glucagon. The source of data was IQVIA-MIDAS (units of glucagon sold), while data on persons with type 1 diabetes in countries were derived from IDF Diabetes Atlas. The use of glucagon has been steady from 2014 to 2019, with a small but significant increase from 2019 to 2021, paradoxically only in countries where new ready-to-use glucagons were not available. The use of glucagon has always been ten fold greater in countries where new ready-to-use glucagons became available than in the other countries (population 108,000,000 vs 28,100,000, 480,291 vs 182,018 persons with type 1 diabetes). A significant correlation was observed in all years between units of glucagon and persons with type 1 diabetes. Availability of new ready-to-use glucagons was associated with a small increase of sales, due only to new ready-to-use glucagons themselves. The use of glucagon (any type) remains low, approximately 1/10 of persons with type 1 diabetes. We conclude that use of glucagon is scarce in most countries, and so far has not been expanded by new ready-to-use glucagons such as the ones considered in this study.

BACKGROUND: Severe hypoglycemic events (SHE) represent a clinical and economic burden in patients with diabetes. Nasal glucagon (NG) is a novel treatment for SHEs with similar efficacy, but with a usability advantage over injectable glucagon (IG) that may translate to improved economic outcomes. The economic implications of this usability advantage on SHE-related spending in Spain were explored in this analysis.
METHODS: A cost-offset and budget impact analysis (BIA) was conducted using a decision tree model, adapted for the Spanish setting. The model calculated average costs per SHE over the SHE treatment pathway following a treatment attempt with IG or NG. Analyses were performed separately in three populations with insulin-treated diabetes: children and adolescents (4-17 years) with type 1 diabetes (T1D), adults with T1D and adults with type 2 diabetes (T2D), with respective population estimates applied in BIA. Treatment probabilities were assumed to be equal for IG and NG, except for treatment success following glucagon administration. Epidemiologic and cost data were obtained from Spanish-specific sources. BIA results were presented at a 3-year time horizon.
RESULTS: On a per SHE level, NG was associated with lower costs compared to IG (children and adolescents with T1D, EUR 820; adults with T1D, EUR 804; adults with T2D, EUR 725). Lower costs were attributed to reduced costs of professional medical assistance in patients treated with NG. After 3 years, BIA showed that relative to IG, the introduction of NG was projected to reduce SHE-related spending by EUR 1,158,969, EUR 142,162,371, and EUR 6,542,585 in children and adolescents with T1D, adults with T1D, and adults with insulin-treated T2D, respectively.
CONCLUSIONS: In Spain, the usability advantage of NG over IG translates to potential cost savings per SHE in three populations with insulin-treated diabetes, and the introduction of NG was associated with a lower budget impact versus IG in each group.

OBJECTIVE: To evaluate ease of use, user preference, and effort required to use nasal glucagon (NG) versus injectable glucagon needing reconstitution (IG) in simulations of severe hypoglycemia (SH)-a challenge for caregivers of a person with diabetes (PWD) in real-life.
METHODS: In this randomized, crossover study, high-fidelity manikins placed in mock representative high-stress environments were used to simulate an SH rescue. Thirty-two trained (by PWDs) and 33 untrained participants attempted NG and IG administrations and then completed questionnaires regarding ease of use, preference, and workload for each device.
RESULTS: More trained users agreed that NG was easy to use (87.1% vs 54.8%) and prepare (80.6% vs 51.6%) and had confidence to use NG correctly (93.5% vs 54.8%) than those who agreed the same for IG (P < .05). Untrained users reported similar differences, favoring NG in all parameters. In direct device comparison across all simulations, 80.6% of trained users and 93.5% of untrained users preferred NG over IG-a preference largely sustained regardless of the success or failure of administration. Among PWDs, 90.3% considered NG device as safer than IG during an SH event. In the assessment of workload required to administer glucagon, the weighted mean National Aeronautics and Space Administration Task Load Index scores were 37.8 for NG and 48.4 for IG (P = .0020).
CONCLUSIONS: Participants in this study considered NG easier, more preferred, required less effort for administration, and more intuitive to use than reconstitutable IG, irrespective of whether there was prior training. NG improves the potential for successful administration of glucagon, better preparedness, and increased adoption of glucagon for SH rescue.

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.