Efficacy, tolerability and pharmacokinetics of survodutide, a glucagon/glucagon-like peptide-1 receptor dual agonist, in cirrhosis.

BACKGROUND & AIMS: Survodutide is a glucagon/glucagon-like peptide-1 receptor dual agonist in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). We investigated the pharmacokinetic and safety profile of survodutide in people with cirrhosis. METHODS: This multinational, non-randomized, open-label, phase I clinical trial initially evaluated a single subcutaneous dose of survodutide 0.3 mg in people with Child-Pugh class A, B or C cirrhosis and healthy individuals with or without overweight/obesity matched for age, sex, and weight; the primary endpoints were the area under the plasma concentration-time curve from 0 to infinity (AUC0-∞) and maximal plasma concentration (Cmax). Subsequently, people with overweight/obesity with or without cirrhosis (Child-Pugh class A or B) received once-weekly subcutaneous doses escalated from 0.3 mg to 6.0 mg over 24 weeks then maintained for 4 weeks; the primary endpoint was drug-related treatment-emergent adverse events, with MASH/cirrhosis-related endpoints explored. RESULTS: In the single-dose cohorts (n = 41), mean AUC0-∞ and Cmax were similar in those with cirrhosis compared with healthy individuals (90% CIs for adjusted geometric mean ratios spanned 1). Drug-related adverse events occurred in 25.0% of healthy individuals and ≤25.0% of those with cirrhosis after single doses, and 82.4% and 87.5%, respectively, of the multiple-dose cohorts (n = 41) over 28 weeks. Liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers were generally reduced after 28 weeks of survodutide treatment. CONCLUSIONS: Survodutide is generally tolerable in people with compensated or decompensated cirrhosis, does not require pharmacokinetic-related dose adjustment, and may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis. IMPACT AND IMPLICATIONS: Survodutide is a glucagon receptor/glucagon-like peptide-1 receptor dual agonist in development for treatment of metabolic dysfunction-associated steatohepatitis (MASH), which causes cirrhosis in ∼20% of cases. This trial delineates the pharmacokinetic and safety profile of survodutide in people with compensated or decompensated cirrhosis, and revealed associated reductions in liver fat content, markers of liver fibrosis and body weight. These findings have potential relevance for people with MASH-including those with decompensated cirrhosis, who are usually excluded from clinical trials of investigational drugs. Based on this study, further investigation of survodutide for MASH-related cirrhosis is warranted. GOV IDENTIFIER: NCT05296733.

Dasiglucagon for the Treatment of Insulin-induced Hypoglycemia in Patients with Type 1 Diabetes Mellitus: A Meta-analysis

Background: The use of conventional glucagon for managing insulin-induced hypoglycemia is obscured by its chemical instability and the need for reconstitution of the lyophilized powder, leading to delayed rescue. Dasiglucagon, a glucagon analog, may potentially overcome these shortcomings. Aims: To evaluate the efficacy and safety of dasiglucagon in insulin-induced hypoglycemia in patients with type 1 diabetes mellitus (T1DM). Study Design: Meta-analysis. Methods: PubMed/MEDLINE, Scopus, Embase, and Cochrane databases along with clinical trial registries were searched to include data from five randomized controlled trials conducted using dasiglucagon for the treatment of insulin-induced hypoglycemia in T1DM patients published until May 2023. We performed a risk of bias assessment to determine the quality of the included studies and a random-effects model analysis for determining the effect size. Subgroup analysis and meta-regression were done as applicable. Results: The time to recovery (in minutes) with dasiglucagon was earlier than placebo [mean difference (MD): -24.73; 95% confidence interval (CI): -30.94 to -18.52; p < 0.00001) or oral glucose (MD: -15.00; 95% CI: -20.33 to -9.67; p < 0.00001); however, the difference between dasiglucagon and glucagon was not statistically significant (MD: -0.76; 95% CI: -2.19 to 0.66; p = 0.29). Conclusion: Dasiglucagon is safer and more effective than placebo or oral glucose for insulin-induced hypoglycemia in T1DM patients; however, it is not superior to conventional glucagon.

Tmem117 in AVP neurons regulates the counterregulatory response to hypoglycemia.

The counterregulatory response to hypoglycemia (CRR), which ensures a sufficient glucose supply to the brain, is an essential survival function. It is orchestrated by incompletely characterized glucose-sensing neurons, which trigger a coordinated autonomous and hormonal response that restores normoglycemia. Here, we investigate the role of hypothalamic Tmem117, identified in a genetic screen as a regulator of CRR. We show that Tmem117 is expressed in vasopressin magnocellular neurons of the hypothalamus. Tmem117 inactivation in these neurons increases hypoglycemia-induced vasopressin secretion leading to higher glucagon secretion in male mice, and this effect is estrus cycle phase dependent in female mice. Ex vivo electrophysiological analysis, in situ hybridization, and in vivo calcium imaging reveal that Tmem117 inactivation does not affect the glucose-sensing properties of vasopressin neurons but increases ER stress, ROS production, and intracellular calcium levels accompanied by increased vasopressin production and secretion. Thus, Tmem117 in vasopressin neurons is a physiological regulator of glucagon secretion, which highlights the role of these neurons in the coordinated response to hypoglycemia.

Cardiovascular and Adverse Effects of Glucagon for the Management of Suspected Beta Blocker Toxicity: a Case Series.

BACKGROUND: Although glucagon use in beta blocker toxicity has been recommended for many years, evidence for its safety and efficacy in humans is limited. This study aims to determine the magnitude of effect of glucagon on heart rate (HR) and systolic blood pressure (SBP) in patients with suspected beta blocker toxicity and describe potential adverse effects of the medication. METHODS: We conducted a retrospective, multi-center case series of patients greater than 12 years of age who received glucagon for suspected beta blocker toxicity. The primary outcome was the mean difference in HR from immediately pre- to 20-minutes post-glucagon administration. Secondary outcomes included the median difference in SBP, and occurrence of nausea, vomiting, and hyperglycemia. RESULTS: A total of 107 patients met inclusion criteria accounting for 144 glucagon orders. The mean difference in HR from pre- to post-glucagon administration was 4 bpm ± 10.6 (95% CI [2.25-5.76], p < 0.001). The median difference (IQR) in SBP was 4.5 (- 6 to 16) mmHg (p = 0.004). Similar increases were observed when patients receiving concomitant vasopressors were excluded. A total of nine glucagon administrations (6.3%) were associated with nausea and 14 (9.7%) with vomiting; however, 52 doses (36.1%) were administered concomitantly with antiemetic medications. Fifteen administrations (10.4%) were associated with hyperglycemia. CONCLUSION: Glucagon administration was associated with a statistically significant increase in HR, but a small absolute difference of uncertain clinical significance. A similar observation was noted for SBP. Few patients experienced adverse events.

Clinical efficacy and safety of dasiglucagon in severe hypoglycemia associated with patients of type 1 diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND AND AIMS: This study was carried out to analyze the clinical safety and efficacy of dasiglucagon for the treatment of severe hypoglycemia in patients with type 1 diabetes mellitus (T1DM). METHODS: We searched PubMed, Cochrane Library, Embase, and ClinicalTrials.gov for randomized controlled trials (RCTs) investigating the safety and efficacy of dasiglucagon in the treatment of hypoglycemia in patients with T1DM. Furthermore, time required for the recovery of blood glucose or to elevate blood glucose levels ≥20.0 mg/dL from baseline was analyzed. The data was analyzed in version 5.4 of review manager 5 (RevMan). RESULTS: We included five published RCTs with a total of 347 patients . Dasiglucagon was significantly better at reducing the recovery time of blood glucose or increasing blood glucose levels 20.0 mg/dL from baseline compared to glucagon [pooled mean difference (PMD): 1.08%, 95% confidence interval (CI): 1.96 to 0.21, p = 0.02] and placebo (PMD: - 23.30%, 95% CI: 23.97 to 22.63, p < 0.00001). Overall, the safety outcome results of dasiglucagon were comparable with the native glucagon. CONCLUSIONS: Dasiglucagon appears to be a promising human glucagon analog peptide for the safe and effective treatment of severe hypoglycemia in T1DM.

[Nasal glucagon (Baqsimi®), new treatment for hypoglycaemic coma]. / Le médicament du mois. Le glucagon nasal (Baqsimi®), nouveau traitement du coma hypoglycémique.

Patients with insulin-treated type 1 diabetes (T1D) are exposed to hypoglycaemia, which may be serious. Serious cognitive impairment (including coma and seizure) that requires the help of a third party is a medical emergency. Besides the intravenous injection of glucose by a health care provider, its treatment consists of the subcutaneous or intramuscular injection of glucagon which may be performed by a family member. However, such an injection is not easy and puts off some people, which retards the initiation of a potentially life-saving therapy. The intranasal administration of 3 mg glucagon has been shown as efficacious as the subcutaneous or intramuscular injection of 1 mg glucagon in controlled studies carried out in both adult and youth patients with T1D. Stimulation and real-life studies among caregivers, patients and acquaintances showed a preference for nasal glucagon because of its easy and quick use. The launch of nasal glucagon (Baqsimi®) offers new perspectives for the ambulatory emergency management of severe hypoglycaemia and hypoglycaemic coma with a special obvious advantage in children.

La personne avec un diabète de type 1 (DT1) traité par insuline est exposée à un risque d'hypoglycémie, parfois grave. L'hypoglycémie sévère qui désigne tout trouble cognitif grave (y compris coma, convulsion) nécessitant l'intervention d'un tiers est une urgence médicale. Outre l'injection de glucose par voie intraveineuse, réservée à un personnel de santé, le traitement consiste en l'injection de glucagon par voie sous-cutanée ou intramusculaire qui peut être réalisée par un membre de l'entourage. Cependant, cette injection n'est pas aisée et rebute certaines personnes, ce qui retarde la mise en route d'un traitement potentiellement salvateur. L'administration nasale de glucagon 3 mg s'est avérée aussi performante que l'injection sous-cutanée ou intramusculaire de 1 mg dans des études contrôlées réalisées chez des patients DT1 adultes ou enfants/adolescents. Des études de simulation et de vraie vie réalisées auprès de soignants, de patients et de connaissances ont montré une préférence pour la forme nasale en raison de sa facilité et rapidité d'utilisation. La commercialisation du glucagon nasal (Baqsimi®) offre de nouvelles perspectives pour le traitement d'urgence ambulatoire de l'hypoglycémie sévère et du coma, avec un avantage particulièrement évident chez les enfants.

Bihormonal Artificial Pancreas With Closed-Loop Glucose Control vs Current Diabetes Care After Total Pancreatectomy: A Randomized Clinical Trial.

Importance: Glucose control in patients after total pancreatectomy is problematic because of the complete absence of α- and ß-cells, leading to impaired quality of life. A novel, bihormonal artificial pancreas (BIHAP), using both insulin and glucagon, may improve glucose control, but studies in this setting are lacking. Objective: To assess the efficacy and safety of the BIHAP in patients after total pancreatectomy. Design, Setting, and Participants: This randomized crossover clinical trial compared the fully closed-loop BIHAP with current diabetes care (ie, insulin pump or pen therapy) in 12 adult outpatients after total pancreatectomy. Patients were recruited between August 21 and November 16, 2020. This first-in-patient study began with a feasibility phase in 2 patients. Subsequently, 12 patients were randomly assigned to 7-day treatment with the BIHAP (preceded by a 5-day training period) followed by 7-day treatment with current diabetes care, or the same treatments in reverse order. Statistical analysis was by Wilcoxon signed rank and Mann-Whitney U tests, with significance set at a 2-sided P < .05. Main Outcomes and Measures: The primary outcome was the percentage of time spent in euglycemia (70-180 mg/dL [3.9-10 mmol/L]) as assessed by continuous glucose monitoring. Results: In total, 12 patients (7 men and 3 women; median [IQR] age, 62.5 [43.1-74.0] years) were randomly assigned, of whom 3 did not complete the BIHAP phase and 1 was replaced. The time spent in euglycemia was significantly higher during treatment with the BIHAP (median, 78.30%; IQR, 71.05%-82.61%) than current diabetes care (median, 57.38%; IQR, 52.38%-81.35%; P = .03). In addition, the time spent in hypoglycemia (<70 mg/dL [3.9 mmol/L]) was lower with the BIHAP (median, 0.00% [IQR, 0.00%-0.07%] vs 1.61% [IQR, 0.80%-3.81%]; P = .004). No serious adverse events occurred. Conclusions and Relevance: Patients using the BIHAP after total pancreatectomy experienced an increased percentage of time in euglycemia and a reduced percentage of time in hypoglycemia compared with current diabetes care, without apparent safety risks. Larger randomized trials, including longer periods of treatment and an assessment of quality of life, should confirm these findings. Trial Registration: trialregister.nl Identifier: NL8871.

Dasiglucagon for treating severe hypoglycemia in patients with diabetes.

INTRODUCTION: Diabetic patients are prone to hypoglycemia when treated with insulin. Dasiglucagon is a water-soluble and ready-to-use glucagon analog developed for treating hypoglycemia in patients with diabetes. AREAS COVERED: A comprehensive literature search was conducted in PubMed. Key search terms included dasiglucagon and hypoglycemia. The pharmacological characteristics, clinical evidence, and place in therapy of dasiglucagon were reviewed. EXPERT OPINION: Dasiglucagon is a glucagon analog that is stable in water-soluble formulation. It can increase plasma glucose in a dose-dependent manner. Clinical studies have shown that dasiglucagon rapidly and effectively improved insulin-induced hypoglycemia in patients with diabetes. Dasiglucagon was well tolerated and the common adverse events included nausea and vomiting.

"Smart" Composite Microneedle Patch Stabilizes Glucagon and Prevents Nocturnal Hypoglycemia: Experimental Studies and Molecular Dynamics Simulation.

Hypoglycemia is a major complication associated with insulin therapy in people with diabetes that could cause life-threatening conditions if untreated. Glucagon, a counter-acting hormone, is thus administered for rescue of severe hypoglycemia. However, due to the instability of glucagon, only limited medications are available for emergency use, which are unsuitable for patients with hypoglycemia unawareness or with the inability to self-administer, especially during sleep (namely, nocturnal hypoglycemia). To prevent unattended and extended hypoglycemia, we designed a "smart" composite microneedle (cMN) patch capable of stabilizing glucagon, sensing hypoglycemia, and delivering glucagon automatically on demand. In this design, native glucagon was encapsulated in glucose-responsive microgels containing a glucagon-stabilizing component rationally selected by molecular dynamics (MD) simulation. A cMN patch was then prepared by incorporating the glucagon microgels with poly(methyl vinyl ether-alt-maleic anhydride) (PMVE-MAH) and poly(ethylene glycol) (PEG) followed by thermal cross-linking. The rationally designed zwitterionic polymer-based microgels preserved the native structure of glucagon and prevented heat-induced fibrillation evidenced by RP-HPLC, circular dichroism, and transmission electron microscopy. MD simulations suggested that the polymeric microgels stabilized glucagon by inhibition of oligomer formation via peptide-polymer noncovalent interactions. The polymer formed multiple hydrogen bonds with the polar and charged amino acid residues of the glucagon molecule, shielding the peptide surface from aggregation. In vivo efficacy studies using streptozotocin-induced type 1 diabetic (T1D) rats demonstrated that the glucagon-loaded cMN patch could prevent hypoglycemia induced by insulin overdose during a 12 h period. The results suggest that this new glucagon "smart" patch may be a promising system for improving the quality of life of those suffering from nocturnal hypoglycemia and hypoglycemia unawareness.

Safety Assessment and Potential Risks of the Glucagon Stimulation Test in the Diagnosis of Secondary Adrenal Insufficiency.

BACKGROUND: Although it takes more time, the Glucagon Stimulation Test (GST) is a reliable measure for assessing growth hormone (GH) and Adrenocorticotropic Hormone (ACTH) secretion. The GST is considered to be a safe test; however, it still has mild side effects and potential risks. OBJECTIVES: The objective of this study was to analyze the side effects of the GST while testing adrenal-insufficient patients. METHODS: This was a prospective study in which GST was performed in eighty-one patients (44 men, 37 women, mean age: 35.83A9.62 years) with the pituitary disorder. The GST consisted of an intramuscular injection of 1 mg of glucagon. Blood samples were collected at baseline, and 30, 60, 90, 120, 150, 180, and 210 min after glucagon injection for cortisol measurements. All patients were asked to report side effects associated with this test. RESULTS: The mean peak blood glucose level under GST was 9.01A.03 mmol/L, and the mean glycemic nadir was 4.34A.75 mmol/L most frequently found during the 30th minute (p <10-3). During the test, 35 subjects (43.2%) had side effects with a mean age of 42.89 A19.75 years. Frequent side effects included: nausea (29.62%), vomiting (27.16%), abdominal cramps (18.51%) and hunger (13.58%). All patients tolerated the test until the end. Adverse effects were significantly more prevalent in patients older than 50 years (p=0.012). CONCLUSIONS: The GST is a reliable alternative to assess the hypothalamic pituitary adrenal axis but should be cautiously used especially in the elderly, despite minor side effects.

Dasiglucagon: an effective medicine for severe hypoglycemia.

PURPOSE: Patients with type 1 diabetes mellitus (T1DM) receiving insulin therapy commonly suffer from insulin-mediated hypoglycemia and require glucagon for glycemic control to achieve normal plasma glucose (PG) levels. Severe hypoglycemia will endanger the life of patients and require intervention. Stable glucagon analog dasiglucagon was approved for the treatment of patients with severe hypoglycemia and is administered via Zegalogue autoinjector/Zegalogue prefilled syringe. The main purpose of this review article is to review the basic properties and clinical effects of dasiglucagon. METHOD: We search related literature on CNKI, Web of Science and PubMed by keywords dasiglucagon, hypoglycemia, type 1 diabetes, glucagon. Carry out a careful review of the included literature. Dasiglucagon information on clinicaltrials.gov and https://www.fda.gov/ has been adopted. RESULTS AND CONCLUSION: Dasiglucagon is a novel peptide analog of human glucagon, which can effectively rescue insulin-induced severe hypoglycemia in patients with T1DM and rapidly increase glycemic levels in a small dose under normal and hypoglycemic conditions. It has been proven that dasiglucagon has definite stability and solubility in aqueous formulations. Dasiglucagon has a higher absorption rate and longer plasma elimination half-life than traditional reconstituted glucagon. In three randomized, double-blind, placebo-controlled trials in children aged 6 to 17 years and adults with T1DM the median time to glycemic recovery in 10 min after dasiglucagon administration was significantly faster than placebo and 99% of patients recovered within 15 min after subcutaneous injection of dasiglucagon in the key phase 3 clinical trial. The most common adverse reactions in these phase 3 trials were vomiting, nausea, diarrhea, headache, and injection site pain.

Dasiglucagon: First Approval.

Dasiglucagon (Zegalogue®) is an antihypoglycaemic agent being developed by Zealand Pharma for the treatment of hypoglycaemia, type 1 diabetes mellitus (T1DM) management and congenital hyperinsulinism. In March 2021, dasiglucagon received its first approval in the USA for the treatment of severe hypoglycaemia in paediatric and adult patients with diabetes aged 6 years and above. Dasiglucagon, a glucagon analogue, is available as a single-dose autoinjector or prefilled syringe for subcutaneous injection. This article summarizes the milestones in the development of dasiglucagon leading to this first approval for hypoglycaemia.

An Evaluation of Glucagon Injection Anxiety and Its Association with the Fear of Hypoglycemia among the Parents of Children with Type 1 Diabetes

Objective: Hypoglycemia is a common acute complication of type 1 diabetes (T1D), which may cause seizure, loss of consciousness, and temporary motor or sensory impairment. Glucagon administration is an effective way of treating severe hypoglycemia, especially in a free-living setting. Nonetheless, families have difficulties in managing severe hypoglycemia due to their anxiety and challenges with current glucagon administration techniques. The aim of the current study was to explore the associations between parental fear of hypoglycemia (FoH) and their general anxiety level, and in particular, their attitudes towards and thoughts on glucagon administration. Methods: Parents of children with T1D completed questionnaires assessing background and clinical information, FoH, generalized anxiety disorder (GAD) and parental anxiety for glucagon administration (PAGA). Results: Sixty-eight parents participated. Positive correlations were found between parental GAD-7 score and both FoH and the number of night-time blood glucose measurements and there was a negative correlation with the child's age. Parents mean self-evaluation score of their competence in glucagon administration was 6 (standard deviation±2.9) on a scale of 0 to 10. Unsurprisingly, this score was negatively correlated with the PAGA scores. There was no significant difference between children using continuous glucose monitoring system and self-monitoring of blood glucose in terms of parental FoH, anxiety and misconceptions about glucagon administration. Conclusion: The results showed that parents of children with T1D had anxiety and fear connected with hypoglycemia and glucagon administration. Structured and practical training should be implemented to increase parents' self-confidence including annual refresher training for home glucagon administration.

Perceptions and expectations of adults with type 1 diabetes for the use of artificial pancreas systems with and without glucagon addition: Results of an online survey.

BACKGROUND AND AIMS: The first hybrid artificial pancreas (AP) systems with insulin only (mono-hormonal) have recently reached the market while next generations systems are under development including those with glucagon addition (bi-hormonal). Understanding the expectations and impressions of future potential users about AP systems is important for optimal use of this clinically effective emerging technology. METHODS AND RESULTS: An online survey about AP systems which consisted of 50 questions was addressed to people with type 1 diabetes in the province of Quebec, Canada. Surveys were completed by 123 respondents with type 1 diabetes (54% women, mean (SD) age 40.2 (14.4) y.o., diabetes duration 23.7 (14.1) years, 58% insulin pump users and 43% glucose sensor users). Of the respondents, 91% understood how AP systems work, 79% trusted them with correct insulin dosing, 73% were willing to replace their current treatment with AP and 80% expected improvement in quality of life. Anxiety about letting an algorithm control their glucose levels was expressed by 18% while the option of ignoring or modifying AP instructions was favoured by 88%. As for bi-hormonal AP systems, 83% of respondents thought they would be useful to further reduce hypoglycemic risks. CONCLUSIONS: Overall, respondents expressed positive views about AP systems use and high expectations for a better quality of life, glycemic control and hypoglycemia reduction. Data from this survey could be useful to health care professionals and developers of AP systems.

Dual-Hormone Closed-Loop System Using a Liquid Stable Glucagon Formulation Versus Insulin-Only Closed-Loop System Compared With a Predictive Low Glucose Suspend System: An Open-Label, Outpatient, Single-Center, Crossover, Randomized Controlled Trial.

OBJECTIVE: To assess the efficacy and feasibility of a dual-hormone (DH) closed-loop system with insulin and a novel liquid stable glucagon formulation compared with an insulin-only closed-loop system and a predictive low glucose suspend (PLGS) system. RESEARCH DESIGN AND METHODS: In a 76-h, randomized, crossover, outpatient study, 23 participants with type 1 diabetes used three modes of the Oregon Artificial Pancreas system: 1) dual-hormone (DH) closed-loop control, 2) insulin-only single-hormone (SH) closed-loop control, and 3) PLGS system. The primary end point was percentage time in hypoglycemia (<70 mg/dL) from the start of in-clinic aerobic exercise (45 min at 60% VO2max) to 4 h after. RESULTS: DH reduced hypoglycemia compared with SH during and after exercise (DH 0.0% [interquartile range 0.0-4.2], SH 8.3% [0.0-12.5], P = 0.025). There was an increased time in hyperglycemia (>180 mg/dL) during and after exercise for DH versus SH (20.8% DH vs. 6.3% SH, P = 0.038). Mean glucose during the entire study duration was DH, 159.2; SH, 151.6; and PLGS, 163.6 mg/dL. Across the entire study duration, DH resulted in 7.5% more time in target range (70-180 mg/dL) compared with the PLGS system (71.0% vs. 63.4%, P = 0.044). For the entire study duration, DH had 28.2% time in hyperglycemia vs. 25.1% for SH (P = 0.044) and 34.7% for PLGS (P = 0.140). Four participants experienced nausea related to glucagon, leading three to withdraw from the study. CONCLUSIONS: The glucagon formulation demonstrated feasibility in a closed-loop system. The DH system reduced hypoglycemia during and after exercise, with some increase in hyperglycemia.

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

AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: This meta-analysis indicates that in conscious T1DM patients IN glucagon and IM/SC glucagon are equally effective in resolution of hypoglycemia.

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.