Novel Use of Dasiglucagon, a Soluble Glucagon Analog, for the Treatment of Hyperinsulinemic Hypoglycemia Secondary to Suspected Insulinoma: A Case Report.

INTRODUCTION: Hyperinsulinemic hypoglycemia is the most common cause of persistent hypoglycemia in children and adults. In adolescents and adults, hyperinsulinemic hypoglycemia is most frequently caused by an insulin-producing tumor. CASE PRESENTATION: A 17-year-old, previously healthy male presented with recurrent and severe episodes of hypoglycemia. Diagnostic evaluation was consistent with hyperinsulinemic hypoglycemia, and an insulinoma was suspected. Multiple imaging studies and surgical exploration failed to identify a lesion. Over the course of months, the patient was found to be refractory to conventional medical interventions. CONCLUSION: Upon approval from the US Food and Drug Administration and the Institutional Review Board, the patient was treated with dasiglucagon, a novel soluble glucagon analog, under a single-patient Investigational New Drug. The patient has tolerated the medication and has been able to achieve appropriate glycemic control.

Dasiglucagon for the Treatment of Congenital Hyperinsulinism: A Randomized Phase 3 Trial in Infants and Children.

CONTEXT: Congenital hyperinsulinism (CHI) is characterized by dysregulated insulin secretion causing hypoglycemia and consequent brain damage. Dasiglucagon is a glucagon analogue under investigation to treat CHI. OBJECTIVE: To evaluate the efficacy and safety of dasiglucagon delivered via continuous subcutaneous infusion to children with CHI and persistent hypoglycemia as add-on to standard of care (SoC). METHODS: In this open-label trial, patients were randomized 1:1 to SoC or SoC + dasiglucagon (10-70 µg/h) for 4 weeks. In the following 4 weeks, all patients received dasiglucagon + SoC. Hypoglycemia was assessed by self-monitored plasma glucose (SMPG) and blinded continuous glucose monitoring (CGM). Primary endpoint was average number of SMPG-detected hypoglycemia episodes/week (SMPG <3.9 mmol/L) during Weeks 2 to 4. RESULTS: Thirty-two patients (0.6-10.9 years) were randomly assigned to dasiglucagon + SoC (n = 16) or SoC (n = 16). The rate of SMPG-detected hypoglycemia decreased from baseline in both groups, but with no statistically significant difference during Weeks 2 to 4 (event rate ratio: 0.85 [0.54; 1.36], P = .5028). However, dasiglucagon administration resulted in a 43% reduction in CGM-detected hypoglycemia (<3.9 mmol/L) vs SoC alone during Weeks 2 to 4 (post hoc analysis; event rate ratio: 0.57 [0.39; 0.83], P = .0029). Dasiglucagon enabled reductions (of 37% to 61%) in all other measures of hypoglycemia assessed by CGM vs SoC alone including extent and percent time in hypoglycemia (post hoc analyses). Dasiglucagon appeared safe and well tolerated. Skin and gastrointestinal events were more frequent with dasiglucagon + SoC than SoC only. CONCLUSION: Clinically meaningful reductions in all CGM-recorded measures of hypoglycemia support using dasiglucagon as a potential treatment for CHI.

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.

Low-Dose Dasiglucagon Versus Oral Glucose for Prevention of Insulin-Induced Hypoglycemia in People With Type 1 Diabetes: A Phase 2, Randomized, Three-Arm Crossover Study.

OBJECTIVE: To compare the efficacy of low-dose subcutaneous dasiglucagon with oral glucose for prevention of insulin-induced hypoglycemia in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: Twenty adults with type 1 diabetes using multiple daily injection or insulin pump therapy completed a phase 2, randomized, three-arm crossover study. On each study visit, an individualized subcutaneous insulin bolus was administered aiming for a plasma glucose (PG) concentration of 3.0 mmol/L (54 mg/dL). When a PG concentration of 4.5 mmol/L (81 mg/dL) was reached, 15 g oral glucose (CHO) from dextrose tablets, 80 µg dasiglucagon (D80), or 120 µg dasiglucagon (D120) was administered. PG was measured frequently for the following 180 min. RESULTS: Hypoglycemia (<3.9 mmol/L [70 mg/dL]) occurred in 10 participants after CHO, in 5 after D80, and in 4 after D120 (CHO vs. D80, P = 0.096; CHO vs. D120, P = 0.034). Time spent in hypoglycemia (<3.9 mmol/L [70 mg/dL]) was 14%, 7%, and 6% for CHO, D80, and D120, respectively (P = 0.273). The median time (95% CI) from intervention to first increase in PG of 1.1 mmol/L (20 mg/dL) was 30 (25-50), 15 (15-20), and 15 (15-20) minutes for CHO, D80, and D120, respectively (CHO vs. D80, P = 0.006; CHO vs. D120, P = 0.003). Episodes of nausea were numerically, but not significantly, higher after dasiglucagon administration. No significant differences in visual analog scale-assessed adverse effects were observed between interventions. CONCLUSIONS: Low-dose dasiglucagon safely and effectively prevented insulin-induced hypoglycemia with a faster glucose-elevating profile than oral glucose.

Dasiglucagon Effectively Mitigates Postbariatric Postprandial Hypoglycemia: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial.

OBJECTIVE: To investigate the efficacy and safety of dasiglucagon, a novel stable glucagon analog in a liquid formulation, in Roux-en-Y gastric bypass (RYGB)-operated individuals suffering from postbariatric hypoglycemia (PBH). RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled, crossover trial, 10 RYGB-operated participants with continuous glucose monitoring-verified PBH were randomly assigned to 3 trial days, each consisting of a 240-min standardized liquid mixed-meal test with the subcutaneous injection of placebo or 80 µg or 200 µg dasiglucagon. RESULTS: Compared with placebo, treatment with both 80 and 200 µg dasiglucagon raised nadir plasma glucose (PG) (placebo: 3.0 ± 0.2 mmol/L [mean ± SEM]; 80 µg dasiglucagon: 3.9 ± 0.3 mmol/L, P = 0.002; 200 µg dasiglucagon: 4.5 ± 0.2 mmol/L, P = 0.0002) and reduced time in hypoglycemia (PG <3.9 mmol/L) by 70.0 min (P = 0.030 and P = 0.008). CONCLUSIONS: Single-dose administration of dasiglucagon effectively mitigated postprandial hypoglycemia.

Dasiglucagon demonstrates reduced costs in the treatment of severe hypoglycemia in a budget impact model.

BACKGROUND: Approximately 7.3 million people with type 1 or type 2 diabetes (T1D/T2D) are treated with insulin, placing them at higher risk of severe hypoglycemia (SH). SH requires assistance of another individual and often necessitates the prompt administration of intravenous glucose, injectable glucagon, or both. Untreated, SH can progress to unconsciousness, seizures, coma, or death. Before 2018, all glucagon rescue treatments required reconstitution. The complexity of reconstitution is often a barrier to successful administration during a severe hypoglycemic event. Studies suggest successful administration of glucagon emergency kits range from 6%-56% of the time. Second-generation glucagon treatments and glucagon analogs do not require reconstitution and have caregiver administration success rates ranging from 94%-100%. Dasiglucagon is a glucagon analog administered via autoinjector or prefilled syringe and has been shown to result in rapid hypoglycemia recovery. Moreover, the autoinjector can be administered successfully 94% of the time by trained caregivers. Previous evaluation of costs in budget impact models (BIMs) demonstrated the potential for second-generation glucagon treatments to reduce the cost of SH events (SHEs). The current model expands on those findings with a treatment pathway and accompanying assumptions reflecting important aspects of real-world SHE treatment. OBJECTIVE: To evaluate the economic impact of dasiglucagon compared with available glucagon treatments for SHE management, considering direct cost of treatment and health care resource utilization. METHODS: A 1-year BIM with a hypothetical US commercial health plan of 1 million lives was developed with a target population of individuals with diabetes at risk of SHE. The treatment pathway model included initial and secondary treatment attempts, treatment administration success and failure, plasma glucose (PG) recovery within 15 minutes, emergency medical services, emergency department (ED) visits, and hospitalizations. A 1-way sensitivity analysis was conducted to assess the sensitivity of the model to changes in parameter values. RESULTS: In a 1 million-covered lives population, it was estimated that 12,006 SHEs would occur annually. The higher rate of initial treatment success and PG recovery within 15 minutes associated with dasiglucagon treatment resulted in lower total health care costs. Total SHE treatment costs with dasiglucagon were estimated at $13.4 million, compared with $16.7 million for injectable native glucagon, $20.7 million for nasal glucagon, $35.3 million for reconstituted glucagon, and $43.8 million for untreated individuals. Compared with untreated people, the number needed to treat (NNT) with dasiglucagon was 6 individuals to avoid 1 hospitalization. NNT for this same comparison was 59 for injectable native glucagon and 27 for nasal glucagon. CONCLUSIONS: Treatment of SH with dasiglucagon decreased total direct medical costs by reducing health care resource utilization (emergency calls, emergency transports, ED visits, and hospitalizations) and accompanying costs associated with the treatment of SH. DISCLOSURES: This research was funded by Zealand Pharma. Bromley, Hinahara, and Goss are employed by Boston Healthcare Associates, Inc., which received funding from Zealand Pharma for development of the health economic model and the manuscript. Kendall and Hammer are employed by Zealand Pharma. Weinzimer has received consulting fees from Zealand Pharma.

A Comparative Study of Dasiglucagon Ready-to-Use Autoinjector and Glucagon Emergency Kit During Rescue from Simulated Severe Hypoglycemia.

Background: Severe hypoglycemic episodes are life-threatening events demanding rapid administration of glucagon by a caregiver or bystander. The glucagon analog dasiglucagon is stable in aqueous formulation and therefore suitable for delivery in a ready-to-use autoinjector, potentially increasing speed and ease of use compared with standard glucagon emergency kits (GEKs). Methods: In an open label, randomized, crossover, comparative device handling study, trained caregivers and untrained bystanders administered the dasiglucagon autoinjector or Eli Lilly GEK to manikins in a simulated emergency hypoglycemia situation. Results: In total, 54 participants were randomized (18 patient-caregiver pairs and 18 bystanders). Overall, 94% of trained caregivers were able to administer the dasiglucagon autoinjector successfully within 15 min, compared with 56% for the GEK (P < 0.05). A greater proportion of trained caregivers and untrained bystanders successfully prepared and administered the dasiglucagon autoinjector within 2 min compared with the GEK (P < 0.005 and P < 0.05, respectively). Time to successful completion was also significantly faster with the dasiglucagon autoinjector than with the GEK (P < 0.005 for both groups). Most study participants preferred the dasiglucagon autoinjector over the GEK (94%, P < 0.001) and rated it as easier (90%, P < 0.001) and less stressful to use (94%, P < 0.001) than the GEK. Conclusion: Dasiglucagon autoinjector was more rapidly and reliably administered, and users reported greater ease of use and usage satisfaction than with the GEK. Thus, dasiglucagon autoinjector has the potential to improve speed and ease of treatment in severe hypoglycemic events, providing a better usage experience for rescuing individuals and enabling faster recovery for patients.

A double-blind, placebo-controlled, single-ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of HM15136, a novel long-acting glucagon analogue, in healthy subjects.

AIM: To evaluate the safety and tolerability, pharmacokinetics, and pharmacodynamics of HM15136, a novel long-acting glucagon analogue under development, in healthy males and females presenting with no childbearing potential. MATERIALS AND METHODS: A randomized, double-blind, placebo-controlled, single-ascending dose study was conducted in 56 subjects who randomly received a single subcutaneous dose of HM15136 or its matching placebo at a ratio of 6:2 at 10, 20, 30, 50, 80, 100, and 120 µg/kg. RESULTS: All adverse events were mild and transient. Neither serious adverse events nor discontinuation as a result of adverse events occurred. The most frequent adverse drug reaction was nausea (5.3%, only in the 100- and 120-µg/kg groups). HM15136, particularly at doses of 50 µg/kg or higher, increased fasting blood glucose, with a maximum increase and area under the curve of 1.5 mmol/L at day 10 (P = .006) and 166.3 day·mmol/L (P = .022) at the dose of 80 µg/kg, while suppressing the secretion of endogenous glucagon, which continued until day 17. HM15136 also significantly reduced gluconeogenic and ketogenic amino acids. Compensatory changes in endogenous insulin and incretin hormones by HM15136 were not apparent. HM15136 was slowly but steadily absorbed and reached a peak concentration at 46-68 hours after a single subcutaneous injection. HM15136 was eliminated with a terminal phase half-life of 77.1-101.1 hours. CONCLUSIONS: A single subcutaneous dose of HM15136 at 10-120 µg/kg was safe and well tolerated. The long half-life of HM15136, coupled with an increase in blood glucose for ~2 weeks, may warrant a weekly dosing regimen.

A glucagon analogue decreases body weight in mice via signalling in the liver.

Glucagon receptor agonists show promise as components of next generation metabolic syndrome pharmacotherapies. However, the biology of glucagon action is complex, controversial, and likely context dependent. As such, a better understanding of chronic glucagon receptor (GCGR) agonism is essential to identify and mitigate potential clinical side-effects. Herein we present a novel, long-acting glucagon analogue (GCG104) with high receptor-specificity and potent in vivo action. It has allowed us to make two important observations about the biology of sustained GCGR agonism. First, it causes weight loss in mice by direct receptor signalling at the level of the liver. Second, subtle changes in GCG104-sensitivity, possibly due to interindividual variation, may be sufficient to alter its effects on metabolic parameters. Together, these findings confirm the liver as a principal target for glucagon-mediated weight loss and provide new insights into the biology of glucagon analogues.

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.

α/Sulfono-γ-AApeptide Hybrid Analogues of Glucagon with Enhanced Stability and Prolonged In Vivo Activity.

Peptide drugs have the advantages of target specificity and good drugability and have become one of the most increasingly important hotspots in new drug research in biomedical sciences. However, peptide drugs generally have low bioavailability and metabolic stability, and therefore, the modification of existing peptide drugs for the purpose of improving stability and retaining activity is of viable importance. It is known that glucagon is an effective therapy for treating severe hypoglycemia, but its short half-life prevents its wide therapeutic use. Herein, we report that combined unnatural residues and long fatty acid conjugation afford potent α/sulfono-γ-AApeptide hybrid analogues of Glucagon with enhanced stability and prolonged in vivo activity. This strategy could be adopted to develop stabilized analogues of other short-acting bioactive peptides.

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.

Immunogenicity of the Novel Glucagon Analogue Dasiglucagon: Results of a Dedicated Immunogenicity Trial in Type 1 Diabetes.

Dasiglucagon is a next-generation glucagon analogue that is stable in aqueous formulation. This dedicated immunogenicity trial to support use as rescue treatment for severe hypoglycemia was conducted to evaluate the immunogenicity of repeated subcutaneous doses of dasiglucagon in subjects with type 1 diabetes. A total of 112 subjects were randomized 1:1 to receive three subcutaneous weekly doses of either 0.6 mg dasiglucagon or 1.0 mg recombinant glucagon (GlucaGen®) according to a double-blind parallel-group trial design. Subjects were followed for 15 weeks, with a multitiered testing approach planned for assessment of antidrug antibody (ADA) formation. For the primary immunogenicity endpoint, the overall ADA incidence was zero, as no subject demonstrated any treatment-induced or treatment-boosted ADA response at any time point in this trial involving three consecutive weekly doses of trial drug. No injection site reactions were reported for subjects receiving dasiglucagon. There were no unexpected safety findings for the trial.

Dasiglucagon, a next-generation glucagon analogue, for treatment of severe hypoglycaemia via an autoinjector device: Results of a phase 3, randomized, double-blind trial.

AIM: To confirm the efficacy and safety of dasiglucagon when administered via an autoinjector device. MATERIALS AND METHODS: In this double-blind trial, 45 participants with type 1 diabetes were randomized 3:1 to receive a single subcutaneous dose of dasiglucagon 0.6 mg or placebo following controlled induction of hypoglycaemia. The primary endpoint was time to plasma glucose recovery, defined as a plasma glucose increase of 20 mg/dL or higher from baseline without rescue intravenous glucose. RESULTS: Median (95% CI) observed time to recovery was 10.0 (8.0; 12.0) minutes for dasiglucagon and 35.0 (20.0; -) minutes for placebo (P < .001). Plasma glucose recovery was achieved within 15 minutes by 88% of participants receiving dasiglucagon versus none receiving placebo (P < .01). Site of injection (buttock or deltoid) was not shown to have any effect on time to recovery (P = .84). No serious adverse events occurred. As expected for glucagon treatment, nausea and vomiting were common adverse events in dasiglucagon-treated participants. CONCLUSIONS: Dasiglucagon provided rapid reversal of hypoglycaemia in adults with type 1 diabetes. Dasiglucagon administration was well tolerated. The aqueous formulation of dasiglucagon in a ready-to-use autoinjector device that can be carried at room temperature may provide a reliable treatment for severe hypoglycaemia.

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.

Dasiglucagon, a next-generation ready-to-use glucagon analog, for treatment of severe hypoglycemia in children and adolescents with type 1 diabetes: Results of a phase 3, randomized controlled trial.

BACKGROUND: Dasiglucagon, a next-generation, ready-to-use aqueous glucagon analog formulation, has been developed to treat severe hypoglycemia in individuals with diabetes. OBJECTIVE: The aim of this trial was to evaluate the safety and efficacy of dasiglucagon in pediatric individuals with type 1 diabetes (T1DM). Participants were children and adolescents (6-17 years) with T1DM. METHODS: In this randomized double-blind trial, 42 participants were randomly allocated (2:1:1) to a single subcutaneous (SC) injection of dasiglucagon (0.6 mg), placebo, or reconstituted glucagon (GlucaGen; dosed per label) during insulin-induced hypoglycemia. The primary endpoint was time to plasma glucose (PG) recovery (first PG increase ≥20 mg/dL after treatment initiation without rescue intravenous glucose). The primary comparison was dasiglucagon vs. placebo; glucagon acted as a reference. RESULTS: The median time (95% confidence interval) to PG recovery following SC injection was 10 min (8-12) for dasiglucagon vs. 30 min (20 to -) for placebo (P < .001); the median time for glucagon was 10 min (8-12), which did not include the time taken to reconstitute the lyophilized powder. PG recovery was achieved in all participants in the dasiglucagon and glucagon groups within 20 min of dosing compared to 2 out of 11 patients (18%) with placebo. The most frequent adverse events were nausea and vomiting, as expected with glucagon treatment. CONCLUSIONS: Consistent with adult phase 3 trials, dasiglucagon rapidly and effectively restored PG levels following insulin-induced hypoglycemia in children and adolescents with T1DM, with an overall safety profile similar to glucagon.

Dasiglucagon-A Next-Generation Glucagon Analog for Rapid and Effective Treatment of Severe Hypoglycemia: Results of Phase 3 Randomized Double-Blind Clinical Trial.

OBJECTIVE: To evaluate the efficacy and safety of dasiglucagon, a ready-to-use, next-generation glucagon analog in aqueous formulation for subcutaneous dosing, for treatment of severe hypoglycemia in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: This randomized, double-blind trial included 170 adult participants with type 1 diabetes, each randomly assigned to receive a single subcutaneous dose of 0.6 mg dasiglucagon, placebo, or 1 mg reconstituted glucagon (2:1:1 randomization) during controlled insulin-induced hypoglycemia. The primary end point was time to plasma glucose recovery, defined as an increase of ≥20 mg/dL from baseline without rescue intravenous glucose. The primary comparison was dasiglucagon versus placebo; reconstituted lyophilized glucagon was included as reference. RESULTS: Median (95% CI) time to recovery was 10 (10, 10) minutes for dasiglucagon compared with 40 (30, 40) minutes for placebo (P < 0.001); the corresponding result for reconstituted glucagon was 12 (10, 12) minutes. In the dasiglucagon group, plasma glucose recovery was achieved within 15 min in all but one participant (99%), superior to placebo (2%; P < 0.001) and similar to glucagon (95%). Similar outcomes were observed for the other investigated time points at 10, 20, and 30 min after dosing. The most frequent adverse effects were nausea and vomiting, as expected with glucagon treatment. CONCLUSIONS: Dasiglucagon provided rapid and effective reversal of hypoglycemia in adults with type 1 diabetes, with safety and tolerability similar to those reported for reconstituted glucagon injection. The ready-to-use, aqueous formulation of dasiglucagon offers the potential to provide rapid and reliable treatment of severe hypoglycemia.