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Aim: To characterize the pharmacokinetic and pharmacodynamic properties of dasiglucagon, a novel, stable and liquid formulated glucagon analogue, during hypoglycaemic and euglycaemic conditions in adult patients with type 1 diabetes mellitus., Research Design and Methods: In this randomized double-blind trial, 17 patients received four single subcutaneous doses (0.03, 0.08, 0.2 and 0.6 mg) of dasiglucagon (4 mg/mL formulation) under euglycaemic (plasma glucose [PG] 5.6 mmol/L [100 mg/dL]) or hypoglycaemic (PG 3.1-3.7 mmol/L [56-66 mg/dL]) conditions. For comparison, three doses (0.03, 0.08 and 0.2 mg) of a commercial glucagon formulation (Eli Lilly) were investigated at euglycaemia., Results: Dasiglucagon led to a dose-dependent and rapid increase in PG levels across all doses tested (mean increases 30 minutes post-dosing of 2.2 to 4.4 mmol/L [39-80 mg/dL] from euglycaemia and 1.3 to 5.2 mmol/L [24-94 mg/dL] from hypoglycaemia), which was higher than the rises elicited by similar doses of commercial glucagon (1.7-3.9 mmol/L [30-71 mg/dL]). The median time (range) to an increase in PG of >1.1 mmol/L (20 mg/dL) was <20 (18-19.5) minutes with 0.03 mg dasiglucagon and, with higher doses, the median times ranged from 9 to 15 minutes (commercial glucagon 13-14 minutes). In hypoglycaemia, 0.03 and 0.08 mg dasiglucagon re-established normoglycaemia (PG ≥3.9 mmol/L [70 mg/dL]) within median times of 14 and 10 minutes, respectively. Nausea and vomiting occurred more frequently with dasiglucagon than with commercial glucagon at identical doses which might be attributable to dasiglucagon's higher potency., Conclusion: Dasiglucagon rapidly increased PG at doses of 0.03 to 0.6 mg in a dose-dependent manner and, therefore, is a good candidate for use in dual-hormone artificial pancreas systems., (© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: Treatment of severe hypoglycemia outside of the hospital setting is limited to glucagon formulations requiring reconstitution before use, which may lead to erroneous or delayed glucagon administration. We compared the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and safety and tolerability of different doses of dasiglucagon, a novel soluble glucagon analog, with approved pediatric and full doses of GlucaGen in insulin-induced hypoglycemia in patients with type 1 diabetes., Research Design and Methods: In this single-center, randomized, double-blind trial, 58 patients with type 1 diabetes received single subcutaneous injections of 0.1, 0.3, 0.6, or 1.0 mg dasiglucagon or 0.5 or 1.0 mg GlucaGen in a state of hypoglycemia (blood glucose target 55 mg/dL) induced by an intravenous insulin infusion., Results: Dasiglucagon demonstrated a dose-dependent and rapid increase in plasma concentrations, reaching a maximum at ∼35 min with a half-life of ∼0.5 h. Dasiglucagon rapidly increased plasma glucose (PG) by ≥20 mg/dL (9-14 min) to PG ≥70 mg/dL (within 6-10 min), similar to GlucaGen, but with a longer-lasting and greater effect on PG. All patients on both treatments reached these end points within 30 min (predefined success criteria). Both treatments were well tolerated. Nausea was the most frequent adverse event, occurring at a similar rate (44-56%)., Conclusions: Dasiglucagon was well tolerated and showed an early PD response similar to that of GlucaGen at corresponding doses, suggesting comparable clinical effects of the two glucagon formulations. Dasiglucagon has the potential to become an effective and reliable rescue treatment for severe hypoglycemia in a ready-to-use pen., (© 2017 by the American Diabetes Association.)

Aims: To perform an integrated analysis of the safety and efficacy of dasiglucagon, a glucagon analogue available in a ready‐to‐use aqueous formulation, to treat severe hypoglycaemia (SH) in type 1 diabetes (T1D). Materials and Methods: An integrated analysis of dasiglucagon safety was conducted on data from two placebo‐controlled trials (placebo‐controlled pool) and two placebo‐controlled and four non‐placebo‐controlled trials (broad pool) in adults with T1D. An integrated analysis of dasiglucagon efficacy was conducted of pooled data and within demographic subgroups from the two placebo‐controlled and two non‐placebo‐controlled trials in adults with T1D. Results: Dasiglucagon had a similar safety and tolerability profile to that of reconstituted glucagon. In the placebo‐controlled datasets, no serious adverse events (AEs), AEs leading to withdrawal from the trial, or deaths were reported. The most common causally related AEs were nausea (56.5%) and vomiting (24.6%). The broad pool safety analysis showed similar results. Dasiglucagon efficacy in time to plasma glucose recovery from insulin‐induced SH was similar to that of reconstituted glucagon (median 10.0 and 12.0 minutes, respectively) and superior to placebo (median 40.0 minutes; P < 0.0001). The median recovery time was consistent across all placebo‐controlled trial subgroups. Conclusions: Dasiglucagon was well tolerated and effective as a rapid rescue agent for insulin‐induced SH in people with T1D. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Many commercially available glucagon products for treatment of severe hypoglycaemia require cumbersome reconstitution and potentially intimidating injection during an emergency. Nasal glucagon (NG) is a novel drug-device combination product consisting of a single-use dosing device that delivers glucagon dry powder through nasal administration. The present study assessed whether 3 mg NG was non-inferior to 1 mg intramuscular glucagon (IMG) in adults with type 1 diabetes. Methods: This randomised, open-label, two-period, crossover trial was conducted at two clinical sites. Hypoglycaemia (plasma glucose [PG] target of < 3.3 mmol/l (60 mg/dl) was induced by an intravenous insulin infusion. Glucagon preparations were given by study staff. Treatment success was defined as an increase in PG to ≥ 3.9 mmol/l (70 mg/dl) or an increase of ≥ 1.1 mmol/l (20 mg/dl) from the PG nadir within 30 min of receiving glucagon. Results: Of the 66 participants included in the primary efficacy analysis who received both NG and IMG, 100% achieved treatment success, thus demonstrating non-inferiority of NG to IMG. All participants achieved treatment success within 25 min with the mean time to treatment success of 11.4 min (NG) and 9.9 min (IMG). No serious adverse events occurred. Forty-eight treatment-emergent adverse events (TEAEs) occurred after NG and 51 after IMG. Most TEAEs were mild and transient. Conclusion: Nasal glucagon was as efficacious and well tolerated as IMG for the treatment of insulin-induced hypoglycaemia in adults and will be as useful as IMG as a rescue treatment for severe hypoglycaemia. Trial Registration: NCT03339453, ClinicalTrials.gov [ABSTRACT FROM AUTHOR]