Low doses of dasiglucagon consistently increase plasma glucose levels from hypoglycaemia and euglycaemia in people with type 1 diabetes mellitus

Abstract

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.

Proglucagon-Derived Peptides as Therapeutics

“…infusion, glucagon emergency kits simply involve reconstitution of glucagon powder, which can be injected into the patient's leg or abdomen (32,55). Moreover, a ready-to use autoinjector preparation termed "Zegalogue ® " has recently gained FDA approval for management of hypoglycaemia (33), further improving ease of use. I.v.…”

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“…It remains to be seen if similar responses to glucagon, and titrated glucagon infusions in particular, will be observed in other cohorts. It will be especially interesting to review patient responses to novel glucagon analogs presently in clinical development (11).…”

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“…However, because of the short observation time, the values for T ½ should be interpreted with caution. Other human studies have conveyed comparable or slightly larger values for T max after SC administration of considerably larger doses [33][34][35][36][37][38][39][40][41]. Although the values are not directly transferable, this may indicate non-superiority of the IP route compared to the SC route in regard to absorption rate to the systemic circulation.…”