Nasal glucagon as a viable alternative for treating insulin-induced hypoglycaemia in Japanese patients with type 1 or type 2 diabetes: A phase 3 randomized crossover study

Abstract

Aim: To compare nasal glucagon (NG) with intramuscular glucagon (IMG) for the treatment of insulin-induced hypoglycaemia in Japanese patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM).

Materials and methods: This phase 3, randomized, open-label, two-treatment, two-period crossover non-inferiority study enrolled Japanese adults with T1DM or T2DM on insulin therapy, with glycated haemoglobin levels ≤86 mmol/mol (≤10%). After ≥8 hours of fasting, hypoglycaemia was induced with human regular insulin (intravenous infusion). Patients received NG 3 mg or IMG 1 mg approximately 5 minutes after insulin termination. The primary endpoint was the proportion of patients achieving treatment success [plasma glucose (PG) increase to ≥3.9 mmol/L (≥70 mg/dL) or ≥1.1 mmol/L (≥20 mg/dL) increase from the PG nadir within 30 minutes of receiving glucagon]. Non-inferiority was declared if the upper limit of the two-sided 95% confidence interval (CI) of the mean difference in the percentage of patients achieving treatment success (IMG minus NG) was <10%.

Results: Seventy-five patients with T1DM (n = 34) or T2DM (n = 41) were enrolled; 72 patients (50 men, 22 women) received ≥1 study drug dose (T1DM, n = 33; T2DM, n = 39). Sixty-eight patients completed the study and were evaluable. All NG- and IMG-treated patients achieved treatment success (treatment arm difference: 0%; upper limit of two-sided 95% CI 1.47%); NG met prespecified conditions defining non-inferiority versus IMG. Glucagon was rapidly absorbed after both nasal and intramuscular administration; PG profiles were similar between administration routes during the first 60 minutes post dose. Study drug-related treatment-emergent adverse events affecting >2 patients were rhinalgia, increased blood pressure, nausea, ear pain and vomiting in the NG group, and nausea and vomiting in the IMG group.

Conclusion: Nasal glucagon was non-inferior to IMG for successful treatment of insulin-induced hypoglycaemia in Japanese patients with T1DM/T2DM, supporting use of NG as a rescue treatment for severe hypoglycaemia.

Keywords: glucagon; hypoglycaemia; pharmacodynamics; pharmacokinetics; type 1 diabetes; type 2 diabetes.

Figure 1

Percentage of patients achieving treatment success. To determine the plasma concentration of glucose, venous blood samples were collected immediately before glucagon administration and at 5, 10, 15, 20, 25, 30, 40, 50, 60, 90, 120 and 240 minutes post dose. All patients in both treatment groups achieved treatment success [defined as either an increase in plasma glucose (PG) ≥3.9 mmol/L (≥70 mg/dL) or a PG increase of ≥1.1 mmol/L (≥20 mg/dL) from nadir within 30 minutes after glucagon administration]. The mean times to treatment success for the overall population, patients with type 1 diabetes mellitus (T1DM), and patients with type 2 diabetes mellitus (T2DM) are shown on the graph. The number of patients with treatment success versus the number of patients at risk at 0, 5, 10, 15, 20, and 25 minutes after glucagon administration is shown underneath the graph. IMG, intramuscular glucagon; NG, nasal glucagon

Figure 2

Change from baseline in plasma glucagon concentration profiles following single doses of nasal glucagon (NG) 3 mg or intramuscular glucagon (IMG) 1 mg (pharmacokinetic population). A, Overall. B, Type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) NG. C, T1DM and T2DM IMG. The arithmetic mean (± SD) on a linear scale is shown. N, population size; PG, plasma glucose

Figure 3

Plasma glucose concentration profile following single doses of nasal glucagon (NG) 3 mg or intramuscular glucagon (IMG) 1 mg. A, Overall pharmacodynamic population. B, patients with type 1 diabetes mellitus (T1DM). C, Patients with type 2 diabetes mellitus (T2DM). Arithmetic means (± SD) are shown. N, population size