Effect of somatostatin receptor 2 antagonism on glucagon counterregulation during a hyperinsulinaemic euglycaemic–hypoglycaemic glucose clamp in adult men and women with long-standing type 1 diabetes: a randomised crossover phase 1 study

AIMS/HYPOTHESIS: The aim of this study was to determine the effect of a novel somatostatin receptor 2 (SSTR2) antagonist, ZT-01, on impaired glucagon counterregulation in hypoglycaemia and its safety in adults with type 1 diabetes. METHODS: 42.1-74.9 mmol/mol and C-peptide <200 pmol/l) underwent three separate hyperinsulinaemic euglycaemic-hypoglycaemic clamps. Participants were randomised, by a third party, in equal proportion to treatment order with placebo, 3 mg ZT-01 or 20 mg ZT-01 administered subcutaneously during euglycaemia (plasma glucose target 5.0 mmol/l), and exposed to level 1 (target 3.5 mmol/l) and level 2 (target 2.6 mmol/l) hypoglycaemia induced with variable-rate insulin infusion without addition of dextrose. Glucagon response was the primary endpoint; plasma glucose, other counterregulatory hormones, symptom scores and safety were also determined. RESULTS: Twenty-four randomised participants (9 female and 15 male) received at least one administration of placebo or ZT-01 and were included for safety analysis. Twenty-two participants completed at least one glucose clamp and were included for pharmacodynamics analysis. Transient increases in plasma glucagon were observed with ZT-01 administration (by 25.7 ± 2.4 ng/l with 3 mg ZT-01 and by 28.4 ± 2.4 ng/l with 20 mg ZT-01), with levels declining to near the pre-dose values before the start of the level 1 hypoglycaemic period. Mean glucagon levels rose again over baseline in both ZT-01 treatment arms during level 1 (by 15.6 ± 2.3 pg/l with 3 mg ZT-01 and by 14.9 ± 2.4 pg/l with 20 mg ZT-01) and level 2 (by 22.8 ± 2.7 pg/l with 3.0 mg ZT-01 and by 29.6 ± 2.8 pg/l with 20 mg ZT-01) hypoglycaemia. With placebo, glucagon levels were unchanged following dosing and during level 1 hypoglycaemia but rose modestly during level 2 hypoglycaemia (by 8.9 ± 2.5 ng/l). Both frequency and amplitude of the increases in glucagon were higher with ZT-01 vs placebo during level 1 and level 2 hypoglycaemia. There were no drug treatment-related adverse events. CONCLUSIONS/INTERPRETATION: Administration of the SSTR2 antagonist ZT-01 increased glucagon responsiveness during insulin-induced hypoglycaemia in individuals with type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05007977.