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.

Methods

In a randomised crossover phase 1b single-site study, blinded to both participants and researchers, participants, aged 18-65 years with BMI 18.5-27 kg/m2 with type 1 diabetes (HbA1c 42.1-74.9 mmol/mol and C-peptide <200 pmol/l) underwent three separate hyperinsulinaemic euglycaemic-hypoglycaemic clamps.

在这项随机交叉的1b期单中心研究中，参与者和研究人员均被蒙蔽，年龄在18-65岁之间，BMI为18.5-27 kg/m2的1型糖尿病患者（HbA1c 42.1-74.9 mmol/mol和C肽<200 pmol/l）接受了三次独立的高胰岛素血糖正常-低血糖钳夹试验。

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.

参与者通过第三方随机分配，以相等比例接受安慰剂、3毫克ZT-01或20毫克ZT-01皮下注射，在正常血糖水平（血浆葡萄糖目标为5.0 mmol/l）下进行，并暴露于通过变速率胰岛素输注诱导的1级（目标3.5 mmol/l）和2级（目标2.6 mmol/l）低血糖水平，期间不添加葡萄糖。

Glucagon response was the primary endpoint; plasma glucose, other counterregulatory hormones, symptom scores and safety were also determined.

胰高血糖素反应是主要终点；同时确定了血浆葡萄糖、其他逆调节激素、症状评分和安全性。

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.

24名随机参与者（9名女性和15名男性）至少接受了一次安慰剂或ZT-01的给药，并被纳入安全性分析。

Twenty-two participants completed at least one glucose clamp and were included for pharmacodynamics analysis.

22名参与者至少完成了一次葡萄糖夹板试验，并被纳入药效学分析。

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.

ZT-01给药后观察到血浆胰高血糖素水平短暂升高（3毫克ZT-01升高25.7 ± 2.4 ng/l，20毫克ZT-01升高28.4 ± 2.4 ng/l），在1级低血糖期开始前水平下降至接近给药前值。

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.

在1级（3毫克ZT-01升高15.6 ± 2.3 pg/l，20毫克ZT-01升高14.9 ± 2.4 pg/l）和2级（3.0毫克ZT-01升高22.8 ± 2.7 pg/l，20毫克ZT-01升高29.6 ± 2.8 pg/l）低血糖期间，ZT-01治疗组的平均胰高血糖素水平再次超过基线水平。

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).

在安慰剂组中，给药后以及在1级低血糖期间胰高血糖素水平保持不变，但在2级低血糖期间水平适度上升（增加了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.

在1级和2级低血糖期间，与安慰剂相比，ZT-01导致胰高血糖素增加的频率和幅度均更高。

There were no drug treatment-related adverse events.

没有出现与药物治疗相关的不良事件。

conclusions/interpretation

Administration of the SSTR2 antagonist ZT-01 increased glucagon responsiveness during insulin-induced hypoglycaemia in individuals with type 1 diabetes.

SSTR2拮抗剂ZT-01在1型糖尿病患者中增加了胰岛素诱导的低血糖期间胰高血糖素的反应性。

trial_registration

ClinicalTrials.gov NCT05007977.

ClinicalTrials.gov NCT05007977。