Dapagliflozin's impact on hormonal regulation and ketogenesis in type 1 diabetes: a randomised controlled crossover trial.

We hypothesise that dapagliflozin increases glucagon-like peptide 1 (GLP-1), glucagon and ketone body concentrations, based on the results of a pilot study.

我们假设基于一项初步研究结果，达格列净会增加胰高血糖素样肽1（GLP-1）、胰高血糖素和酮体浓度。

Methods

The study was designed as a randomised, placebo-controlled, open-label, crossover intervention study with two periods (dapagliflozin and placebo intake), including patients of the Department of Diabetes, Endocrinology, Clinical Nutrition & Metabolism, Inselspital, Bern University Hospital, University of Bern.

该研究设计为一项随机、安慰剂对照、开放标签、交叉干预研究，包含两个阶段（达格列净和安慰剂摄入），涉及伯尔尼大学医院伯尔尼大学内分泌科、糖尿病科、临床营养与代谢科的患者。

Individuals with type 1 diabetes (C-peptide concentrations <0.1 nmol/l) with a duration >5 years and a BMI of 20-29 kg/m2 were included.

纳入研究的个体为1型糖尿病患者（C肽浓度<0.1 nmol/l），病程超过5年，体重指数（BMI）在20-29 kg/m2之间。

They received 10 mg of dapagliflozin or placebo daily for 7 days throughout two independent treatment periods, separated by a 14 day washout period.

他们在两个独立的治疗周期中，每天接受10毫克的达格列净或安慰剂，持续7天，两个治疗周期之间有14天的洗脱期。

Allocation was done by a computed randomisation tool (REDCap), without blinding of the participants or the investigators.

分配是通过计算随机化工具（REDCap）进行的，没有对参与者或调查员进行盲法处理。

On day 7 of each treatment period, hyperinsulinaemic-euglycaemic clamps (HECs) and OGTT clamps (OGTTCs) were performed to assess changes in the secretion of GLP-1, glucagon, somatostatin and total ketone bodies.

在每个治疗周期的第7天，进行了高胰岛素-等血糖钳制（HECs）和口服葡萄糖耐量钳制（OGTTCs），以评估GLP-1、胰高血糖素、生长抑素和总酮体分泌的变化。

The objective was to evaluate the effects of adding the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin to insulin therapy on GLP-1 during OGTTC (primary endpoint), GLP-1 secretion during HEC, and glucagon, somatostatin and ketogenesis during OGTTC and HEC (secondary endpoints).

目的是评估将钠-葡萄糖共转运蛋白2（SGLT2）抑制剂达格列净添加到胰岛素治疗中对OGTTC期间GLP-1（主要终点）的影响，HEC期间GLP-1的分泌，以及OGTTC和HEC期间胰高血糖素、生长抑素和酮体生成的影响（次要终点）。

The primary endpoint was concentrations of GLP-1 during OGTTC.

主要终点是在口服葡萄糖耐量试验（OGTTC）期间的胰高血糖素样肽-1（GLP-1）浓度。

Secondary endpoints included GLP-1 during HEC and glucagon, somatostatin and ketone body concentrations during OGTTC and HEC.

次要终点包括在高能量餐（HEC）期间的胰高血糖素样肽-1（GLP-1）以及在口服葡萄糖耐量测试（OGTTC）和高能量餐（HEC）期间的胰高血糖素、生长抑素和酮体浓度。

Results

A total of 13 individuals with type 1 diabetes were included and randomised.

共有13名1型糖尿病患者被纳入并随机分配。

All of them received dapagliflozin and placebo, finished the sequences per protocol and were analysed per protocol.

所有患者均接受了达格列净和安慰剂治疗，按照方案完成了治疗序列，并按方案进行了分析。

GLP-1 concentrations did not differ significantly between treatments in the OGTTC (median [IQR] dapagliflozin 192.8 [129.8-257.2] pmol/l vs placebo 176.3 [138.4-227.4] pmol/l; p=0.7) or HEC (median [IQR] dapagliflozin 208.6 [133.6-294.0] pmol/l vs placebo 203.1 [150.2-291.8] pmol/l; p=0.7).

GLP-1浓度在OGTTC（中位数[IQR]达格列净192.8 [129.8-257.2] pmol/l vs 安慰剂176.3 [138.4-227.4] pmol/l; p=0.7）或HEC（中位数[IQR]达格列净208.6 [133.6-294.0] pmol/l vs 安慰剂203.1 [150.2-291.8] pmol/l; p=0.7）治疗间没有显著差异。

Glucagon concentrations did not significantly differ between treatments in the OGTTC (median [IQR] dapagliflozin 1.54 [0.84-3.68] ng/l vs placebo 1.54 [0.82-4.64] ng/l; p=0.8) or HEC (median [IQR] dapagliflozin 1.59 [0.87-3.54] ng/l vs placebo 1.63 [0.91-3.96] ng/l; p=0.3).

胰高血糖素浓度在OGTTC（中位数[IQR]达格列净1.54 [0.84-3.68] ng/l vs 安慰剂1.54 [0.82-4.64] ng/l; p=0.8）或HEC（中位数[IQR]达格列净1.59 [0.87-3.54] ng/l vs 安慰剂1.63 [0.91-3.96] ng/l; p=0.3）治疗间没有显著差异。

Somatostatin concentrations remained comparable between treatments during the HEC (median [IQR] dapagliflozin 41.1 [26.8-73.8] pmol/l vs placebo 47.0 [23.0-77.6] pmol/l; p=0.2) and OGTTC (median [IQR] dapagliflozin 51.1 [31.1-77.0] pmol/l vs placebo 45.3 [30.0-70.5] pmol/l; p=0.2).

在HEC期间，治疗组之间的生长抑素浓度保持可比性（中位数[IQR]：达格列净41.1 [26.8-73.8] pmol/l 对比安慰剂47.0 [23.0-77.6] pmol/l；p=0.2）以及OGTTC期间（中位数[IQR]：达格列净51.1 [31.1-77.0] pmol/l 对比安慰剂45.3 [30.0-70.5] pmol/l；p=0.2）。

Plasma ketone bodies were higher with dapagliflozin during the HEC (median [IQR] dapagliflozin 0.15 [0.04-0.47] mmol/l vs placebo 0.03 [0.01-0.12] mmol/l; p<0.001) and OGTTC (median [IQR] dapagliflozin 0.10 [0.03-0.22] mmol/l vs placebo 0.03 [0.01-0.12] mmol/l; p<0.001).

在HEC期间，达格列净组的血浆酮体水平高于安慰剂组（中位数[IQR]：达格列净0.15 [0.04-0.47] mmol/l 对比安慰剂0.03 [0.01-0.12] mmol/l；p<0.001），在OGTTC期间也是如此（中位数[IQR]：达格列净0.10 [0.03-0.22] mmol/l 对比安慰剂0.03 [0.01-0.12] mmol/l；p<0.001）。

conclusions/interpretation

Short-term dapagliflozin treatment in type 1 diabetes increases plasma ketone concentrations without affecting the secretion of GLP-1, glucagon or somatostatin.

短期达格列净治疗1型糖尿病可增加血浆酮体浓度，但不影响GLP-1、胰高血糖素或生长抑素的分泌。

Higher ketone body concentrations highlight the elevated risk of diabetic ketoacidosis associated with the adjunct intake of dapagliflozin.

较高的酮体浓度突显了与达格列净辅助摄入相关的糖尿病酮症酸中毒的增加风险。

trial_registration

ClinicalTrials.gov NCT04035031.

ClinicalTrials.gov 注册号 NCT04035031。

funding

Swiss National Science Foundation, project number 32003B_185019.

瑞士国家科学基金会，项目编号 32003B_185019。