经皮迷走神经刺激治疗糖尿病患者胃肠道症状的随机、双盲、假刺激对照、多中心试验。

AIMS/HYPOTHESIS: Diabetic gastroenteropathy frequently causes debilitating gastrointestinal symptoms. Previous uncontrolled studies have shown that transcutaneous vagal nerve stimulation (tVNS) may improve gastrointestinal symptoms. To investigate the effect of cervical tVNS in individuals with diabetes suffering from autonomic neuropathy and gastrointestinal symptoms, we conducted a randomised, sham-controlled, double-blind (participants and investigators were blinded to the allocated treatment) study. METHODS: This study included adults (aged 20-86) with type 1 or 2 diabetes, gastrointestinal symptoms and autonomic neuropathy recruited from three Steno Diabetes Centres in Denmark. Participants were randomly allocated 1:1 to receive active or sham stimulation. Active cervical tVNS or sham stimulation was self-administered over two successive study periods: 1 week of four daily stimulations and 8 weeks of two daily stimulations. The primary outcome measures were gastrointestinal symptom changes as measured using the gastroparesis cardinal symptom index (GCSI) and the gastrointestinal symptom rating scale (GSRS). Secondary outcomes included gastrointestinal transit times and cardiovascular autonomic function. RESULTS: Sixty-eight participants were randomised to the active group, while 77 were randomised to the sham group. Sixty-three in the active and 68 in the sham group remained for analysis in study period 1, while 62 in each group were analysed in study period 2. In study period 1, active and sham tVNS resulted in similar symptom reductions (GCSI: -0.26 ± 0.64 vs -0.17 ± 0.62, p=0.44; GSRS: -0.35 ± 0.62 vs -0.32 ± 0.59, p=0.77; mean ± SD). In study period 2, active stimulation also caused a mean symptom decrease that was comparable to that observed after sham stimulation (GCSI: -0.47 ± 0.78 vs -0.33 ± 0.75, p=0.34; GSRS: -0.46 ± 0.90 vs -0.35 ± 0.79, p=0.50). Gastric emptying time was increased in the active group compared with sham (23 min vs -19 min, p=0.04). Segmental intestinal transit times and cardiovascular autonomic measurements did not differ between treatment groups (all p>0.05). The tVNS was well-tolerated. CONCLUSIONS/INTERPRETATION: Cervical tVNS, compared with sham stimulation, does not improve gastrointestinal symptoms among individuals with diabetes and autonomic neuropathy. TRIAL REGISTRATION: ClinicalTrials.gov NCT04143269 FUNDING: The study was funded by the Novo Nordisk Foundation (grant number NNF180C0052045).

目的/假设：糖尿病性胃肠病常导致使人虚弱的胃肠道症状。以前未经控制的研究表明，经皮迷走神经刺激（tVNS）可能改善胃肠道症状。为了研究颈椎 tVNS 对患有自主神经病变和胃肠道症状的糖尿病患者的影响，我们进行了一项随机、假对照、双盲（参与者和研究人员对分配的治疗方案不知情）研究。

方法：本研究纳入了来自丹麦三个 Steno 糖尿病中心的成年（年龄 20-86 岁）1 型或 2 型糖尿病患者、有胃肠道症状和自主神经病变的患者。参与者被随机分配 1:1 接受活性或假刺激。活性颈椎 tVNS 或假刺激在连续两个研究期内自我给药：连续 4 天每天刺激 4 次，然后连续 8 天每天刺激 2 次。主要结局测量指标是使用胃轻瘫关键症状指数（GCSI）和胃肠道症状评分量表（GSRS）测量的胃肠道症状变化。次要结局包括胃肠道转运时间和心血管自主功能。

结果：68 名参与者被随机分配到活性组，77 名参与者被随机分配到假刺激组。在研究期 1 中，63 名参与者在活性组和 68 名参与者在假刺激组中进行了分析，在研究期 2 中，每组各有 62 名参与者进行了分析。在研究期 1 中，活性和假 tVNS 引起的症状减轻相似（GCSI：-0.26±0.64 与-0.17±0.62，p=0.44；GSRS：-0.35±0.62 与-0.32±0.59，p=0.77；均值±SD）。在研究期 2 中，活性刺激也引起了可与假刺激后观察到的症状降低相当的平均症状减轻（GCSI：-0.47±0.78 与-0.33±0.75，p=0.34；GSRS：-0.46±0.90 与-0.35±0.79，p=0.50）。与假刺激相比，活性组的胃排空时间增加（23 分钟比-19 分钟，p=0.04）。肠道转运时间和心血管自主神经测量在治疗组之间没有差异（均 p>0.05）。tVNS 耐受性良好。

结论/解释：与假刺激相比，颈椎 tVNS 并不能改善糖尿病伴自主神经病变患者的胃肠道症状。

试验注册：ClinicalTrials.gov NCT04143269 基金：该研究由诺和诺德基金会（资助编号 NNF180C0052045）资助。