AIMS/HYPOTHESIS Praliciguat (IW-1973), a soluble guanylate cyclase stimulator, amplifies nitric oxide signalling. This exploratory trial investigated the safety, tolerability, pharmacokinetic profile and pharmacodynamic effects of praliciguat in individuals with type 2 diabetes and hypertension. METHODS This Phase IIA, double-blind, placebo-controlled trial investigated praliciguat in 26 participants with type 2 diabetes and hypertension on stable glucose- and BP-lowering therapies. Participants were randomly allocated in a 3:5:5 ratio to three groups: placebo (n = 6), praliciguat 40 mg once daily for days 1-14 (n = 10), or praliciguat 20 mg twice daily for days 1-7 then 40 mg once daily for days 8-14 (n = 10). Assessments were made in clinic and included treatment-emergent adverse events, pharmacokinetics, metabolic variables, 24 h BP and heart rate, platelet function, reactive hyperaemia index (RHI) and plasma biomarkers. Participants, the sponsor, the investigator and clinic study staff (except designated pharmacy personnel) were blinded to group assignment. RESULTS Participants treated for 14 days with praliciguat had least-square mean change-from-baseline differences vs placebo (95% CI) of -0.7 (-1.8, 0.4) mmol/l for fasting plasma glucose, -0.7 (-1.1, -0.2) mmol/l for total cholesterol, -0.5 (-1.0, -0.1) mmol/l for LDL-cholesterol, -23 (-56, 9) for HOMA-IR in those not being treated with insulin, and -5 (-10, 1) mmHg and 3 (-1, 6) beats/min for average 24 h mean arterial pressure and heart rate, respectively. Apart from one serious adverse event (SAE; upper gastrointestinal haemorrhage), praliciguat was well tolerated. Praliciguat did not affect platelet function or RHI. Among exploratory biomarkers, plasma levels of asymmetric dimethylarginine decreased in praliciguat vs placebo recipients. CONCLUSIONS/INTERPRETATION In participants with type 2 diabetes and hypertension on standard therapies, over 14 days praliciguat was well tolerated, except for a single SAE, and showed positive trends in metabolic and BP variables. These results support further clinical investigation of praliciguat. TRIAL REGISTRATION ClinicalTrials.gov NCT03091920. FUNDING This trial was funded by Cyclerion Therapeutics.

中文翻译：

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一项针对2型糖尿病和高血压患者的可溶性鸟苷酸环化酶刺激剂praliciguat的探索性，随机，安慰剂对照，14天试验。

目的/假说Praliciguat（IW-1973）是一种可溶性鸟苷酸环化酶刺激剂，可放大一氧化氮信号。这项探索性试验研究了帕拉西瓜对2型糖尿病和高血压患者的安全性，耐受性，药代动力学特征和药效学作用。方法该IIA期双盲，安慰剂对照试验研究了26名2型糖尿病和高血压参与者的帕拉西卡特，采用稳定的降糖和降压疗法。参与者以3：5：5的比例随机分为三组：安慰剂（n = 6），普拉利瓜40 mg每天一次，持续1-14天（n = 10），或普拉利瓜20 mg每天两次，持续1-7天。然后每天一次40毫克，持续8-14天（n = 10）。在临床中进行评估，包括治疗紧急不良事件，药代动力学，代谢变量，24小时血压和心率，血小板功能，反应性充血指数（RHI）和血浆生物标志物。参与者，申办者，研究者和临床研究人员（指定药房人员除外）对小组分配不知情。结果：对于接受禁食的血浆葡萄糖治疗的14天参与者，与安慰剂（95％CI）相比，空腹血糖为-0.7（-1.8，0.4）mmol / l，与基线相比的最小平方平均差异为-0.7（-1.1，-对于未经胰岛素治疗的患者，总胆固醇为0.2）mmol / l，LDL-胆固醇为-0.5（-1.0，-0.1）mmol / l，HOMA-IR为-23（-56，9），而-5（平均24小时平均动脉压和心率分别为-10、1）mmHg和3（-1、6）次/分钟。除了一种严重的不良事件（SAE；上消化道出血），对拉西瓜的耐受性良好。Praliciguat不影响血小板功能或RHI。在探索性生物标志物中，拉西瓜与安慰剂接受者的血浆不对称二甲基精氨酸水平降低。结论/解释在接受标准疗法的2型糖尿病和高血压患者中，除单一SAE外，对praliciguat的耐受性良好，超过14天，并且在代谢和BP变量方面呈阳性趋势。这些结果支持进一步的扑热息痛的临床研究。试验注册ClinicalTrials.gov NCT03091920。资助该试验由Cyclerion Therapeutics资助。在14天内，除单一SAE外，对praliciguat的耐受性良好，并且在代谢和BP变量方面显示出积极的趋势。这些结果支持进一步的帕拉利瓜临床研究。试验注册ClinicalTrials.gov NCT03091920。资助该试验由Cyclerion Therapeutics资助。在14天内，除单一SAE外，对praliciguat的耐受性良好，并且在代谢和BP变量方面显示出积极的趋势。这些结果支持进一步的扑热息痛的临床研究。试验注册ClinicalTrials.gov NCT03091920。资助该试验由Cyclerion Therapeutics资助。