OBJECTIVE There is substantial interest in how GLP-1RA (glucagon-like peptide-1 receptor agonists) and SGLT2 (sodium-glucose cotransporter 2) inhibitors reduce cardiovascular and renal events; yet, robust mechanistic data in humans remain sparse. We conducted a narrative review of published and ongoing mechanistic clinical trials investigating the actions of SGLT2 inhibitors and GLP-1RAs to help the community appreciate the extent of ongoing work and the variety and design of such trials. Approach and Results: To date, trials investigating the mechanisms of action of SGLT2 inhibitors have focused on pathways linked to glucose metabolism and toxicity, hemodynamic/volume, vascular and renal actions, and cardiac effects, including those on myocardial energetics. The participants studied have included those with established cardiovascular disease (including coronary artery disease and heart failure), liver disease, renal impairment, obesity, and hypertension; some of these trials have enrolled patients both with and without type 2 diabetes mellitus. GLP-1RA mechanistic trials have focused on glucose-lowering, insulin-sparing, weight reduction, and blood pressure-lowering effects, as well as possible direct vascular, cardiac, and renal effects of these agents. Very few mechanisms of action of SGLT2 inhibitors or GLP-1RAs have so far been convincingly demonstrated. One small trial (n=97) of SGLT2 inhibitors has investigated the cardiac effects of these drugs, where a small reduction in left ventricular mass was found. Data on vascular effects are limited to one trial in type 1 diabetes mellitus, which suggests some beneficial actions. SGLT2 inhibitors have been shown to reduce liver fat. We highlight the near absence of mechanistic data to explain the beneficial effects of SGLT2 inhibitors in patients without diabetes mellitus. GLP-1RAs have not been found to have major cardiovascular mechanisms of action in the limited, completed trials. Conflicting data around the impact on infarct size have been reported. No effect on left ventricular ejection fraction has been demonstrated. CONCLUSIONS We have tabulated the extensive ongoing mechanistic trials that will report over the coming years. We report 2 exemplar ongoing mechanistic trials in detail to give examples of the designs and techniques employed. The results of these many ongoing trials should help us understand how SGLT2 inhibitors and GLP-1RAs improve cardiovascular and renal outcomes and may also identify unexpected mechanisms suggesting novel therapeutic applications.

中文翻译：

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SGLT2（钠葡萄糖共转运蛋白2）抑制剂和GLP-1（胰高血糖素样肽1）受体激动剂如何减少心血管疾病的结果？：正在进行的机械试验。

目的人们对GLP-1RA（胰高血糖素样肽1受体激动剂）和SGLT2（钠-葡萄糖共转运蛋白2）抑制剂如何减少心血管和肾脏事件产生了浓厚兴趣。然而，人类中强大的机械数据仍然很少。我们对已发表和正在进行的机制性临床试验进行了叙述性综述，以研究SGLT2抑制剂和GLP-1RA的作用，以帮助社区了解正在进行的工作的范围以及此类试验的多样性和设计。方法和结果：迄今为止，研究SGLT2抑制剂作用机理的试验都集中在与葡萄糖代谢和毒性，血液动力学/容量，血管和肾脏作用以及心脏影响有关的途径，包括对心肌能量的影响。研究对象包括患有心血管疾病（包括冠状动脉疾病和心力衰竭），肝病，肾功能不全，肥胖和高血压的人；其中一些试验招募了患有和不患有2型糖尿病的患者。GLP-1RA机制试验的重点是降低葡萄糖，降低胰岛素，减轻体重和降低血压的作用，以及这些药物可能对血管，心脏和肾脏的直接作用。迄今为止，几乎没有令人信服的方法证明了SGLT2抑制剂或GLP-1RA的作用机理。一项SGLT2抑制剂的小型试验（n = 97）研究了这些药物的心脏作用，发现左心室质量有少量降低。血管效应的数据仅限于1型糖尿病的一项试验，这表明了一些有益的行动。SGLT2抑制剂已显示可减少肝脏脂肪。我们强调了几乎没有机理数据来解释SGLT2抑制剂对无糖尿病患者的有益作用。在有限的完整试验中，尚未发现GLP-1RA具有主要的心血管作用机制。据报道，对梗塞面积的影响存在矛盾的数据。没有证明对左心室射血分数的影响。结论我们已经列出了将在未来几年报告的广泛的正在进行的机械试验。我们将详细报告2个示例性正在进行的机械试验，以提供所用设计和技术的示例。