Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective antidiabetic drugs with potential cardiovascular benefits. Despite their well-established role in reducing the risk of major adverse cardiovascular events (MACE), their impact on heart failure (HF) remains unclear. Therefore, our study examined the cardioprotective effects of tirzepatide (TZT), a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist. A three-steps approach was designed: (i) Meta-analysis investigation with the primary objective of assessing major adverse cardiovascular events (MACE) occurrence from major randomized clinical trials.; (ii) TZT effects on a human cardiac AC16 cell line exposed to normal (5 mM) and high (33 mM) glucose concentrations for 7 days. The gene expression and protein levels of primary markers related to cardiac fibrosis, hypertrophy, and calcium modulation were evaluated. (iii) In silico data from bioinformatic analyses for generating an interaction map that delineates the potential mechanism of action of TZT. Meta-analysis showed a reduced risk for MACE events by TZT therapy (HR was 0.59 (95% CI 0.40–0.79, Heterogeneity: r2 = 0.01, I2 = 23.45%, H2 = 1.31). In the human AC16 cardiac cell line treatment with 100 nM TZT contrasted high glucose (HG) levels increase in the expression of markers associated with fibrosis, hypertrophy, and cell death (p < 0.05 for all investigated markers). Bioinformatics analysis confirmed the interaction between the analyzed markers and the associated pathways found in AC16 cells by which TZT affects apoptosis, fibrosis, and contractility, thus reducing the risk of heart failure. Our findings indicate that TZT has beneficial effects on cardiac cells by positively modulating cardiomyocyte death, fibrosis, and hypertrophy in the presence of high glucose concentrations. This suggests that TZT may reduce the risk of diabetes-related cardiac damage, highlighting its potential as a therapeutic option for heart failure management clinical trials. Our study strongly supports the rationale behind the clinical trials currently underway, the results of which will be further investigated to gain insights into the cardiovascular safety and efficacy of TZT.

中文翻译：

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有证据表明替西帕肽可预防糖尿病相关的心脏损害

胰高血糖素样肽 1 受体激动剂 (GLP-1RA) 是有效的抗糖尿病药物，具有潜在的心血管益处。尽管它们在降低主要不良心血管事件 (MACE) 风险方面具有明确的作用，但它们对心力衰竭 (HF) 的影响仍不清楚。因此，我们的研究检查了替西帕肽 (TZT) 的心脏保护作用，替西帕肽是一种新型葡萄糖依赖性促胰岛素多肽 (GIP) 和胰高血糖素样肽 1 (GLP-1) 受体激动剂。设计了一个三步法：（i）荟萃分析调查，主要目的是评估主要随机临床试验中主要不良心血管事件（MACE）的发生情况。 (ii) TZT 对暴露于正常 (5 mM) 和高 (33 mM) 葡萄糖浓度 7 天的人心脏 AC16 细胞系的影响。评估与心脏纤维化、肥大和钙调节相关的主要标志物的基因表达和蛋白质水平。 (iii) 来自生物信息学分析的计算机数据，用于生成描绘 TZT 潜在作用机制的相互作用图。荟萃分析显示，TZT 疗法可降低 MACE 事件的风险（HR 为 0.59（95% CI 0.40–0.79，异质性：r2 = 0.01，I2 = 23.45%，H2 = 1.31）。在人类 AC16 心脏细胞系治疗中， 100 nM TZT 对比高葡萄糖 (HG) 水平，与纤维化、肥大和细胞死亡相关的标记物的表达增加（所有研究标记物的 p < 0.05）。生物信息学分析证实了分析的标记物与在中发现的相关途径之间的相互作用。 TZT 影响 AC16 细胞凋亡、纤维化和收缩性，从而降低心力衰竭的风险。我们的研究结果表明，TZT 在高葡萄糖浓度下积极调节心肌细胞死亡、纤维化和肥大，从而对心肌细胞产生有益影响。这表明 TZT 可以降低糖尿病相关心脏损伤的风险，凸显其作为心力衰竭管理临床试验的治疗选择的潜力。我们的研究强烈支持目前正在进行的临床试验背后的基本原理，其结果将得到进一步研究深入了解 TZT 的心血管安全性和有效性。