Cinti Francesca, Laborante Renzo, Cappannoli Luigi, Morciano Cassandra, Gugliandolo Shawn, Pontecorvi Alfredo, Burzotta Francesco, Donniacuo Maria, Cappetta Donato, Patti Giuseppe, Giaccari Andrea, D'Amario Domenico
Centro Malattie Endocrine e Metaboliche, Dipartimento di Scienze Mediche e Chirurgiche, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy.
Dipartimento di Scienze Cardiovascolari- CUORE, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
Cardiovasc Diabetol. 2025 May 14;24(1):208. doi: 10.1186/s12933-025-02767-9.
The rising prevalence of Type 2 diabetes (T2D) has been closely associated with an increased incidence of cardiovascular diseases, particularly heart failure with preserved ejection fraction (HFpEF). Cardiometabolic disturbances in T2D, such as insulin resistance, hyperglycemia, and dyslipidemia, contribute to both microvascular and macrovascular complications, thereby intensifying the risk of heart failure. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), initially developed as glucose-lowering agents for T2D, have demonstrated promising cardiovascular benefits in patients with heart failure, including those with preserved ejection fraction (HFpEF), regardless of T2D status. These benefits include reduced heart failure hospitalization rates and improvements in various metabolic parameters. This review aims to critically examine the effects of SGLT2i on cardiac metabolism in HFpEF, evaluating whether the observed benefits can truly be attributed to their impact on myocardial energy regulation or whether they represent other, potentially confounding, mechanisms. We will focus on the key metabolic processes possibly modulated by SGLT2i, including myocardial glucose utilization, fatty acid oxidation, and mitochondrial function, and explore their effects on heart failure pathophysiology. Additionally, we will address the role of SGLT2i in other pathogenetic factors involved in HFpEF, such as sodium and fluid balance, inflammation, and fibrosis, and question the extent to which these mechanisms contribute to the observed clinical benefits. By synthesizing the current evidence, this review will provide an in-depth analysis of the mechanisms through which SGLT2i may influence cardiac metabolism in HFpEF, assessing whether their effects are supported by robust scientific data or remain speculative. We will also discuss the potential for personalized treatment strategies, based on individual patient characteristics, to optimize the therapeutic benefits of SGLT2i in managing both T2D and cardiovascular risk. This review seeks to clarify the true clinical utility of SGLT2i in the management of cardiometabolic diseases and HFpEF, offering insights into their role in improving long-term cardiovascular outcomes.
2型糖尿病（T2D）患病率的上升与心血管疾病发病率的增加密切相关，尤其是射血分数保留的心力衰竭（HFpEF）。T2D中的心脏代谢紊乱，如胰岛素抵抗、高血糖和血脂异常，会导致微血管和大血管并发症，从而增加心力衰竭的风险。钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）最初是作为T2D的降糖药物开发的，已在心力衰竭患者中显示出有前景的心血管益处，包括射血分数保留的患者（HFpEF），无论其T2D状态如何。这些益处包括降低心力衰竭住院率和改善各种代谢参数。本综述旨在批判性地研究SGLT2i对HFpEF心脏代谢的影响，评估观察到的益处是否真的可归因于它们对心肌能量调节的影响，或者它们是否代表其他潜在的混杂机制。我们将关注可能由SGLT2i调节的关键代谢过程，包括心肌葡萄糖利用、脂肪酸氧化和线粒体功能，并探讨它们对心力衰竭病理生理学的影响。此外，我们将讨论SGLT2i在HFpEF涉及的其他致病因素中的作用，如钠和液体平衡、炎症和纤维化，并质疑这些机制在多大程度上促成了观察到的临床益处。通过综合现有证据，本综述将深入分析SGLT2i可能影响HFpEF心脏代谢的机制，评估其效果是否有可靠的科学数据支持或仍属推测。我们还将讨论基于个体患者特征的个性化治疗策略的潜力，以优化SGLT2i在管理T2D和心血管风险方面的治疗益处。本综述旨在阐明SGLT2i在心脏代谢疾病和HFpEF管理中的真正临床效用，深入了解它们在改善长期心血管结局中的作用。
