Handford Carla, Stirling-Barros Laura, Ganji-Arjenaki Mahboube, Mahmod Masliza, Nazarzadeh Milad, Wamil Malgorzata
Green Templeton College, University of Oxford, Oxford OX2 6HG, UK.
Department of Medical Bioinformatics, School of Advanced Technologies, Shahrekord University of Medical Sciences, Shahrekord 9W47+P62, Iran.
Biomedicines. 2025 Aug 26;13(9):2080. doi: 10.3390/biomedicines13092080.
Heart failure (HF) is associated with high morbidity, mortality, and healthcare costs. Its prevalence continues to rise, particularly in the context of ageing populations and increasing rates of metabolic comorbidities such as type 2 diabetes and obesity. We aimed to assess the therapeutic potential of repurposing PPARα agonists for the treatment of HF. We conducted a comprehensive literature review to evaluate preclinical and clinical evidence investigating the potential of PPARα agonist drugs in reducing HF. We did not apply any restrictions on the study design. The current body of evidence consists of preclinical mechanistic studies, emerging pharmacogenetic data, and post hoc analyses of large randomised clinical trials (RCTs) that included HF endpoints. No dedicated, HF-specific RCTs of PPARα agonists were identified. These studies support the hypothesis that PPARα agonists may link metabolic modulation with cardiac remodelling. Preclinical models demonstrate potential therapeutic benefits, such as enhanced myocardial energy metabolism and attenuation of fibrosis and inflammation, as well as context-dependent risks, including possible deleterious effects in advanced HF or off-target mechanisms. Prior failures of fibrates to improve cardiovascular outcomes in some trials and concerns in PPARα-deficient states underscore the complexity of metabolic therapies in HF. These findings support a more stratified, phenotype-driven approach to therapy. RCTs specifically designed to evaluate HF outcomes are essential to clarify whether PPARα agonists can complement established neurohormonal treatments, particularly in the context of the rising burden of HFpEF associated with obesity and type 2 diabetes. PPARα agonists represent a promising class within the emerging therapeutic framework of metabolic heart failure. They are inexpensive, generally well tolerated, and address several pathophysiological mechanisms of HF. Preliminary evidence suggests that fenofibrate may delay or prevent HF in high-risk diabetic populations. However, rigorous, dedicated trials are needed to establish their clinical utility.
心力衰竭（HF）与高发病率、高死亡率及高昂的医疗费用相关。其患病率持续上升，尤其是在人口老龄化以及2型糖尿病和肥胖等代谢合并症发病率不断增加的背景下。我们旨在评估重新利用过氧化物酶体增殖物激活受体α（PPARα）激动剂治疗HF的潜力。我们进行了一项全面的文献综述，以评估临床前和临床证据，这些证据研究了PPARα激动剂药物在降低HF方面的潜力。我们对研究设计未作任何限制。目前的证据包括临床前机制研究、新出现的药物遗传学数据以及对包含HF终点的大型随机临床试验（RCT）的事后分析。未发现专门针对PPARα激动剂的HF特异性RCT。这些研究支持了PPARα激动剂可能将代谢调节与心脏重塑联系起来的假设。临床前模型显示出潜在的治疗益处，如增强心肌能量代谢以及减轻纤维化和炎症，同时也存在与背景相关的风险，包括在晚期HF中可能产生的有害影响或脱靶机制。在一些试验中贝特类药物未能改善心血管结局，以及对PPARα缺陷状态的担忧，凸显了HF代谢疗法的复杂性。这些发现支持采用更分层、以表型为导向的治疗方法。专门设计用于评估HF结局的RCT对于阐明PPARα激动剂是否可以补充既定的神经激素治疗至关重要，特别是在与肥胖和2型糖尿病相关的射血分数保留的HF（HFpEF）负担不断增加的背景下。PPARα激动剂在新兴的代谢性心力衰竭治疗框架中是一个有前景的类别。它们价格低廉，通常耐受性良好，并且能解决HF的多种病理生理机制。初步证据表明非诺贝特可能延缓或预防高危糖尿病人群发生HF。然而，需要进行严格的、专门的试验来确定它们的临床效用。
