Targeting Cardiac Metabolism in Heart Failure with PPARα Agonists: A Review of Preclinical and Clinical Evidence.

Background and objective: 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. Method: 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. Results: 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. Conclusions: 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.