Cardiorenal and Metabolic Dimensions of Cardiomyopathies and Heart Failure: Focus on SGLT2i, GLP1-RA, and ns-MRA

Purpose of the Review: Metabolic disorders represent a growing epidemiological and clinical challenge, associated with worsening prognosis of cardiovascular disease. These conditions cluster in patients with heart failure and cardiomyopathies, limiting therapeutic options. Although cardiomyopathies contribute substantially to the burden of heart failure, the impact of metabolic disorders on their progression remains underexplored. This review explores the complex cardiorenal and metabolic dimensions of cardiomyopathies, focusing on pathophysiological mechanisms, therapeutic innovations, and future organizational models. Recent Findings: Metabolic disorders likely modulate genotype-phenotype expression, aggravate myocardial dysfunction, and accelerate disease progression through converging molecular mechanisms and pathways leading to energetic imbalance, inflammation and fibrosis. Novel therapies act on these pathways favouring microscopic and macroscopic reverse remodelling. A holistic and multidisciplinary approach is required to select appropriate therapies, improve disease progression and quality of life of these patients. Summary: Cardiomyopathies exemplify the complexity of heart failure, where genetic and metabolic dysfunctions coexist and act as both triggers and amplifiers of myocardial damage. DCM, HCM, HCM phenocopies and ARVC all present the burden of metabolic disorders and some of them benefit from novel therapies. SGLT2i, GLP1-RA, and non-steroidal MRA represent the forefront of a new therapeutic era, aiming at pleiotropic targets beyond neurohormonal blockade. Integrated care models will reshape disease management and improve patients’ outcomes. Future research should investigate on metabolic disorders prevalence in cardiomyopathies and better characterize molecular pathways and phenotypic profiles that mostly benefit from novel therapies.