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

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.

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.

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.

Central Figure. The image shows the continuum of cardiomyopathies phenotypes across a spectrum ranging from dilated to hypertrophic cardiomyopathy. Phenotype expression is determined by genetic and metabolic modulators, such as obesity, diabetes mellitus and chronic kidney dysfunction that present converging pathways associated to altered bioenergetics, chronic inflammation, and increased myocardial fibrosis. These modulators interact dynamically to determine the clinical phenotype, disease progression, and response to therapy. At the bottom, emerging drugs, including angiotensin receptor-neprilysin inhibitors (ARNi), sodium–glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA) and non-steroidal mineralocorticoid receptor antagonists (ns-MRA), that showed potential reverse-remodelling activity thanks to anti-fibrotic, anti-inflammatory and metabolic balancing effects. Anti-arrhythmic and epigenetic effects are under investigation. Collectively, the figure underscores the multidimensional nature of cardiomyopathies and the need for integrated, mechanism-based treatment approaches targeting the cardiorenal–metabolic axis. Created in BioRender. Guarnaccia, A. (2025) https://BioRender.com/myirj71.

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