Metabolic Modulation in Hypertrophic Cardiomyopathy: A Systematic Review of Clinical and Observational Evidence

Background: Hypertrophic cardiomyopathy (HCM) is characterised by left ventricular hypertrophy, microvascular dysfunction and chronic energetic inefficiency. Current therapies relieve symptoms or left ventricular outflow tract obstruction but do not directly target these metabolic abnormalities. Methods: We systematically searched PubMed, Embase, Google Scholar and ClinicalTrials.gov from 1 January 2000 to 31 May 2025 for randomised trials, observational cohorts, registries and case series (≥3 patients) evaluating fatty acid oxidation inhibitors (perhexiline, trimetazidine), late sodium current inhibition (ranolazine) or sodium–glucose cotransporter 2 inhibitors (SGLT2I) in adults with HCM. Outcomes included exercise capacity, diastolic indices, symptoms, arrhythmia burden and safety. Results: Seven HCM-specific studies met inclusion criteria: trimetazidine (one randomised controlled trial [RCT]), perhexiline (one RCT), ranolazine (one RCT, one real-world cohort and one case series) and SGLT2I (one prospective controlled cohort, one nationwide registry). Most enrolled predominantly non-obstructive or mixed HCM. Trimetazidine had neutral effects on peak VO₂, diastolic function and biomarkers. Perhexiline improved phosphocreatine-to-adenosine triphosphate ratios, diastolic indices, peak VO₂ and New York Heart Association class. Ranolazine consistently reduced angina and ventricular ectopy but did not increase peak VO₂. In the included HCM studies, empagliflozin/dapagliflozin exposure in a small prospective cohort was associated with improved E/e′ and New York Heart Association class, while broader SGLT2I use in a diabetic HCM registry was associated with lower mortality and hospitalisation for heart failure. Conclusion: Metabolic modulators and SGLT2I could improve diastolic parameters, symptoms and arrhythmia burden in selected, mainly non-obstructive HCM populations but have not demonstrated consistent gains in exercise capacity. Larger, phenotype-stratified randomised trials are needed to define their role alongside contemporary HCM therapies.