Abstract
AIMS: Hyperglycaemic conditions increase cardiac stress, a common phenomenon associated with inflammation, aging, and metabolic imbalance. Sodium-glucose cotransporter 2 inhibitors, a class of anti-diabetic drugs, showed to improve cardiovascular functions although their mechanism of action has not yet been fully established. This study investigated the effects of empagliflozin on cardiomyocytes following high glucose exposure, specifically focusing on inflammatory and metabolic responses. METHODS AND RESULTS: A three-part strategy was formulated: (i) a meta-analysis of selected randomized clinical trials was carried out to assess the anti-inflammatory effects of empagliflozin in diabetic patients; (ii) the impact of empagliflozin on human cardiomyocyte AC16 cells exposed to normal (5 mM) and high (33 mM) glucose concentrations for 2 and 7 days was explored by evaluating gene expression and protein levels of pivotal markers associated with cardiac inflammation, stress, endoplasmic reticulum damage, and calcium modulation; (iii) in silico data from bioinformatic analyses were exploited to construct an interaction map delineating the potential mechanism of action of empagliflozin on cardiac tissue. Empagliflozin reversed high-glucose mediated alterations at the transcriptional level, decreasing inflammatory, metabolic, and aging signatures. Specifically, in vitro experiments on human cardiomyocytes, meta-analyses of clinical data on inflammatory biomarkers from diabetic peripheral blood samples, and sequencing of pathological human heart tissues, all support that empagliflozin exerts anti-inflammatory effects both systemically and directly in cardiac tissue, on cardiomyocytes. CONCLUSION: Our study provides insights based on robust mechanistic data for optimizing heart failure management and highlights the intricate interplay between diabetes, inflammation, aging, and cardiovascular health.