Canagliflozin Orchestrates the Hepato-Cardiac Protection Axis via Upregulation of Liver-Derived FGF21: A Study in Mice and a Randomized Controlled Trial

Background Canagliflozin (CANA), an SGLT2 inhibitor, offers cardiometabolic benefits ; however, the role of Fibroblast Growth Factor 21 (FGF21) in its protective mechanism against obesity-related organ injury remains unclear. We investigated whether CANA mitigates cardiac and hepatic injury via FGF21 modulation. Methods Male C57BL/6J mice were randomized to receive either a high-fat diet (HFD) or normal diet, with or without canagliflozin (CANA) administration, for 8 weeks. In vitro, H9c2 cardiomyocytes subjected to lipotoxic stress were treated with recombinant FGF21. To assess clinical translation, 41 patients with T2DM were enrolled in a randomized controlled trial receiving either CANA or standard care for 4 weeks. Statistical significance was assessed using ANOVA or t -tests as appropriate. Results In HFD mice, CANA attenuated body weight, hepatic steatosis, and cardiac fibrosis. Mechanistically, this was associated with upregulated hepatic and circulating FGF21, activated p38/Akt signaling, and reduced cardiomyocyte apoptosis. In vitro, FGF21 suppressed lipotoxicity-induced caspase-3 activation. Clinically, 4-week CANA treatment improved MRI-derived liver fibrosis scores and metabolic markers (ALT, GGT, and ferritin); however, circulating FGF21 levels remained unchanged in this patient cohort. Conclusions CANA alleviates obesity-associated hepatic and cardiac injury in mice and humans. While experimental data identify an FGF21/p38/Akt signaling axis as a key driver of anti-apoptotic and anti-fibrotic effects, the clinical benefits occurred independent of systemic FGF21 elevation. These findings support CANA’s therapeutic potential in targeting the cardio-hepatic-metabolic axis. Trial registration ClinicalTrials.gov, NCT05764811. Registered January 26, 2023.