Canagliflozin Possible Roles: A Potential Antifibrotic Agent in Diabetic Idiopathic Pulmonary Fibrosis in comparison with Metformin

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease characterized by extensive fibrosis, leading to respiratory failure and significant mortality. The disease pathogenesis remains poorly understood, but evidence suggests that diabetes mellitus (DM), particularly type 2 diabetes, may exacerbate IPF progression through hyperglycemia-induced oxidative stress, chronic inflammation, and profibrotic signaling pathways. The increasing prevalence of both DM and IPF underscores the urgent need for novel therapeutic strategies targeting overlapping mechanisms of these diseases. Recent studies suggest that metformin has beneficial role as antifibrotic agent in IPF, also certain antidiabetic agent particularly canagliflozin, may exhibit antifibrotic properties beyond its glucose-lowering effects. Canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, has shown potential in reducing inflammation, oxidative stress, and fibrosis in various organ systems, including the kidneys and heart. Its ability to modulate transforming growth factor-beta (TGF-β) and nuclear factor-kappa B (NF-κB) pathways may contribute to its antifibrotic effects. Similarly, metformin, a widely used biguanide, has demonstrated pleiotropic benefits, including antifibrotic properties through activation of AMP-activated protein kinase (AMPK). AMPK activation downregulates TGF-β and connective tissue growth factor (CTGF), both critical mediators of fibrotic processes. Emerging preclinical studies suggest that Canagliflozin may attenuate fibrotic changes in experimental models of lung fibrosis, providing a rationale for its exploration in IPF management. This review highlights the dual benefits of canagliflozin and metformin in the context of DM and IPF, focusing on their antifibrotic mechanisms. We discuss preclinical and clinical evidence, mechanisms underlying fibrosis modulation, and their translational potential in IPF therapy. Additionally, the review explores the safety profile and possible synergistic effects of combining these agents. While promising, the current evidence is preliminary, necessitating robust clinical trials to establish Canagliflozin efficacy and safety in IPF. The therapeutic repurposing of these antidiabetic drugs offers a novel avenue to address the unmet needs of patients with diabetic IPF, providing hope for a disease with limited treatment options.