Incretin-Based Therapies and Pulmonary Fibrosis: Preclinical Evidence, Body Composition, and Translational Perspectives: A Narrative Review

Pulmonary fibrosis comprises a heterogeneous group of interstitial lung diseases characterized by progressive extracellular matrix deposition and structural remodeling. Although currently available antifibrotic therapies can slow disease progression, additional biological pathways remain under investigation. Incretin-based therapies, including glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, have attracted increasing interest because their biological effects extend beyond glucose regulation and may involve pathways relevant to pulmonary fibrogenesis. Preclinical studies suggest that incretin-related pathways may modulate transforming growth factor-β signaling, fibroblast activation, extracellular matrix deposition, mesenchymal transition, inflammation, oxidative stress, and metabolic mechanisms involved in fibrosis. However, these findings remain predominantly experimental, and evidence of antifibrotic efficacy in patients with fibrotic interstitial lung disease is currently lacking. A complementary aspect is represented by the profound effects of incretin-based therapies on body weight and composition. This is particularly relevant in pulmonary fibrosis, where excess adiposity may contribute to metabolic and functional burden, whereas low body mass index, unintentional weight loss, and skeletal muscle depletion are associated with adverse outcomes. Incretin-induced weight loss predominantly reflects reduction in adipose tissue, but is accompanied by variable reductions in lean or fat-free mass, whose implications for skeletal muscle and functional reserve remain incompletely defined. This narrative review integrates current preclinical evidence on the potential antifibrotic effects of incretin-related pathways with clinical evidence on body weight, adiposity, and skeletal muscle in pulmonary fibrosis. Future clinical and translational studies are required to determine whether the potential pulmonary and metabolic effects of incretin-based therapies translate into meaningful clinical benefits in fibrotic interstitial lung disease.