Glucagon-like peptide-1 receptor agonist-induced lipidome remodelling is associated with improved liver, kidney and inflammatory markers in type 2 diabetes

Introduction: Lipids are considered both drivers and biomarkers of cardiometabolic diseases. As glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for diabetes and obesity management, it is crucial to understand how they affect the related comorbidities through the circulating lipidome. This study investigated the lipidomic changes induced by liraglutide treatment when compared to placebo in people with type 2 diabetes (T2D) to characterise lipid remodelling and its association with clinical outcomes. Research design and methods: This post-hoc study analysed plasma samples using liquid chromatography-mass spectrometry (LC-MS/MS) from LIRAFLAME, a randomised, double-blind, placebo-controlled, parallel-group trial. A hundred people with T2D received up to 1.8 mg of liraglutide or placebo once daily for 26 weeks. Plasma samples were collected at baseline, week 13 and week 26. Results: Liraglutide treatment resulted in a statistically significant increase in multiple lysophospholipid subclasses, including LPCs, LPC(O)s, LPC(P)s, LPEs, and LPE(P)s, observed at 13 weeks and sustained at 26 weeks compared to placebo. These increases were not mediated by the change in BMI. Triglyceride concentrations decreased at 13 weeks, while fatty acid levels declined at 26 weeks, consistent with enhanced lipid remodelling. The increase in LPC(O)s was associated with favourable decreases in ALAT, MCP-1, and UACR, suggesting anti-inflammatory effects with hepatic, renal, and cardiovascular benefits. Conclusions: Compared to placebo, 26 weeks of liraglutide treatment resulted in a favourable lipidomic shift from a triglyceride-rich profile towards one enriched in lysophospholipids. This lipid remodelling was associated with improvements in hepatic, renal, and inflammatory markers.