Baseline monocyte GIP receptor mRNA expression is associated with reductions in body weight and FIB-4 index after switching to tirzepatide in patients with type 2 diabetes

Abstract Background Tirzepatide improves body weight and glycemic control in patients with type 2 diabetes, but factors associated with inter-individual differences after switching remain unclear. We examined whether baseline monocyte glucose-dependent insulinotropic polypeptide receptor (GIPR) mRNA expression was associated with changes in body weight and the fibrosis-4 (FIB-4) index after switching from glucagon-like peptide−1 receptor agonists (GLP-1RAs) to tirzepatide. Methods This single-center retrospective study included 90 patients with type 2 diabetes who had received a GLP-1RA for at least 6 months before switching. Baseline monocyte GIPR mRNA expression was measured by quantitative real-time polymerase chain reaction. Associations with percentage body-weight change and FIB-4 index change during the 6 months after tirzepatide initiation were assessed by correlation and multivariable regression. Exploratory ex vivo assays were performed to assess monocyte responses to native GIP. Results Higher baseline monocyte GIPR mRNA expression was associated with greater reductions in body weight and the FIB-4 index and remained significant in multivariable models. The association with the FIB-4 index remained significant after additional adjustment for percentage body-weight change at 6 months after tirzepatide initiation. GIPR mRNA expression was not associated with body-weight change during the preceding 6 months of GLP-1RA therapy. Native GIP suppressed lipopolysaccharide-induced interleukin-6 and tumor necrosis factor-alpha responses in monocytes. Conclusions Baseline monocyte GIPR mRNA expression was associated with body-weight and FIB-4 index reductions after switching to tirzepatide. It may represent an exploratory marker of clinical changes, but treatment specificity, causal GIPR-dependent mechanisms, and structural liver fibrosis regression were not established. Graphical abstract Summary of the study design and main finding. Baseline GIPR mRNA expression in peripheral blood monocytes was associated with reductions in body weight and the FIB-4 index after switching to tirzepatide in patients with type 2 diabetes. In exploratory ex vivo assays, native GIP suppressed LPS-induced inflammatory responses, supporting monocyte GIPR expression as a candidate exploratory marker requiring further validation.