Pirro V, Roth KD, Lin Y, et al. - Individuals with type 2 diabetes (T2D) show substantially reduced HbA1c and body weight on receiving tirzepatide when compared with receiving the GLP-1 receptor agonist dulaglutide. As per findings from this study, tirzepatide results in reduction in body weight and improvement in glycemic control and unique modulation of metabolites linked with T2D risk and metabolic dysregulation in a direction consistent with improved metabolic health.

• Phase 2b trial was performed including 259 individuals with T2D and these were randomly assigned to receive weekly subcutaneous tirzepatide, dulaglutide, or placebo for 26 weeks.

• Post hoc exploratory metabolomics and lipidomics analyses revealed modulation of a cluster of metabolites and lipids associated with IR, obesity, and future T2D risk, at 26 weeks in correlation with receiving higher dose tirzepatide.

• There was a reduction in branched-chain amino acids, direct catabolic products glutamate, 3-hydroxyisobutyrate, branched-chain ketoacids, and indirect byproducts like 2-hydroxybutyrate when compared with baseline and placebo.

• Tirzepatide resulted in significantly larger changes when compared with dulaglutide; the changes were directly proportional to reductions of HbA1c, HOMA2-IR indices, and proinsulin levels.

• Proportional to metabolite changes, there was a significant lowering in triglycerides and diglycerides when compared with baseline, dulaglutide, and placebo, with a bias towards shorter and highly saturated species.