CONTEXT: Tirzepatide substantially reduced hemoglobin A1c (HbA1c) and body 
weight in subjects with type 2 diabetes (T2D) compared with the glucagon-like 
peptide 1 receptor agonist dulaglutide. Improved glycemic control was associated 
with lower circulating triglycerides and lipoprotein markers and improved 
markers of beta-cell function and insulin resistance (IR), effects only 
partially attributable to weight loss.
OBJECTIVE: Assess plasma metabolome changes mediated by tirzepatide.
DESIGN: Phase 2b trial participants were randomly assigned to receive weekly 
subcutaneous tirzepatide, dulaglutide, or placebo for 26 weeks. Post hoc 
exploratory metabolomics and lipidomics analyses were performed.
SETTING: Post hoc analysis.
PARTICIPANTS: 259 subjects with T2D.
INTERVENTION(S): Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), or 
placebo.
MAIN OUTCOME MEASURE(S): Changes in metabolite levels in response to tirzepatide 
were assessed against baseline levels, dulaglutide, and placebo using 
multiplicity correction.
RESULTS: At 26 weeks, a higher dose tirzepatide modulated a cluster of 
metabolites and lipids associated with IR, obesity, and future T2D risk. 
Branched-chain amino acids, direct catabolic products glutamate, 
3-hydroxyisobutyrate, branched-chain ketoacids, and indirect byproducts such as 
2-hydroxybutyrate decreased compared to baseline and placebo. Changes were 
significantly larger with tirzepatide compared with dulaglutide and directly 
proportional to reductions of HbA1c, homeostatic model assessment 2-IR indices, 
and proinsulin levels. Proportional to metabolite changes, triglycerides and 
diglycerides were lowered significantly compared to baseline, dulaglutide, and 
placebo, with a bias toward shorter and highly saturated species.
CONCLUSIONS: Tirzepatide reduces body weight and improves glycemic control and 
uniquely modulates metabolites associated with T2D risk and metabolic 
dysregulation in a direction consistent with improved metabolic health.