Tirzepatide regulates metabolites, lipids in T2D

Treatment with tirzepatide leads to a reduction in body weight and improvement in glycaemic control in individuals with type 2 diabetes (T2D), reports a study. In addition, it modulates metabolites associated with T2D risk and metabolic dysregulation that is consistent with improved metabolic health.

A total of 259 patients with T2D were randomized to receive weekly subcutaneous tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), or placebo for 26 weeks. The investigators performed post hoc exploratory metabolomics and lipidomics, as well as post hoc analysis. Using multiplicity correction, they assessed changes in metabolic levels in response to tirzepatide against baseline levels, dulaglutide, and placebo.

A higher dose of tirzepatide regulated a cluster of metabolites and lipids related to insulin resistance (IR), obesity, and T2D risk at 26 weeks. Branched-chain amino acids, direct catabolic products glutamate, 3-hydroxyisobutyrate, branched-chain ketoacids, and indirect byproducts also decreased relative to baseline and placebo.

Changes were significantly greater with tirzepatide vs dulaglutide and directly proportional to reductions in HbA1c, homeostatic model assessment 2-IR indices, and proinsulin levels. Proportional to metabolite changes, triglycerides and diglycerides significantly decreased relative to baseline, dulaglutide, and placebo, with a bias toward shorter and highly saturated species.

“Tirzepatide substantially reduced HbA1c and body weight in [individuals] with T2D compared with the glucagon-like peptide 1 receptor agonist dulaglutide,” the investigators said. “Improved glycaemic control was associated with lower circulating triglycerides and lipoprotein markers and improved markers of beta-cell function and IR, effects only partially attributable to weight loss.”