Effects of Tirzepatide, a Dual GIP and GLP-1 RA, on Lipid and Metabolite Profiles in Subjects With Type 2 Diabetes.
J Clin Endocrinol Metab
; 107(2): 363-378, 2022 01 18.
Article
em En
| MEDLINE
| ID: mdl-34608929
ABSTRACT
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.Palavras-chave
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Bases de dados:
MEDLINE
Assunto principal:
Polipeptídeo Inibidor Gástrico
/
Diabetes Mellitus Tipo 2
/
Hipoglicemiantes
Tipo de estudo:
Clinical_trials
Idioma:
En
Revista:
J Clin Endocrinol Metab
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos