Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes

• Published in: The journal of clinical endocrinology and metabolism 2021-02, Vol.106 (2), p.388-396
• Main Authors: Thomas, Melissa K, Nikooienejad, Amir, Bray, Ross, Cui, Xuewei, Wilson, Jonathan, Duffin, Kevin, Milicevic, Zvonko, Haupt, Axel, Robins, Deborah A
• Format: Article
• Language: English
• Subjects: Adiponectin; Adolescent; Adult; Aged; Agonists; Antidiabetics; Beta cells; Biomarkers; Biomarkers - analysis; Blood Glucose - analysis; Clinical s; Clinical Trials, Phase II as Topic; Comparative analysis; Dextrose; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Fasting; Female; Follow-Up Studies; Gastric Inhibitory Polypeptide - agonists; Gastric Inhibitory Polypeptide - therapeutic use; GIP protein; GLP-1 receptor agonists; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide-1 Receptor - agonists; Glucose; Glycated Hemoglobin A - analysis; Glycosylated hemoglobin; Hemoglobin; Humans; Hypoglycemic Agents - therapeutic use; Insulin; Insulin Resistance; Insulin-like growth factor-binding protein 1; Insulin-like growth factor-binding protein 2; Insulin-Secreting Cells - drug effects; Laboratory testing; Male; Metformin; Middle Aged; Pancreatic beta cells; Peptides; Pharmaceutical industry; Placebos; Prognosis; Regression analysis; Triglycerides; Type 2 diabetes; Young Adult
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgaa863

Abstract Context Novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist (RA) tirzepatide demonstrated substantially greater glucose control and weight loss (WL) compared with selective GLP-1RA dulaglutide. Objective Explore mechanisms of glucose control by tirzepatide. Design Post hoc analyses of fasting biomarkers and multiple linear regression analysis. Setting Forty-seven sites in 4 countries. Patients or other Participants Three hundred and sixteen subjects with type 2 diabetes. Interventions Tirzepatide (1, 5, 10, 15 mg), dulaglutide (1.5 mg), placebo. Main Outcome Measures Analyze biomarkers of beta-cell function and insulin resistance (IR) and evaluate WL contributions to IR improvements at 26 weeks. Results Homeostatic model assessment (HOMA) 2-B significantly increased with dulaglutide and tirzepatide 5, 10, and 15 mg compared with placebo (P ≤ .02). Proinsulin/insulin and proinsulin/C-peptide ratios significantly decreased with tirzepatide 10 and 15 mg compared with placebo and dulaglutide (P ≤ .007). Tirzepatide 10 and 15 mg significantly decreased fasting insulin (P ≤ .033) and tirzepatide 10 mg significantly decreased HOMA2-IR (P = .004) compared with placebo and dulaglutide. Markers of improved insulin sensitivity (IS) adiponectin, IGFBP-1, and IGFBP-2 significantly increased by 1 or more doses of tirzepatide (P < .05). To determine whether improvements in IR were directly attributable to WL, multiple linear regression analysis with potential confounding variables age, sex, metformin, triglycerides, and glycated hemoglobin A1c was conducted. WL significantly (P ≤ .028) explained only 13% and 21% of improvement in HOMA2-IR with tirzepatide 10 and 15 mg, respectively. Conclusions Tirzepatide improved markers of IS and beta-cell function to a greater extent than dulaglutide. IS effects of tirzepatide were only partly attributable to WL, suggesting dual receptor agonism confers distinct mechanisms of glycemic control.