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Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes
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Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes
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Journal Article
Dual GIP and GLP-1 Receptor Agonist Tirzepatide Improves Beta-cell Function and Insulin Sensitivity in Type 2 Diabetes
2021
Overview
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.
Publisher
Oxford University Press
Subject
/ Adult
/ Aged
/ Agonists
/ Clinical Trials, Phase II as Topic
/ 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
/ Gastric Inhibitory Polypeptide - agonists
/ Gastric Inhibitory Polypeptide - therapeutic use
/ Glucagon
/ Glucagon-Like Peptide-1 Receptor - agonists
/ Glucose
/ Glycated Hemoglobin A - analysis
/ Humans
/ Hypoglycemic Agents - therapeutic use
/ Insulin
/ Insulin-like growth factor-binding protein 1
/ Insulin-like growth factor-binding protein 2
/ Insulin-Secreting Cells - drug effects
/ Male
/ Peptides
/ Placebos
