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.