Effects of Tirzepatide vs Semaglutide on β-Cell Function, Insulin Sensitivity, and Glucose Control During a Meal Test.
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
tirzepatide 15 mg | decrease | fasting glucose | patients with type 2 diabetes treated with metformin | - | significantly reduced | #1 |
tirzepatide 15 mg | decrease | MMTT total glucose area under the curve (AUC) | patients with type 2 diabetes treated with metformin | - | significantly reduced | #2 |
tirzepatide 15 mg | no change | incremental glucose AUC | patients with type 2 diabetes treated with metformin | - | did not differ significantly | #3 |
tirzepatide 15 mg | decrease | total ISR AUC | patients with type 2 diabetes treated with metformin | - | greater reduction | #4 |
tirzepatide 15 mg | increase | insulin sensitivity | patients with type 2 diabetes treated with metformin | - | greater improvement | #5 |
tirzepatide 15 mg | increase | ISR at 7.2-mmol/L glucose (ISR7.2) | patients with type 2 diabetes treated with metformin | - | significantly increased | #6 |
tirzepatide 15 mg | increase | β-cell glucose sensitivity (β-CGS) | patients with type 2 diabetes treated with metformin | - | improved | #7 |
tirzepatide 15 mg | increase | MMTT-derived β-CGS | patients with type 2 diabetes treated with metformin | - | increased but not significantly different | #8 |
tirzepatide 15 mg | decrease | fasting glucagon | patients with type 2 diabetes treated with metformin | - | reduced | #9 |
tirzepatide 15 mg | decrease | total glucagon AUC | patients with type 2 diabetes treated with metformin | - | reduced | #10 |
tirzepatide 15 mg | no change | estimated hepatic insulin-to-glucagon ratio | patients with type 2 diabetes treated with metformin | - | did not change substantially | #11 |
semaglutide 1 mg | no change | incremental glucose AUC | patients with type 2 diabetes treated with metformin | - | did not differ significantly | #12 |
semaglutide 1 mg | decrease | fasting glucagon | patients with type 2 diabetes treated with metformin | - | reduced | #13 |
semaglutide 1 mg | decrease | total glucagon AUC | patients with type 2 diabetes treated with metformin | - | reduced | #14 |
semaglutide 1 mg | no change | estimated hepatic insulin-to-glucagon ratio | patients with type 2 diabetes treated with metformin | - | did not change substantially | #15 |
CONTEXT: In a clinical study, tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1RA), provided superior glycemic control vs the GLP-1RA semaglutide. The physiologic mechanisms are incompletely understood. OBJECTIVE: This work aimed to evaluate treatment effects by model-based analyses of mixed-meal tolerance test (MMTT) data. METHODS: A 28-week double-blind, randomized, placebo-controlled trial of patients with type 2 diabetes treated with metformin was conducted at 2 clinical research centers in Germany. Interventions included tirzepatide 15 mg, semaglutide 1 mg, and placebo. Main outcome measures included glycemic control, model-derived β-cell function indices including insulin secretion rate (ISR) at 7.2-mmol/L glucose (ISR7.2), β-cell glucose sensitivity (β-CGS), insulin sensitivity, and estimated hepatic insulin-to-glucagon ratio. RESULTS: Tirzepatide significantly reduced fasting glucose and MMTT total glucose area under the curve (AUC) vs semaglutide (P < .01). Incremental glucose AUC did not differ significantly between treatments; therefore, greater total glucose AUC reduction with tirzepatide was mainly attributable to greater suppression of fasting glucose. A greater reduction in total ISR AUC was achieved with tirzepatide vs semaglutide (P < .01), in the context of greater improvement in insulin sensitivity with tirzepatide (P < .01). ISR7.2 was significantly increased with tirzepatide vs semaglutide (P < .05), showing improved β-CGS. MMTT-derived β-CGS was increased but not significantly different between treatments. Both treatments reduced fasting glucagon and total glucagon AUC, with glucagon AUC significantly reduced with tirzepatide vs semaglutide (P < .01). The estimated hepatic insulin-to-glucagon ratio did not change substantially with either treatment. CONCLUSION: These results suggest that the greater glycemic control observed for tirzepatide manifests as improved fasting glucose and glucose excursion control, due to improvements in ISR, insulin sensitivity, and glucagon suppression.