What drives the beneficial effects of tirzepatide on glycaemic control?

Use of tirzepatide results in better glycaemic control when compared with semaglutide, as shown by improved fasting glucose and glucose excursion control brought about by improvements in insulin secretion rate (ISR), insulin sensitivity, and glucagon suppression, according to a study.

In this 28-week double-blind, randomized, placebo-controlled trial at two clinical research centres in Germany, researchers assessed patients with type 2 diabetes treated with metformin. Participants were assigned to receive tirzepatide 15 mg, semaglutide 1 mg, or placebo.

The following outcomes were measured: glycaemic control, model-derived β-cell function indices including ISR at 7.2–mmol/L glucose (ISR7.2), β-cell glucose sensitivity (β-CGS), insulin sensitivity, and estimated hepatic insulin-to-glucagon ratio.

Tirzepatide provided significant reductions in fasting glucose and mixed-meal tolerance test (MMTT) total glucose area under the curve (AUC) relative to semaglutide (p<0.01). Incremental glucose AUC did not differ significantly between treatment groups, indicating that greater total glucose AUC decrease with tirzepatide was driven by greater fasting glucose suppression.

Tirzepatide also resulted in greater reduction in total ISR AUC compared with semaglutide (p<0.01), which was attributed to greater insulin sensitivity improvement (p<0.01).

The tirzepatide group also had significantly increased ISR7.2 (p<0.05) and improved β-CGS. On the other hand, MMTT-derived β-CGS was increased but showed no significant between-group difference.

In addition, “both treatments reduced fasting glucagon and total glucagon AUC, with glucagon AUC significantly reduced with tirzepatide vs semaglutide (p<0.01),” the researchers said. “The estimated hepatic insulin-to-glucagon ratio did not change substantially with either treatment.” 

Tirzepatide is a glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist.