Institute of Neuroscience
National Research Council

Presenter of 1 Presentation

Mechanisms of action of tirzepatide in humans: beta and alpha cells effects and insulin sensitivity

Session Type
Parallel Session
Date
Fri, 29.04.2022
Session Time
16:40 - 18:00
Room
Hall 115
Lecture Time
16:40 - 16:55

Abstract

Abstract Body

Tirzepatide, a novel dual GIP/GLP-1 receptor agonist, has shown in clinical trials consistent efficacy as treatment for type 2 diabetes, with marked improvement of glycemic control, decrease of HbA1c and weight loss. These changes have been shown to be superior to those obtained with long-acting GLP-1 receptor agonists.

A recent study has been performed to clarify the mechanisms underlying such a marked improvement in glucose control. The study assessments included a euglycemic hyperinsulinemic clamp to measure insulin sensitivity, a hyperglycemic clamp to assess insulin secretion and beta-cell function, and a meal test to evaluate the treatment effects in physiological conditions and in particular the glucagon response. The 28-week randomized controlled study included both placebo and GLP-1 receptor agonist semaglutide 1mg as comparators.

The study has confirmed greater improvement in HbA1c and weight loss with tirzepatide compared to semaglutide. Consistently with the superior improvement in HbA1c, both fasting and mean glucose during the meal test were reduced to a greater extent with tirzepatide.

The study of the underlying mechanisms of action has revealed a considerably larger improvement in insulin sensitivity with tirzepatide compared to semaglutide, which was paralleled by similar results obtained from the meal-based insulin sensitivity surrogates. Enhancement of insulin secretion from the hyperglycemic clamp, as both first- and second-phase secretion, was larger with tirzepatide vs. semaglutide. During the meal test, both fasting and mean glucagon concentration decreased more with tirzepatide than with semaglutide.

The combined effects on insulin sensitivity and insulin secretion, assessed with disposition index (the product of insulin sensitivity and total insulin secretion normalized to glucose, from the clamps), were largely superior with tirzepatide, which showed an almost double disposition index increase compared to semaglutide.

In conclusion, large improvements in insulin sensitivity and insulin secretion and glucagon suppression underlie the strong effects of tirzepatide on glycemic control.

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