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28-04-2022 | Diabetes | News | Article

Mechanisms underlying tirzepatide efficacy revealed

Author: Eleanor McDermid

medwireNews: Tirzepatide improves glucose control more than semaglutide in people with type 2 diabetes by improving beta-cell function as well as boosting insulin sensitivity and reducing glucagon secretion, shows a randomized trial.

“Although dual actions on insulin secretion and insulin sensitivity have been previously reported for exenatide and semaglutide, our data show greater concurrent and larger improvements in islet function and insulin sensitivity with tirzepatide, leading to near-normalisation of glucose handling,” say the researchers.

“The net effect of these improvements with tirzepatide is to reduce β-cell workload, which might support sustained improvements in β-cell function and longer-term glycaemic control.”

Participants in the phase 1 study underwent a hyperinsulinemic euglycemic clamp and a hyperglycemic clamp at baseline and after 28 weeks of treatment.

Zvonko Milicevic (Eli Lilly, Indianapolis, Indiana, USA) and study co-authors used the results of these to calculate the disposition index: an overall measure accounting for both beta-cell function and insulin sensitivity.

Of the 102 people with type 2 diabetes included in the primary outcome analysis, the 39 randomly assigned to take tirzepatide, titrated up to 15 mg/week, had a large increase in the disposition index, from a least squares mean of 0.3 to 2.3 pmol m−2 L min−2 kg−1.

A further 39 people took semaglutide – titrated up to 1 mg/week, which was the highest dose approved at the time – and also had an increase in the disposition index, from 0.3 to 1.4 pmol m−2 L min−2 kg−1, whereas the 24 people given placebo had no change.

Both active treatments produced a significantly larger improvement in the disposition index compared with placebo, and there was also a significant difference between the two active treatments favoring tirzepatide.

“The significant increase with tirzepatide versus placebo far exceeded the effect anticipated in the power calculation,” the researchers comment in The Lancet Diabetes & Endocrinology.

The improvement in the disposition index was driven by increases in both insulin secretion and insulin sensitivity, they report.

First- and second-phase insulin responses increased 6.2-fold and 4.2-fold, respectively, in people taking tirzepatide and by a corresponding 4.7-fold and 3.6-fold in those taking semaglutide, whereas these both decreased slightly in the placebo group.

Again, the differences were significant between tirzepatide and semaglutide and for both active treatments versus placebo. Likewise, there were significant improvements in insulin resistance in people taking both active treatments versus placebo, with tirzepatide producing a significantly larger improvement than semaglutide.

Milicevic and team note that the 63% increase in insulin sensitivity came “in the context of a least squares mean weight loss of 11.2 kg.”

They say: “Notably, the plateau in weight loss had not been reached at the end of our study, indicating the potential for additional weight loss after 28 weeks of treatment and suggesting possible further improvement in insulin sensitivity with longer treatment.”

The majority of study participants were men, almost all were White, their average glycated hemoglobin level was around 62 mmol/mol (7.8%), and their average diabetes duration was about 10 years. Interventions were given in addition to metformin, with any other antihyperglycemic medications stopped 4 weeks before baseline.

The participants also underwent a mixed-meal tolerance test, showing large reductions in fasting and total glucose and insulin between baseline and week 28 with tirzepatide or semaglutide, as well as in glucagon. All changes were significant versus placebo and most were significantly larger for tirzepatide versus semaglutide.

The team says that the reduction in glucagon secretion likely contributed to the reduced glucose levels during the mixed-meal tolerance test, “thereby reducing insulin secretion requirements.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

Lancet Diabetes Endocrinol 2022; doi:10.1016/S2213-8587(22)00085-7

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