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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ABSTRACT

Background and aims: The effect of tirzepatide, a novel dual GIP/GLP-1 receptor agonist, vs insulin degludec (IDeg) on liver fat content (LFC) and visceral and abdominal subcutaneous adipose tissue (VAT and ASAT) was assessed with MRI techniques in a subpopulation of participants in the SURPASS-3 trial.

Methods: Insulin-naive participants with type 2 diabetes and Fatty Liver Index ≥60 had an MRI scan performed before randomisation (1:1:1:1) to once-weekly tirzepatide (5, 10, 15 mg) or once-daily IDeg as add-on to metformin with/without sodium-glucose co-transporter-2 inhibitors (SGLT-2i). The primary outcome was the change from baseline in LFC at Week 52 using pooled data from tirzepatide 10/15-mg arms vs IDeg. Secondary outcomes compared the individual tirzepatide doses vs IDeg at Week 52 for LFC, VAT and ASAT volumes; proportions of participants achieving LFC targets.

Results: A total of 296 participants had evaluable MRI data during the study (mean baseline age, 56.2 years; diabetes duration, 8.3 years; HbA_1c, 8.2%; weight, 94.4 kg; BMI, 33.5 kg/m²; 30% on SGLT-2i). The reduction from baseline in LFC at Week 52 was significantly greater for the pooled tirzepatide 10/15-mg arms vs IDeg arm and for all individual tirzepatide doses vs IDeg. The proportions of participants achieving LFC targets were significantly greater in each tirzepatide arm vs IDeg arm. All tirzepatide doses reduced VAT and ASAT volumes at Week 52 while IDeg increased both. The results were similar regardless of the concomitant use of SGLT-2i.

Conclusions: Tirzepatide demonstrated clinically meaningful reductions in LFC and VAT and ASAT volumes compared to IDeg in this SURPASS-3 substudy.