Michael A. Nauck MD, PhD

Tirzepatide is a novel peptide gut hormone receptor dual agonist addressing glucose-dependent insulinotropic polypeptide (GIP) as well as glucagon-like peptide-1 (GLP-1) receptors. Typical biological (and pharmacological) actions relate to the insulinotropic action (stimulation of insulin secretion), which may explain improvements in glycaemic control. Further, GLP-1 reduces appetite and energy intake, leading in the long run to reductions in body weight. In animal experiments GIP also interacts with hypothalamic neurons equipped with GIP receptors, and is associated with reduced food intake and body weight reduction. Although experiments in humans have been reported, they do not confirm the findings corroborated in rodents. Whatever the mechanisms may be, tirzepatide elicits remarkable effects on HbA1c and body weight.

Karagiannis et al. performed a meta-analysis of results from pivotal clinical trials supporting the approval of tirzepatide as a novel treatment for type 2 diabetes (T2D). They focused on dose-response relationships, since tirzepatide is available in three doses (5, 10, and 15 mg per week). They also looked at comparisons to placebo in order to draw conclusions about the general effectiveness of tirzepatide, and at comparisons with GLP-1 receptor agonists (GLP-1RA) in order to look for additional effects, putatively supported by the additional stimulation of GIP receptors. The results indicate that tirzepatide dose-dependently reduces HbA1c and body weight, significantly better than placebo and compared to selective GLP-1RA (dulaglutide and semaglutide). Regarding adverse events, tirzepatide at any dose did not elicit nausea or vomiting in a significantly higher proportion of patients as compared to GLP-1RA-treated patients, despite being more effective on glycaemic control and body weight.

The impressive results with tirzepatide in T2D patients can alternatively be presented as the proportion of patient cohorts achieving certain treatment targets, e.g., HbA1c <5.7 % or a body weight reduction >15 % versus baseline. Such targets have rarely been achieved with any glucose-lowering medications studied in the past, and have now reported in approximately 50% and 40% of patients treated with the 15 mg dose for HbA1c <5.7 and body weight reduction by >15%, respectively. Target achievements were not part of the analysis by Karagiannis et al., but could probably characterize the effectiveness of tirzepatide even more impressively, since HbA1c <5.7% stands for an equivalent of completely normalized glucose metabolism, and a weight loss of at least 15% versus baseline offers a good chance of inducing diabetes remission. Tirzepatide will also be a good experimental tool to test the hypothesis that addressing glycaemic control and reducing body weight in obese patients with T2D will result in superior outcomes regarding long-term diabetes complications compared to the conventional approach that focuses on the control of plasma glucose.

Another point not addressed in the systematic review and meta-analysis is that the two SURPASS studies compared tirzepatide to basal insulins degludec and glargine, and found superior glycaemic control with all doses of tirzepatide plus major weight differences – further substantiating the guideline recommendation to use incretin-based glucose-lowering medications as the first injectable treatment for T2D no longer controlled with diet and oral agents.

Overall, the manuscript by Karagiannis et al. summarizes important aspects of the clinical trial program for tirzepatide and its use in the treatment of T2D, which emphasize the outstanding effectiveness of the dual GIP/GLP-1RA tirzepatide, even if compared to potent selective GLP-1RA mono-agonists.