Mazdutide belongs to a novel class of dual incretin-based agonists that bind to glucagon receptors (GCGRs) and glucagon-like peptide-1 receptors (GLP-1Rs). In cell culture, it has been demonstrated that mazdutide can stimulate the activity of adenylyl cyclases via both GCGR and GLP-1R. Recently, mazdutide was approved in China for use in body weight management in adults and in glycaemic control in adults with type 2 diabetes. The objective of this study was to test the hypothesis that mazdutide increases the force of contraction in the human atrium.
Human right atrial preparations (HAP) were obtained from adult patients undergoing open-heart surgery due to severe coronary heart disease. The force of contraction was measured in isolated, electrically paced (1 Hz) preparations of HAP in Tyrode's solution (37°C). Using the same setup, but without electrical stimulation, isolated, spontaneously beating right atrial preparations (RA) from adult wild-type mice were prepared to investigate the effect of mazdutide on the beating rate as this parameter could not be measured in the human preparations.
It was observed that in the presence of cilostamide, a phosphodiesterase III inhibitor, cumulatively applied mazdutide starting at 10 nM (up to 100 nM, the highest concentration tested) increased the force of contraction in HAP in a concentration- and time-dependent manner (p < 0.05, n = 9). While isoprenaline significantly shortened the time to relaxation (p < 0.05, n = 5), indicating a cAMP-dependent process, this was not as clear with mazdutide (n = 9). The positive inotropic effects of mazdutide in HAP were attenuated by 100 nM of the GLP-1-R-antagonist exendin(9-39) and by 10 µM of the GCGR-antagonist adomeglivant. The efficacy of mazdutide was found to be inferior to that of isoprenaline in enhancing the force of contraction in HAP. Even in the presence of 10 µM propranolol and 100 nM cilostamide, 100 nM mazdutide increased force of contraction in HAP (p < 0.05, n = 5). Moreover, mazdutide exerted a positive chronotropic effect in mouse RA (p < 0.05, n = 8), indicating that mazdutide can stimulate the sinus node in the mammalian heart.
In summary, it can be suggested that, at least in mice (in the mouse sinus node, only the GCGR is functionally expressed [1]), mazdutide increases the beating rate via GCGR and stimulates the force of contraction in the human atrium and probably also in the sinus node via GLP-1R and GCGR. This could explain the cardiac side effects observed in patients treated with mazdutide.
[1] Neumann et al. Naunyn Schmiedebergs Arch Pharmacol. 2025, doi: 10.1007/s00210-025-04335-0
