As drug developers combine GLP-1 activity with additional metabolic targets, researchers are uncovering important differences between how experimental treatments act in mouse and human hearts.
Review: Future GLP-1 receptor co-agonists and their cardiac effects. Image Credit: Love Employee / Shutterstock
In a recent brief report published in the journal Naunyn-Schmiedeberg’s Archives of Pharmacology, researchers discussed glucagon-like peptide 1 (GLP-1) receptor (GLP-1R) co-agonists and their cardiac effects.
GLP-1 and GLP-1R agonists (GLP-1RAs) have attracted significant research interest. GLP-1, an incretin hormone, induces insulin secretion in the pancreas and reduces gastric emptying. At elevated blood glucose levels, GLP-1 stimulates insulin secretion and inhibits glucagon release from the pancreas. Exenatide was the first GLP-1RA approved for clinical use, and later, derivatives with longer half-lives were developed.
Subsequent efforts focused on developing GLP-1R co-agonists, viz., those that also act on the glucagon receptor (GCGR), the glucose-dependent insulinotropic polypeptide receptor (GIPR), or other receptors. Studies are underway investigating the risks and benefits of GLP-1RAs and GLP-1R co-agonists in heart failure.
GLP-1R-based therapies have been shown to decrease major cardiovascular events in patients with or without type 2 diabetes (T2D), while the cardiovascular effects of newer co-agonists remain under investigation. Reports also suggest direct cardiac effects, including increased contractile force, but the authors note that these effects could be beneficial or detrimental and may carry arrhythmic implications. In the present brief report, researchers summarized selected emerging GLP-1R co-agonists and their cardiac effects.
Agonists at GLP-1R and GIPR
CT-388, or enicepatide, is a unimolecular peptide agonist at GIPR and GLP-1R, with similar efficiency at both receptors. GLP-1R and GIPR stimulation can increase contractile force in isolated human atrial preparations. CT-388 has been shown to reduce body weight and plasma glucose, and to increase plasma insulin, in humans and animals. It has been reported to increase heart rate and reduce systolic blood pressure (SBP) in patients, indicating direct/indirect cardiac effects.
CT-868 is a unimolecular hybrid peptide agonist at GIPR and GLP-1R. It is more effective for weight reduction in mice and has a longer glucose-lowering effect than the selective GLP-1RA, liraglutide. A clinical study reported reductions in blood glucose and body weight, and improvements in glycated hemoglobin (HbA1c) and increases in plasma insulin levels with once-daily CT-868 in patients with T2D; in addition, small changes in heart rate and reductions in SBP and DBP were observed.
Agonists at GCGR and GLP-1R
Efinopegdutide is a dual GCGR/GLP-1R agonist based on a modified sequence of the endogenous peptide oxyntomodulin, which physiologically stimulates these receptors. It was effective in reducing weight but failed to normalize metabolic parameters. Efinopegdutide was more effective than semaglutide in reducing liver fat among patients. Reductions in SBP and DBP, and increases in heart rate, were greater with efinopegdutide than with semaglutide, with these differences most apparent early in treatment.
Pemvidutide, another dual GCGR/GLP-1R agonist, has similar potency at both receptors. In mice, pemvidutide reduced body weight, inflammation, and fibrosis. In patients, it has been reported to decrease body weight, liver fat content, SBP, and DBP, without affecting heart rate. One study found that pemvidutide increased the proportion of patients achieving MASH resolution compared with placebo.
Agonists at GLP-1R, GCGR, and GIPR
MAR723 is the first triple agonist at GIPR, GLP-1R, and GCGR, and a precursor to retatrutide and other agents. It is more potent than endogenous peptides and has a similar affinity for the three receptors. In mice with a knockout of GIPR, GLP-1R, or GCGR, a study reported that MAR723-induced insulin secretion was mainly mediated by its agonism at GLP-1R. Because retatrutide can increase the force of contraction in human cardiac preparations, the authors predict that MAR723 may exert a similar effect.
Further, MAR423 is an investigational drug and a modified form of MAR723. MAR423 was found to reduce body weight and stimulate heart rate in mice. In humans, MAR423 has been found to induce weight loss. Heart rate was also higher in humans with MAR423 in a time- and concentration-dependent manner. Efocipegtrutide is another triple agonist under investigation in phase 2b in MASH patients. Like its analog, retatrutide, the authors expect it to increase the force of cardiac contraction, but this has not been tested directly in human cardiac preparations.
Agonists at GLP-1R and other receptors
Tesaglitazar is a dual agonist of peroxisome proliferator-activated receptor-alpha (PPARα) and -gamma (PPARγ), originally developed for the treatment of T2D, and was discontinued after side effects emerged. One study later linked tesaglitazar to a GLP-1RA and showed improvements in glucose control in animals. This new molecule was also more efficient than its individual components.
GLP-1RA/tesaglitazar may induce cardiac effects via GLP-1R, but this requires experimental testing. Amycretin is a dual agonist at the amylin receptor and GLP-1R, and has been shown to induce weight loss. Its direct effect on contractile force in isolated human cardiac preparations has not yet been tested. The authors predict that its GLP-1 component could increase contractile force, whereas its amylin component may contribute little to this effect.
Concluding remarks
Collectively, the development of agonists at GLP-1R and additional receptors could yield clinical benefits. There are marked species differences in acute cardiac effects; human cardiac preparations can be more sensitive to these drugs than mouse preparations. As such, the lack of a cardiac response to new agents in mice does not necessarily imply that the same response would be absent in humans.
The authors also caution that findings from acute experiments may differ during chronic treatment because receptor regulation and other compensatory mechanisms can alter drug responses. Results from ongoing trials would shed more light on the cardiac effects of these co-agonists.
