Cardioprotective effects of a ‘twincretin’ drug tirzepatide in heart failure following myocardial infarction

This editorial refers to ‘GIP/GLP-1 receptor agonist tirzepatide promotes BCAA catabolism to prevent myocardial infarction in non-diabetic mice’ by M. Chen et al., https://doi.org/10.1093/cvr/cvaf005. Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are gut-derived incretin hormones that act on islets within the pancreas to promote glucose-dependent insulin secretion. These incretins also exhibit pleiotropic actions beyond the pancreas. In this regard, GLP-1 receptor (GLP-1R) activation in the brain inhibits food intake, leading to weight reduction. As such, GLP-1-based medicines are used for treatment of both Type 2 diabetes (T2D) and obesity. Intriguingly, in preclinical and clinical studies, their extra-pancreatic actions are also beneficial for diabetes- and obesity-related metabolic complications, supporting the use of these medicines in people living with metabolic liver diseases, chronic kidney diseases, and cardiovascular diseases.1,2 It is worth noting that the pre-specified analysis of the SELECT trial also reported that the cardiovascular benefit with semaglutide (a GLP-1 agonist) in obesity was achieved irrespective of the amount of weight reduction.1,3 The cardioprotective effect of semaglutide was observed within months of the study, before any meaningful weight reduction occurred, suggesting a weight-independent action of GLP-1 receptor agonists (GLP-1RAs) which may involve its anti-inflammatory effects or non-receptor-dependent pathways. Tirzepatide, a unimolecular peptide that stimulates both GIP and GLP-1 receptors (also known as a ‘twincretin’), has been approved for use in people with T2D and obesity and exerts potent effects on glycaemic control and body weight reduction as compared to a GLP-1RA alone. While GLP-1 science has received considerable attention, the cardiovascular actions of GIP are less well understood. There are currently no completed cardiovascular outcome trials for GIP-based therapies to understand the contribution of GIP that is relevant to the development of heart diseases. In experimental models, both stimulation and inactivation of GIP receptor (GIPR) signalling have shown protective actions against atherosclerosis development4 and ischaemic injury.5 However, in mice, tirzepatide exhibits a distinct pharmacological receptor affinity, favouring the GLP-1R over the GIPR, which has been reported to be the opposite in human incretin receptors. From a translational perspective, the role of GIPR activation by tirzepatide in cardiovascular disease remains to be further explored. In the SURPASS-4 trial, tirzepatide exhibited cardiovascular safety with numerically fewer myocardial infarctions (MIs) and strokes.6 Two Phase 3 cardiovascular outcome trials are underway with tirzepatide investigating its safety compared with dulaglutide, a GLP-1 receptor agonist in people with T2D and established cardiovascular disease (SURPASS-CVOT; NCT04255433), and a separate trial assessing its cardiovascular safety in people with obesity (SURMOUNT-MMO; NCT05556512). These trials will provide more evidence on how tirzepatide influences the rates of MI and other major cardiovascular events in patients with T2D and obesity. Chen et al.7 interrogated the potential cardioprotective action of tirzepatide in an animal model of heart failure following MI induced by tying off the left descending coronary artery. The authors found that tirzepatide reduced mortality following MI, decreased the infarct area, attenuated cardiomyocyte necrosis and left ventricular hypertrophy, and restored left ventricular function. These effects were associated with improvements in defective branched-chain amino acid (BCAA) catabolism pathway. Augmented levels of plasma BCCA are associated with the increased incidence of chronic heart failure, and BCAA accumulation in the heart has been observed after MI, interfering with cardiac growth and metabolism by activating mechanistic target of rapamycin (mTOR) signalling.8 Tirzepatide reduced mitochondrial branched-chain keto acid dehydrogenase complex (BCKDHA) phosphorylation (a potential binding affinity was suggested between tirzepatide and BCKDHA), which activates the enzyme. This enhances BCAA (valine, leucine, and isoleucine) degradation pathways to produce acetyl coenzyme A and succinyl coenzyme A that undergo mitochondrial oxidative phosphorylation and respiration for energy production. Tirzepatide also inhibited the overactivation of the mTOR signalling pathway, a key regulator of processes that has been implicated in insulin resistance, cardiac remodelling, pathological cardiac hypertrophy, and cardiac dysfunction.9 Mice fed a low BCAA diet post-MI had reduced cardiomyocyte necrosis, increased fibrosis repair, and decreased inflammatory infiltration. These cardioprotective effects were further enhanced with tirzepatide administration. These results offer mechanistic insights into the role of tirzepatide in BCAA metabolic alternations following MI, supporting its clinical use in treating heart failure following MI (Figure 1). Potential mechanism by which tirzepatide is protective against heart failure after MI. The first step in BCAAs metabolism is their conversion into BCKAs by the two isozymes, BCAT 1/2. The enzyme complex, BCKDHA (whose activity is inhibited by phosphorylation), then produces acetyl coenzyme A and succinyl coenzyme A that undergo mitochondrial oxidative phosphorylation and respiration for energy production. Tirzepatide improves the defective BCAA catabolism pathway in MI mice by potentially biding to BCKDHA to increase its activity. This increases energy production, in addition to reducing mTORC1, that is known to control many cellular functions including pathological cardiac remodelling and reduction in insulin sensitivity. The highlighted amino acids in the structure of tirzepatide indicates special modifications to the existing GLP-1, GIP, and exenatide sequences. BCAA, branched-chain amino acid; BCKA, branched-chain keto acids; BCAT, branched-chain amino acid transaminase; BCKDH, branched-chain alpha-keto acid dehydrogenase complex. Despite the novelty of the present study, there are some issues that still need resolving. The authors, using a molecular docking technique, proposed that tirzepatide physically interacted with BCKDHA to attenuate its phosphorylation. However, whether a peptide like tirzepatide can effectively penetrate cell or mitochondrial membranes to directly influence enzyme activity remains unclear. Further experiments are needed to validate the predicted binding affinities in both human and murine models. The other unaddressed question is the cellular targets for the incretin receptor-mediated effects. Although the distribution of GLP-1R in the heart differs between humans and mice, GLP-1R activation remains broadly cardioprotective in both preclinical and clinical studies. GLP-1RAs reduce the rates of major adverse cardiovascular events in patients with T2D, obesity and heart failure with preserved ejection fraction. Research using gain- and loss-of-function animal models of heart disease suggests that the canonical GLP-1R, expressed in the vasculature and heart, mediates the key cardiovascular effects of GLP-1RAs. In multiple preclinical models of MI, GLP-1RAs have been shown to protect against MI–reperfusion injury.10 Liraglutide-mediated protective effects on MI size were blunted by depletion of GLP-1R in Tie2 + endothelial cells (EC) in mice,11 indicating a potential role for EC in modulating this effect. Whether tirzepatide also acts on the EC or other GLP-1R-expressing cell types to reduce MI size remains an area for further investigation. Although less extensively studied, loss-of-function study using whole-body Gipr knockout and selective Gipr depletion in mouse cardiomyocytes protected against ischaemic cardiac injury and ventricular remodelling through modulating hormone-sensitive lipase activity and cardiac lipid accumulation.5 The existing studies on GIPR agonism and antagonism in heart diseases are inconclusive and require additional studies. Given the superior efficacy of tirzepatide on glycaemic control and body weight reduction, numerous incretin-based compounds have emerged and are currently being investigated in preclinical and clinical studies. Understanding mechanisms of action is essential for optimizing their therapeutic potential and advancing the development of next-generation therapies with enhanced cardiovascular safety and efficacy. This work was supported by operating grants from the Institute of Nutrition, Metabolism and Diabetes, Canadian Institutes of Health Research (CIHR PJT-178134), and Diabetes Canada (OG-3-21-5585-BR). There are no new data associated with this article.

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