Bridging the gap between GLP1-receptor agonists and cardiovascular outcomes: evidence for the role of tirzepatide

Tirzepatide (LY3298176) is the first peptide dual agonist for type 2 diabetes mellitus (T2DM), which targets both GIPR and GLP1R. According to primary trials in T2DM, tirzepatide significantly reduces clinical outcomes like body weight, glycated hemoglobin (HbA1c), lipid profiles, and glucose-adjusted glucagon secretion compared to typical glucagon-like peptide1 receptor agonists (GLP1RAs) [1, 2]. Additionally, new research indicates that tirzepatide potentially has some advantages over traditional metabolic regulation, such as insulin sensitivity improvement and anti-inflammatory effect [2]. The dual mechanism of tirzepatide has a synergistic impact that is strong enough to significantly lower the risk of cardiovascular events [3, 4]. Studies suggest tirzepatide may help improve cardiometabolic risk factors and reduce the risk of atherosclerotic cardiovascular disease (CVD). These risk factors include blood pressure, cholesterol, and chronic inflammation [3]. In SURPASS 4 The risk of suffering from any major adverse cardiovascular event MACE-4 and MACE-3 (including myocardial infarction, stroke, hospitalization for angina, and all-cause death) with the highest dose of tirzepatide (15 mg per week) has been estimated at 0·50 (0·26–0·95), which was intended to provide initial proof of the cardiovascular safety of tirzepatide [2, 5]. The FIGHT trial specifically evaluated using the GLP-1RAs, liraglutide, in patients with HF with reduced ejection fraction (HFrEF). Although the trial did not show a significant advantage in reducing cardiovascular events [6], or hospitalizations, it provided insights into liraglutide’s safety and tolerability in this patient population [6]. Ongoing research, such as the SUMMIT trial, is presently assessing the safety and efficacy of tirzepatide in HF patients with preserved ejection fraction (HFpEF). However, comprehensive data on the direct effects of HF are still being developed (NCT04847557↗). Additionally, the positive outcomes of ongoing trials SURPASS-CVOT and SURMOUNT-MMO will provide definitive evidence regarding the cardiovascular safety and efficacy of tirzepatide compared to dulaglutide and reduction in morbiditiy and mortality in adults with obesity respectively. CVOT trial will help determine if tirzepatide can demonstrate superior cardiovascular safety and potential additional cardiovascular benefits compared to the currently approved GLP-1RA dulaglutide. the data from these two large, well-powered clinical trials will provide robust evidence on the cardiovascular and metabolic benefits of tirzepatide, potentially expanding the treatment options for adults with T2DM, obesity, and related cardiovascular complications [7] (Clinical Traials.gov). SURMOUNT-1 trial suggests that tirzepatide may have a promising future as a therapy for obesity, HF, and non-alcoholic fatty liver disease (NAFLD) [5, 8]. Previous meta-analyses have indicated that tirzepatide might potentially decrease the risk of cardiovascular events by affecting cardiac cells, the pancreas, and other tissues directly and indirectly [2]. Also, the efficacy and safety of tirzepatide may have a wider perspective for its use beyond patients with T2DM or obesity [9, 10]. This review will discuss the limitation of GLP1RAs in patients with HF, along with ongoing trials assessing the safety and effectiveness of tirzepatide, look into the existing data, and elucidate tirzepatides potential impact on cardiovascular disease.

Human atrial and ventricular cardiomyocytes express the GLP1R within each of all chambers, and the sinoatrial (SA) node shows the highest level of GLP1R expression [11, 12]. GIPR, unlike the GLP1R, is extensively expressed in the ventricular myocardium of both rodents and humans. Boosting GIPR activity could directly affect the myocardium and indirectly influence cardiovascular function and outcomes through its systemic effects on other organs [13]. Identifying GLP1R and GIPR in endothelial cells, vascular smooth muscle cells, and blood has underscored their significant roles in vascular function [11]. The activation of GLP1R and GIPR by specific ligands triggers intracellular signaling cascades that regulate the structure and function of the heart. Both receptors canonical signaling pathway involves coupling to Gαs proteins, and in turn, triggers adenylyl cyclase activation and leads to the production of cyclic adenosine monophosphate (cAMP). The increased cAMP levels in cardiac cells activate exchange protein directly activated by cAMP (EPAC) and protein kinase A (PKA), which regulate a multitude of downstream effectors involved in cardiac contractility, relaxation, and hypertrophy [14]. and GIP receptors have also been demonstrated to activate phosphoinositide 3-kinase (PI3K) and its downstream effector Akt, which modulates mitochondrial function, metabolism, and cell survival. Recent data indicates that both receptors may interact through β-arrestin-dependent pathways, potentially contributing to their cardioprotective properties without involving G protein signaling [15]. Interestingly, the rise in hormone-sensitive lipase (HSL) phosphorylation within cardiac myocytes appears to rely on a GIPR-mediated increase in ERK phosphorylation. This implies that GIP activity may regulate myocardial triacylglycerol (TAG) metabolism. Additionally, the infusion of native human GIP (1–42) into cardiac myocytes isolated from embryonic mouse hearts inhibited the increase in brain natriuretic peptide (BNP) and transforming growth factor- β (TGF- β 1) mRNA expression induced by angiotensin II (Ang II) [13]. This could be the key to tirzepatide’s remarkable efficacy. It is expected that tirzepatide will occupy a greater percentage of GIPR than GLP1R (4.1, 4.6, and 6.3 fold, respectively, at 15, 10, and 5 mg) [16]. Tirzepatide is formulated to mimic the function of native GIP at the GIPR while also interacting with the GLP1R in a manner different from native GLP1. Additionally, tirzepatide was designed to bind to the GIPR with an affinity 5-fold stronger than that for the GLP1R, resulting in greater potency and selectivity in engaging the GIPR over the GLP1R. Also, experiments conducted in primary islet cells have shown that β-arrestin1 restricts the insulin secretion response to GLP1R activation, but not to GIPR activation or tirzepatide. This indicates that the biased agonism properties of tirzepatide, which preferentially activates specific signaling pathways, enhance its ability to stimulate insulin secretion [17, 18]. Additionally, tirzepatide demonstrates bias at the GLP1R, favoring the synthesis of cAMP over the recruitment of β-arrestin [1]. Studies have found that tirzepatide’s hormone-secreting activities depend on GIPR, highlighting the critical role that GIPR plays in the medication’s mechanism of action and its therapeutic effects [19]. Tirzepatide appears to activate GIPR stronger than GLP1R in cell systems with high levels of both gene expressions [20]. Tirzepatide has three critical improvements over first-generation GLP1RAs. Firstly, it alters multiple residues in the peptide structure to mimic GIP role at GIPR. Additionally, it extends the C-terminal with a sequence of exenatide, and thirdly, it has an attached fatty acid side chain, similar to semaglutide, to prolong its half-life [16].

Up to 85% of cardiovascular deaths are related to atherosclerotic heart disease, which occurs as heart attacks and strokes. In the cardiovascular system, atherosclerosis becomes apparent as the “invisible killer.” Atherosclerosis causes cerebral ischemia, or angina pectoris, with the development of atherosclerotic plaques. This may result in severe clinical manifestations like myocardial infarction (MI) and HF [22–24]. In the LEADER trial, liraglutide demonstrated cardiovascular benefit, and GLP1RAs have similar effects, aligning with liraglutide’s anti-atherosclerotic effect. GLP1RAs have shown the ability to decrease the development and advancement of atherosclerosis in preclinical and clinical investigations [25, 26]. There is also a current clinical study examining injectable semaglutide’s effect on coronary atherosclerosis development [27]. Moreover, a decrease in atherosclerotic cardiovascular disease (ASCVD) has been found in people treated with semaglutide who were obese or overweight, but, this trend was not statistically significant [28]. Based on SURMOUNT-1 data analysis, tirzepatide decreased the 10-year estimated risk of ASCVD for obese or overweight patients. It has been shown that tirzepatide can lower the risk of ASCVD by improving lipid, glucose, and HbA1c levels, as well as blood pressure and waist circumference. Interestingly enough, patients with higher baseline ASCVD risk with tirzepatide therapy showed significantly more reductions in risk [3]. It is crucial to address ASCVD disease in T2DM at an earlier stage, with more intensively and precision. Several factors contribute to the heightened risk of atherosclerosis, and a comprehensive approach is essential for preventing or reducing atherosclerotic events[29]. Preclinical studies have indicated that GLP1RAs, such as tirzepatide, may directly impact the vasculature by enhancing endothelial function and decreasing inflammation, which are important in preventing atherosclerosis[30]. Tirzepatide has the potential to prevent atherosclerosis risk in T2DM patients without pre-existing lesions. For those with established atherosclerosis, the focus would be on managing the existing condition and preventing further progression [31]. Tirzepatide has been shown in clinical trials to reduce the risk of cardiovascular events at various doses, suggesting a potential treatment option for patients who are obese or overweight [2]. According to the study conducted by Nagashima et al., treatment of 17-week-old mice with GIP via subcutaneous injection showed a significant decrease in the size of aortic atherosclerotic lesions and macrophage infiltration. These findings emphasize the importance of GIPR activity and its anti-sclerotic role [32–34]. Moreover, according to research by Ojima et al., a GIP concentration of 50 pM effectively suppressed the generation of reactive oxygen species (ROS) in human umbilical vein endothelial cells (HUVECs) exposed to AGE. A reduction in the expression levels of the AGE receptor facilitated this effect. The study also noted a decrease in the expression level of pro-atherogenic molecule factors such as plasminogen activator inhibitor-1 (Pai-1) [35]. GIP may reduce oxidative stress in endothelial cells and visceral adipose tissue and decrease the secretion of inflammatory cytokines [36]. Moreover, activation of endothelial nitric oxide synthase (NOS) in HUVECs by GIP at 1 nM decreased inflammatory inducible NOS expression levels. It increased the production of NO, which is an anti-atherogenic molecule [37, 38]. Moreover, GIP at pharmaceutical doses may prevent atherosclerosis, causing obesity, and the positive benefits of GIP may also be maintained in animals [39]. Tirzepatide, with a dual activity target GIP and GLP1 receptor, may have consequences for preventing or mitigating atherosclerosis due to its impact on GIPR activity.

The research examined eight large cohorts of T2DM patients, with cardiovascular outcome trials (CVOTs), for main MACE outcomes, including cardiovascular death, nonfatal MI, and nonfatal stroke, which were studied with GLP1RAs [40]. The primary and secondary outcome endpoints of MACE and nonfatal stroke demonstrated significant reductions in the dulaglutide-treated REWIND trial and the subcutaneous semaglutide-treated SUSTAIN-6 study [41]. Recent evidence has suggested that GLP1RAs may decrease the incidence of stroke in people with T2DM. To evaluate the incidence of MACE-4 events in patients treated with tirzepatide compared to the control group, a meta-analysis was conducted using data from 7778 patients enrolled in the SURPASS-4 study, SURPASS Clinical Trails Program (which includes 7 randomized clinical trials), and SURMOUNT-1. The overall hazard ratio (HR) estimate was 0.59 (95% CI 0.40–0.79), indicating that tirzepatide resulted from a significant reduction in the risk of MACE-4 compared to the control group [21]. As tirzepatide was compared to controls, the hazard ratios for MACE-4 were 0.80 (95% confidence interval [CI], 0.57–1.11), cardiovascular death was 0.90 (95% CI, 0.50–1.61), and all-cause death was 0.80 (95% CI, 0.51–1.25) [2]. It is essential to keep in mind that the current data suggests tirzepatide may be efficient in downgrading the possibility of stroke; however, trials developed mainly to evaluate the long-term impact of tirzepatide on cardiovascular events, including stroke, are currently in progress [42].

Heart failure is a prevalent disease that impacts nearly 2% of the global population. Diagnosis of HF requires the presence of an underlying cardiac abnormality. Usually, this is a cardiac abnormality that results in either diastolic or systolic ventricular dysfunction (e.g., myocardial infarction or coronary artery disease). Moreover, damage or weakness in the heart muscle itself, disorders of the valves such as stenosis or regurgitation, endocardium, cardiac conduction and rhythm, pericardium, or all of these changes can cause HF [43, 44]. Also, both systolic and diastolic dysfunction stemming from the interplay between atherosclerotic coronary disease and diabetic cardiomyopathy are associated with the underlying pathophysiology of HF in patients with T2DM [45, 46]. Several mechanisms may contribute to the positive effects of GLP1RAs in preventing HF and influencing the outcomes for patients with either HFpEF or HFrEF. Also GLP1RAs have been found to decrease epicardial fat, which may help explain their potential in lowering the risk of atherosclerosis. On the other hand the GLP1R in both cardiomyocytes and sinoatrial node cells can activate cyclic AMP (cAMP)-dependent signaling pathways. This may lead to an excessive influx of calcium into cells. This calcium dysregulation could be associated with the pathophysiology of HF in patients with diabetes [47]. Sardu et al. found that GLP1RAs significantly raised LVEF and 6-minute walking test (6MWT) in T2DM with HF [48]. According to previous studies, liraglutide attenuates myocardial hypertrophy and fibrosis following angiotensin II infusion by suppressing TGF-β1/Smads signaling pathways [49]. Nevertheless, GLP1RAs did not statistically significantly improve systolic function, as demonstrated by Kumarathurai et al. [50]. The findings revealed that GLP1RAs could extend 6MWT and lower the risk of HF hospitalization in people without a history of HF; however, their effects on HF hospitalization with a history of HF, NT-proBNP levels, and quality of life were not statistically significant. GLP1RAs significantly decreased E-wave velocity, E/A ratio, E/e _ ratio, and EDT but did not affect LVEF. In addition, patients with HF can have their cardiac function and prognosis assessed using 6MWT, NT-proBNP, and QoL [51]. A single trial that evaluated GLP1RAs in patients with a history of HF and HFpEF demonstrated reduced HF hospitalizations. However, this trial was limited by small sample size and potential flaws in the selection of endpoints (NCT04916470↗ and NCT05371496↗) [52]. The SUMMIT study assesses tirzepatide’s impact on HF with HFpEF in obese patients. The research suggests that for patients with HF with HFrEF, the dual therapy of tirzepatide and guideline-directed medical therapy (GDMT) may be a viable treatment approach. GDMT for HFrEF typically includes evidence-based beta-blockers, angiotensin receptor neprilysin inhibitors (ARNIs), angiotensin receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors, mineralocorticoid receptor antagonists (MRA), and sodium-glucose cotransporter 2 inhibitors (SGLT2is), particularly in patients with obesity or T2DM [53]. Despite the lack of research on tirzepatide, especially in HF patients, its cardiovascular effects indicate potential benefits for this population. Tirzepatide is presently being examined in a clinical trial (NCT04847557↗) for patients with moderate HF (NYHA class II-IV) with HFpEF [54]. The research outcomes suggest that human cardiac cells treatment with tirzepatide resulted in an augmentation of Sarco/Endoplasmic Reticulum Calcium ATPase 2 (SERCA2) and p-Phospholamban (p-PLN) activity and expression while reducing Calcium/Calmodulin-Dependent ProtienKinase II (CAMKII) expression. These markers are pivotal in regulating calcium signaling, and the intervention effectively mitigates calcium overload in cardiomyocytes exposed to elevated glucose levels. Furthermore, the study showed that tirzepatide correlated with a marked decrease in the levels of key indicators associated with fibrosis and hypertrophy, such as TGF- β, Matrix Metalloprotieinase-9 (MMP9), Collagen Type I Alpha 1 (COLIA1) and F-box only protein 32 (FBXO32) [21].

A new drug named tirzepatide has been approved to treat T2DM, and it is expected to be approved for weight loss by activating both GLP-1 and GIP receptors through a unique mechanism. Currently, there are other dual GIPR/GLP-1R agonists available, such as GLP-1R/GR (glucagon receptor), GLP-1R/AR (amylin receptor), and GLP-1R/NPYR (peptide YY binds to neuropeptide Y receptors) [36, 115] and even triple agonists that can activate GIPR to treat obesity and T2DM. This has led to renewed interest in understanding the safety of GIP/GIPR in humans. It is essential to gain a deeper understanding of GIP safety to guide future research projects and develop GIP-based treatments [116]. The post hoc analysis found that tirzepatide at all doses investigated reduced the prevalence of metabolic syndrome related to cardiovascular risk factors more than placebo, semaglutide 1 mg, insulin degludec, and insulin glargine [117]. Comparing tirzepatide to GLP1RAs using the results of prior comparison trials is challenging. However, the added agonism of GIPR seems to have a more positive impact on weight loss. It is important to develop a single pharmacological medication with multiple functions, such as tirzepatide. This medication can increase insulin sensitivity, decrease weight, and treat dyslipidemia at an early clinical stage, while also dramatically lowering blood sugar levels. Therefore, it seems that tirzepatide is more than just a new antidiabetic drug. The development of further dual GLP-1/GIP receptor agonists seems to be a promising next step in managing various cardiovascular disease. However, further research is needed to determine the long-term impacts of these substances. The role of tirzepatide in therapy will become more evident as more research is conducted.

F.T., G.P., M.B. concept, design and writing. R.A.F., L.S., A.Pe., M.G.B., P.G., M.F., G.T., A.P., M.T.V., A.C. drafting of the manuscript. All authors have read and agreed to the published version of the manuscript. All authors read and approved the final manuscript.

This work was supported by: open access funding provided by the: National Plan for NRRP Complementary Investments (PNC, established with the decree-law 6 May 2021, n. 59, converted by law n. 101 of 2021) in the call for the funding of research initiatives for technologies and innovative trajectories in the health and care sectors (Directorial Decree n. 931 of 06-06-2022) - project n. PNC0000003 - AdvaNced Technologies for Human-centrEd Medicine (project acronym: ANTHEM). This work reflects only the authors’ views and opinions, neither the Ministry for University and Research nor the European Commission can be considered responsible for them. PRIN: PROGETTI DI RICERCA DI RILEVANTE INTERESSE NAZIONALE / Bando 2022 Prot. 2022CX7HTJ; PNRR-MAD-2022-12376543.

No datasets were generated or analysed during the current study.