Evidence that tirzepatide protects against diabetes-related cardiac damages

Abstract

Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective antidiabetic drugs with potential cardiovascular benefits. Despite their well-established role in reducing the risk of major adverse cardiovascular events (MACE), their impact on heart failure (HF) remains unclear. Therefore, our study examined the cardioprotective effects of tirzepatide (TZT), a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist. Methods A three-steps approach was designed: (i) Meta-analysis investigation with the primary objective of assessing major adverse cardiovascular events (MACE) occurrence from major randomized clinical trials.; (ii) TZT effects on a human cardiac AC16 cell line exposed to normal (5 mM) and high (33 mM) glucose concentrations for 7 days. The gene expression and protein levels of primary markers related to cardiac fibrosis, hypertrophy, and calcium modulation were evaluated. (iii) In silico data from bioinformatic analyses for generating an interaction map that delineates the potential mechanism of action of TZT. Results Meta-analysis showed a reduced risk for MACE events by TZT therapy (HR was 0.59 (95% CI 0.40–0.79, Heterogeneity: r2 = 0.01, I2 = 23.45%, H2 = 1.31). In the human AC16 cardiac cell line treatment with 100 nM TZT contrasted high glucose (HG) levels increase in the expression of markers associated with fibrosis, hypertrophy, and cell death (p < 0.05 for all investigated markers). Bioinformatics analysis confirmed the interaction between the analyzed markers and the associated pathways found in AC16 cells by which TZT affects apoptosis, fibrosis, and contractility, thus reducing the risk of heart failure. Conclusion Our findings indicate that TZT has beneficial effects on cardiac cells by positively modulating cardiomyocyte death, fibrosis, and hypertrophy in the presence of high glucose concentrations. This suggests that TZT may reduce the risk of diabetes-related cardiac damage, highlighting its potential as a therapeutic option for heart failure management clinical trials. Our study strongly supports the rationale behind the clinical trials currently underway, the results of which will be further investigated to gain insights into the cardiovascular safety and efficacy of TZT. Graphical Abstract

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

“…This highlights tirzepatide’s potential as an alternative treatment for clinical outcomes related to HF management. However, further research is needed to evaluate its impact on HF outcomes in clinical settings [ 21 ].…”

“…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 ].…”

“…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 ].…”

“…Additionally, it significantly reduced the activation of CASP3, a crucial component of apoptotic pathways. It also led to a significant reduction in the autophagy biomarkers Beclin1 and p62, which indicates an increase in autophagy flux [ 21 ] Fig. 1 .…”