Tirzepatide, a dual GIP/GLP1-receptor co-agonist preserves cardiac function and improves survival in angiotensin II-induced heart failure model in mice: comparison to liraglutide

Abstract

Background: Incretin analogues, used for the treatment of type 2 diabetes mellitus and obesity, such as GLP1-receptor agonist liraglutide (Lira) have been shown to reduce major adverse cardiac events in recent clinical trials of heart failure. Tirzepatide (TZP), a dual GIP/GLP1-receptor agonist has shown promising results in the SUMMIT trial as improved cardiovascular outcomes in patients with heart failure with preserved ejection fraction (HFpEF). However, data regarding their use in heart failure with reduced ejection fraction (HFrEF) is lacking. We performed a head-to-head comparative study in a mouse model of non-ischaemic cardiac injury induced by continuous angiotensin II (AngII) infusion, as AngII is a key driver of both heart failure forms.

Methods: Osmotic minipumps were inserted for subcutaneous (s.c.) administration of AngII (1.5 mg/kg/day) in 5-month-old male Balb/c mice or sham surgery was performed. Animals were treated with vehicle (Veh), Lira (300 µg/day i.p.) or TZP (48 µg/day s.c.) for 14 days in the following groups: Sham/Veh (n = 7), AngII/Veh (n = 15), Sham/Lira (n = 7), AngII/Lira (n = 15), Sham/TZP (n = 8), AngII/TZP (n = 15). Cardiac structural, functional and molecular characteristics were assessed by echocardiography, ECG, immunohistochemistry, flow cytometry and qRT-PCR.

Results: Mortality was significantly higher in AngII/Veh animals compared to controls, while AngII/TZP mice showed significantly reduced mortality after 14 days of treatment. Both Lira and TZP caused significant weight reduction compared to controls. AngII given alone also reduced body mass, and this reduction was further enhanced by TZP. Treatment with both compounds preserved cardiac systolic and diastolic function compared with AngII/Veh animals, as shown by normal ejection fraction and E/e', respectively. Both Lira and TZP decreased the AngII-induced elevation of cardiac fibrosis and hypertrophy markers, including Ctgf, Col1a1, Col3a1, and Nppa, while TZP also reduced the elevated Nppb level. TZP also reduced systemic inflammation, as shown by the reduction in serum CRP levels.

Conclusions: Lira and TZP preserved cardiac function and decreased markers of hypertrophy and fibrosis in mice with AngII-induced heart failure, whereas TZP also significantly decreased mortality. In addition to HFpEF, the use of incretin analogues may also be of clinical relevance in the treatment of HFrEF. However, as patients with heart failure, AngII level is elevated and can cause weight loss/cachexia, the usage of incretin analogues to treat non-obese heart failure patients should be considered.

Keywords: HFrEF; Heart failure; Incretin analogues; Liraglutide; Tirzepatide.

Fig. 1

Tirzepatide significantly reduced the mortality of angiotensin II infusion. Percent of survival animals during the follow-up period A and on the day of termination B Kaplan–Meier method, log-rank Mantel–Cox test, *P < 0.05

Fig. 2

Tirzepatide and liraglutide treatment led to robust weight reduction combined with AngII. Body weight changes during the treatment period in grams A, Mean ± SEM) and in percent B, and on the day of termination C. Two-way ANOVA followed by Holm–Sidak post-hoc test, *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001

Fig. 3

Tirzepatide and liraglutide preserved cardiac function. Functional parameters of the heart after one A and two weeks B of AngII infusion. Two-way ANOVA followed by Holm–Sidak post-hoc test, *P < 0.05, **P < 0.01, and ****P < 0.0001

Fig. 4

Both drugs attenuate the extent of remodelling caused by angiotensin II infusion. Structural changes of the heart at one week A and two weeks B Continuous AngII infusion led to the remodelling of the left ventricle. Representatives C from the long-axis view M-mode of the heart show the wall thickness increase due to AngII infusion and treatment with TZP. Two-way ANOVA followed by Holm–Sidak post-hoc test, *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001

Fig. 5

Angiotensin II produced conduction and repolarization abnormalities, mitigated by tirzepatide and liraglutide. Representative electrocardiograms from lead II A and QRS width measured in lead III B Two-way ANOVA followed by Holm–Sidak post-hoc test, *P < 0.05

Fig. 6

Tirzepatide and liraglutide alleviate the fibrosis and hypertrophy caused by angiotensin II infusion. Representatives of Sirius red staining in the heart A show that AngII infusion led to higher fibrosis compared to the controls. Markers of fibrosis and hypertrophy B Two-way ANOVA followed by Holm–Sidak post-hoc test, *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001

Fig. 7

Tirzepatide reduces hypertrophy and increases capillary density of the heart in angiotensin II-induced cardiac injury. Representatives of lectin histochemistry from the heart cross-sectional area A cell surface area (CSA), capillary density, and capillary count were calculated from the captured pictures with ImageJ B Two-way ANOVA followed by Holm–Sidak post-hoc test, *P < 0.05, **P < 0.01, ***P < 0.001

Fig. 8

Angiotensin II infusion led to a mild-systemic inflammation, which was reduced by tirzepatide. C-reaction protein (CRP) concentration in the serum A Correlation analysis B demonstrates a negative correlation between CRP level and body surface area (BSA). Two-way ANOVA followed by Holm–Sidak post-hoc test, *P < 0.05, **P < 0.01, Spearman’s correlation test, **P < 0.0021

Fig. 9

Angiotensin II infusion did not lead to inflammation at the tissue level of the heart. Characterization of immune cell infiltration in the heart with immunohistochemistry and qRT-PCR A Expression level of inflammatory markers in the heart B Two-way ANOVA followed by Holm–Sidak post-hoc test