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

Area of Science:

• Cardiology
• Pharmacology
• Molecular Biology

Background:

• Incretin analogues (GLP1-receptor agonists like liraglutide and dual GIP/GLP1-receptor agonists like tirzepatide) show cardiovascular benefits in type 2 diabetes and obesity.
• Clinical trials indicate liraglutide reduces major adverse cardiac events in heart failure patients.
• Tirzepatide demonstrated improved cardiovascular outcomes in heart failure with preserved ejection fraction (HFpEF).

Purpose of the Study:

• To compare the efficacy of liraglutide and tirzepatide in a mouse model of non-ischaemic heart failure with reduced ejection fraction (HFrEF).
• To investigate the effects of these incretin analogues on cardiac structure, function, and molecular markers in response to angiotensin II-induced cardiac injury.

Main Methods:

• Angiotensin II infusion in mice to induce non-ischaemic cardiac injury, mimicking heart failure.
• Subcutaneous administration of liraglutide or tirzepatide for 14 days.
• Assessment of cardiac function (echocardiography, ECG), fibrosis, hypertrophy markers, and inflammation.

Main Results:

• Tirzepatide significantly reduced mortality in the heart failure model compared to vehicle control.
• Both liraglutide and tirzepatide preserved cardiac systolic and diastolic function and reduced cardiac fibrosis and hypertrophy markers.
• Tirzepatide further reduced body weight loss induced by angiotensin II and decreased systemic inflammation (serum CRP levels).

Conclusions:

• Liraglutide and tirzepatide demonstrate cardioprotective effects, preserving cardiac function and reducing fibrosis/hypertrophy markers in a mouse model of HFrEF.
• Tirzepatide showed a significant survival benefit, highlighting its potential therapeutic role in HFrEF.
• Incretin analogues may be clinically relevant for treating HFrEF, even in non-obese patients with elevated angiotensin II levels.