Bella Haake, PharmD, M Health Fairview
Background: The 2022 ACC/AHA/HFSA Heart Failure Guidelines define heart failure as “a complex clinical syndrome with symptoms and signs that result from any structural or functional impairment of ventricular filling or ejection of blood.” Heart failure with preserved ejection fraction (HFpEF) is defined as having a left ventricle ejection fraction ≥ 50%. Obesity is a risk factor for HFpEF, and together, are associated with an increase in total heart volume including epicardial and pericardial adipose tissue. Tirzepatide is a combined glucagon-like peptide 1 (GLP-1) receptor agonist and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist currently FDA approved for the treatment of type II diabetes, chronic weight management, and obstructive sleep apnea. It does not yet have any clinical indications for cardiovascular uses. Semaglutide, a similarly used GLP-1 receptor agonist, is approved for use in reducing the risk of major cardiovascular events in adults with type II diabetes and established cardiovascular disease. Semaglutide has previously been studied in obesity-related HFpEF by Solomon et al., though semaglutide was not found to reduce left ventricle (LV) mass or epicardial adipose tissue. This is the first study analyzing the effects of tirzepatide in this population.
Objective: To analyze the effects of tirzepatide use in obesity-related HFpEF, specifically determining structural changes to cardiac tissue including reduction in LV mass or changes to volume of epicardial or pericardial adipose tissue.
Study Design: This is the cardiac magnetic resonance (CMR) substudy of the SUMMIT trial, a phase 3, double-blind, randomized, placebo controlled-trial studying the effects of tirzapatide vs placebo in the setting of HFpEF and obesity. Participants for this CMR substudy were chosen if they met all criteria for the SUMMIT trial (heart failure diagnosis, EF ≥ 50%, and BMI ≥ 30kg/m2), and if their study site had the capability for CMR imaging. Participants were randomly assigned to placebo or treatment (up to 15 mg tirzepatide injected subcutaneously once weekly) for 52 weeks of treatment. Cardiac magnetic resonance imaging was used in a controlled manner and analyzed at both baseline and after completion of the treatment period to determine LV mass, the volume of the epicardial/pericardial tissue, LV and left atrium (LA) volumes, and LV and LA strain. The same cardiac scanner was used at baseline and follow-up imaging for each participant. All images were blindly analyzed by the same analyst with 25 years of experience.
Results: A total of 106 patients completed the 52 week treatment period and had adequate CMR imaging at baseline and follow-up. The median age of participants was 65.1 years, with 55% being female. Participants were largely from Argentina and Brazil, making up 80% of the entire population. 64% of all participants had a baseline BMI >35 kg/m2, and 51% had type II diabetes with an overall median HbA1c of 6.3%. The placebo-corrected reduction in LV mass in the treatment group was statistically significant at -11 g (95% CI: -19 to -4 g; P = 0.004). Also significant was the between-group difference of change in stroke volume at -8 mL (95% CI: -14 to -2 mL; P = 0.011) and the placebo-corrected difference in pericardial adipose tissue reduction at -43 g (95% CI: -65 to -21 g; P < 0.001). Additionally, the placebo-corrected reduction in paracardiac adipose tissue was significant at -45 mL (95% CI: -69 to -22 mL; P < 0.001). The change in both LV end-diastolic volume and epicardial adipose tissue were reduced in the treatment group, though not statistically significant. There were no between-group differences in changes to end-systolic volume, cardiac output, or ejection fraction. Of note, the change in LV mass was statistically significantly correlated with a change in body weight (r = 0.34; P < 0.02).
Conclusions: The use of tirzepatide in obesity-related HFpEF led to reduced LV mass, stroke volume, and volume of both pericardial and paracardiac adipose tissue. Participants taking tirzepatide therapy had an average reduction in LV mass of -11 g over placebo. The reduction in LV mass was correlated with reduction in body weight.
Key Points: The data from this trial may explain the reduced heart failure events seen in the SUMMIT trial overall, and may lead to further use of GLP-1/GIP therapy for heart failure.
Published March 7, 2025
Reference:
- Kramer CM, Borlaug BA, Zile M MR, et al. Tirzepatide Reduces LV Mass and Paracardiac Adipose Tissue in Obesity-Related Heart Failure: SUMMIT CMR Substudy. J Am Coll Cardiol. Published online November 5, 2024. doi:10.1016/j.jacc.2024.11.001
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022 May 3;145(18):e1033. doi: 10.1161/CIR.0000000000001073
- Solomon SD, Ostrominski JW, Wang X, et al. Effect of Semaglutide on Cardiac Structure and Function in Patients With Obesity-Related Heart Failure. J Am Coll Cardiol. 2024;84(17):1587-1602. doi:10.1016/j.jacc.2024.08.021
- Packer M, Zile MR, Kramer CM, et al. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. Published online November 16, 2024. doi:10.1056/NEJMoa2410027