Data from the SUMMIT trial indicates that tirzepatide lowers circulatory pressure-volume overload and reduces end-organ damage in the kidney and heart among patients with heart failure with preserved ejection fraction (HFpEF) and obesity. The findings, presented at the American Heart Association (AHA) Scientific Sessions 2024, build on the established benefits of tirzepatide, a long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist (GLP-1 RA), in treating obesity-related HFpEF.
Impact on Pathophysiological Components
Barry A. Borlaug, MD, from the Mayo Clinic, highlighted that tirzepatide appears to act through multiple pathways, affecting both hemodynamic and volume-loading aspects, as well as inflammation, which are critical in obesity-related HFpEF.
The SUMMIT trial, a double-blind study, randomized 731 participants with NYHA Class II-IV heart failure, an ejection fraction (EF) of ≥50%, and a body mass index (BMI) ≥30 kg/m2 to either tirzepatide (n = 364) or placebo (n = 367). Tirzepatide was titrated up to a maximum weekly tolerated dose of 15 mg subcutaneously.
Key Biomarker Changes
Researchers, led by Borlaug, analyzed blood pressure, anthropometrics, estimated plasma volume, and blood samples at baseline and 52 weeks to determine biomarkers of cardiorenal function. The primary outcomes of the SUMMIT trial revealed that tirzepatide reduced the risk of cardiovascular death or worsening heart failure (HR, 0.62; 95% CI, 0.41–0.95; P = .026).
Participants in the trial presented with borderline hypertension (systolic blood pressure [SBP], ~128 mmHg), volume expansion (estimated plasma volume, ~3.3 L), chronic kidney disease (urine albumin/creatinine ratio [UACR], ~2.8 g/mol), and subclinical myocardial injury (troponin T, ~11 ng/L).
Significant Reductions in Blood Pressure and Plasma Volume
Tirzepatide treatment, compared to placebo, reduced SBP by approximately 6 mmHg (95% CI, –8 to –4; P <.001) at 24 weeks and by –5 mmHg (95% CI, –7 to –3; P <.001) at 52 weeks. Additionally, tirzepatide decreased the estimated plasma volume by about 0.32 L (95% CI, –0.36 to –0.27; P <.001) at 52 weeks.
Improvements in Renal Function and Myocardial Injury Markers
The study also observed an increase in eGFR at 52 weeks (~1.85 ml/min/1.73 m2; 95% CI, 0.19–3.51; P = .029), decreases in microalbuminuria at 24 weeks (–25.0%; 95% CI, –36 to –13; P <.001) and 52 weeks (–15%; 95% CI, –28 to 0.1; P = .051), and a reduction in troponin T at 24 weeks (–9.8%; 95% CI, –16.0 to –3.3; P = .004) and 52 weeks (–10.4%; 95% CI, –16.7 to –3.6; P = .003).
Clinical Implications
Borlaug emphasized the potential for wider use of incretin-based drugs like tirzepatide in treating individuals with obesity-related HFpEF.
