Abstract Body (Do not enter title and authors here): Background: Patients with obesity-related heart failure and a preserved ejection fraction (HFpEF) display circulatory pressure and volume overload, contributing to end organ kidney and myocardial damage. We hypothesized that tirzepatide (TZP), a long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist, would reduce pressure-volume overload, and thus improve end-organ cardiorenal function in HFpEF.
Methods: In this double-blind trial, we randomly assigned 731 patients with class II-IV heart failure, ejection fraction ≥50% and body mass index (BMI) ≥30 kg/m² to tirzepatide (titrated to a maximum tolerated dose of up to 15 mg subcutaneously weekly) (n=364) or placebo (n=367). Blood pressure (BP), anthropometrics, estimated plasma volume (PV), and blood samples were obtained at baseline and out to 52 weeks for all participants to assess biomarkers indicative of cardiorenal function.
Results: As reported separately at this meeting, tirzepatide decreased cardiovascular death or worsening heart failure (hazard ratio, 0.62; 95% CI, 0.41 to 0.95; P=0.026). At baseline, participants exhibited borderline hypertension (systolic BP ~128 mmHg), volume expansion (PV~3.3 L), and chronic kidney disease (eGFR ~65 ml/min/1.73m²), with low-grade microalbuminuria (urine albumin/creatinine ~2.8 g/mol) and subclinical myocardial injury (troponin T ~11 ng/L). As compared to placebo, treatment with tirzepatide reduced systolic BP (estimated treatment difference [ETD] at 24 weeks -6 mmHg, 95% CI -8, -4, p<.001; 52 weeks -5 mmHg, 95% CI -7, -3, p<.001) and decreased PV (ETD 52 weeks -0.32 L, 95% CI -0.36, -0.27, p<0.001). These changes were coupled with increases in eGFR at 52 weeks (ETD 1.85 ml/min/1.73m², 95% CI 0.19, 3.51; p=0.029), decreases in microalbuminuria (ETD 24 weeks, -25.0%, 95% CI -36,-13; p<.001, 52 weeks -15%, 95% CI -28, 0.1; p=0.051), and a reduction in troponin T (ETD 24 weeks -9.8% [95%CI -16.0,-3.3], p=0.004, 52 weeks -10.4% [95% CI -16.7,-3.6], p=0.003) with tirzepatide compared to placebo.
Conclusions: Tirzepatide reduced circulatory pressure-volume overload and mitigated end organ damage in the kidney and heart in patients with HFpEF and obesity, providing new insight into the mechanisms of benefit from tirzepatide in patients with obesity-related HFpEF.