Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial

Abstract

Patients with obesity-related heart failure with preserved ejection fraction (HFpEF) display circulatory volume expansion and pressure overload contributing to cardiovascular-kidney end-organ damage. In the SUMMIT trial, patients with HFpEF and obesity were randomized to the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist tirzepatide (n = 364, 200 women) or placebo (n = 367, 193 women). As reported separately, tirzepatide decreased cardiovascular death or worsening heart failure. Here, in this mechanistic secondary analysis of the SUMMIT trial, tirzepatide treatment at 52 weeks, as compared with placebo, reduced systolic blood pressure (estimated treatment difference (ETD) -5 mmHg, 95% confidence interval (CI) -7 to -3; P < 0.001), decreased estimated blood volume (ETD -0.58 l, 95% CI -0.63 to -0.52; P < 0.001) and reduced C-reactive protein levels (ETD -37.2%, 95% CI -45.7 to -27.3; P < 0.001). These changes were coupled with an increase in estimated glomerular filtration rate (ETD 2.90 ml min^-1 1.73 m^-2 yr^-1, 95% CI 0.94 to 4.86; P = 0.004), a decrease in urine albumin-creatinine ratio (ETD 24 weeks, -25.0%, 95% CI -36 to -13%; P < 0.001; 52 weeks, -15%, 95% CI -28 to 0.1; P = 0.051), a reduction in N-terminal prohormone B-type natriuretic peptide levels (ETD 52 weeks -10.5%, 95% CI -20.7 to 1.0%; P = 0.07) and a reduction in troponin T levels (ETD 52 weeks -10.4%, 95% CI -16.7 to -3.6; P = 0.003). In post hoc exploratory analyses, decreased estimated blood volume with tirzepatide treatment was significantly correlated with decreased blood pressure, reduced microalbuminuria, improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and increased 6-min walk distance. Moreover, decreased C-reactive protein levels were correlated with reduced troponin T levels and improved 6-min walk distance. In conclusion, tirzepatide reduced circulatory volume-pressure overload and systemic inflammation and mitigated cardiovascular-kidney end-organ injury in patients with HFpEF and obesity, providing new insights into the mechanisms of benefit from tirzepatide. ClinicalTrials.gov registration: NCT04847557 .

Fig. 1. Effects of tirzepatide on pressure overload and volume expansion.

a, Least-squares mean changes from baseline in systolic BP (SBP) plotted as a function of duration of treatment in participants randomized to tirzepatide (red circles) or placebo (black squares). b, The estimated mean treatment difference in the change in BV versus baseline with tirzepatide (TZP) compared with placebo plotted as a function of duration of treatment. The error bars represent s.e.m. for both panels; two-sided P < 0.001 for each time point comparison for a and b based upon comparing the least-squares means calculated from a mixed-model repeated-measures model incorporating baseline value, sex, history of HF decompensation within 12 months, diabetes status, baseline BMI group (<35, ≥35 kg m⁻²), treatment assignment, time, and treatment × time interaction. No correction was made for multiple hypothesis testing.

Fig. 2. Effects of tirzepatide on systemic inflammation, cardiac injury and natriuretic peptide levels.

a, Least-squares mean changes from baseline in CRP plotted as a function of duration of treatment in participants randomized to tirzepatide (red circles) or placebo (black squares). b, The estimated mean treatment difference in the change in troponin T and NT-proBNP with tirzepatide (TZP) to baseline compared with placebo plotted as a function of duration of treatment. The error bars represent the s.e.m. for all panels; P values are two-sided for each time point comparison for a and b based upon comparing the least-squares means calculated from a mixed-model repeated-measures model incorporating baseline value, history of HF decompensation within 12 months, diabetes status, baseline BMI group (<35, ≥35 kg m⁻²), treatment assignment, time, and treatment × time interaction. No correction was made for multiple hypothesis testing.

Fig. 3. Effects of tirzepatide on kidney function and albuminuria.

a, Top: least-squares mean changes from baseline in eGFR plotted as a function of duration of treatment in participants randomized to tirzepatide (red circles) or placebo (black squares). Bottom: the estimated mean treatment difference in the change in eGFR with tirzepatide versus baseline compared with placebo plotted as a function of duration of treatment. b, The least-squares mean change in UACR in participants treated with tirzepatide (red) and placebo (black) as a function of duration of treatment. The error bars represent the s.e.m. for all panels; P values are two-sided for each time point comparison for a and b based upon comparing the least-squares means calculated from a mixed-model repeated-measures model incorporating baseline value, sex, history of HF decompensation within 12 months, diabetes status, baseline BMI group (<35, ≥35 kg m⁻²), treatment assignment, time, and treatment × time interaction. No correction was made for multiple hypothesis testing.