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.

Borlaug BA, Zile MR, Kramer CM, Baum SJ, Hurt K, Litwin SE, Murakami M, Ou Y, Upadhyay N, Packer M

Nature medicine17 Nov 2024Cited by 117 (Europe PMC)

PMID39551891PMCIDPMC11835708DOI10.1038/s41591-024-03374-zPepBankPUB-39551891

Summary

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 .

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study10

10 results from studies that gave the peptide. 10 results from people.

01HumanRandomized controlled trialMechanism
In adults with HFpEF and obesity on tirzepatide, decreased estimated blood volume was significantly correlated with decreased blood pressure, reduced microalbuminuria, improved KCCQ Clinical Summary Score and increased 6-min walk distance in post hoc exploratory analyses.
In plain wordsIn adults with heart failure and obesity on tirzepatide, a bigger blood volume drop was linked to better blood pressure, kidney, symptom and walking results.
Peptide
Tirzepatide
Outcome
Not applicableCorrelation of blood volume decrease with blood pressure, microalbuminuria, KCCQ-CSS and 6-min walk distance
Study
n: not reported in source
Analysis
Exploratory
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated · 52 weeksAs given in this study (human).
Source sentences
Summary
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.
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-3955189109
02HumanRandomized controlled trialMechanism
In adults with HFpEF and obesity on tirzepatide, decreased C-reactive protein levels were correlated with reduced troponin T levels and improved 6-min walk distance.
In plain wordsIn adults with heart failure and obesity on tirzepatide, a bigger CRP drop was linked to lower troponin T and longer walking distance.
Peptide
Tirzepatide
Outcome
Not applicableCorrelation of C-reactive protein decrease with troponin T and 6-min walk distance
Study
n: not reported in source
Analysis
Exploratory
Outcome group
Inflammation markers · Immune and inflammation
Studied dose
Dose not stated · 52 weeksAs given in this study (human).
Source sentences
Summary
Moreover, decreased C-reactive protein levels were correlated with reduced troponin T levels and improved 6-min walk distance.
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-3955189110
03HumanRandomized controlled trialEfficacy outcome
In adults with HFpEF and obesity, tirzepatide reduced systolic blood pressure at 52 weeks versus placebo (estimated treatment difference -5 mmHg).
In plain wordsIn adults with heart failure and obesity, tirzepatide lowered systolic blood pressure more than placebo at 52 weeks.
Peptide
Tirzepatide
Outcome
DecreaseSystolic blood pressure at 52 weeks
Study
n = 731
Comparator
Placebo
Outcome group
Blood pressure · Cardiovascular
Studied dose
Dose not stated · 52 weeksAs given in this study (human).
Measurements
Estimated treatment difference in systolic blood pressure
−5 mmHg
52 weeks
Source sentences
Summary
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)
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-3955189101
04HumanRandomized controlled trialEfficacy outcome
In adults with HFpEF and obesity, tirzepatide decreased estimated blood volume at 52 weeks versus placebo (estimated treatment difference -0.58 l).
In plain wordsIn adults with heart failure and obesity, tirzepatide lowered estimated blood volume more than placebo at 52 weeks.
Peptide
Tirzepatide
Outcome
DecreaseEstimated blood volume at 52 weeks
Study
n = 731
Comparator
Placebo
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated · 52 weeksAs given in this study (human).
Measurements
Estimated treatment difference in blood volume
−0.58 l
52 weeks
Source sentences
Summary
decreased estimated blood volume (ETD -0.58 l, 95% CI -0.63 to -0.52; P < 0.001)
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-3955189102
05HumanRandomized controlled trialEfficacy outcome
In adults with HFpEF and obesity, tirzepatide reduced C-reactive protein levels at 52 weeks versus placebo (estimated treatment difference -37.2%).
In plain wordsIn adults with heart failure and obesity, tirzepatide lowered the inflammation marker CRP more than placebo at 52 weeks.
Peptide
Tirzepatide
Outcome
DecreaseC-reactive protein at 52 weeks
Study
n = 731
Comparator
Placebo
Outcome group
Inflammation markers · Immune and inflammation
Studied dose
Dose not stated · 52 weeksAs given in this study (human).
Measurements
Estimated treatment difference in C-reactive protein
−37.2%
52 weeks
Source sentences
Summary
reduced C-reactive protein levels (ETD -37.2%, 95% CI -45.7 to -27.3; P < 0.001)
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-3955189103
06HumanRandomized controlled trialEfficacy outcome
In adults with HFpEF and obesity, tirzepatide increased estimated glomerular filtration rate versus placebo (estimated treatment difference 2.90 ml min-1 1.73 m-2 yr-1).
In plain wordsIn adults with heart failure and obesity, tirzepatide increased a measure of kidney filtration more than placebo.
Peptide
Tirzepatide
Outcome
IncreaseEstimated glomerular filtration rate
Study
n = 731
Comparator
Placebo
Outcome group
Kidney function · Kidney and urinary
Studied dose
Dose not stated · 52 weeksAs given in this study (human).
Measurements
Estimated treatment difference in eGFR
2.9 ml min-1 1.73 m-2 yr-1
Source sentences
Summary
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)
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-3955189104
07HumanRandomized controlled trialEfficacy outcome
In adults with HFpEF and obesity, tirzepatide decreased urine albumin-creatinine ratio at 24 weeks versus placebo (estimated treatment difference -25.0%).
In plain wordsIn adults with heart failure and obesity, tirzepatide lowered urine albumin more than placebo at 24 weeks.
Peptide
Tirzepatide
Outcome
DecreaseUrine albumin-creatinine ratio at 24 weeks
Study
n = 731
Comparator
Placebo
Outcome group
Kidney function · Kidney and urinary
Studied dose
Dose not stated · 24 weeksAs given in this study (human).
Measurements
Estimated treatment difference in urine albumin-creatinine ratio
−25%
24 weeks
Source sentences
Summary
a decrease in urine albumin-creatinine ratio (ETD 24 weeks, -25.0%, 95% CI -36 to -13%; P < 0.001
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-3955189105
08HumanRandomized controlled trialEfficacy outcome
In adults with HFpEF and obesity, the decrease in urine albumin-creatinine ratio at 52 weeks versus placebo was not statistically significant (estimated treatment difference -15%, P = 0.051).
In plain wordsIn adults with heart failure and obesity, the lower urine albumin with tirzepatide at 52 weeks was not clearly different from placebo.
Peptide
Tirzepatide
Outcome
No significant changeUrine albumin-creatinine ratio at 52 weeks
Study
n = 731
Comparator
Placebo
Outcome group
Kidney function · Kidney and urinary
Studied dose
Dose not stated · 52 weeksAs given in this study (human).
Measurements
Estimated treatment difference in urine albumin-creatinine ratio
−15%
52 weeks
Source sentences
Summary
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)
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-3955189106
09HumanRandomized controlled trialEfficacy outcome
In adults with HFpEF and obesity, the reduction in N-terminal prohormone B-type natriuretic peptide at 52 weeks versus placebo was not statistically significant (estimated treatment difference -10.5%, P = 0.07).
In plain wordsIn adults with heart failure and obesity, the lower NT-proBNP heart strain marker with tirzepatide at 52 weeks was not clearly different from placebo.
Peptide
Tirzepatide
Outcome
No significant changeNT-proBNP at 52 weeks
Study
n = 731
Comparator
Placebo
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated · 52 weeksAs given in this study (human).
Measurements
Estimated treatment difference in NT-proBNP
−10.5%
52 weeks
Source sentences
Summary
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)
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-3955189107
10HumanRandomized controlled trialEfficacy outcome
In adults with HFpEF and obesity, tirzepatide reduced troponin T levels at 52 weeks versus placebo (estimated treatment difference -10.4%).
In plain wordsIn adults with heart failure and obesity, tirzepatide lowered troponin T, a heart injury marker, more than placebo at 52 weeks.
Peptide
Tirzepatide
Outcome
DecreaseTroponin T at 52 weeks
Study
n = 731
Comparator
Placebo
Outcome group
Heart function · Cardiovascular
Studied dose
Dose not stated · 52 weeksAs given in this study (human).
Measurements
Estimated treatment difference in troponin T
−10.4%
52 weeks
Source sentences
Summary
a reduction in troponin T levels (ETD 52 weeks -10.4%, 95% CI -16.7 to -3.6; P = 0.003).
1 context sentence(design, population, supporting numbers)
Summary · context
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).
Show in the study text Report a problemFND-3955189108

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Registered trials2

Trials this study reports on, or that list this study as a reference. Registry data from ClinicalTrials.gov.

2 trials · 1 not yet recruiting · 1 completed · 1 with posted results · source ClinicalTrials.gov (opens in a new tab)

Not yet recruitingPhase 3NCT07738276

Evaluation of the Efficacy and Safety of Tirzepatide, a Dual GLP-1/GIP Agonist, on Functional Capacity in Reduced Ejection Fraction Heart Failure Patients With Obesity

Shahid Beheshti University of Medical Sciencesn = 60est. 18 Jul 2026 to est. 22 Dec 2027

Heart Failure and Reduced Ejection Fraction · Obesity & Overweight · Tirzepatide

Trial page ClinicalTrials.govUpdated 3 Aug 2026

CompletedPhase 3Results postedNCT04847557

A Study of Tirzepatide (LY3298176) in Participants With Heart Failure With Preserved Ejection Fraction (HFpEF) and Obesity: The SUMMIT Trial

Eli Lilly and Companyn = 73120 Apr 2021 to 2 Jul 2024

Obesity · Heart Failure With Preserved Ejection Fraction (HFpEF)

Trial page ClinicalTrials.govUpdated 20 Aug 2025

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
12 Oct 2026, 12:58 UTC
Study results updated
Version 1
9 Oct 2026, 03:07 UTC
First added · source update from Europe PMC

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