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
- Design
- Randomized trial · Mixed outcome
- Match to healthy normal-weight adults aged 55–75
- Different population[Auto] Participants had obesity/overweight (age/BMI not reported in abstract).
- Could weight loss explain it?
- Possibly[Auto] Participants had obesity and/or type 2 diabetes and the abstract does not separate direct drug effects from weight loss or glycaemic improvement.
- Study tier
- Study tier 3[Auto] Small or short randomized trial (auto-provisional).
- Assessment
- Version 1 · automatic, not yet reviewed by a person · Sep 13, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
[Auto, unreviewed; last sentences of abstract] 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 .
01Findings
What the study reported
- Drugs
- Tirzepatide
- Comparator
- placebo
- Primary outcome
- Not extracted
- Effect
- Not extracted
- 95% confidence interval
- Not extracted
- Follow-up
- 52 weeks
- Adverse events
- Not extracted
- Limitations
- Auto-classified from abstract only; effect estimates, adverse events and limitations not extracted. Requires manual review.
Who was studied
- Obesity status
- obesity/overweight present (all or most)
- Cvd status
- cardiovascular disease present in population (see abstract)
- Baseline condition
- heart failure with preserved ejection fraction
Study quality details
- Study design
- Randomized controlled trial
- Sample size
- not extracted
- Randomization
- yes
- Blinding
- not stated
- Comparator
- placebo
- Follow up duration
- 52 weeks
- Outcome type
- mixed
- Replication
- not assessed (auto)
- Consistency with other evidence
- not assessed (auto)
- Population applicability
- INDIRECT
- Statistical precision
- CI reported: 95% confidence interval (CI
- Funding conflicts
- no
- Peer review status
- yes
01bRisk of bias
How much the result can be relied on
Risk of bias is judged per result, not per paper: the same study can report one marker at low risk and another at high. Two reviewers assess each result independently against a written guide, and every domain judgment below carries its reasoning and the sentences it rests on.
These words are not quality scores. On the RoB 2 scale, High risk of bias is the worst rating a result can receive and Low risk of bias is the best — the opposite of how the same words read on some other scales. Levels are always written out in full here for that reason.
High-sensitivity CRP, % change from baseline (tirzepatide vs placebo), SUMMIT trial secondary mechanistic analysis · 52 weeks
High risk of bias · RoB 2 · Two reviewers agreed on every domain
How the overall was reached: RoB 2 algorithm: any domain High makes the result High overall. D5 is High on affirmative author evidence that the assessed CRP analysis was an exploratory outcome reported without any multiplicity adjustment among a large set of simultaneously reported mechanistic endpoints and timepoints, with the protocol/SAP not retrievable to verify the outcome definition and model. D3 adds Some concerns from wholly unreported attrition at 52 weeks. D1, D2 and D4 are Low (D1 by presumption, not verification). The direction and size of the CRP effect are large and internally consistent across 24 and 52 weeks, so this is a reporting/selection concern rather than an indication that the estimate is implausible.
| Domain | Judgment and reasoning |
|---|---|
| D1 · Randomisation process Low risk of bias | Randomization is stated with 1:1 double-blind allocation and three stratification factors, and the parent trial is identified by name (SUMMIT) and registration (NCT04847557) in the Methods. The concealment mechanism (IVRS/IWRS or equivalent) is NOT described in the retrieved sources; allocation concealment is therefore PRESUMED, not verified, under guide item 6 (large-industry-trial presumption reaching the parent trial), the identifying source being the Methods sentence naming SUMMIT and NCT04847557. The presumption is not rebutted: the paper reports no baseline differences, and the Table 1 / Table 2 arm values (age 65.5 vs 65.0 y; BMI 38.3 vs 38.2; median CRP 3.1 vs 3.4 mg/l) are compatible with chance.Following screening, eligible patients were randomized double blind (1:1) to receive placebo or tirzepatide 2.5 mg per week subcutaneously, in addition to usual therapy. Randomization was stratified by (1) HF decompensation within 12 months; (2) type 2 diabetes; (3) BMI ≥35 kg m − 2 or <35 kg m −2 . The registration identifier on clinicaltrials.gov is NCT04847557 . The sponsor was Eli Lilly and Company. |
| D2 · Deviations from intended interventions Low risk of bias | Double-blind design with matching placebo and forced titration in both arms, and the analysis is explicitly an assignment-based (treatment-policy) estimand, i.e. irrespective of adherence, which matches the effect of interest. Per the collection rule, D2 for a lab biomarker outcome is judged on discontinuation imbalance and ITT handling rather than on GLP-1-related unblinding; the estimand is ITT-consistent. The paper reports no discontinuation counts by arm, so imbalance cannot be checked directly - recorded as a limitation rather than a downgrade, since the treatment-policy estimand is stated.Analyses were guided by the treatment policy estimand that represents the efficacy irrespective of adherence to study intervention. The dose of the double-blind study medication was increased by 2.5 mg every 4 weeks as tolerated until a dose of 15.0 mg per week of tirzepatide or matching placebo could be achieved after 20 weeks, which was maintained until the end of the trial. |
| D3 · Missing outcome data Some concerns about risk of bias | No information. The retrieved sources give no number of participants contributing a 52-week CRP value in either arm, no flow diagram, and no statement about missing samples or imputation; the MMRM uses all available observations under an implicit MAR assumption and no sensitivity analysis for value-dependent missingness is reported. Neither guide D3 prong (>20% missing; >5-point arm difference) can be evaluated, so "data available for nearly all" is NI rather than Y, and the domain cannot be Low. This is a 52-week endpoint in a trial of an agent with known GI-driven discontinuation, so the unquantified attrition is not obviously trivial, but there is no evidence it depends on the true CRP value, so High is not reached either. |
| D4 · Measurement of the outcome Low risk of bias | hs-CRP is an objective laboratory biomarker measured by a single named turbidimetric assay on a single named platform at fixed protocol visits, identically in both arms, with no indication of an assay change partway through; assessors were in any case blinded by the double-blind design. Per the collection rule, measurement bias for central-lab CRP is Low absent assay change or between-arm difference.Systemic inflammation was assessed by high-sensitivity CRP, measured by turbidimetric assay (Roche Cobas Chemistry Analyzer) at baseline and 12, 24 and 52 weeks. |
| D5 · Selection of the reported result High risk of bias | Subset test, stated explicitly as required: the assessed result (CRP ETD at 52 weeks, MMRM, Table 3) falls OUTSIDE the named post hoc subset. That subset is confined to estimated BV and PV and to the exploratory linear regressions - "All analyses presented were prespecified, with the exception of estimated BV and PV, and the results of linear regression analyses exploring correlations between changes in different variables, which are exploratory and post hoc." CRP is neither. D5 is nonetheless High, because guide item 7 bullet 1 is independently triggered for THIS result by two author statements about it: the Methods state that all of the outcomes assessed, CRP included, were "prespecified as exploratory outcomes", and the Table 3 footnote carrying this very estimate states that "No correction was made for multiple hypothesis testing", with the Statistical methods confirming adjustment for multiplicity was deliberately not performed. An author statement that the assessed analysis was exploratory or unadjusted for multiplicity is affirmative evidence under item 7 and sets High; it is quoted below. The paper's own claim that CRP was prespecified is not verification (item 7 bullet 3): the protocol and SAP are said to be in Supplementary Information but are not in the retrieved bundle, so the outcome definition, timepoint and model could not be checked against any retrieved source. Even on the narrower reading that only the post hoc subset triggers High, this result could not go below the Some concerns floor.All analyses presented were prespecified, with the exception of estimated BV and PV, and the results of linear regression analyses exploring correlations between changes in different variables, which are exploratory and post hoc. All of the outcomes assessed were prespecified as exploratory outcomes, with the exception of estimated BV and PV, which were post hoc and not prespecified. |
02Funding
Funding and conflicts
- Funding
- NHLBI NIH HHS
- Industry funded
- No
- Manufacturer
- Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Boehringer Ingelheim, Amgen, Roche, Innovent
- Sponsor role
- no manufacturer funding identified
- Author conflicts
- Competing interests: B.A.B. receives research support from the National Institutes of Health (NIH) and the US Department of Defense, as well as research grant funding from AstraZeneca, Axon, Corvia, Novo Nordisk and Tenax Therapeutics. B.A.B. has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT and VADovations and is named inventor (US patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat HF. M.R.Z. receives research support from the Department of Veterans Affairs and serves as a consultant for Abbott, Adona Medical, Aria CV, Avery Therapeutics, Inc., Boehringer Ingelheim, Boston Scientific, Cardiovascular Research Foundation (CRF) Clinical Trials Center, CVRx, DIASTOL Therapeutics, LLC, EBR, Edwards, Lilly, GenKardia, Innoventric, Kestra Medical, Medtronic, Merck, Morphic Therapeutics, Novartis, Pulnovo, Salubris Biotherapeutics, Sonata, sRNAlytics Inc., V-WAVE and Vectorious. C.M.K. has served as a consultant for Eli Lilly. S.J.B. has served as consultant for Altimmune, Amgen, Beren Therapeutics, Boehringer Ingelheim, Lilly, Esperion, Ionis Pharmaceuticals, Madrigal Pharmaceuticals, Merck, Novartis and Regeneron. S.E.L. reported being on the patient selection committee for Corvia and Axon and being a consultant for Novo Nordisk and Lilly. K.H., M.M., Y.O. and N.U. are employed by
- Independent replication
- unknown
- Notes
- Authors declare relationships with the drug's manufacturer: Eli Lilly
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
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 .
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| pubmed | Sep 13, 2026 | 39551891 first ingestion |