CoChat
Sign Up
Cited by 77Heart Failure Treatment and ManagementDiabetes Treatment and ManagementCardiovascular Function and Risk Factors

Effects of Tirzepatide on the Clinical Trajectory of Patients With Heart Failure, Preserved Ejection Fraction, and Obesity

Open access
Zile, Michael R., Borlaug, Barry A., Kramer, Christopher M., Baum, Seth J., Litwin, Sheldon E., Menon, Venu, Ou, Yang, Weerakkody, Govinda J. +5 more·2025·Circulation
DOI 10.1161/circulationaha.124.072679PMC PMC11893002
Open this paper in CoChat — free account

Abstract

BACKGROUND: Patients with heart failure with preserved ejection fraction and obesity have significant disability and frequent exacerbations of heart failure. We hypothesized that tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, would improve a comprehensive suite of clinical end points, including measures of health status, functional capacity, quality of life, exercise tolerance, patient well-being, and medication burden, in these patients. METHODS: We randomized (double-blind) 731 patients with class II to IV heart failure, ejection fraction ≥50%, and body mass index ≥30 kg/m 2 to tirzepatide (titrated up to 15 mg SC weekly; n=364) or placebo (n=367) added to background therapy for a median of 104 weeks (quartile 1, 66; quartile 3, 126 weeks). The primary end points were whether tirzepatide reduced the combined risk of cardiovascular death or worsening heart failure and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score. The current expanded analysis included sensitivity analyses of the primary end points, 6-minute walk distance, EQ-5D-5L health state index, Patient Global Impression of Severity Overall Health score, New York Heart Association class, use of heart failure medications, and a hierarchical composite based on all-cause death, worsening heart failure, and 52-week changes in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and 6-minute walk distance. RESULTS: Patients were 65.2±10.7 years of age; 53.8% (n=393) were female; body mass index was 38.2±6.7 kg/m 2 ; Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was 53.5±18.5; 6-minute walk distance was 302.8±81.7 m; and 53% (n=388) had a worsening heart failure event in the previous 12 months. Compared with placebo, tirzepatide produced a consistent beneficial effect across all composites of death and worsening heart failure events, analyzed as time to first event (hazard ratios, 0.41–0.67). At 52 weeks, tirzepatide increased the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score by 6.9 points (95% CI, 3.3–10.6; P <0.001), 6-minute walk distance 18.3 meters (95% CI, 9.9–26.7; P <0.001), and EQ-5D-5L 0.06 (95% CI, 0.03–0.09; P <0.001). The tirzepatide group shifted to a more favorable Patient Global Impression of Severity Overall Health score (proportional odds ratio, 1.99 [95% CI, 1.44–2.76]) and New York Heart Association class (proportional odds ratio, 2.26 [95% CI, 1.54–3.31]; both P <0.001) and required fewer heart failure medications ( P =0.015). The broad spectrum of effects was reflected in benefits on the hierarchical composite (win ratio, 1.63 [95% CI, 1.17–2.28]; P =0.004). CONCLUSIONS: Tirzepatide produced a comprehensive, meaningful improvement in heart failure across multiple complementary domains; enhanced health status, quality of life, functional capacity, exercise tolerance, and well-being; and reduced symptoms and medication burden in patients with heart failure with preserved ejection fraction and obesity. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04847557.

AI snapshot

Written from the paper’s full text.

TL;DR

In patients with heart failure with preserved ejection fraction and obesity, tirzepatide improved a broad set of clinical, functional, and patient-reported outcomes over a median 104 weeks. The expanded SUMMIT analysis reports consistent reductions in worsening heart failure events and meaningful gains in health status, exercise tolerance, well-being, and medication burden.

Key findings

Tirzepatide reduced the composite of cardiovascular death or worsening heart failure events (HR, 0.62 [95% CI, 0.41–0.95]; P=0.026), with sensitivity-analysis hazard ratios ranging from 0.41 to 0.67; worsening heart failure events requiring hospitalization or urgent intravenous therapy had an HR of 0.41 (95% CI, 0.22–0.75; P=0.004). At 52 weeks, tirzepatide increased KCCQ-CSS by 6.9 points (95% CI, 3.3–10.6; P<0.001), 6-minute walk distance by 18.3 m (95% CI, 9.9–26.7; P<0.001), and EQ-5D-5L health state index by 0.06 (95% CI, 0.03–0.09; P<0.001). Tirzepatide shifted PGIS Overall Health favorably (proportional OR, 1.99 [95% CI, 1.44–2.76]) and NYHA class favorably (proportional OR, 2.26 [95% CI, 1.54–3.31]; both P<0.001), reduced HF medication burden (P=0.015), and improved the hierarchical composite (win ratio, 1.63 [95% CI, 1.17–2.28]; P=0.004). More tirzepatide-treated patients met clinically meaningful thresholds: KCCQ-CSS ≥20-point improvement (47.6% vs 35.2%; OR, 1.82 [95% CI, 1.25–2.65]; P=0.002) and 6MWD ≥25-m improvement (51.7% vs 34.0%; OR, 2.1 [95% CI, 1.5–2.9]; P<0.001).

Methods

Double-blind randomized trial of 731 patients with class II–IV heart failure, ejection fraction ≥50%, and BMI ≥30 kg/m² assigned to tirzepatide titrated to 15 mg SC weekly (n=364) or placebo (n=367) added to background therapy, with median follow-up 104 weeks (quartile 1, 66; quartile 3, 126 weeks). The current expanded analysis evaluated sensitivity analyses of the primary end points plus 6-minute walk distance, EQ-5D-5L health state index, PGIS Overall Health, NYHA class, HF medication use, and a hierarchical composite based on all-cause death, worsening HF events, and 52-week changes in KCCQ-CSS and 6MWD. Analyses were intention-to-treat with multiple imputation where specified; methods included Cox proportional hazards models, stratified Wilcoxon tests, mixed-effects repeated-measures models, logistic regression, proportional odds models, and win ratio analysis, with on-treatment sensitivity analyses.

Limitations

Stated: the trial was prospectively designed to evaluate long-term major adverse HF outcomes, but effects on KCCQ-CSS, 6MWD, EQ-5D-5L health state index, PGIS Overall Health, and NYHA functional class were assessed only at 24 and 52 weeks, and further study of durability beyond 1 year is warranted. Evident from the text: this is an expanded analysis of SUMMIT, with primary results reported separately, so some primary-outcome details depend on the prior publication. Evident from the text: baseline NT-proBNP was lower than in several other HFpEF trials, which the authors note may affect comparisons with those trials.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1161/circulationaha.124.072679

Cites

50 of 50 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 65 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The on-treatment estimand for the mean effect of tirzepatide on 6-minute walk distance was 30.3 m (95% CI, 20.3-40.3; P<0.001).

    “the on-treatment estimand for the mean effect of tirzepatide was 30.3 m (95% CI, 20.3–40.3; P<0.001; Figure S2).”
    Quote in the paperSubstantial claim
  • Findingown data

    At 52 weeks, a significantly greater proportion of participants treated with tirzepatide met the minimum clinically meaningful improvement threshold of 25 m compared with the placebo group (51.7% versus 34.0%; odds ratio, 2.1; 95% CI, 1.5-2.9; P<0.001).

    “At 52 weeks, a significantly greater proportion of participants treated with tirzepatide met the minimum clinically meaningful improvement threshold of 25 m compared with the placebo group (51.7% versus 34.0%; odds ratio, 2.1 [95% CI, 1.5–2.9]; P<0.001).”
    Quote in the paperSubstantial claim
  • Findingown data

    The proportion of subjects who reached threshold changes of ≥10-, ≥20-, and ≥30-m increase in 6-minute walk distance at 52 weeks showed odds ratios ranging from 2.0 to 2.2.

    “The proportion of subjects who reached threshold changes of ≥10-, ≥20-, and ≥30-m increase in 6MWD at 52 weeks using intention to treat is displayed in Figure 4B, showing odds ratios ranging from 2.0 to 2.2.”
    Quote in the paperSubstantial claim
  • Findingown data

    The difference in EQ-5D-5L between tirzepatide and placebo was evident at 24 weeks of treatment.

    “The difference between tirzepatide and placebo was also evident at 24 weeks of treatment.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The treatment difference in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was evident at 24 weeks.

    “The treatment difference was evident at 24 weeks.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 25
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Findingown data

    The effect of tirzepatide was driven by an effect on worsening heart failure events requiring hospitalization or the use of intravenous medications in an urgent care setting; the hazard ratio for this analysis was 0.41 (95% CI, 0.22-0.75; P=0.004).

    “The effect of tirzepatide was driven by an effect on worsening HF events requiring hospitalization or the use of intravenous medications in an urgent care setting; the hazard ratio for this analysis was 0.41 (95% CI, 0.22–0.75; P=0.004; Figure 1B).”
    • Also stated in: § What Is New? · plain
      “Tirzepatide reduced the risk of worsening heart failure events requiring hospitalization or the use of intravenous medications in an urgent care setting; the hazard ratio for this analysis was 0.41 (95% CI, 0.22–0.75; P=0.004).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Favorable effects of tirzepatide were consistently demonstrated in all sensitivity analyses of the primary composite events end point, with hazard ratios ranging from 0.41 to 0.67.

    “Favorable effects of tirzepatide were consistently demonstrated in all sensitivity analyses (Figures 1 and 2).”
    • Also stated in: § Effect of Tirzepatide on Outcomes · plain
      “The hazard ratios for all sensitivity analyses of the primary composite events end point ranged from 0.41 to 0.67 (Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Tirzepatide increased the proportion of patients reaching each Kansas City Cardiomyopathy Questionnaire Clinical Summary Score threshold (≥5, ≥10, ≥15, and ≥20 points) compared with placebo, with odds ratios ranging from 1.8 to 2.0.

    “Tirzepatide increased the proportion of patients reaching each threshold compared with placebo, with odds ratios ranging from 1.8 to 2.0.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In the SUMMIT trial, patients in the tirzepatide group underwent less intensification of background therapy for HF and were more likely to have a reduction in the doses of HF treatments.

    “In the SUMMIT trial, we showed an improvement in numerous measures of the clinical trajectory of HF, although patients in the tirzepatide group underwent less intensification of background therapy for HF and were more likely to have a reduction in the doses of HF treatments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the SUMMIT trial, tirzepatide improved 6MWD, EQ-5D-5L health state index, and PGIS Overall Health.

    “In the SUMMIT trial, tirzepatide reduced the risk of cardiovascular death or worsening HF events by 38% and improved KCCQ-CSS by 6.9 points, as well as 6MWD, EQ-5D-5L health state index, and PGIS Overall Health; the odds ratios for threshold changes in all these metrics were 1.8 to 2.2.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 52 weeks, by intention to treat, participants in the tirzepatide group were significantly more likely to show improvement and less likely to show worsening New York Heart Association functional class; the proportional odds ratio for a favorable shift was 2.26 (95% CI, 1.54-3.31; P<0.001).

    “At 52 weeks, by intention to treat, participants in the tirzepatide group were significantly more likely to show improvement and less likely to show worsening NYHA functional class (Figure 6A). The proportional odds ratio for a favorable shift in NYHA class with tirzepatide versus placebo was 2.26 (95% CI, 1.54–3.31; P<0.001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 52 weeks, by intention to treat, compared with placebo, patients in the tirzepatide group were more likely to show Patient Global Impression of Severity Overall Health improvement (55.2% versus 38.5%) and were less likely to report worsening (7.4% versus 11.3%); the proportional odds ratio for a favorable effect was 1.99 (95% CI, 1.44-2.76; P<0.001).

    “At 52 weeks, by intention to treat, compared with the placebo group, patients in the tirzepatide group were more likely to show PGIS Overall Health improvement (55.2% versus 38.5%) and were less likely to report PGIS Overall Health worsening (7.4% versus 11.3%); the proportional odds ratio for a favorable effect was 1.99 (95% CI, 1.44–2.76; P<0.001; Figure 5B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The differences in changes in diuretics were notable, with approximately 50% fewer diuretic dose increases and 50% more frequent diuretic dose decreases in the tirzepatide group compared with the placebo group (P<0.001).

    “The differences in changes in diuretics (as a single category) was especially notable, with ≈50% fewer diuretic dose increases and 50% more frequent diuretic dose decreases in the tirzepatide group compared with the placebo group (P<0.001).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    The difference in Patient Global Impression of Severity Overall Health between tirzepatide and placebo was evident at 24 weeks of treatment.

    “The difference between tirzepatide and placebo was also evident at 24 weeks of treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Every prespecified measurement of patient- and physician-reported health status, functional capacity, quality of life, patient global impression of severity overall health, exercise tolerance, and medication burden was substantially improved by tirzepatide compared with placebo.

    “In addition, every prespecified measurement of patient- and physician-reported health status, functional capacity, quality of life, patient global impression of severity overall health, exercise tolerance, and medication burden was substantially improved by tirzepatide compared with placebo.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At 52 weeks, intensification of heart failure medications in the aggregate occurred less frequently in the tirzepatide group, whereas the use of these heart failure medications was reduced more frequently in the tirzepatide group (Wilcoxon rank-sum test, P=0.015).

    “At 52 weeks, intensification of HF medications in the aggregate (inclusive of the use of inhibitors of the renin-angiotensin system and neprilysin, beta-blockers, mineralocorticoid receptor antagonists, SGLT2 inhibitors, and diuretics) occurred less frequently in the tirzepatide group, whereas the use of these HF medications was reduced more frequently in the tirzepatide group (Wilcoxon rank-sum”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Over the past decade, medications effective in heart failure with reduced ejection fraction have been evaluated in large-scale trials in patients with heart failure with mildly reduced ejection fraction and patients with heart failure with preserved ejection fraction.

    “Over the past decade, the use of medications that have been demonstrated to be effective in patients with HF with reduced ejection fraction (angiotensin receptor neprilysin inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 [SGLT2] inhibitors) has been evaluated in large-scale trials in patients with HF and mildly reduced ejection fraction and patients with HFpE”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [3] Solomon SD McMurray JJV Anand IS Ge J Lam CSP Maggioni AP Martinez F Packer M Pfeffer MA Pieske B; PARAGON-HF Investigators and Committees. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019; 381: 1609– 1620. doi: 10.1056/NEJMoa1908655 31475794 source

      Not checked in the free run.

    • cites [4] Anker SD Butler J Filippatos G Ferreira JP Bocchi E Böhm M Brunner-La Rocca HP Choi DJ Chopra V Chuquiure-Valenzuela E; EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021; 385: 1451– 1461. doi: 10.1056/NEJMoa2107038 34449189 source

      Not checked in the free run.

    • cites [5] Solomon SD McMurray JJV Claggett B de Boer RA DeMets D Hernandez AF Inzucchi SE Kosiborod MN Lam CSP Martinez F; DELIVER Trial Committees and Investigators. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022; 387: 1089– 1098. doi: 10.1056/NEJMoa2206286 36027570 source

      Not checked in the free run.

    • cites [6] Solomon SD McMurray JJV Vaduganathan M Claggett B Jhund PS Desai AS Henderson AD Lam CSP Pitt B Senni M. Finerenone in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2024; 391: 1475– 1485. doi: 10.1056/NEJMoa2407107 39225278 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Weight-loss interventions such as gastric bypass surgery and glucagon-like peptide-1 receptor agonists can reduce the risk of incident heart failure and improve symptoms in patients with established heart failure with preserved ejection fraction.

    “weight-loss interventions (eg, gastric bypass surgery and glucagon-like peptide-1 receptor agonists) can reduce the risk of incident HF and improve symptoms in patients with established HFpEF.16–20”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [16] Savji N Meijers WC Bartz TM Bhambhani V Cushman M Nayor M Kizer JR Sarma A Blaha MJ Gansevoort RT. The association of obesity and cardiometabolic traits with incident HFpEF and HFrEF. JACC Heart Fail. 2018; 6: 701– 709. doi: 10.1016/j.jchf.2018.05.018 30007554 PMC6076337 source

      Not checked in the free run.

    • cites [17] Höskuldsdóttir G Sattar N Miftaraj M Näslund I Ottosson J Franzén S Svensson AM Eliasson B. Potential effects of bariatric surgery on the incidence of heart failure and atrial fibrillation in patients with type 2 diabetes mellitus and obesity and on mortality in patients with preexisting heart failure: a nationwide, matched, observational cohort study. J Am Heart Assoc. 2021; 10: e019323. doi: 10.1161/JAHA.120.019323 33754795 PMC8174344 source

      Not checked in the free run.

    • cites [18] Lincoff AM Brown-Frandsen K Colhoun HM Deanfield J Emerson SS Esbjerg S Hardt-Lindberg S Hovingh GK Kahn SE Kushner RF; SELECT Trial Investigators. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023; 389: 2221– 2232. doi: 10.1056/NEJMoa2307563 37952131 source

      Not checked in the free run.

    • cites [19] Kosiborod MN Abildstrøm SZ Borlaug BA Butler J Rasmussen S Davies M Hovingh GK Kitzman DW Lindegaard ML Møller DV; STEP-HFpEF Trial Committees and Investigators. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med. 2023; 389: 1069– 1084. doi: 10.1056/NEJMoa2306963 37622681 source

      Not checked in the free run.

    • cites [20] Kosiborod MN Petrie MC Borlaug BA Butler J Davies MJ Hovingh GK Kitzman DW Møller DV Treppendahl MB Verma S; STEP-HFpEF DM Trial Committees and Investigators. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. N Engl J Med. 2024; 390: 1394– 1407. doi: 10.1056/NEJMoa2313917 38587233 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    None of the medications developed for heart failure with preserved ejection fraction target obesity, one of the primary mechanisms that drive the development of heart failure with preserved ejection fraction.

    “None of the medications developed for HFpEF target obesity, one of the primary mechanisms that drive the development of HFpEF.13–15”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] Borlaug BA Jensen MD Kitzman DW Lam CSP Obokata M Rider OJ. Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. Cardiovasc Res. 2023; 118: 3434– 3450. doi: 10.1093/cvr/cvac120 35880317 PMC10202444 source

      Not checked in the free run.

    • cites [14] Oguntade AS Taylor H Lacey B Lewington S. Adiposity, fat-free mass and incident heart failure in 500 000 individuals. Open Heart. 2024; 11: e002711. doi: 10.1136/openhrt-2024-002711 38964877 PMC11227841 source

      Not checked in the free run.

    • cites [15] Packer M Kitzman DW. Obesity-related heart failure with a preserved ejection fraction: the mechanistic rationale for combining inhibitors of aldosterone, neprilysin, and sodium-glucose cotransporter-2. JACC Heart Fail. 2018; 6: 633– 639. doi: 10.1016/j.jchf.2018.01.009 29525327 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    The trial randomized patients double-blind (1:1) to placebo or tirzepatide.

    “After screening, eligible patients were randomized double-blind (1:1) to receive placebo or 2.5 mg of tirzepatide subcutaneously per week in addition to usual therapy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Patients with heart failure with preserved ejection fraction have severe functional disability and an unfavorable clinical disease trajectory characterized by frequent exacerbations of heart failure.

    “Patients with heart failure (HF) with preserved ejection fraction (HFpEF) have severe functional disability and an unfavorable clinical disease trajectory, characterized by frequent exacerbations of HF.1,2”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Redfield MM Borlaug BA. Heart failure with preserved ejection fraction: a review. JAMA. 2023; 329: 827– 838. doi: 10.1001/jama.2023.2020 36917048 source

      Not checked in the free run.

    • cites [2] Borlaug BA Sharma K Shah SJ Ho JE. Heart failure with preserved ejection fraction: JACC scientific statement. J Am Coll Cardiol. 2023; 81: 1810– 1834. doi: 10.1016/j.jacc.2023.01.049 37137592 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tirzepatide is a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors.

    “Tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors,21”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Willard FS Douros JD Gabe MB Showalter AD Wainscott DB Suter TM Capozzi ME van der Velden WJ Stutsman C Cardona GR. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020; 5: e140532. doi: 10.1172/jci.insight.140532 32730231 PMC7526454 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Analyses were performed according to the intention-to-treat principle based on data from all randomized participants, regardless of adherence to study medication, and with multiple imputation methods for missing data when specified.

    “Analyses were performed according to the intention-to-treat principle based on data from all randomized participants, regardless of adherence to study medication, and with multiple imputation methods for missing data (conducted when specified); sensitivity analyses were based on the on-treatment estimands.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Randomization was stratified by heart failure decompensation within 12 months, type 2 diabetes, and body mass index ≥35 kg/m2.

    “Randomization was stratified by HF decompensation within 12 months, type 2 diabetes, and BMI ≥35 kg/m2.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tirzepatide has been shown to produce approximately 12% to 21% weight loss in patients with obesity.

    “has been shown to produce ≈12% to 21% weight loss in patients with obesity.22”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Qin W Yang J Ni Y Deng C Ruan Q Ruan J Zhou P Duan K. Efficacy and safety of once-weekly tirzepatide for weight management compared to placebo: an updated systematic review and meta-analysis including the latest SURMOUNT-2 trial. Endocrine. 2024; 86: 70– 84. doi: 10.1007/s12020-024-03896-z 38850440 PMC11445313 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All events were blindly adjudicated by a clinical events committee.

    “All events were blindly adjudicated by a clinical events committee.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    The trial was prospectively designed to evaluate the long-term effects of tirzepatide on the risk of major adverse HF outcomes, but the effects on KCCQ-CSS, 6MWD, EQ-5D-5L health state index, PGIS Overall Health, and NYHA functional class were designed to be assessed only at 24 and 52 weeks.

    “The trial was prospectively designed to evaluate the long-term effects of tirzepatide on the risk of major adverse HF outcomes, but the effects on KCCQ-CSS, 6MWD, EQ-5D-5L health state index, PGIS Overall Health, and NYHA functional class were designed to be assessed only at 24 and 52 weeks.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The magnitude of the decline in NT-proBNP in SUMMIT was less marked than the 18% decrease observed in the STEP-HFpEF trials, potentially because of lower baseline value and smaller decrease in body weight with semaglutide compared with tirzepatide.

    “The magnitude of the decline in NT-proBNP was less marked than the 18% decrease observed in the STEP-HFpEF trials,36 potentially because of our much lower baseline value and because of the smaller decrease in body weight produced by semaglutide (ie, ≈8%–9%) compared with tirzepatide.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Petrie MC Borlaug BA Butler J Davies MJ Kitzman DW Shah SJ Verma S Jensen TJ Einfeldt MN Liisberg K; STEP-HFpEF Trial Committees and Investigators. Semaglutide and NT-proBNP in obesity-related HFpEF: insights from the STEP-HFpEF Program. J Am Coll Cardiol. 2024; 84: 27– 40. doi: 10.1016/j.jacc.2024.04.022 38819334 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Despite lower NT-proBNP levels, patients enrolled in SUMMIT had a significantly increased rate of cardiovascular death or worsening HF events because patients were required to have a KCCQ-CSS <80 and impaired renal function or a recent worsening HF event.

    “Despite the lower NT-proBNP levels, patients enrolled in SUMMIT had a significantly increased rate of cardiovascular death or worsening HF events because patients were required to have a KCCQ-CSS <80 and impaired renal function or a recent worsening HF event.23”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Packer M Zile MR Kramer CM Baum SJ Litwin SE Menon V Ge J Weerakkody GJ Ou Y Bunck MC. Tirzepatide for heart failure with preserved ejection fraction and obesity [published online November 26, 2024]. N Engl J Med. doi: 10.1056/NEJMoa2410027. https://nejm.org/doi/full/10.1056/NEJMoa2410027 39555826 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    In the SUMMIT trial, we did not use such imputations.

    “we did not use such imputations in the SUMMIT trial.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The magnitude of the tirzepatide-mediated improvement in the win ratio was large and similar to the effect of transcatheter mitral valve repair in patients with HF and secondary mitral regurgitation.

    “The magnitude of the tirzepatide-mediated improvement in the win ratio was large and similar to the effect of transcatheter mitral valve repair in patients with HF and secondary mitral regurgitation.32”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Stone GW Lindenfeld J Abraham WT Kar S Lim DS Mishell JM Whisenant B Grayburn PA Rinaldi M Kapadia SR; COAPT Investigators. Transcatheter mitral-valve repair in patients with heart failure. N Engl J Med. 2018; 379: 2307– 2318. doi: 10.1056/NEJMoa1806640 30280640 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    In the SUMMIT trial, cardiovascular death and worsening HF events made up the primary end point.

    “in contrast, cardiovascular death and worsening HF events made up the primary end point of the SUMMIT trial.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The median NT-proBNP in SUMMIT was significantly lower than in the STEP-HFpEF program (median ≈470 pg/mL) and substantially lower than in other large-scale outcome trials in HFpEF (median 900-1400 pg/mL).

    “This level was significantly lower than that in the STEP-HFpEF program (median, ≈470 pg/mL)36 and substantially lower than in other large-scale outcome trials in HFpEF (median 900–1400 pg/mL).3–6”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [36] Petrie MC Borlaug BA Butler J Davies MJ Kitzman DW Shah SJ Verma S Jensen TJ Einfeldt MN Liisberg K; STEP-HFpEF Trial Committees and Investigators. Semaglutide and NT-proBNP in obesity-related HFpEF: insights from the STEP-HFpEF Program. J Am Coll Cardiol. 2024; 84: 27– 40. doi: 10.1016/j.jacc.2024.04.022 38819334 source

      Not checked in the free run.

    • cites [3] Solomon SD McMurray JJV Anand IS Ge J Lam CSP Maggioni AP Martinez F Packer M Pfeffer MA Pieske B; PARAGON-HF Investigators and Committees. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019; 381: 1609– 1620. doi: 10.1056/NEJMoa1908655 31475794 source

      Not checked in the free run.

    • cites [4] Anker SD Butler J Filippatos G Ferreira JP Bocchi E Böhm M Brunner-La Rocca HP Choi DJ Chopra V Chuquiure-Valenzuela E; EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021; 385: 1451– 1461. doi: 10.1056/NEJMoa2107038 34449189 source

      Not checked in the free run.

    • cites [5] Solomon SD McMurray JJV Claggett B de Boer RA DeMets D Hernandez AF Inzucchi SE Kosiborod MN Lam CSP Martinez F; DELIVER Trial Committees and Investigators. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022; 387: 1089– 1098. doi: 10.1056/NEJMoa2206286 36027570 source

      Not checked in the free run.

    • cites [6] Solomon SD McMurray JJV Vaduganathan M Claggett B Jhund PS Desai AS Henderson AD Lam CSP Pitt B Senni M. Finerenone in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2024; 391: 1475– 1485. doi: 10.1056/NEJMoa2407107 39225278 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The treatment of patients with HFpEF and obesity with tirzepatide produced a broad spectrum of large and clinically meaningful benefits on the trajectory of HF, evident across multiple domains including improved health status and well-being, enhanced functional capacity and exercise tolerance, reduced symptom and medication burden, and prevention of worsening HF events.

    “The treatment of patients with HFpEF and obesity with tirzepatide produced a broad spectrum of large and clinically meaningful benefits on the trajectory of HF, evident across multiple domains and including improved health status and well-being, enhanced functional capacity and exercise tolerance, reduced symptom and medication burden, and prevention of worsening HF events.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The improvements observed in KCCQ-CSS, 6MWD, EQ-5D-5L, PGIS Overall Health, and NYHA class are clinically meaningful.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The increase in NT-proBNP after marked weight loss may contribute to the natriuresis observed after marked weight loss.

    “This increase in NT-proBNP may contribute to the natriuresis observed after marked weight loss.40”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Docherty NG Fändriks L le Roux CW Hallersund P Werling M. Urinary sodium excretion after gastric bypass surgery. Surg Obes Relat Dis. 2017; 13: 1506– 1514. doi: 10.1016/j.soard.2017.04.002 28571926 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The favorable effects of tirzepatide on HF may be related to an amelioration of blood volume expansion that characterizes obesity-related HF, and the decrease in adipocyte mass would be expected to minimize the antinatriuretic effects of secreted adipocytokines (particularly leptin and aldosterone).

    “The favorable effects of tirzepatide on HF may be related to an amelioration of the blood volume expansion that characterizes obesity-related HF,41 and the decrease in adipocyte mass would be expected to minimize the antinatriuretic effects of secreted adipocytokines (particularly leptin and aldosterone).42–44”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [41] Obokata M Reddy YNV Pislaru SV Melenovsky V Borlaug BA. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation. 2017; 136: 6– 19. doi: 10.1161/CIRCULATIONAHA.116.026807 28381470 PMC5501170 source

      Not checked in the free run.

    • cites [42] Packer M. Leptin-aldosterone-neprilysin axis: identification of its distinctive role in the pathogenesis of the three phenotypes of heart failure in people with obesity. Circulation. 2018; 137: 1614– 1631. doi: 10.1161/CIRCULATIONAHA.117.032474 29632154 source

      Not checked in the free run.

    • cites [43] Hartman ML Sanyal AJ Loomba R Wilson JM Nikooienejad A Bray R Karanikas CA Duffin KL Robins DA Haupt A. Effects of novel dual GIP and GLP-1 receptor agonist tirzepatide on biomarkers of nonalcoholic steatohepatitis in patients with type 2 diabetes. Diabetes Care. 2020; 43: 1352– 1355. doi: 10.2337/dc19-1892 32291277 PMC7245348 source

      Not checked in the free run.

    • cites [44] Wilson JM Lin Y Luo MJ Considine G Cox AL Bowsman LM Robins DA Haupt A Duffin KL Ruotolo G. The dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist tirzepatide improves cardiovascular risk biomarkers in patients with type 2 diabetes: a post hoc analysis. Diabetes Obes Metab. 2022; 24: 148– 153. doi: 10.1111/dom.14553 34542221 PMC9292792 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Tirzepatide produced a comprehensive, meaningful improvement in heart failure across multiple complementary domains; enhanced health status, quality of life, functional capacity, exercise tolerance, and well-being; and reduced symptoms and medication burden in patients with heart failure with preserved ejection fraction and obesity.

    “Tirzepatide produced a comprehensive, meaningful improvement in heart failure across multiple complementary domains; enhanced health status, quality of life, functional capacity, exercise tolerance, and well-being; and reduced symptoms and medication burden in patients with heart failure with preserved ejection fraction and obesity.”
    • Also stated in: § What Is New? · plain
      “Tirzepatide also improved a broad range of measures of heart failure severity, which included health status, functional capacity, global well-being, quality of life, exercise tolerance, and medication burden.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Somewhat more meaningful effects of SGLT2 inhibitors on KCCQ and 6MWD have been reported in patients with HFpEF and obesity.

    “Somewhat more meaningful effects of SGLT2 inhibitors on KCCQ and 6MWD have been reported in patients with HFpEF and obesity.31”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Nassif ME Windsor SL Borlaug BA Kitzman DW Shah SJ Tang F Khariton Y Malik AO Khumri T Umpierrez G. The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial. Nat Med. 2021; 27: 1954– 1960. doi: 10.1038/s41591-021-01536-x 34711976 PMC8604725 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In PARAGON-HF, neprilysin inhibition reduced the risk of cardiovascular death and total hospitalizations by 13%, improved KCCQ by 1.0 points, and had no overall effect on the EuroQol Visual Analog Scale.

    “In the PARAGON-HF trial (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction), neprilysin inhibition reduced the risk of cardiovascular death and total hospitalizations by 13%, improved KCCQ by 1.0 points, and had no overall effect on the EuroQol Visual Analog Scale.3,9”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Solomon SD McMurray JJV Anand IS Ge J Lam CSP Maggioni AP Martinez F Packer M Pfeffer MA Pieske B; PARAGON-HF Investigators and Committees. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019; 381: 1609– 1620. doi: 10.1056/NEJMoa1908655 31475794 source

      Not checked in the free run.

    • cites [9] Chandra A Polanczyk CA Claggett BL Vaduganathan M Packer M Lefkowitz MP Rouleau JL Liu J Shi VC Schwende H. Health-related quality of life outcomes in PARAGON-HF. Eur J Heart Fail. 2022; 24: 2264– 2274. doi: 10.1002/ejhf.2738 36394533 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In EMPEROR-Preserved and DELIVER, SGLT2 inhibition reduced the risk of cardiovascular death and worsening HF events by 18% to 21% and improved KCCQ-CSS by 1.5 to 2.3 points, with odds ratios for threshold improvements in KCCQ-CSS of 1.1 to 1.2.

    “In the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction) and DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), SGLT2 inhibition reduced the risk of cardiovascular death and worsening HF events by 18% to 21%4,5 and improved KCCQ-CSS by 1.5 to 2.3 points”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [4] Anker SD Butler J Filippatos G Ferreira JP Bocchi E Böhm M Brunner-La Rocca HP Choi DJ Chopra V Chuquiure-Valenzuela E; EMPEROR-Preserved Trial Investigators. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021; 385: 1451– 1461. doi: 10.1056/NEJMoa2107038 34449189 source

      Not checked in the free run.

    • cites [5] Solomon SD McMurray JJV Claggett B de Boer RA DeMets D Hernandez AF Inzucchi SE Kosiborod MN Lam CSP Martinez F; DELIVER Trial Committees and Investigators. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022; 387: 1089– 1098. doi: 10.1056/NEJMoa2206286 36027570 source

      Not checked in the free run.

    • cites [10] Kosiborod MN Bhatt AS Claggett BL Vaduganathan M Kulac IJ Lam CSP Hernandez AF Martinez FA Inzucchi SE Shah SJ. Effect of dapagliflozin on health status in patients with preserved or mildly reduced ejection fraction. J Am Coll Cardiol. 2023; 81: 460– 473. doi: 10.1016/j.jacc.2022.11.006 36526515 source

      Not checked in the free run.

    • cites [11] Butler J Filippatos G Jamal Siddiqi T Brueckmann M Böhm M Chopra VK Pedro Ferreira J Januzzi JL Kaul S Piña IL. Empagliflozin, health status, and quality of life in patients with heart failure and preserved ejection fraction: the EMPEROR-Preserved trial. Circulation. 2022; 145: 184– 193. doi: 10.1161/CIRCULATIONAHA.121.057812 34779658 PMC8763045 source

      Not checked in the free run.

35 of 35

  • The paper relies on this without support.

    The improvements observed in KCCQ-CSS, 6MWD, EQ-5D-5L, PGIS Overall Health, and NYHA class are clinically meaningful.

    “The treatment of patients with HFpEF and obesity with tirzepatide produced a broad spectrum of large and clinically meaningful benefits on the trajectory of HF”

  • The paper relies on this without support.

    The hierarchical composite endpoint win ratio of 1.63 reflects a clinical benefit.

    “Compared with placebo, patients treated with tirzepatide were more likely to show clinical benefit according to the hierarchical composite end point (win ratio, 1.63 [95% CI, 1.17–2.28]; P=0.004).”

  • The paper relies on this without support.

    The comparison of tirzepatide effects with those of other HFpEF therapies is valid despite differences in trial populations, endpoints, and background therapy.

    “The substantial effects of tirzepatide in the SUMMIT trial should be contrasted with the modest effects seen with neurohormonal antagonists and SGLT2 inhibitors in large-scale trials of patients with HFpEF.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Twelve-week assessments conflict with the stated assessment schedule

    Minor

    The limitations section says these measures were designed to be assessed only at 24 and 52 weeks, but the statistical methods describe analyses of KCCQ-CSS, 6MWD, and EQ-5D-5L at 12 weeks as well.

  • Conflicting lower confidence limits for the same hazard ratio

    Minor

    The text and Figure 1A caption report the same all-cause-death-or-worsening-HF analysis with a hazard ratio of 0.67 and P=0.045, but give different lower limits for its 95% confidence interval: 0.46 and 0.45.

  • Baseline KCCQ eligibility threshold changes from ≤80 to <80

    Minor

    The study-patient criteria permit a baseline KCCQ-CSS of exactly 80, but the discussion says patients were required to have a score below 80.

3 of 3

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Zile, M. R., Borlaug, B. A., Kramer, C. M., Baum, S. J., Litwin, S. E., Menon, V., Ou, Y., Weerakkody, G. J., Hurt, K. C., Kanu, C., Murakami, M., Packer, M., & for the SUMMIT Trial Study Group
Affiliations
  • Medical University of South Carolina (US)
  • Mayo Clinic (US)
  • University of Virginia Health System (US)
  • Flourish Research, Boca Raton, FL (S.J.B.).
  • Cleveland Clinic (US)
  • Eli Lilly (United States) (US)
  • Baylor University Medical Center (US)
Corresponding author
Zile, Michael R.
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2025-03-11
Volume
151
Issue
10
Pages
656-668
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.124.072679
PMC
PMC11893002
OpenAlex
W4404479815
Semantic Scholar
ffe5db4cb8c907be729987dda5d4ae305747105d
Cited by
74
References
50
Citations by year
2026: 40 · 2025: 34
FWCI
22.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Circulation (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
Eli Lilly and Company
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Keywords
tirzepatide, heart failure with preserved ejection fraction, obesity, GLP-1 receptor agonists, GIP receptor agonist, Kansas City Cardiomyopathy Questionnaire, 6-minute walk distance, health-related quality of life, functional capacity, cardiovascular mortality, worsening heart failure, heart failure medications, NYHA functional class, patient-reported outcomes, medication burden, comorbidities
MeSH terms
Tirzepatide, Aged, Double-Blind Method, Female, Heart Failure, Humans, Male, Middle Aged, Obesity, Quality of Life, Stroke Volume, Treatment Outcome, Exercise Tolerance

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review