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Cited by 166Heart Failure Treatment and ManagementCardiovascular Function and Risk FactorsDiabetes Treatment and Management

The DOI matches its Crossref record; 43 of the 43 references it cites were found in a registry or an index; 32 of the 65 sources its claims cite were checked for support.

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

Open access
Borlaug, Barry A., Zile, Michael R., Kramer, Christopher M., Baum, Seth J., Hurt, Karla, Litwin, Sheldon E., Murakami, Masahiro, Ou, Yang, Upadhyay, Navneet, Packer, Milton·2025·Nature Medicine
DOI 10.1038/s41591-024-03374-zPMC PMC11835708
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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 .

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In a mechanistic secondary analysis of the SUMMIT trial, tirzepatide reduced circulatory volume–pressure overload and systemic inflammation in patients with obesity-related HFpEF. These changes were accompanied by improved kidney function, reduced albuminuria and myocardial injury, with estimated blood volume reductions correlating with clinical improvement.

Key findings

  • At 52 weeks, tirzepatide versus placebo reduced systolic blood pressure (ETD −4.7 mmHg, 95% CI −6.8 to −2.5; P < 0.001), estimated blood volume (ETD −0.58 l, 95% CI −0.63 to −0.52; P < 0.001), estimated plasma volume (ETD −0.32 l, 95% CI −0.36 to −0.27; P < 0.001) and pulse pressure (ETD −3.9 mmHg, 95% CI −5.6 to −2.2; P < 0.001); diastolic blood pressure effects were not statistically significant.
  • Tirzepatide reduced high-sensitivity CRP at 52 weeks (ETD −37.2%, 95% CI −45.7 to −27.3; P < 0.001), troponin T at 52 weeks (ETD −10.4%, 95% CI −16.7 to −3.6; P = 0.003), and NT-proBNP at 52 weeks (ETD −10.5%, 95% CI −20.7 to 1.0; P = 0.072). Among patients with elevated baseline CRP, normalization occurred in 40.4% with tirzepatide versus 19.4% with placebo (odds ratio 2.90, 95% CI 1.82 to 4.64; P < 0.001).
  • Kidney outcomes: eGFR improved at 52 weeks with tirzepatide versus placebo (ETD 2.9 ml min−1 1.73 m−2, 95% CI 0.9 to 4.9; P = 0.004), and UACR decreased at 24 weeks (ETD −25.0%, 95% CI −35.5 to −12.7; P < 0.001) and 52 weeks (ETD −15.1%, 95% CI −28.0 to 0.1; P = 0.051).
  • In post hoc exploratory analyses, reductions in estimated blood volume with tirzepatide correlated with decreases in systolic blood pressure (slope 6.12, 95% CI 3.47 to 8.78; P < 0.001), decreases in albuminuria (slope 46.7, 95% CI 11.48 to 81.87; P = 0.009), improved KCCQ-CSS (slope −6.287, 95% CI −8.091 to −4.482; P < 0.001) and increased 6-min walk distance (slope −1.175, 95% CI −1.810 to −0.539; P < 0.001). Decreased CRP correlated with reduced troponin T (slope 0.239, 95% CI 0.029 to 0.450; P = 0.026) and improved 6-min walk distance (slope −0.002, 95% CI −0.004 to 0.000; P = 0.016).

Methods

  • Secondary mechanistic analysis of the SUMMIT trial (NCT04847557), a randomized, double-blind, placebo-controlled trial in 731 patients with obesity-related HFpEF: tirzepatide n = 364, placebo n = 367, at 129 centers in 9 countries. Tirzepatide was titrated to 15.0 mg per week subcutaneously as tolerated.
  • Assessed outcomes included blood pressure, estimated blood volume and plasma volume, eGFR, urine albumin–creatinine ratio, high-sensitivity CRP, high-sensitivity troponin T and NT-proBNP at baseline and 12, 24 and 52 weeks. Primary eGFR analysis used cystatin C–based CKD-EPI; sensitivity analyses used creatinine-based and combined creatinine–cystatin C formulas.
  • Main analysis used mixed-effects model repeated measures including treatment, time, treatment-by-time interaction, stratification factors and baseline value; linear and logistic regression explored correlations. Estimated blood volume/plasma volume and regression analyses were post hoc/exploratory; no correction was made for multiple hypothesis testing.

Limitations

  • The paper states that plasma volume was estimated using a weight-based formula (Kaplan–Hakim), so weight loss with tirzepatide would mathematically be expected to reduce estimated plasma volume; the magnitude of blood/plasma volume reduction may therefore be overestimated. Direct indicator-dilution measurement was considered impractical in a large multicenter trial.
  • The paper states that estimated blood volume/plasma volume and the regression analyses were post hoc and exploratory, so these data should be treated as hypothesis-generating; all other outcomes were prespecified. No adjustment was made for multiple hypothesis testing.
  • The paper notes that follow-up for most measures was 52 weeks, limiting conclusions about longer-term effects. It also notes that troponin T can be elevated in skeletal muscle disorders, though such patients were excluded, and that weight loss may reduce skeletal muscle and affect creatinine-based eGFR, which is why cystatin C was used; kidney benefits were consistent across eGFR formulas. Evident from the text: NT-proBNP was only slightly elevated on average and elevated NT-proBNP was not required for eligibility, limiting the ability to detect further reductions.

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

Integrity signals

Registry

Crossref · 10.1038/s41591-024-03374-z

Cites

43 of 43 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

32 of 65 cited sources checked · 8 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Hypertension, CKD and blood volume expansion are the three features that best distinguish obesity-related HFpEF from asymptomatic individuals with obesity but no HF.

    “Indeed, hypertension, CKD and BV expansion are the three features that best distinguish obesity-related HFpEF from asymptomatic individuals with obesity but no HF9.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [9] Morgen, C. S. et al. Obesity, cardiorenal comorbidities, and risk of hospitalization in patients with heart failure with preserved ejection fraction. Mayo Clin. Proc. 98, 1458–1468 (2023). source

      Tables 1 and 2 show more hypertension and CKD in the HFpEF group than in BMI-matched controls, and the Discussion reports greater volume expansion. The paper does not identify these as the three features that best distinguish the groups; it also reports differences in other cardiometabolic comorbidities. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    Reduction in adipocyte mass with tirzepatide may reduce adipocyte-derived factors that promote sodium retention and volume expansion, including leptin and aldosterone.

    “It is noteworthy that adipocytes release factors that promote sodium retention and volume expansion, including leptin and aldosterone, and the reduction in adipocyte mass with tirzepatide may reduce these influences23.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [23] 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 137, 1614–1631 (2018). source

      The Conclusions (page not provided) say leptin may contribute to plasma volume expansion and that aldosterone is secreted by adipocytes. The section on renal leptin signaling also links leptin and aldosterone to sodium retention. The paper does not address tirzepatide or establish that reducing adipocyte mass with it reduces these influences. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    Pulse pressure is inversely correlated with arterial compliance.

    “Pulse pressure is inversely correlated with arterial compliance, which is frequently impaired in patients with HFpEF, where increases in aortic stiffness contribute to elevation in cardiac filling pressures, especially during exercise24.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [24] Reddy, Y. N. V. et al. Arterial stiffening with exercise in patients with heart failure and preserved ejection fraction. J. Am. Coll. Cardiol. 70, 136–148 (2017). source

      The Methods (Arterial Waveform Analysis) define total arterial compliance as stroke volume index divided by central pulse pressure, supporting an inverse relationship when stroke volume is held constant. The Results (Arterial Reserve With Submaximal Exercise) report lower compliance in HFpEF and an association between lower compliance and higher filling pressures during exercise. The Discussion (Vascular Stiffening in HFpEF) explicitly says this study cannot prove causality, so the sentence's assertion that increased stiffness contributes to elevated filling pressures is stronger than the evidence establishes. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Interpretationcitation

    Reducing circulating volume may decrease cardiac filling pressures in obesity-related HFpEF.

    “Volume expansion in obesity-related HFpEF exacerbates elevation in cardiac filling pressures that develop due to impairments in left ventricular distensibility3, and thus, reducing circulating volume may decrease cardiac filling pressures.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [3] Borlaug, B. A. et al. Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. Cardiovasc. Res. 118, 3434–3450 (2023). source
  • Findingown data

    In the SUMMIT trial, decreases in estimated BV at 52 weeks were not related to improvements in eGFR.

    “In the SUMMIT trial, decreases in estimated BV at 52 weeks (potentially related to the suppression of adipocytokines) were associated with reduction in albuminuria, but we observed no relationship with the improvements in eGFR.”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim. 32
  • It may state two separate claims as one. 37

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Endothelial dysfunction, inflammation and CKD in HFpEF can underlie the development of microalbuminuria, which is correlated with greater cardiac dysfunction and congestion, along with higher risk for HF hospitalization or death.

    “Endothelial dysfunction, inflammation and CKD in HFpEF can underlie the development of microalbuminuria, which is correlated with greater cardiac dysfunction and congestion, along with higher risk for HF hospitalization or death10–12.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [10] Katz, D. H., Burns, J. A., Aguilar, F. G., Beussink, L. & Shah, S. J. Albuminuria is independently associated with cardiac remodeling, abnormal right and left ventricular function, and worse outcomes in heart failure with preserved ejection fraction. JACC Heart Fail. 2, 586–596 (2014). source

      The Discussion links albuminuria in HFpEF to possible inflammation and endothelial dysfunction, and the Results associate higher UACR with CKD, cardiac dysfunction, and higher BNP. The Results also associate higher UACR with cardiovascular hospitalization (including HF hospitalization) or death. They do not establish that CKD causes microalbuminuria, directly demonstrate greater congestion, or report HF hospitalization or death as a separate endpoint. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [11] Selvaraj, S. et al. Prognostic value of albuminuria and influence of spironolactone in heart failure with preserved ejection fraction. Circ. Heart Fail. 11, e005288 (2018). source
    • cites [12] Boorsma, E. M. et al. Albuminuria as a marker of systemic congestion in patients with heart failure. Eur. Heart J. 44, 368–380 (2023). source

      The Discussion (Endothelial dysfunction; Congestion) proposes endothelial dysfunction as a possible cause of albuminuria and reports correlations with congestion, while cautioning that causality cannot be assessed. The Results (Cox regression analysis) associate albuminuria with mortality and heart-failure hospitalization and find no significant difference in that association between HFpEF and HFrEF. The copy does not establish inflammation or CKD as causes of microalbuminuria in HFpEF, or specifically demonstrate the claimed link with greater cardiac dysfunction in HFpEF. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Over half of patients with heart failure have preserved ejection fraction, and roughly two-thirds of these patients have obesity.

    “Over half of patients with heart failure (HF) have a preserved ejection fraction (HF with preserved ejection fraction, HFpEF), and roughly two-thirds of these patients have obesity1–3.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [1] Redfield, M. M. & Borlaug, B. A. Heart failure with preserved ejection fraction: a review. JAMA 329, 827–838 (2023). source
    • cites [2] Borlaug, B. A., Sharma, K., Shah, S. J. & Ho, J. E. Heart failure with preserved ejection fraction: JACC Scientific Statement. J. Am. Coll. Cardiol. 81, 1810–1834 (2023). source

      The Epidemiology of HFpEF passage says HFpEF prevalence is expected to exceed that of heart failure with reduced ejection fraction in the near future; it does not say that over half of current heart-failure patients have HFpEF. The obesity passage says obesity is highly prevalent in HFpEF, but gives no two-thirds figure for obesity. Its two-thirds figure refers instead to epicardial coronary disease. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [3] Borlaug, B. A. et al. Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. Cardiovasc. Res. 118, 3434–3450 (2023). source

      The passages from §4 (Diabetes, obesity, and HFpEF) give percentages for diabetes and prediabetes, not obesity. The supplied passages and searches for HFpEF prevalence and obesity prevalence found no statement that over half of patients with heart failure have HFpEF or that roughly two-thirds of those patients have obesity; the supplied references do not establish either figure. (LLM, conf=0.70)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Obesity-related HFpEF represents the most advanced form of cardiovascular-kidney-metabolic disease, a syndrome recognized by the American Heart Association.

    “Obesity-related HFpEF represents the most advanced form of cardiovascular–kidney–metabolic disease, a syndrome recognized by the American Heart Association4.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [4] Ndumele, C. E. et al. Cardiovascular–kidney–metabolic health: a presidential advisory from the American Heart Association. Circulation 148, 1606–1635 (2023). source

      The advisory’s “Stage 4: CVD in CKM Syndrome With and Without Kidney Failure” section places clinical heart failure in stage 4 CKM syndrome and notes a disproportionate risk of HFpEF with obesity. It does not identify obesity-related HFpEF as the single most advanced form of CKM disease; stage 4 also includes other cardiovascular diseases and distinguishes cases with kidney failure (stage 4b). Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Patients with HFpEF frequently display chronic low-grade myocardial injury as reflected by elevated levels of troponin, and this degree of myocardial injury is correlated with severity of cardiac dysfunction, hemodynamic congestion, impairment in functional capacity and risk for HF hospitalization.

    “Patients with HFpEF also frequently display chronic low-grade myocardial injury as reflected by elevated levels of troponin13,14, and like albuminuria, this degree of myocardial injury in HFpEF is correlated with the severity of cardiac dysfunction, hemodynamic congestion, impairment in functional capacity and risk for HF hospitalization13,14.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [13] Obokata, M. et al. Myocardial injury and cardiac reserve in patients with heart failure and preserved ejection fraction. J. Am. Coll. Cardiol. 72, 29–40 (2018). source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [14] Fudim, M. et al. High-sensitivity troponin I in hospitalized and ambulatory patients with heart failure with preserved ejection fraction: insights from the Heart Failure Clinical Research Network. J. Am. Heart Assoc. 7, e010364 (2018). source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The magnitude of improvement in arterial compliance with dapagliflozin was correlated with the magnitude of weight loss.

    “The magnitude of improvement in arterial compliance with dapagliflozin was correlated with the magnitude of weight loss.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Tada, A. et al. Dapagliflozin enhances arterial and venous compliance during exercise in heart failure with preserved ejection fraction: insights from the CAMEO-DAPA trial. Circulation 150, 997–1009 (2024). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Obesity can contribute to CKD through multiple mechanisms including volume expansion leading to glomerular hyperfiltration and adipocytokines (leptin and aldosterone) causing renal injury and fibrosis.

    “Obesity can contribute to CKD through multiple mechanisms including volume expansion (leading to glomerular hyperfiltration) and the effect of adipocytokines (leptin and aldosterone) to cause renal injury and fibrosis23,26.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [23] 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 137, 1614–1631 (2018). source

      The section on renal leptin signaling says obesity-related leptin activity promotes renal sodium retention and plasma volume expansion. The section on epicardial fat says elevated leptin can promote kidney inflammation, helping explain renal fibrosis in experimental obesity-related HFpEF, and associates high leptin with declining renal function. The paper does not establish the claimed volume-expansion-to-glomerular-hyperfiltration pathway or say that aldosterone causes renal injury and fibrosis. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [26] Yau, K., Kuah, R., Cherney, D. Z. I. & Lam, T. K. T. Obesity and the kidney: mechanistic links and therapeutic advances. Nat. Rev. Endocrinol. 20, 321–335 (2024). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Circulating troponin levels are commonly elevated in HFpEF, where they are associated with greater risk for HF hospitalization or death.

    “Circulating troponin levels are commonly elevated in HFpEF, where they are associated with greater risk for HF hospitalization or death14.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] Fudim, M. et al. High-sensitivity troponin I in hospitalized and ambulatory patients with heart failure with preserved ejection fraction: insights from the Heart Failure Clinical Research Network. J. Am. Heart Assoc. 7, e010364 (2018). source

      The Conclusions report that high-sensitivity troponin I was elevated in a large majority of hospitalized HFpEF patients and more than half of ambulatory patients. The Results (Outcomes in Initially Hospitalized HFpEF; page not provided) associate higher levels with a 60-day composite of emergency-room visits, readmissions, and death. That supports an association with adverse outcomes, but the paper does not establish a separate association with HF hospitalization or death, and it assessed clinical outcomes only in the initially hospitalized cohort. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim.

    Premisecitation

    Increases in aortic stiffness contribute to elevation in cardiac filling pressures, especially during exercise, in patients with HFpEF.

    “Pulse pressure is inversely correlated with arterial compliance, which is frequently impaired in patients with HFpEF, where increases in aortic stiffness contribute to elevation in cardiac filling pressures, especially during exercise24.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [24] Reddy, Y. N. V. et al. Arterial stiffening with exercise in patients with heart failure and preserved ejection fraction. J. Am. Coll. Cardiol. 70, 136–148 (2017). source

      The Discussion section reports that arterial stiffening in HFpEF was associated with abnormal hemodynamics, including filling pressures measured during exercise, and argues that it likely plays an important role. It also explicitly says the study cannot prove causality, so the claim that stiffness contributes to elevated filling pressures is stronger than the evidence establishes. Page numbers were not provided in our copy. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Obesity-related HFpEF is the most common phenotype of this disorder, and its emergence is causally related to the growing burden of cardiovascular-kidney-metabolic disorders observed worldwide.

    “Obesity-related HFpEF is the most common phenotype of this disorder3,9, and its emergence is causally related to the growing burden of cardiovascular–kidney–metabolic disorders observed worldwide4.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [3] Borlaug, B. A. et al. Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. Cardiovasc. Res. 118, 3434–3450 (2023). source

      The citation to this source is attached to the first clause, not the later claim about cardiovascular–kidney–metabolic disorders. The Abstract says many patients with HFpEF are overweight or obese, and the Conclusion calls obesity one of the most important causes of HFpEF. Neither passage establishes that obesity-related HFpEF is the most common phenotype. (LLM, conf=0.81)

      Experimental — accuracy not yet measured
    • cites [9] Morgen, C. S. et al. Obesity, cardiorenal comorbidities, and risk of hospitalization in patients with heart failure with preserved ejection fraction. Mayo Clin. Proc. 98, 1458–1468 (2023). source

      The Results report obesity in 57.8% of patients with HFpEF who had BMI data, supporting that obesity-related HFpEF was common in this US dataset. The paper does not establish that it is the most common phenotype worldwide. The causal claim is attached to a different citation in the citing sentence and is not judged here. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [4] Ndumele, C. E. et al. Cardiovascular–kidney–metabolic health: a presidential advisory from the American Heart Association. Circulation 148, 1606–1635 (2023). source

      The Stage 4 CKM section says obesity and physical inactivity are associated with a disproportionate risk of HFpEF, and the CKM overview links CKM syndrome to heart failure. Those passages support a relationship, but do not establish that the emergence of obesity-related HFpEF is caused by a growing worldwide burden of CKM disorders. The separate 'most common phenotype' clause is attached to other citations, not this source. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim.

    Premisecitation

    Weight loss in the absence of HF leads to increases in NT-proBNP.

    “The latter is notable because weight loss in the absence of HF leads to increases in NT-proBNP32,33.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [32] Abrahamsson, N., Engstrom, B. E., Sundbom, M. & Karlsson, F. A. Gastric bypass surgery elevates NT-ProBNP levels. Obes. Surg. 23, 1421–1426 (2013). source
    • cites [33] Kistorp, C., Bliddal, H., Goetze, J. P., Christensen, R. & Faber, J. Cardiac natriuretic peptides in plasma increase after dietary induced weight loss in obesity. BMC Obes. 1, 24 (2014). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Dapagliflozin reduces aortic stiffness, systolic BP and pulse pressure during exercise after 24 weeks, and these changes correlate with reductions in left ventricular filling pressures.

    “Treatment with the sodium–glucose cotransporter 2 inhibitor dapagliflozin was recently shown to reduce aortic stiffness, systolic BP and pulse pressure during exercise after just 24 weeks, and these changes were correlated with reductions in left ventricular filling pressures25.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Tada, A. et al. Dapagliflozin enhances arterial and venous compliance during exercise in heart failure with preserved ejection fraction: insights from the CAMEO-DAPA trial. Circulation 150, 997–1009 (2024). source

      The Results report lower exercise systolic BP, pulse pressure, and proximal aortic characteristic impedance after dapagliflozin treatment; the Discussion interprets the impedance change as likely reduced aortic wall stiffness. The Discussion and Abstract report that the reduction in exercise systolic BP correlated with reduced pulmonary capillary wedge pressure, a measure of left ventricular filling pressure. Our copy does not report that the stiffness and pulse-pressure changes themselves correlated with filling-pressure reductions, as “these changes” suggests. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Mineralocorticoid receptor antagonists ameliorate the progression of CKD.

    “Leptin is an important determinant of the decline in eGFR in the general population, and mineralocorticoid receptor antagonists ameliorate the progression of CKD23,27.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [23] 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 137, 1614–1631 (2018). source

      The References section lists mineralocorticoid receptor antagonism for cardiac diastolic dysfunction and spironolactone studies in heart failure, but those entries do not address CKD progression. Searches for CKD progression, chronic kidney disease, and renal effects of mineralocorticoid receptor antagonists found no passage stating that these drugs ameliorate CKD progression. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [27] Vaduganathan, M. et al. Finerenone in heart failure and chronic kidney disease with type 2 diabetes: FINE-HEART pooled analysis of cardiovascular, kidney and mortality outcomes. Nat. Med. https://doi.org/10.1038/s41591-024-03264-4 (2024). source

      The Results and Discussion (page unavailable) report that finerenone, a mineralocorticoid receptor antagonist, reduced a kidney composite outcome by about 20%, with benefits driven by trials in people with CKD and type 2 diabetes. This supports a benefit for finerenone in that population, but the paper does not establish that mineralocorticoid receptor antagonists as a class slow CKD progression generally. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    As compared with nonobese HFpEF, patients with obesity-related HFpEF display distinct pathophysiologic features, including greater volume expansion, more severe inflammation, increases in visceral and paracardiac adipose tissue and more severe myocardial injury.

    “As compared with nonobese HFpEF, patients with obesity-related HFpEF display distinct pathophysiologic features, including greater volume expansion5,17, more severe inflammation6,7, increases in visceral and paracardiac adipose tissue5,15,18,19 and more severe myocardial injury15.”
    Quote in the paperSubstantial claim5 of 7 sources checked
    • cites [5] Obokata, M., Reddy, Y. N., Pislaru, S. V., Melenovsky, V. & Borlaug, B. A. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation 136, 6–19 (2017). source

      The Discussion reports greater estimated plasma volume in obese than nonobese HFpEF, and the Results report greater epicardial fat thickness, supporting volume expansion and increased fat around the heart. This paper does not establish an increase in visceral adipose tissue. In the printed sentence, the inflammation and myocardial-injury assertions are attached to other citations, not this one. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [17] Miller, W. L. & Borlaug, B. A. Impact of obesity on volume status in patients with ambulatory chronic heart failure. J. Card. Fail. 26, 112–117 (2020). source
    • cites [6] Reddy, Y. N. V. et al. Characterization of the obese phenotype of heart failure with preserved ejection fraction: a RELAX trial ancillary study. Mayo Clin. Proc. 94, 1199–1209 (2019). source
    • cites [7] Alogna, A. et al. Interleukin-6 in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 11, 1549–1561 (2023). source
    • cites [15] Obokata, M. et al. Uncoupling between intravascular and distending pressures leads to underestimation of circulatory congestion in obesity. Eur. J. Heart Fail. 24, 353–361 (2022). source

      The “Mechanism for underestimation of filling pressures in obesity” section says obesity may increase external cardiac pressure partly through plasma volume retention, which supports the volume-expansion point attached to this citation. It does not directly establish greater blood volume in obesity-related versus nonobese HFpEF: the study compared patients with and without severe obesity who had unexplained dyspnoea, not exclusively patients with HFpEF. The other listed features have separate citations in the citing sentence. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [18] Koepp, K. E., Obokata, M., Reddy, Y. N. V., Olson, T. P. & Borlaug, B. A. Hemodynamic and functional impact of epicardial adipose tissue in heart failure with preserved ejection fraction. JACC Heart Fail. 8, 657–666 (2020). source

      In the Discussion section “Obesity, Epicardial Fat, and HFpEF” (page not provided), the paper reports increased epicardial adipose tissue in obesity-related HFpEF compared with nonobese HFpEF and links epicardial fat to visceral fat content. It does not establish the cited increase in paracardiac adipose tissue, which is distinct from the epicardial tissue studied here. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [19] Sorimachi, H. et al. Pathophysiologic importance of visceral adipose tissue in women with heart failure and preserved ejection fraction. Eur. Heart J. 42, 1595–1605 (2021). source

      The Sex-stratified differences in fat distribution section reports greater visceral adipose tissue in women with HFpEF than in BMI-matched women without heart failure. That is not a comparison of obesity-related with nonobese HFpEF. The Subject characteristics section says epicardial fat thickness was similar between groups, and the passages found do not establish more severe myocardial injury. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    Sensitivity analyses were performed using eGFR calculated with the 2021 creatinine-based CKD-EPI formula and separately with the combined creatinine-cystatin C CKD-EPI formula.

    “Sensitivity analyses were also performed using eGFR calculated determined using the 2021 creatinine-based CKD-EPI formula43, and separately using the combined creatinine-cystatin C CKD-EPI formula (Supplementary Appendix 2)19.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [43] Inker, L. A. et al. New creatinine- and cystatin C-based equations to estimate GFR without race. N. Engl. J. Med 385, 1737–1749 (2021). source
    • cites [19] Sorimachi, H. et al. Pathophysiologic importance of visceral adipose tissue in women with heart failure and preserved ejection fraction. Eur. Heart J. 42, 1595–1605 (2021). source

      The cited paper’s baseline-characteristics table (labeled Conclusions; page unavailable) reports estimated GFR, but does not identify the formula used. Searches for the combined creatinine–cystatin C CKD-EPI formula and cystatin C sensitivity analyses found no passage addressing them. The 2021 creatinine-based formula has a separate citation in the citing sentence. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Individuals with the obesity phenotype have higher troponin levels than those without obesity.

    “Patients with HFpEF and elevated troponin have more severe elevation in filling pressures, reduced myocardial stress reserve and poorer exercise capacity compared with those without injury13, and individuals with the obesity phenotype have higher troponin levels than those without obesity15.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [15] Obokata, M. et al. Uncoupling between intravascular and distending pressures leads to underestimation of circulatory congestion in obesity. Eur. J. Heart Fail. 24, 353–361 (2022). source

  • It may state two separate claims as one.

    Study design and conductreasoning

    Because weight loss with tirzepatide is expected to reduce both fat and skeletal muscle mass, creatinine could be less accurate as a measure of kidney function; therefore, eGFR was calculated using cystatin C in place of creatinine.

    “Reductions in body weight with tirzepatide would be expected to reduce skeletal muscle to some extent, which could influence creatinine dependent of changes in kidney function, and for this reason, we calculated eGFR using cystatin C in place of creatinine.”
    • Also stated in: § Study procedures · hedged
      “Because weight loss with tirzepatide is expected to reduce both fat and skeletal muscle mass, creatinine could be less accurate as a measure of kidney function. Therefore, for the primary analysis, eGFR was calculated from cystatin C level alone, using the 2012 chronic kidney disease-epidemiology (CKD-EPI) cystatin C formula, at baseline and 12, 24 and 52 weeks42.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [42] Inker, L. A. et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N. Engl. J. Med. 367, 20–29 (2012). source

  • It may state two separate claims as one.

    Findingown data

    Tirzepatide reduced systemic inflammation as measured by high-sensitivity CRP at 24 weeks and to greater extent at 52 weeks, but with no significant effect at 12 weeks.

    “Tirzepatide reduced systemic inflammation as measured by high-sensitivity CRP at 24 weeks and to greater extent at 52 weeks, but with no significant effect at 12 weeks (Table 3 and Fig. 2a).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    As compared with placebo, treatment with tirzepatide reduced systolic BP, an effect evident after 4 weeks, with a progressive decline up to 24 weeks, maintained after 52 weeks.

    “As compared with placebo, treatment with tirzepatide reduced systolic blood pressure (BP), an effect that was evident after 4 weeks, with a progressive decline up to 24 weeks, which was maintained after 52 weeks (Table 3 and Fig. 1a).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Participants in SUMMIT displayed typical characteristics of obesity-related HFpEF, with mean BMI exceeding 38 kg m−2, increased waist circumference and high prevalence of comorbidities including coronary disease and atrial fibrillation.

    “Participants displayed typical characteristics of obesity-related HFpEF, with mean body mass index (BMI) exceeding 38 kg m−2, increased waist circumference and high prevalence of comorbidities including coronary disease and atrial fibrillation, with no baseline differences in those randomized to tirzepatide or placebo (Table 1).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The effects of tirzepatide on diastolic BP were minimal and not statistically significant at 24 or 52 weeks of treatment.

    “In contrast, the effects on diastolic BP were minimal and not statistically significant at 24 or 52 weeks of treatment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    Nearly half the SUMMIT participants had experienced a hospitalization or urgent care visit for worsening HF in the preceding 12 months.

    “and nearly half the participants had experienced a hospitalization or urgent care visit for worsening HF in the preceding 12 months.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Patients with HFpEF in SUMMIT displayed systemic inflammation, with median C-reactive protein of 3.2 mg l−1, and 66% had elevated CRP (>2.0 mg l−1).

    “Patients with HFpEF also displayed systemic inflammation, with median C-reactive protein (CRP) of 3.2 mg l−1, and 66% had elevated CRP (>2.0 mg l−1).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Participants displayed borderline hypertension at baseline, with increased estimated blood volume and plasma volume in keeping with the diagnosis of obesity-related HFpEF.

    “Participants displayed borderline hypertension at baseline, with increased estimated BV and plasma volume (PV) in keeping with the diagnosis of obesity-related HFpEF (Table 2).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Using creatinine-based formulas, there was a statistically significant decrease in eGFR versus placebo at 12 weeks, which reversed by 52 weeks, showing an improvement in eGFR with tirzepatide across all estimates.

    “but using the creatinine-based formulas, there was a statistically significant decrease in eGFR versus placebo at 12 weeks, which again reversed by 52 weeks, showing an improvement in eGFR with tirzepatide across all estimates (Extended Data Table 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    Kidney dysfunction was common in SUMMIT participants, with a baseline mean estimated glomerular filtration rate of 55.3 ml min−1 1.73 m−2.

    “Kidney dysfunction was common, with a baseline mean estimated glomerular filtration rate (eGFR) of 55.3 ml min−1 1.73 m−2.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The reduction in estimated BV and PV with tirzepatide was evident after 12 weeks and further increased at 24 and 52 weeks.

    “Here, we show that tirzepatide reduced circulatory volume expansion using estimates of BV and PV, an effect that was evident after just 12 weeks of treatment and that further increased at 24 and 52 weeks.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Findingown data

    Over half of SUMMIT participants had stage 3 or greater CKD, over one-quarter had microalbuminuria and a smaller proportion had macroalbuminuria.

    “Over half of the participants had stage 3 or greater CKD, over one-quarter had microalbuminuria and a smaller proportion had macroalbuminuria.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Individuals with obesity-related HFpEF have a high burden of hypertension and chronic kidney disease, which develops in response to marked blood volume expansion and chronic systemic inflammation.

    “Individuals with obesity-related HFpEF have a high burden of hypertension and chronic kidney disease (CKD), which develops in response to marked blood volume (BV) expansion and chronic systemic inflammation5–8.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [5] Obokata, M., Reddy, Y. N., Pislaru, S. V., Melenovsky, V. & Borlaug, B. A. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation 136, 6–19 (2017). source
    • cites [6] Reddy, Y. N. V. et al. Characterization of the obese phenotype of heart failure with preserved ejection fraction: a RELAX trial ancillary study. Mayo Clin. Proc. 94, 1199–1209 (2019). source
    • cites [7] Alogna, A. et al. Interleukin-6 in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 11, 1549–1561 (2023). source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [8] Litwin, S. E. et al. Obesity in heart failure with preserved ejection fraction: Insights from the REDUCE LAP-HF II trial. Eur. J. Heart Fail. 26, 177–189 (2024). source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Interpretationown data

    These effects of tirzepatide on BP and circulatory volume expansion were observed early and were sustained with longer duration of treatment.

    “These effects were observed early and were sustained with longer duration of treatment.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    In the SUMMIT trial, tirzepatide reduced the combined risk of cardiovascular death or worsening HF and improved health status and exercise tolerance in patients with obesity-related HFpEF.

    “In the SUMMIT trial, tirzepatide reduced the combined risk of cardiovascular death or worsening HF, and improved health status and exercise tolerance in patients with obesity-related HFpEF16.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Packer, M. et al. Tirzepatide for heart failure with preserved ejection fraction and obesity. N. Engl. J. Med. (in the press).

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    P values are two-sided for each time point comparison 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.

    “P values are two-sided for each time point comparison 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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Arterial compliance is frequently impaired in patients with HFpEF.

    “Pulse pressure is inversely correlated with arterial compliance, which is frequently impaired in patients with HFpEF, where increases in aortic stiffness contribute to elevation in cardiac filling pressures, especially during exercise24.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Reddy, Y. N. V. et al. Arterial stiffening with exercise in patients with heart failure and preserved ejection fraction. J. Am. Coll. Cardiol. 70, 136–148 (2017). source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    No correction was made for multiple hypothesis testing.

    “No correction was made for multiple hypothesis testing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Leptin is an important determinant of the decline in eGFR in the general population.

    “Leptin is an important determinant of the decline in eGFR in the general population, and mineralocorticoid receptor antagonists ameliorate the progression of CKD23,27.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] 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 137, 1614–1631 (2018). source
    • cites [27] Vaduganathan, M. et al. Finerenone in heart failure and chronic kidney disease with type 2 diabetes: FINE-HEART pooled analysis of cardiovascular, kidney and mortality outcomes. Nat. Med. https://doi.org/10.1038/s41591-024-03264-4 (2024). source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Interpretationown data

    Tirzepatide reduced myocardial injury compared with placebo, reflected by a significant decrease in troponin T, along with a reduction in NT-proBNP.

    “Tirzepatide reduced myocardial injury compared with placebo, reflected by a significant decrease in troponin T, along with a reduction in NT-proBNP.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    In this mechanistic analysis of the SUMMIT trial, compared with placebo, treatment with tirzepatide reduced BP and estimates of circulatory volume expansion in patients with obesity-related HFpEF.

    “In this mechanistic analysis of the SUMMIT trial, we found that, compared with placebo, treatment with the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist tirzepatide reduced BP and estimates of circulatory volume expansion in patients with obesity-related HFpEF.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Tirzepatide reduced systemic inflammation, but this effect was observed later than the hemodynamic effects.

    “Tirzepatide reduced systemic inflammation, but this effect was observed later than the hemodynamic effects.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Decreases in systemic inflammation with tirzepatide were correlated with reductions in cardiac injury with tirzepatide, along with a modest correlation with improvements in 6MWD.

    “Conversely, decreases in systemic inflammation with tirzepatide were correlated with reductions in cardiac injury with tirzepatide, along with a modest correlation with improvements in 6MWD.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Tirzepatide resulted in an early trend to reduction in eGFR at 12 weeks, but this was followed by an improvement in eGFR compared with placebo with longer duration treatment, and reduction in microalbuminuria.

    “Tirzepatide resulted in an early trend to reduction in eGFR at 12 weeks, but this was followed by an improvement in eGFR compared with placebo with longer duration treatment, and reduction in microalbuminuria.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Tirzepatide reduced circulatory volume-pressure overload and systemic inflammation and mitigated cardiovascular-kidney end-organ injury in patients with HFpEF and obesity.

    “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.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The mechanisms underlying the favorable effects of tirzepatide in obesity-related HFpEF remain unclear.

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationown data

    These findings provide new insights into the mechanisms by which tirzepatide leads to clinical improvement in HFpEF.

    “These findings provide new insights into the mechanisms by which tirzepatide leads to clinical improvement in HFpEF.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The mechanisms underlying the favorable effects of tirzepatide in obesity-related HFpEF remain unclear.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Systemic hypertension has been linked to the development of obesity-related CKD.

    “Systemic hypertension has been linked to the development of obesity-related CKD26, but we observed a direct relationship between decreases in systolic BP and decreases in eGFR at multiple time points.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Yau, K., Kuah, R., Cherney, D. Z. I. & Lam, T. K. T. Obesity and the kidney: mechanistic links and therapeutic advances. Nat. Rev. Endocrinol. 20, 321–335 (2024). source

  • It may state two separate claims as one.

    Interpretationreasoning

    Novel treatments that reduce circulatory volume-pressure overload (or its determinants), improve kidney function, reduce inflammation and mitigate cardiac injury may improve clinical status in people with obesity-related HFpEF.

    “Collectively, these observations suggest that novel treatments that reduce circulatory volume–pressure overload (or its determinants), improve kidney function, reduce inflammation and mitigate cardiac injury may improve clinical status in people with obesity-related HFpEF.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    The correlation analyses were post hoc exploratory.

    “In post hoc exploratory analyses”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Reductions in estimated BV with tirzepatide were correlated with decreases in systolic BP, reduction in UACR and improvements in both KCCQ-CSS score and 6MWD, suggesting that mitigation of circulatory volume expansion (or factors responsible for volume expansion) may play a central role in mediating the benefits of tirzepatide.

    “Reductions in estimated BV with tirzepatide were correlated with decreases in systolic BP, reduction in UACR and improvements in both KCCQ-CSS score and 6MWD, suggesting that mitigation of circulatory volume expansion (or factors responsible for volume expansion) may play a central role in mediating the benefits of tirzepatide.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    The trial was approved by the ethics committee at each investigative site, and all patients provided written informed consent.

    “The ethics committee at each investigative site approved the trial, and all patients provided written informed consent.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Interpretationcitation

    The association between CRP reduction and 6MWD improvement may relate in part to myocardial benefits or potentially improvements in skeletal muscle function and peripheral oxygen uptake, which are more dramatically impaired in patients with HFpEF and more severe inflammation.

    “This may relate in part to myocardial benefits, as noted above, or potentially improvements in skeletal muscle function and peripheral oxygen uptake, which are more dramatically impaired in patients with HFpEF and more severe inflammation35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Tada, A. et al. Autoimmune disorders in heart failure with preserved ejection fraction. JACC Heart Fail. 12, 1257–1269 (2024). source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Patients with significant musculoskeletal disease were excluded from SUMMIT by protocol.

    “However, patients with significant musculoskeletal disease were excluded from SUMMIT by protocol.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Patients with active chronic noninflammatory myopathy and myositis may have mild elevation in troponin T independent of myocardial injury.

    “Patients with active chronic noninflammatory myopathy and myositis may have mild elevation in troponin T independent of myocardial injury41.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] du Fay de Lavallaz, J. et al. Skeletal muscle disorders: a noncardiac source of cardiac troponin T. Circulation 145, 1764–1779 (2022). source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Study design and conductcitation

    The analysis estimated PV using a weight-based formula (the Kaplan-Hakim equation), and according to this formula, the weight loss produced by tirzepatide would be mathematically expected to reduce PV.

    “The major limitation of this analysis centers on the fact that we estimated PV using a weight-based formula (the Kaplan–Hakim equation)36, and according to this formula, the weight loss produced by tirzepatide would be mathematically expected to reduce PV.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Ling, H. Z. et al. Calculated plasma volume status and prognosis in chronic heart failure. Eur. J. Heart Fail. 17, 35–43 (2015). source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Premisecitation

    PV/BV is inherently linked to body weight, and thus PV/BV necessarily declines as weight is lost.

    “However, such an effect is physiologically inescapable, since PV/BV is inherently linked to body weight37, and thus, PV/BV necessarily declines as weight is lost.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Feldschuh, J. & Enson, Y. Prediction of the normal blood volume. Relation of blood volume to body habitus. Circulation 56, 605–612 (1977). source

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductown data

    The SUMMIT trial randomized eligible patients double blind (1:1) to receive placebo or tirzepatide 2.5 mg per week subcutaneously, in addition to usual therapy.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductreasoning

    Adjustment for multiple hypothesis testing was not performed because the focus was on mechanistic understanding rather than clinical indications.

    “Given that the focus was on mechanistic understanding rather than clinical indications, adjustment for multiple hypothesis testing was not performed.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Weight-independent formulas to estimate changes in PV have been proposed, but these are relevant only for short-term interventions and are not applicable when there are meaningful changes in weight over months.

    “We understand that weight-independent formulas to estimate changes in PV have been proposed40, but these are relevant only for short-term interventions and are not applicable when there are meaningful changes in weight over months.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Strauss, M. B., Davis, R. K., Rosenbaum, J. D. & Rossmeisl, E. C. Water diuresis produced during recumbency by the intravenous infusion of isotonic saline solution. J. Clin. Invest. 30, 862–868 (1951). source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The low-grade myocardial injury in HFpEF as observed at baseline in SUMMIT is believed to be related to cardiomyocyte loss due to repetitive elevations in cardiac filling pressures during stress, along with adverse loading conditions caused by ventricular-vascular stiffening.

    “The low-grade myocardial injury in HFpEF as observed at baseline in SUMMIT is believed to be related to cardiomyocyte loss due to repetitive elevations in cardiac filling pressures during stress, along with adverse loading conditions caused by ventricular–vascular stiffening13,34.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] Obokata, M. et al. Myocardial injury and cardiac reserve in patients with heart failure and preserved ejection fraction. J. Am. Coll. Cardiol. 72, 29–40 (2018). source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [34] Canty, J. M. Jr. Myocardial injury, troponin release, and cardiomyocyte death in brief ischemia, failure, and ventricular remodeling. Am. J. Physiol. Heart Circ. Physiol. 323, H1–H15 (2022). source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Randomization was stratified by HF decompensation within 12 months, type 2 diabetes, and BMI ≥35 or <35 kg m−2.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Patients with HFpEF and elevated troponin have more severe elevation in filling pressures, reduced myocardial stress reserve and poorer exercise capacity compared with those without injury.

    “Patients with HFpEF and elevated troponin have more severe elevation in filling pressures, reduced myocardial stress reserve and poorer exercise capacity compared with those without injury13, and individuals with the obesity phenotype have higher troponin levels than those without obesity15.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Obokata, M. et al. Myocardial injury and cardiac reserve in patients with heart failure and preserved ejection fraction. J. Am. Coll. Cardiol. 72, 29–40 (2018). source

      Checked before — its earlier verdict is held back until a new check runs.

57 of 57

  • The paper relies on this without support.

    The mechanisms underlying the favorable effects of tirzepatide in obesity-related HFpEF remain unclear.

    “The mechanisms underlying these favorable effects of tirzepatide remain unclear.”

  • The paper relies on this without support.

    The mechanisms underlying clinical improvement with incretins such as tirzepatide and semaglutide in patients with obesity-related HFpEF have remained unclear.

    “but the mechanisms underlying clinical improvement with incretins such as tirzepatide and semaglutide in patients with obesity-related HFpEF have remained unclear.”
2 of 2

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?

  • These observations suggest that semaglutide may rapidly improve disease trajectory through cardiometabolic mechanisms independent of weight loss.

    “These observations suggest that semaglutide may rapidly improve disease trajectory through cardiometabolic mechanisms independent of weight loss, although the underlying pathophysiology requires further investigation.48-52”

    From Semaglutide and Tirzepatide in Patients With Heart Failure With Preserved Ejection Fraction (2025) · cites this paper as [50]

    The Discussion reports that semaglutide improved health status and exercise capacity in patients with obesity-related HFpEF. It does not establish rapid improvement or a mechanism independent of weight loss; instead, it says the improvements correlated with weight reduction and that the mechanisms remain unclear. The early hemodynamic effects analyzed in this paper concern tirzepatide, not semaglutide. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Changes in eGFR-creatinine may be skewed in patients receiving GLP-1 receptor agonists due to the effect of these drugs to reduce muscle mass and thereby serum creatinine.

    “However, because changes in eGFR-creatinine may be skewed in patients receiving GLP-1 receptor agonists due to the effect of these drugs to reduce muscle mass (and thereby serum creatinine), in the current report, we focused (in a post hoc analysis) on eGFR based on cystatin C (eGFR-cystatin C),51 although we also report all results based on eGFR-creatinine.”

    From Interplay of Chronic Kidney Disease and the Effects of Tirzepatide in Patients With Heart Failure, Preserved Ejection Fraction, and Obesity (2025) · cites this paper as [51]

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.

  • A 12-week plasma-volume estimate is reported without a 12-week hematocrit measurement

    Minor

    The stated plasma-volume formula requires hematocrit, but hematocrit is said to have been measured only at baseline, 24 weeks and 52 weeks. Table 3 nevertheless reports estimated plasma volume at 12 weeks.

  • Body-weight treatment difference has the opposite sign from its confidence interval

    Minor

    The reported body-weight ETD is positive, whereas both endpoints of its 95% confidence interval are negative.

2 of 2

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Metadata

Authors
Borlaug, B. A., Zile, M. R., Kramer, C. M., Baum, S. J., Hurt, K., Litwin, S. E., Murakami, M., Ou, Y., Upadhyay, N., & Packer, M.
Affiliations
  • Mayo Clinic (US)
  • Medical University of South Carolina (US)
  • University of Virginia Health System (US)
  • Eli Lilly (United States) (US)
  • Baylor University Medical Center (US)
Corresponding author
Borlaug, Barry A.
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2024-11-17
Volume
31
Issue
2
Pages
544-551
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/s41591-024-03374-z
PMC
PMC11835708
OpenAlex
W4404448817
Semantic Scholar
9e45ced488de6f3d503280df9f45d4dbd4862fc5
Cited by
166
References
43
Citations by year
2026: 83 · 2025: 81 · 2024: 2
FWCI
46.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Eli Lilly and Company
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
tirzepatide, heart failure with preserved ejection fraction, obesity, circulatory overload, blood volume, blood pressure, C-reactive protein, glomerular filtration rate, albuminuria, natriuretic peptides, troponin T, SUMMIT trial, GIP/GLP-1 receptor agonist
MeSH terms
Tirzepatide, Aged, Blood Pressure, C-Reactive Protein, Female, Heart Failure, Humans, Male, Middle Aged, Obesity, Peptide Fragments, Stroke Volume, Natriuretic Peptide, Brain

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.

A language model drew the claims from the paper on 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

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 ›

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