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

In the paper

“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.”

What the sources say

• Partly supported

  The Results (Subject Characteristics; page unavailable) report more comorbidities and lower eGFR in HFpEF subjects than controls, while the Discussion reports greater plasma-volume expansion in obese HFpEF and describes systemic inflammation as part of obesity-related HFpEF pathophysiology. The paper does not establish that hypertension and CKD specifically develop in response to blood-volume expansion and chronic systemic inflammation. (LLM, conf=0.86)

  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). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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
• Partly supported

  The Discussion describes a greater burden of inflammation in obesity-related HFpEF and worse renal function in patients with higher IL-6. The Potential Mechanisms section mentions plasma volume expansion only as a possible explanation for lower hemoglobin. It does not establish a high burden of hypertension and CKD in this phenotype or show that those conditions develop in response to marked blood-volume expansion and inflammation (page numbers unavailable in our copy). (LLM, conf=0.86)

  cites [7] Alogna, A. et al. Interleukin-6 in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 11, 1549–1561 (2023). sourceExperimental — accuracy not yet measured
• Partly supported

  The demographics and comorbidities table (section labelled Conclusions; page unavailable) reports high rates of hypertension and chronic kidney disease in the trial population, including patients with obesity. The Introduction lists increased blood volume and inflammation as proposed mechanisms linking obesity to HFpEF, but does not establish that hypertension or CKD develops in response to those mechanisms, or describe the blood-volume expansion as marked. (LLM, conf=0.88)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• Supported

  The Discussion links albuminuria in HFpEF to chronic kidney disease, endothelial dysfunction and systemic inflammation, and reports associations with impaired cardiac function and possible renal venous congestion. The Results report higher risks of HF hospitalization and cardiovascular death in the microalbuminuria group. The source frames the proposed mechanisms and congestion link as possibilities, consistent with the claim's hedged wording. (LLM, conf=0.88)

  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
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Redfield, M. M. & Borlaug, B. A. Heart failure with preserved ejection fraction: a review. JAMA 329, 827–838 (2023). source
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• ?Could not verify

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“Obesity-related HFpEF represents the most advanced form of cardiovascular–kidney–metabolic disease, a syndrome recognized by the American Heart Association4.”

What the sources say

• Partly supported

  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)

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

In the paper

“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.”

What the sources say

• Partly supported

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

  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). sourceExperimental — accuracy not yet measured
• Partly supported

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

  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). sourceExperimental — accuracy not yet measured

In the paper

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

What the sources say

• Supported

  The Results section (‘Relationships between Vascular Effects, Body Weight, and Hemodynamics’) reports that improvements in total arterial compliance during exercise were associated with decreases in body weight on treatment. The paper describes this as a correlation, not evidence that weight loss caused the improvement. (LLM, conf=0.94)

  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

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

What the sources say

• Supported

  The Conclusions state that people with HFpEF display impaired arterial compliance reserve during exercise. The Results (Arterial Reserve With Submaximal Exercise) report lower total arterial compliance in HFpEF subjects than in controls during exercise, supporting the claim while specifying when the impairment was observed. (LLM, conf=0.91)

  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

In the paper

“Leptin is an important determinant of the decline in eGFR in the general population, and mineralocorticoid receptor antagonists ameliorate the progression of CKD23,27.”

What the sources say

• Partly supported

  The section 'Role of Epicardial Fat in the Interplay of Adipokines and Heart Failure' (page unavailable) says higher leptin levels are accompanied by faster renal-function decline, particularly in women. It discusses this in the context of obesity-related heart failure; it does not establish leptin as a determinant of eGFR decline in the general population. (LLM, conf=0.85)

  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). sourceExperimental — accuracy not yet measured
• ?Could not verify

  The quoted claim concerns leptin as a determinant of eGFR decline in the general population. Our copy’s Results and Methods discuss eGFR and kidney outcomes but do not address leptin; a search for leptin and general-population eGFR decline found no relevant passage. The Results do support the separate, citation-adjacent statement that finerenone reduced kidney outcomes. (LLM, conf=0.76)

  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). sourceExperimental — accuracy not yet measured

In the paper

“Circulating troponin levels are commonly elevated in HFpEF, where they are associated with greater risk for HF hospitalization or death14.”

What the sources say

• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  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)

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

In the paper

“The latter is notable because weight loss in the absence of HF leads to increases in NT-proBNP32,33.”

What the sources say

• ?Not checked — no full text of the sourcecites [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
• Supported

  The Discussion reports that NT-proBNP increased after substantial diet-induced weight loss in obese subjects without heart disease. It also states that participants had no heart-disease symptoms and their baseline NT-proBNP levels were below the recommended heart-failure cutoff. (LLM, conf=0.92)

  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

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“Leptin is an important determinant of the decline in eGFR in the general population, and mineralocorticoid receptor antagonists ameliorate the progression of CKD23,27.”

What the sources say

• ?Could not verify

  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)

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [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
• ?Not checked — no full text of the sourcecites [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
• Supported

  The source describes obesity-related HFpEF as a distinct phenotype with greater inflammation, qualified as reflected by CRP levels (introductory passage under Abstract > Conclusions; page not provided). Its Discussion section, “IL-6 and Obesity in HFpEF,” also reports higher IL-6 levels in patients with greater body fat. This supports the inflammation portion of the citing sentence, to which this citation is attached. (LLM, conf=0.91)

  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
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

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

  cites [35] Tada, A. et al. Autoimmune disorders in heart failure with preserved ejection fraction. JACC Heart Fail. 12, 1257–1269 (2024). source

In the paper

“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.”

What the sources say

• ?Could not verify

  The available passage labelled Abstract says plasma volume status was calculated from clinical indices, but it does not identify a weight-based Kaplan–Hakim equation. Searches for Kaplan–Hakim, body weight, and the formula found no passage establishing that detail. The tirzepatide inference is the citing authors’ own, rather than a finding attributed to this source. (LLM, conf=0.72)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The citation to this paper is attached to the combined creatinine–cystatin C CKD-EPI formula, not to the citing authors’ sensitivity analyses. The Methods and Discussion (page not available in our copy) identify and evaluate the paper’s new eGFRcr-cys equations, supporting that identification. (LLM, conf=0.92)

  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
• ?Could not verify

  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)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Subject characteristics section reports higher troponin T levels in Group B. Table 2 identifies Group B as BMI ≥35 kg/m² and Group A as BMI <35 kg/m², with high-sensitivity troponin T levels of 12.4 versus 7.9 ng/L (p=0.04). Biomarkers were measured in a subset of 58 participants. (LLM, conf=0.94)

  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

In the paper

“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.”

What the sources say

• Partly supported

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

  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). sourceExperimental — accuracy not yet measured
• Partly supported

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

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Supported

  The Discussion states that cystatin C is less affected by muscle mass than creatinine and discusses its use for estimating GFR in patients with muscle wasting. That supports the cited rationale for using cystatin C when a change in skeletal muscle could affect creatinine independently of kidney function. (LLM, conf=0.88)

  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

In the paper

“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.”

What the sources say

• Supported

  The Results section reports that HFpEF patients with abnormal troponin had poorer exercise measures of myocardial reserve than those with normal troponin. It also reports associations between higher troponin, higher filling pressures, and reduced peak aerobic capacity. Page numbers are unavailable in our copy. (LLM, conf=0.91)

  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

In the paper

“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).”

In the paper

“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).”

In the paper

“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).”

In the paper

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

In the paper

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

In the paper

“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).”

In the paper

“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).”

In the paper

“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).”

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

“These effects were observed early and were sustained with longer duration of treatment.”

In the paper

“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.”

What the sources say

• ?Not matched

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

  cites [16] Packer, M. et al. Tirzepatide for heart failure with preserved ejection fraction and obesity. N. Engl. J. Med. (in the press).

In the paper

“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.”

In the paper

“No correction was made for multiple hypothesis testing.”

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

In the paper

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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [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

In the paper

“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.”

In the paper

“In post hoc exploratory analyses”

In the paper

“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.”

In the paper

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

In the paper

“However, patients with significant musculoskeletal disease were excluded from SUMMIT by protocol.”

In the paper

“Patients with active chronic noninflammatory myopathy and myositis may have mild elevation in troponin T independent of myocardial injury41.”

What the sources say

• Not checked yet

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

  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

In the paper

“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.”

What the sources say

• ?Not checked — no full text of the sourcecites [37] Feldschuh, J. & Enson, Y. Prediction of the normal blood volume. Relation of blood volume to body habitus. Circulation 56, 605–612 (1977). source

In the paper

“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.”

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yet

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

  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

In the paper

“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.”