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Cited by 66Heart Failure Treatment and ManagementDiabetes Treatment and ManagementCardiovascular Function and Risk Factors

The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index; 31 of the 76 sources its claims cite were checked for support.

Semaglutide and Tirzepatide in Patients With Heart Failure With Preserved Ejection Fraction

Open access
Krüger, Nils, Schneeweiss, Sebastian, Fuse, Kenshiro, Matseyko, Sofiya, Sreedhara, Sushama Kattinakere, Hahn, Georg, Schunkert, Heribert, Wang, Shirley V.·2025·JAMA
DOI 10.1001/jama.2025.14092PMC PMC12400167
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Abstract

Importance: Heart failure with preserved ejection fraction (HFpEF) is a major cause of hospitalization, often occurring in patients with cardiometabolic comorbidities such as obesity and type 2 diabetes. Although early trials of semaglutide and tirzepatide have shown promising results in improving symptoms, those findings were based on few clinical events, leaving treatment recommendations uncertain. Objective: To evaluate the effectiveness and safety of semaglutide and tirzepatide in patients with cardiometabolic HFpEF in clinical practice. Design, Setting, and Participants: Five cohort studies using national US health care claims data from 2018 to 2024. Two cohort studies emulated the STEP-HFpEF DM (semaglutide) and SUMMIT (tirzepatide) trials to benchmark results. Eligibility criteria were then expanded to evaluate treatment effects in patients typically treated in clinical practice. Finally, a head-to-head comparison of tirzepatide and semaglutide was implemented. Follow-up was up to 52 weeks. Exposures: New use of semaglutide, tirzepatide, or sitagliptin as a placebo proxy. Main Outcomes and Measures: The primary end point was a composite of hospitalization for heart failure or all-cause mortality. Negative control outcomes, secondary end points, subgroups, and sensitivity analyses were prespecified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by fitting proportional hazards models with propensity score weighting to adjust for a comprehensive set of pretreatment patient characteristics. Results: Benchmarking of the 2 trial emulations demonstrated high agreement on all prespecified metrics. In analyses using expanded eligibility criteria, 58 333 patients were included in the semaglutide vs sitagliptin cohort, 11 257 for tirzepatide vs sitagliptin, and 28 100 for tirzepatide vs semaglutide. Initiators of semaglutide (HR, 0.58 [95% CI, 0.51-0.65]) and tirzepatide (HR, 0.42 [95% CI, 0.31-0.57]) had substantially lower risk of the primary end point compared with sitagliptin. Tirzepatide had no meaningfully lowered risk compared with semaglutide (HR, 0.86 [95% CI, 0.70-1.06]). Negative controls, secondary end points, subgroups, and sensitivity analyses showed consistent results. No substantially increased risk was observed for select safety end points. Conclusions and Relevance: In patients with cardiometabolic HFpEF, semaglutide and tirzepatide showed more than 40% risk reduction for the composite of hospitalization for heart failure or all-cause mortality compared with a placebo proxy. Tirzepatide showed no meaningful benefit over semaglutide. Trial Registration: ClinicalTrials.gov Identifiers: NCT06914102 , NCT06914154 , NCT06914141

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In US claims data, semaglutide and tirzepatide were associated with substantially lower 1-year risk of heart failure hospitalization or all-cause mortality vs sitagliptin in patients with cardiometabolic HFpEF, with no meaningful difference between tirzepatide and semaglutide. Trial emulations benchmarked well against STEP-HFpEF DM and SUMMIT before expanded and head-to-head analyses.

Key findings

  • In the expanded semaglutide vs sitagliptin cohort (58,333 patients), semaglutide was associated with lower risk of the primary composite endpoint (HR, 0.58 [95% CI, 0.51-0.65]); 1-year risk was 5.5% vs 8.6%, risk difference −3.2%, number needed to treat 31.
  • In the expanded tirzepatide vs sitagliptin cohort (11,257 patients), tirzepatide was associated with lower risk (HR, 0.42 [95% CI, 0.31-0.57]); 1-year risk was 3.6% vs 7.5%, risk difference −3.9%, number needed to treat 26.
  • In the head-to-head tirzepatide vs semaglutide cohort (28,100 patients), there was no meaningful difference (HR, 0.86 [95% CI, 0.70-1.06]); 1-year risk was 3.3% vs 3.4%, risk difference −0.1%, number needed to treat 1000.
  • Benchmarking showed agreement with trials: semaglutide real-world HR 0.57 vs RCT HR 0.40; tirzepatide real-world HR 0.39 vs RCT HR 0.62; both met all 3 prespecified agreement metrics. Negative controls were null, and no substantially increased risk was observed for select safety endpoints.

Methods

  • Five active-comparator, new-user cohort studies using 3 US claims databases: Medicare Parts A, B, and D (2018-2020), Optum Clinformatics Data Mart (2018-November 2024), and Merative MarketScan (2018-2022). Patients had obesity-related HFpEF and type 2 diabetes, with at least 12 months of continuous enrollment before cohort entry.
  • Two cohorts emulated STEP-HFpEF DM (semaglutide vs sitagliptin) and SUMMIT (tirzepatide vs sitagliptin) for benchmarking; eligibility was then expanded to routine-care populations, and a head-to-head tirzepatide vs semaglutide comparison was conducted. Exposures were new use of semaglutide, tirzepatide, or sitagliptin as a placebo proxy.
  • The primary endpoint was hospitalization for heart failure or all-cause mortality, with follow-up up to 52 weeks in an as-treated approach. Propensity score overlap weighting, Cox proportional hazards models, and fixed-effects meta-analysis across databases were used; negative controls, subgroups, and sensitivity analyses were prespecified.

Limitations

  • The paper states that treatment allocation was not randomized, so unmeasured confounding may remain despite extensive propensity score overlap weighting; medication use was inferred from dispensing records and may not capture adherence; heart failure symptoms and ejection fraction were not from standardized assessments but from a validated claims-based algorithm with positive predictive value 91%; and the study assumes sitagliptin has no relevant effect on the primary endpoint as a placebo proxy.
  • The text makes evident that as-treated follow-up was short (mean on-treatment duration roughly 161-183 days across cohorts) and discontinuation was the most common reason for censoring (37%-45%); as-started sensitivity analyses attenuated hazard ratios, and a broader heart failure hospitalization definition also attenuated estimates, so findings may depend on exposure and outcome definitions.

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

Integrity signals

Registry

Crossref · 10.1001/jama.2025.14092

Cites

61 of 61 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

31 of 76 cited sources checked · 11 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    The early randomized trials of semaglutide and tirzepatide in obesity-related HFpEF were limited by small study sizes with few cardiovascular outcomes and highly restrictive eligibility criteria.

    “However, these trials were limited by small study sizes with few cardiovascular outcomes and highly restrictive eligibility criteria.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [6] Packer M, Zile MR, Kramer CM,; SUMMIT Trial Study Group. Tirzepatide for heart failure with preserved ejection fraction and obesity. N Engl J Med 2025; 392(5): 427– 437. doi: 10.1056/NEJMoa241002 39555826 source
    • cites [7] Kosiborod MN, Abildstrøm SZ, Borlaug BA,; STEP-HFpEF Trial Committees and Investigators. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. 2023; 389(12): 1069– 1084. doi: 10.1056/NEJMoa2306963 37622681 source

      The Randomization and Participant Characteristics section reports 529 participants, and the Discussion says the trial was not adequately powered to evaluate clinical events such as heart-failure hospitalizations. The Trial Participants section lists multiple eligibility requirements and excludes people with diabetes. These passages support the characterization of the semaglutide trial, but this paper does not assess the tirzepatide trial or establish that the same limitations applied to both trials. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [8] Kosiborod MN, Petrie MC, Borlaug BA,; STEP-HFpEF DM Trial Committees and Investigators. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. N Engl J Med. 2024; 390(15): 1394– 1407. doi: 10.1056/NEJMoa2313917 38587233 source

      The Abstract reports results from a semaglutide trial in patients with obesity-related HFpEF and type 2 diabetes, but the passages in our copy do not assess whether its size, cardiovascular outcomes, or eligibility criteria were limiting. Searches for those limitations and for tirzepatide found no passage addressing the claim. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
  • Premisecitation

    Early randomized clinical trials demonstrated that semaglutide and tirzepatide improved symptoms in patients with obesity-related HFpEF.

    “Recent randomized clinical trials demonstrated that the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide and the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide improved symptoms in patients with obesity-related HFpEF.6-8”
    • Also stated in: § IMPORTANCE · hedged
      “Although early trials of semaglutide and tirzepatide have shown promising results in improving symptoms, those findings were based on few clinical events, leaving treatment recommendations uncertain.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [6] Packer M, Zile MR, Kramer CM,; SUMMIT Trial Study Group. Tirzepatide for heart failure with preserved ejection fraction and obesity. N Engl J Med 2025; 392(5): 427– 437. doi: 10.1056/NEJMoa241002 39555826 source
    • cites [7] Kosiborod MN, Abildstrøm SZ, Borlaug BA,; STEP-HFpEF Trial Committees and Investigators. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. 2023; 389(12): 1069– 1084. doi: 10.1056/NEJMoa2306963 37622681 source
    • cites [8] Kosiborod MN, Petrie MC, Borlaug BA,; STEP-HFpEF DM Trial Committees and Investigators. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. N Engl J Med. 2024; 390(15): 1394– 1407. doi: 10.1056/NEJMoa2313917 38587233 source
  • Premisecitation

    Guideline committees withheld formal recommendations for semaglutide and tirzepatide in HFpEF pending confirmation of benefits on clinical outcomes.

    “Similarly, guideline committees withheld formal recommendations pending confirmation of benefits on clinic al outcomes to complement these trial findings.9-12”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [9] McDonagh TA, Metra M, Adamo M,; ESC Scientific Document Group. 2023 Focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023; 44(37): 3627– 3639. doi: 10.1093/eurheartj/ehad195 37622666 source

      Section 3 (Chronic heart failure; page unavailable) discusses recommendations for other HFpEF therapies, including SGLT2 inhibitors, but does not address withholding recommendations for semaglutide or tirzepatide pending clinical-outcome evidence. Searches for both drug names and related recommendation language found no passage addressing that claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [10] Novo Nordisk. Q2 2024 Novo Nordisk A/S earnings conference call. Accessed March 13, 2025. https://edge.media-server.com/mmc/p/n7putxx6/
    • cites [11] Kittleson MM, Panjrath GS, Amancherla K, 2023 ACC expert consensus decision pathway on management of heart failure with preserved ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2023; 81(18): 1835– 1878. doi: 10.1016/j.jacc.2023.03.393 37137593 source

      Section 7.3 says semaglutide and tirzepatide had not yet been rigorously evaluated in people with heart failure and that ongoing HFpEF trials could clarify their benefits and safety. It does not say that guideline committees formally withheld recommendations pending confirmation of clinical outcomes; it also says these drugs should be considered for patients with HFpEF, type 2 diabetes, and elevated ASCVD risk. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [12] Kittleson MM, Benjamin EJ, Blumer V, 2025 ACC scientific statement on the management of obesity in adults with heart failure: a report of the American College of Cardiology. J Am Coll Cardiol. 2025; S0735– 1097(25)06481-2. 40512113 source
  • Interpretationreasoning

    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”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [48] Plutzky J, Ostrominski JW, Aroda VR, Deanfield J, Lincoff AM. Early clinical benefit of semaglutide in adults with overweight or obesity and cardiovascular disease: a secondary analysis of the SELECT trial. Presented at: European Congress on Obesity 2025; May 13, 2025; Malaga, Spain.
    • cites [49] Shah SJ, Sharma K, Borlaug BA, Semaglutide and diuretic use in obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF-DM trials. Eur Heart J. 2024; 45(35): 3254– 3269. doi: 10.1093/eurheartj/ehae322 38739118 PMC11400859 source
    • cites [50] Borlaug BA, Zile MR, Kramer CM, 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. Nat Med. 2025; 31(2): 544– 551. doi: 10.1038/s41591-024-03374-z 39551891 PMC11835708 source

      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
    • cites [51] Petrie MC, Borlaug BA, Butler J,; STEP-HFpEF Trial Committees and Investigators. Semaglutide and NT-proBNP in obesity-related HFpEF: insights from the STEP-HFpEF program. J Am Coll Cardiol. 2024; 84(1): 27– 40. doi: 10.1016/j.jacc.2024.04.022 38819334 source
    • cites [52] Hullon D, Subeh GK, Volkova Y, Janiec K, Trach A, Mnevets R. The role of glucagon-like peptide-1 receptor (GLP-1R) agonists in enhancing endothelial function: a potential avenue for improving heart failure with preserved ejection fraction (HFpEF). Cardiovasc Diabetol. 2025; 24(1): 70. doi: 10.1186/s12933-025-02607-w 39920668 PMC11806760 source

      The 'Data from clinical studies' section (page unavailable) reports that semaglutide improved HFpEF-related measures and reduced cardiovascular events, supporting the possibility of an improved disease trajectory. It does not establish that these benefits occur rapidly or independently of weight loss; the reported HFpEF improvements included weight loss and were assessed over 52 weeks. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Study design and conductcitation

    An advanced methodological approach was applied using the RCT-DUPLICATE design, data, and analytics framework to emulate key aspects of randomized studies.

    “Second, an advanced methodological approach was applied using the RCT-DUPLICATE design, data, and analytics framework to emulate key aspects of randomized studies.33,63”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [33] Franklin JM, Pawar A, Martin D, Nonrandomized real-world evidence to support regulatory decision making: process for a randomized trial replication project. Clin Pharmacol Ther. 2020; 107(4): 817– 826. doi: 10.1002/cpt.1633 31541454 source
    • cites [63] Krüger N, Krefting J, Kessler T,; DigiMed Bayern Consortium. Ticagrelor vs prasugrel for acute coronary syndrome in routine care. JAMA Netw Open. 2024; 7(12): e2448389. doi: 10.1001/jamanetworkopen.2024.48389 39621344 PMC11612834 source

      The Methods (Study Design; page unavailable) describe using claims data, a new-user cohort, and propensity-score matching to emulate key aspects of a randomized trial. Our copy does not identify the approach as the RCT-DUPLICATE design, data, and analytics framework, so that specific attribution is not established. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Probably not a substantial claim. 11
  • It may state two separate claims as one. 13

  • Probably not a substantial claim.

    Study design and conductreasoning

    The findings were first benchmarked against results from the STEP-HFpEF DM and SUMMIT trials.

    “these findings were first benchmarked against results from the STEP-HFpEF DM and SUMMIT trials.9-11,55”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [9] McDonagh TA, Metra M, Adamo M,; ESC Scientific Document Group. 2023 Focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023; 44(37): 3627– 3639. doi: 10.1093/eurheartj/ehad195 37622666 source

      The Chronic heart failure section discusses results from EMPEROR-Preserved and DELIVER, but does not describe benchmarking findings against STEP-HFpEF DM or SUMMIT. Searches of our full-text copy for both trial names and for the proposed benchmarking found no passage addressing it; the paper’s discussion of other trials does not establish that the benchmarking occurred. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [10] Novo Nordisk. Q2 2024 Novo Nordisk A/S earnings conference call. Accessed March 13, 2025. https://edge.media-server.com/mmc/p/n7putxx6/
    • cites [11] Kittleson MM, Panjrath GS, Amancherla K, 2023 ACC expert consensus decision pathway on management of heart failure with preserved ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2023; 81(18): 1835– 1878. doi: 10.1016/j.jacc.2023.03.393 37137593 source

      In §7.3, Management of Comorbidities (page unavailable), the source describes SUMMIT and STEP-HFpEF as ongoing trials that may provide future insight, not as trials with results available for benchmarking. It does not identify STEP-HFpEF DM or report results from either trial. (LLM, conf=0.85)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [55] Makary MA, Prasad V. Priorities for a new FDA. JAMA. Published online June 10, 2025. doi: 10.1001/jama.2025.10116 40493446 source

  • It may state two separate claims as one.

    Premisecitation

    Sitagliptin served as a placebo proxy regarding heart failure outcomes because it showed no effect on heart failure events in a major randomized clinical trial and previously served as a placebo proxy in claims data analyses.

    “The comparator, sitagliptin, served as a placebo proxy regarding the outcome of interest as it showed no effect on heart failure events in a major randomized clinical trial and previously successfully served as a placebo proxy in claims data analyses.15,18,19”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [15] Wang SV, Schneeweiss S, Franklin JM,; RCT-DUPLICATE Initiative. Emulation of randomized clinical trials with nonrandomized database analyses: results of 32 clinical trials. JAMA. 2023; 329(16): 1376– 1385. doi: 10.1001/jama.2023.4221 37097356 PMC10130954 source
    • cites [18] Fu EL, Patorno E, Everett BM, Sodium-glucose cotransporter 2 inhibitors vs. sitagliptin in heart failure and type 2 diabetes: an observational cohort study. Eur Heart J. 2023; 44(24): 2216– 2230. doi: 10.1093/eurheartj/ehad273 37259575 PMC10290872
    • cites [19] Green JB, Bethel MA, Armstrong PW,; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015; 373(3): 232– 242. doi: 10.1056/NEJMoa1501352 26052984 source

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

    Interpretationcitation

    The current findings align closely with early and underpowered evidence from randomized trials with few clinical end points.

    “This aligns closely with early and underpowered evidence from randomized trials with few clinical end points”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [6] Packer M, Zile MR, Kramer CM,; SUMMIT Trial Study Group. Tirzepatide for heart failure with preserved ejection fraction and obesity. N Engl J Med 2025; 392(5): 427– 437. doi: 10.1056/NEJMoa241002 39555826 source
    • cites [7] Kosiborod MN, Abildstrøm SZ, Borlaug BA,; STEP-HFpEF Trial Committees and Investigators. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. 2023; 389(12): 1069– 1084. doi: 10.1056/NEJMoa2306963 37622681 source
    • cites [8] Kosiborod MN, Petrie MC, Borlaug BA,; STEP-HFpEF DM Trial Committees and Investigators. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. N Engl J Med. 2024; 390(15): 1394– 1407. doi: 10.1056/NEJMoa2313917 38587233 source

      The Results and Conclusions in the Abstract report favorable outcomes for semaglutide in a randomized trial, providing evidence with which later findings could align. The passages in our copy do not establish that the trial was underpowered or had few clinical end points, so those characterizations are not supported. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [13] Abbasi A, Rivera D, Curtis LH, Califf RM. Post-approval evidence generation: a shared responsibility for healthcare. Nat Med. 2024; 30(11): 3046– 3049. doi: 10.1038/s41591-024-03241-x 39271845 source

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

    Interpretationreasoning

    This study exemplifies how real-world evidence can meaningfully complement randomized trials through structured and rigorous analyses.

    “This study also exemplifies how real-world evidence can meaningfully complement randomized trials through structured and rigorous analyses.13-16”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [13] Abbasi A, Rivera D, Curtis LH, Califf RM. Post-approval evidence generation: a shared responsibility for healthcare. Nat Med. 2024; 30(11): 3046– 3049. doi: 10.1038/s41591-024-03241-x 39271845 source
    • cites [14] Schneeweiss S, Krüger N. Non-randomized database analyses to complement randomized clinical trials: promising approaches for cardiovascular medicine. Circulation. 2025; 151(21): 1495– 1497. doi: 10.1161/CIRCULATIONAHA.125.073235 40424331 source
    • cites [15] Wang SV, Schneeweiss S, Franklin JM,; RCT-DUPLICATE Initiative. Emulation of randomized clinical trials with nonrandomized database analyses: results of 32 clinical trials. JAMA. 2023; 329(16): 1376– 1385. doi: 10.1001/jama.2023.4221 37097356 PMC10130954 source
    • cites [16] Wang SV, Russo M, Glynn RJ, A benchmark, expand, and calibration (BenchExCal) trial emulation approach for using real-world evidence to support indication expansions: design and process for a planned empirical evaluation. Clin Pharmacol Ther. 2025; 117(6): 1820– 1828. doi: 10.1002/cpt.3621 40067205 PMC12087693 source

  • It may state two separate claims as one.

    Premisecitation

    Linagliptin is commonly prescribed for patients with kidney impairment, which could lead to increased confounding in contrast to sitagliptin.

    “This contrasts with saxagliptin, another dipeptidyl peptidase-4 inhibitor, which has raised concerns regarding potential increased risks of heart failure, and linagliptin, which is commonly prescribed for patients with kidney impairment, and thus could lead to increased confounding in contrast to our comparator sitagliptin.20-25”
    Quote in the paperSubstantial claim3 of 6 sources checked
    • cites [20] Scirica BM, Bhatt DL, Braunwald E,; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013; 369(14): 1317– 1326. doi: 10.1056/NEJMoa1307684 23992601 source

      The Discussion reports increased hospitalization for heart failure with saxagliptin, and the Randomization and Study Treatment section describes dose adjustments for patients with renal impairment. Neither passage addresses linagliptin prescribing, a comparison with sitagliptin, or the proposed confounding (searched: linagliptin, renal impairment, sitagliptin, confounding). (LLM, conf=0.77)

      Experimental — accuracy not yet measured
    • cites [21] Scirica BM, Braunwald E, Raz I,; SAVOR-TIMI 53 Steering Committee and Investigators. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014; 130(18): 1579– 1588. doi: 10.1161/CIRCULATIONAHA.114.010389 25189213 source
    • cites [22] Filion KB, Azoulay L, Platt RW,; CNODES Investigators. A multicenter observational study of incretin-based drugs and heart failure. N Engl J Med. 2016; 374(12): 1145– 1154. doi: 10.1056/NEJMoa1506115 27007958 source
    • cites [23] Toh S, Hampp C, Reichman ME, Risk for hospitalized heart failure among new users of saxagliptin, sitagliptin, and other antihyperglycemic drugs: a retrospective cohort study. Ann Intern Med. 2016; 164(11): 705– 714. doi: 10.7326/M15-2568 27110660 PMC5178978 source

      The Discussion mentions linagliptin only when reporting a heart-failure odds ratio from a meta-analysis; it does not discuss prescribing linagliptin to patients with kidney impairment. Although the Abstract lists residual confounding as a limitation, our copy does not link it to linagliptin or compare it with sitagliptin on that basis (searched: linagliptin, kidney impairment, renal prescribing, confounding). (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [24] Patorno E, Gopalakrishnan C, Bartels DB, Brodovicz KG, Liu J, Schneeweiss S. Preferential prescribing and utilization trends of diabetes medications among patients with renal impairment: emerging role of linagliptin and other dipeptidyl peptidase 4 inhibitors. Endocrinol Diabetes Metab. 2017; 1(1): e00005. doi: 10.1002/edm2.5 30815542 PMC6360917 source
    • cites [25] Gallwitz B. Safety and efficacy of linagliptin in type 2 diabetes patients with common renal and cardiovascular risk factors. Ther Adv Endocrinol Metab. 2013; 4(3): 95– 105. doi: 10.1177/2042018813486165 23730503 PMC3666443

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.

    Interpretationcitation

    Expanded analyses in populations representative of routine care strengthen the relevance of the current findings for clinical and regulatory decision-making.

    “while expanded analyses in populations representative of routine care strengthen the relevance of the current findings for clinical and regulatory decision-making.6-8,13”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [6] Packer M, Zile MR, Kramer CM,; SUMMIT Trial Study Group. Tirzepatide for heart failure with preserved ejection fraction and obesity. N Engl J Med 2025; 392(5): 427– 437. doi: 10.1056/NEJMoa241002 39555826 source
    • cites [7] Kosiborod MN, Abildstrøm SZ, Borlaug BA,; STEP-HFpEF Trial Committees and Investigators. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. 2023; 389(12): 1069– 1084. doi: 10.1056/NEJMoa2306963 37622681 source

      The Statistical Analysis section describes analyses of the randomized trial population, not expanded analyses in populations representative of routine care. A limitations passage notes that the low number of non-White participants may limit generalizability. Searches for routine-care representativeness and clinical or regulatory decision-making found no passage addressing the claim. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [8] Kosiborod MN, Petrie MC, Borlaug BA,; STEP-HFpEF DM Trial Committees and Investigators. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. N Engl J Med. 2024; 390(15): 1394– 1407. doi: 10.1056/NEJMoa2313917 38587233 source

      The indexed Abstract reports semaglutide trial outcomes in patients with obesity-related heart failure and type 2 diabetes, but does not address whether expanded analyses represent routine-care populations or strengthen clinical and regulatory decision-making. Searches for routine care, generalizability, and regulatory relevance found no passage addressing that point. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [13] Abbasi A, Rivera D, Curtis LH, Califf RM. Post-approval evidence generation: a shared responsibility for healthcare. Nat Med. 2024; 30(11): 3046– 3049. doi: 10.1038/s41591-024-03241-x 39271845 source

  • It may state two separate claims as one.

    Interpretationcitation

    The early benefits observed in this study align closely with findings from the SELECT trial, where semaglutide reduced cardiovascular events, including heart failure and mortality, from the first 3 months onwards, often before meaningful weight loss or full dose titration.

    “The early benefits observed in this study align closely with findings from the SELECT trial, where semaglutide reduced cardiovascular events, including heart failure and mortality, from the first 3 months onwards, often before meaningful weight loss or full dose titration.47,48”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [47] Lincoff AM, Brown-Frandsen K, Colhoun HM,; SELECT Trial Investigators. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023; 389(24): 2221– 2232. doi: 10.1056/NEJMoa2307563 37952131 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
    • cites [48] Plutzky J, Ostrominski JW, Aroda VR, Deanfield J, Lincoff AM. Early clinical benefit of semaglutide in adults with overweight or obesity and cardiovascular disease: a secondary analysis of the SELECT trial. Presented at: European Congress on Obesity 2025; May 13, 2025; Malaga, Spain.

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

    Study design and conductreasoning

    This stepwise approach anchored in trial evidence strengthens confidence in the validity and applicability of the current results.

    “This stepwise approach anchored in trial evidence strengthens confidence in the validity and applicability of the current results, reinforcing the role of GLP-1-based therapies beyond previously established benefits in the evolving management of cardiometabolic HFpEF.54,56-62”
    Quote in the paperNot a substantial claim3 of 8 sources checked
    • cites [54] Frías JP, Davies MJ, Rosenstock J,; SURPASS-2 Investigators. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. 2021; 385(6): 503– 515. doi: 10.1056/NEJMoa2107519 34170647 source
    • cites [56] Hage C. GLP-1 receptor agonists in heart failure: how far to expand use? Lancet. 2024; 404(10456): 909– 911. doi: 10.1016/S0140-6736(24)01763-X 39222643
    • cites [57] Xie Y, Choi T, Al-Aly Z. Mapping the effectiveness and risks of GLP-1 receptor agonists. Nat Med. 2025; 31(3): 951– 962. doi: 10.1038/s41591-024-03412-w 39833406 source
    • cites [58] Marso SP, Bain SC, Consoli A,; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016; 375(19): 1834– 1844. doi: 10.1056/NEJMoa1607141 27633186 source

      The Trial Design and Oversight and Cardiovascular Outcomes sections establish that this is randomized trial evidence for semaglutide’s cardiovascular effects in patients with type 2 diabetes at high cardiovascular risk. The claim about a stepwise approach strengthening confidence in the citing paper’s results is the citing authors’ own assessment; this source does not evaluate those results or establish applicability to cardiometabolic HFpEF. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [59] Wilding JPH, Batterham RL, Calanna S,; STEP 1 Study Group. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021; 384(11): 989– 1002. doi: 10.1056/NEJMoa2032183 33567185 source

      The Trial Design and Oversight and Statistical Analysis sections describe a randomized semaglutide trial, so the paper provides trial evidence. It does not evaluate the citing authors’ stepwise approach or the validity and applicability of their current results; its reported outcomes concern adults with overweight or obesity, not HFpEF. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • cites [60] Jastreboff AM, Aronne LJ, Ahmad NN,; SURMOUNT-1 Investigators. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022; 387(3): 205– 216. doi: 10.1056/NEJMoa2206038 35658024 source
    • cites [61] Malhotra A, Grunstein RR, Fietze I,; SURMOUNT-OSA Investigators. Tirzepatide for the treatment of obstructive sleep apnea and obesity. N Engl J Med. 2024; 391(13): 1193– 1205. doi: 10.1056/NEJMoa2404881 38912654 PMC11598664 source

      The Discussion reports benefits of tirzepatide in obstructive sleep apnea and related cardiovascular risk factors, providing trial evidence for a GLP-1-based therapy beyond its previously established benefits. The cited trials did not study HFpEF, however, so they do not establish the therapy's role in managing cardiometabolic HFpEF; the 'stepwise approach' is the citing authors' own framing. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [62] Jastreboff AM, le Roux CW, Stefanski A,; SURMOUNT-1 Investigators. Tirzepatide for obesity treatment and diabetes prevention. N Engl J Med. 2025; 392(10): 958– 971. doi: 10.1056/NEJMoa2410819 39536238 source

  • It may state two separate claims as one.

    Findingown data

    In the head-to-head comparison, 1-year risk of the primary outcome was 3.3% for tirzepatide and 3.4% for semaglutide, with a risk difference of -0.1% and a number needed to treat of 1000.

    “the 1-year risk of the primary outcome was 3.3% (95% CI, 2.8% to 3.9%) for tirzepatide and 3.4% (95% CI, 2.9% to 4.1%) for semaglutide, with a risk difference of −0.1% (95% CI, −0.9% to 0.7%; number needed to treat = 1000).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingcitation

    The database studies were on average 19-fold larger than the trials and showed strong concordance in prespecified agreement metrics.

    “The database studies, which were on average 19-fold larger than the trials, showed strong concordance in prespecified agreement metrices.33”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Franklin JM, Pawar A, Martin D, Nonrandomized real-world evidence to support regulatory decision making: process for a randomized trial replication project. Clin Pharmacol Ther. 2020; 107(4): 817– 826. doi: 10.1002/cpt.1633 31541454 source

  • It may state two separate claims as one.

    Findingown data

    In the expanded tirzepatide vs sitagliptin cohort, 1-year absolute risk of the primary outcome was 3.6% for tirzepatide and 7.5% for sitagliptin, with a risk difference of -3.9% and a number needed to treat of 26.

    “The 1-year absolute risk of the primary outcome in the routine care population was 3.6% (95% CI, 2.7% to 4.8%) for tirzepatide and 7.5% (95% CI, 6.0% to 9.2%) for sitagliptin, resulting in a risk difference of −3.9% (95% CI, −5.7% to −2.1%; number needed to treat = 26)”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In the expanded semaglutide vs sitagliptin cohort, pooled 1-year risk of the primary endpoint was 5.5% for semaglutide and 8.6% for sitagliptin, with a pooled risk difference of -3.2% and a number needed to treat of 31.

    “the pooled 1-year risk of the primary end point from the 3 databases was 5.5% (95% CI, 4.9% to 6.1%) for semaglutide and 8.6% (95% CI, 7.9% to 9.3%) for sitagliptin, with a pooled risk difference of −3.2% (95% CI, −4.1% to −2.3%) and a number needed to treat of 31.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    This study is aligned with RECORD-PE and STROBE reporting guidance.

    “This study is aligned with guidance from the Reporting of Studies Conducted Using Observational Routinely Collected Health Data for Pharmacoepidemiology (RECORD-PE) statement and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidance.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Study design and conductreasoning

    This enabled benchmarking against existing trial evidence, highlighting the validity of outcome capture in claims data, and allowed for confident expansion to populations more representative of patients treated in clinical practice.

    “This enabled benchmarking against existing trial evidence, highlighting the validity of outcome capture in claims data, and allowed for confident expansion to populations more representative of patients treated in clinical practice.14,16”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Schneeweiss S, Krüger N. Non-randomized database analyses to complement randomized clinical trials: promising approaches for cardiovascular medicine. Circulation. 2025; 151(21): 1495– 1497. doi: 10.1161/CIRCULATIONAHA.125.073235 40424331 source
    • cites [16] Wang SV, Russo M, Glynn RJ, A benchmark, expand, and calibration (BenchExCal) trial emulation approach for using real-world evidence to support indication expansions: design and process for a planned empirical evaluation. Clin Pharmacol Ther. 2025; 117(6): 1820– 1828. doi: 10.1002/cpt.3621 40067205 PMC12087693 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 conductreasoning

    Unmeasured differences in risk factors between groups may remain.

    “unmeasured differences in risk factors between groups may remain”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Study design and conductcitation

    The primary study end point was a composite of hospitalization for heart failure, defined by inpatient primary diagnosis claims with positive predictive value 98%, or all-cause mortality, with sensitivity greater than 99% compared with the National Death Index.

    “The primary study end point was a composite of hospitalization for heart failure (defined by inpatient primary diagnosis claims; positive predictive value = 98%) or all-cause mortality (sensitivity >99% compared with the National Death Index).31,32”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [31] Desai RJ, Levin R, Lin KJ, Patorno E. Bias implications of outcome misclassification in observational studies evaluating association between treatments and all-cause or cardiovascular mortality using administrative claims. J Am Heart Assoc. 2020; 9(17): e016906. doi: 10.1161/JAHA.120.016906 32844711 PMC7660765 source

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

    • cites [32] Bates BA, Akhabue E, Nahass MM, Validity of International Classification of Diseases (ICD)-10 diagnosis codes for identification of acute heart failure hospitalization and heart failure with reduced versus preserved ejection fraction in a national Medicare sample. Circ Cardiovasc Qual Outcomes. 2023; 16(2): e009078. doi: 10.1161/CIRCOUTCOMES.122.009078 36688301 source

  • It may state two separate claims as one.

    Study design and conductown data

    Both the STEP-HFpEF DM and SUMMIT trial emulations met all 3 prespecified agreement metrics.

    “Both benchmarks met all 3 prespecified agreement metrics.”
    • Also stated in: § RESULTS · boosted
      “Benchmarking of the 2 trial emulations demonstrated high agreement on all prespecified metrics.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Study design and conductown data

    Before overlap weighting, patients treated with semaglutide or tirzepatide were younger, more likely to be White, and exhibited higher BMI and insulin use relative to patients treated with sitagliptin.

    “Before overlap weighting, patients treated with semaglutide or tirzepatide were younger, more likely to be White, and exhibited higher BMI and insulin use relative to patients treated with sitagliptin.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All subgroup and sensitivity analyses were prespecified in detail.

    “All subgroup and sensitivity analyses were prespecified in detail (eMethods in Supplement 1).”
    • Also stated in: § MAIN OUTCOMES AND MEASURES · plain
      “Negative control outcomes, secondary end points, subgroups, and sensitivity analyses were prespecified.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Study design and conductcitation

    The study design and analytic protocols were fully prespecified and publicly registered before outcome analyses, with comprehensive methods and code algorithms available to ensure transparency and reproducibility.

    “Third, the study design and analytic protocols were fully prespecified and publicly registered before outcome analyses, with comprehensive methods and code algorithms available to ensure transparency and reproducibility.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Wang SV, Schneeweiss S. Data checks before registering study protocols for health care database analyses. JAMA. 2024; 331(17): 1445– 1446. doi: 10.1001/jama.2024.2988 38587830 source

  • Probably not a substantial claim.

    Premisecitation

    Regulatory agencies and guideline committees have emphasized the need for further evidence for major clinical outcomes in heart failure.

    “Because regulatory agencies and guideline committees have emphasized the need for further evidence for major clinical outcomes in heart failure”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [9] McDonagh TA, Metra M, Adamo M,; ESC Scientific Document Group. 2023 Focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023; 44(37): 3627– 3639. doi: 10.1093/eurheartj/ehad195 37622666 source

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

    • cites [10] Novo Nordisk. Q2 2024 Novo Nordisk A/S earnings conference call. Accessed March 13, 2025. https://edge.media-server.com/mmc/p/n7putxx6/
    • cites [11] Kittleson MM, Panjrath GS, Amancherla K, 2023 ACC expert consensus decision pathway on management of heart failure with preserved ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2023; 81(18): 1835– 1878. doi: 10.1016/j.jacc.2023.03.393 37137593 source
    • cites [55] Makary MA, Prasad V. Priorities for a new FDA. JAMA. Published online June 10, 2025. doi: 10.1001/jama.2025.10116 40493446 source

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

    Study design and conductnone given

    Medication use was inferred from dispensing records, which may not capture adherence.

    “Second, medication use was inferred from dispensing records, which may not capture adherence.”
    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.

    Study design and conductcitation

    The study protocols, design, and coding algorithms were aligned across all 3 databases and deposited in ClinicalTrials.gov before any inferential outcome analyses were started.

    “The study protocols, design, and coding algorithms were aligned across all 3 databases and deposited in ClinicalTrials.gov (NCT06914102, NCT06914154, NCT06914141) before any inferential outcome analyses were started.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Wang SV, Schneeweiss S. Data checks before registering study protocols for health care database analyses. JAMA. 2024; 331(17): 1445– 1446. doi: 10.1001/jama.2024.2988 38587830 source
23 of 23

  • The paper relies on this without support.

    No unmeasured confounding remains after propensity score overlap weighting and negative control assessment, so the observed associations reflect causal effects of semaglutide and tirzepatide.

    “We used propensity score overlap weighting to minimize confounding.43”
    “To assess potential residual confounding, we evaluated 2 negative control outcomes: new occurrence of lumbar radiculopathy and abdominal hernia.”

  • The paper relies on this without support.

    The 3 US claims databases and the expanded eligibility criteria are representative enough of routine clinical practice populations with cardiometabolic HFpEF to generalize the study results.

    “Using data from 3 US insurance claims databases, 2 placebo-controlled trials, STEP-HFpEF DM and SUMMIT, were first emulated using the RCT-DUPLICATE approach to benchmark results and increase confidence in the study design and analytic framework.14-16”

  • The paper relies on this without support.

    Regulatory authorities did not grant label expansions requesting additional evidence on hard end points in broader patient populations.

    “Consequently, regulatory authorities did not grant label expansions requesting additional evidence on hard end points in broader patient populations.”

  • The authors state this as an assumption.

    Sitagliptin has no relevant effects on the primary end point under study and can be considered a placebo proxy.

    “Fourth, the study was conducted under the assumption that sitagliptin has no relevant effects on the primary end point under study, and can thus be considered a placebo proxy.”
    “This assumption is supported by the TECOS trial, previous database analyses, and the current benchmarking study, with similar outcome rates observed.6,8,15,18,19”
4 of 4

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Novo Nordisk. Q2 2024 Novo Nordisk A/S earnings conference call. Accessed March 13, 2025. https://edge.media-server.com/mmc/p/n7putxx6/

Cited by

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Related

Metadata

Authors
Krüger, N., Schneeweiss, S., Fuse, K., Matseyko, S., Sreedhara, S. K., Hahn, G., Schunkert, H., & Wang, S. V.
Affiliations
  • Brigham and Women's Hospital (US)
  • Deutsches Herzzentrum München (DE)
Corresponding author
Krüger, Nils
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2025-10-14
Volume
334
Issue
14
Pages
1255
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2025.14092
PMC
PMC12400167
OpenAlex
W4413855967
Cited by
66
References
61
Citations by year
2026: 53 · 2025: 13
FWCI
40.85
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Funders
National Heart, Lung, and Blood Institute (R01HL141505)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
Keywords
heart failure with preserved ejection fraction, semaglutide, tirzepatide, sitagliptin, GLP-1 receptor agonists, cardiometabolic comorbidities, obesity, type 2 diabetes, heart failure hospitalization, all-cause mortality, real-world effectiveness, head-to-head comparison, health care costs, health care utilization
MeSH terms
Administrative Claims, Healthcare, Sitagliptin Phosphate, Glucagon-Like Peptide-1 Receptor Agonists, Tirzepatide, Semaglutide, Aged, Diabetes Mellitus, Type 2, Female, Follow-Up Studies, Heart Failure, Hospitalization, Humans, Male, Middle Aged, Obesity, Stroke Volume, Cohort Studies, Glucagon-Like Peptide 1

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.

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