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Cited by 74Cardiovascular Function and Risk FactorsHeart Failure Treatment and ManagementCardiovascular Disease and Adiposity

The cardioprotective effects of semaglutide exceed those of dietary weight loss in mice with HFpEF

Open access
Withaar, Coenraad, Meems, Laura M.G., Nollet, Edgar E., Schouten, E. Marloes, Schroeder, Marie A., Knudsen, Lotte B., Niss, Kristoffer, Madsen, Christian T. +6 more·2023·JACC: Basic to Translational Science
DOI 10.1016/j.jacbts.2023.05.012PMC PMC10714176
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Abstract

Obesity-related heart failure with preserved ejection fraction (HFpEF) has become a well-recognized HFpEF subphenotype. Targeting the unfavorable cardiometabolic profile may represent a rational treatment strategy. This study investigated semaglutide, a glucagon-like peptide-1 receptor agonist that induces significant weight loss in patients with obesity and/or type 2 diabetes mellitus and has been associated with improved cardiovascular outcomes. In a mouse model of HFpEF that was caused by advanced aging, female sex, obesity, and type 2 diabetes mellitus, semaglutide, compared with weight loss induced by pair feeding, improved the cardiometabolic profile, cardiac structure, and cardiac function. Mechanistically, transcriptomic, and proteomic analyses revealed that semaglutide improved left ventricular cytoskeleton function and endothelial function and restores protective immune responses in visceral adipose tissue. Strikingly, treatment with semaglutide induced a wide array of favorable cardiometabolic effects beyond the effect of weight loss by pair feeding. Glucagon-like peptide-1 receptor agonists may therefore represent an important novel therapeutic option for treatment of HFpEF, especially when obesity-related.

AI snapshot

Written from the paper’s full text.

TL;DR

In aged female mice with a multifactorial HFpEF-like phenotype, semaglutide improved cardiac function and structure beyond the effects of pair-fed weight loss. The benefits were linked to endothelial GLP-1 receptor expression and anti-inflammatory/antioxidant pathways, supporting ongoing clinical trials in obesity-related HFpEF.

Key findings

  • Semaglutide and pair feeding (PF) produced similar weight loss, mainly from fat mass reduction over 4 weeks (19.4–6.2 g for semaglutide; 19.8–8.3 g for PF). Semaglutide reduced food intake by ∼60% in week 1, ∼30% in week 2, and ∼10% in weeks 3–4.
  • Semaglutide, but not PF, improved glycemic control (fasting glucose and oral glucose tolerance test AUC) and exercise capacity. It also improved global longitudinal strain and reverse peak longitudinal strain rate, while LVEF was preserved in all groups with no significant differences.
  • Semaglutide reduced LV hypertrophy (LV weight/tibia, cardiomyocyte size, LV wall thickness), atrial and lung weights, fibrosis, and mRNA markers including ANP, Col1a1, Col3a1, TIMP-1, IL-6, galectin-3, and GDF-15. Intrinsic cardiomyocyte stiffness (Fpassive) was not affected by any intervention.
  • Omics analyses showed GLP-1 receptor mainly in endothelial cells; semaglutide enriched endothelial actin/ATP/metabolic and cardiomyocyte contraction/mitochondrial/anti-apoptotic pathways. Plasma proteomics identified 240 semaglutide-associated proteins versus 116 with PF, with antioxidant/oxidative-stress pathways; VAT showed up-regulated T-cell/interferon-γ and down-regulated extracellular matrix pathways.

Methods

  • Aged female C57BL6/J mice (18–22 months) were fed high-fat diet (HFD) for 12 weeks; after 8 weeks, angiotensin-II (1.25 mg/kg/d) was infused via osmotic minipump. Control mice (n = 10) received low-fat diet.
  • After pump implantation, HFD mice received semaglutide (n = 12; uptitrated over 5 days to 9 nmol/kg/d, then continued 23 days), vehicle (n = 16), or pair feeding (n = 8) for the final 4 weeks.
  • Outcomes included echocardiography, oral glucose tolerance test, body composition, voluntary wheel running, histology, qPCR, passive force measurements, plasma ketones, VAT RNA sequencing, LV single-nucleus RNA sequencing, and LV/plasma LC-MS/MS proteomics. Statistical comparisons used Kruskal-Wallis with Dunn tests; P < 0.05 was significant.

Limitations

  • The paper states the multifactorial mouse model does not represent the entire HFpEF spectrum, used only aged female mice, and cannot determine whether semaglutide prevents incident HFpEF or attenuates prevalent HFpEF because treatment began after 8 weeks of HFD and at the start of ANGII infusion. The role of endothelial GLP-1 receptor requires lengthy follow-up studies in old animals.
  • Evident from the text: omics analyses used n = 6 per group, and the study is preclinical, so it cannot establish clinical outcomes or causality in patients.

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

Integrity signals

Registry

Crossref · 10.1016/j.jacbts.2023.05.012

Cites

84 of 84 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 54 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Gene set enrichment analyses on up-regulated proteins in semaglutide-treated mice identified pathways related to cardiac cytoskeleton processes and actin filament organization.

    “Using gene set enrichment analyses on up-regulated proteins in semaglutide-treated mice, we identified pathways related to cardiac cytoskeleton processes and actin filament organization (Figure 4C).”
    Quote in the paperSubstantial claim
  • Findingown data

    Semaglutide treatment significantly reduced inflammatory markers such as interleukin-6, galectin-3, and growth derived factor-15.

    “Furthermore, semaglutide treatment significantly reduced inflammatory markers such as interleukin-6, galectin-3, and growth derived factor-15.”
    Quote in the paperSubstantial claim
  • Findingown data

    Semaglutide treatment significantly reduced messenger RNA levels of the cardiac stretch marker atrial natriuretic peptide.

    “In line with the functional improvements, semaglutide treatment significantly reduced messenger RNA levels of cardiac stretch marker (atrial natriuretic peptide) (Supplemental Table 3).”
    Quote in the paperSubstantial claim
  • Findingown data

    Intrinsic cardiomyocyte stiffness was not affected by any of the interventions (semaglutide or pair feeding).

    “Nevertheless, intrinsic cardiomyocyte stiffness was not affected by any of the interventions, suggesting that in this preclinical model intrinsic stiffness is not involved in HFpEF pathophysiology (Figure 3C).”
    Quote in the paperSubstantial claim
  • Findingown data

    Single nucleus RNA sequencing identified 13 major cell types in the LV: T cells, natural killer cells, B cells, macrophages, smooth muscle cells, pericytes, endothelial cells, fibroblasts, endocardial cells, Schwann cells, mesothelial cells, lymphatic cells, and ventricular cardiomyocytes.

    “Cell clustering and combined manual and automatic annotation identified 13 major cell types: T cells, natural killer cells, B cells, macrophages, smooth muscle cells, pericytes, endothelial cells, fibroblasts, endocardial cells, Schwann cells, mesothelial cells, lymphatic cells, and ventricular cardiomyocytes, as visualized in a uniform manifold approximation and projection (Figure 4D)”
    Quote in the paperNot a substantial claim
  • May combine two claims. 32
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 26

  • May combine two claims.

    Findingown data

    HFD+ANGII resulted in elevated plasma total ketone bodies, and this remained with semaglutide treatment and pair feeding.

    “HFD+ANGII resulted in elevated plasma total ketone bodies, in both this remained with semaglutide treatment and PF (Supplemental Figure 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    LVEF was preserved in all treatment groups, with no significant differences among groups.

    “LVEF was preserved in all treatment groups, with no significant differences among groups (Figure 2A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Running distance, measured by voluntary wheel running, improved in mice treated with semaglutide and not in mice on pair feeding.

    “Running distance, measured by voluntary wheel running, improved in mice treated with semaglutide and not in mice on PF (Figure 1G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Semaglutide treatment, but not pair feeding, improved glycemic control with reduced fasting glucose levels and improved glucose tolerance in aged female mice with HFD+ANGII-induced HFpEF.

    “Treatment with semaglutide, but not PF, improved glycemic control with a significant reduction in fasting glucose levels and improved glucose tolerance, as demonstrated by significantly decreased area under the curve for semaglutide versus vehicle-treated mice (Figures 1E and 1F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither semaglutide nor pair feeding down-regulated genes were associated with significant enriched pathways in cardiomyocytes.

    “Neither semaglutide nor PF down-regulated genes were associated with significant enriched pathways in cardiomyocytes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    A total of 240 proteins were identified with semaglutide treatment and 116 proteins with pair feeding in plasma.

    “A total of 240 proteins were identified with semaglutide treatment and 116 proteins with PF (Figure 5A).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Semaglutide had a clear effect on gene expression levels in VAT, but pair feeding did not.

    “We observed that semaglutide had a clear effect on gene expression levels, but this was not the case for mice on PF (Figure 6A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Semaglutide significantly reduced LV hypertrophy compared to pair feeding, as reflected by reduced LV weight, smaller cardiomyocyte size, and reduced LV wall thickness.

    “As compared to PF, semaglutide significantly reduced LV hypertrophy as reflected by reduced LV weight (Figure 2E) and smaller cardiomyocyte size (Figures 2F and 2G), and reduced LV wall thickness on echocardiography (Supplemental Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In cardiomyocytes, semaglutide was associated with up-regulated genes enriched for muscle contraction, mitochondrial function, and negative regulation of apoptotic processes; pair feeding up-regulated genes were enriched for cardiac muscle cell development.

    “In cardiomyocytes, semaglutide was associated with multiple pathways enriched for up-regulated genes involved in muscle contraction and mitochondrial function and negative regulation of apoptotic processes. In PF up-regulated genes were enriched, among others, for cardiac muscle cell development (Figures 4K and 4L).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Semaglutide and pair feeding resulted in similar weight loss, caused by a reduction in fat mass, in aged female mice with HFD+ANGII-induced HFpEF.

    “PF resulted in similar weight loss (Figure 1C).”
    • Also stated in: § Semaglutide and PF both resulted in weight loss caused by a reduction in fat mass · plain
      “In both groups, weight loss was caused by a significant reduction in fat mass in 4 weeks of treatment (19.4-6.2 g for semaglutide; 19.8-8.3 g for PF), as compared to vehicle-treated mice (Figure 1D).”
    • Also stated in: § Discussion · plain
      “We observed that, by design, semaglutide and PF were associated with the exact degree of weight loss mainly caused by fat mass reduction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Semaglutide treatment significantly improved global longitudinal strain and reverse peak longitudinal strain rate, but pair feeding did not.

    “In semaglutide-treated mice, we observed a significant improvement of global longitudinal strain and reverse peak longitudinal strain rate, but this was not the case in mice on PF (Figures 2B to 2D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Semaglutide resulted in an ∼60% food reduction in week 1, ∼30% in week 2, and ∼10% in weeks 3 and 4.

    “Semaglutide resulted in an ∼60% food reduction in week 1, ∼30% in week 2, and ∼10% in weeks 3 and 4.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In our HFpEF animal model, the GLP-1 receptor is mainly present in endothelial cells and not in cardiomyocytes.

    “In our HFpEF animal model, we show that the GLP-1 receptor is mainly present in endothelial cells and not in cardiomyocytes”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment with semaglutide resulted in improved cardiac function with less myocardial diastolic stiffness.

    “treatment with semaglutide resulted in improved cardiac function with less myocardial diastolic stiffness.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In VAT, semaglutide significantly enriched pathways related to protective inflammatory responses, whereas PF did not have these additional positive effects.

    “In VAT, semaglutide significantly enriched pathways related to protective inflammatory responses, whereas PF—which was able to reduce fat content in a similar manner—did not have these additional positive effects.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Treatment with semaglutide results in enriched pathways related to cytoskeleton organization and mitochondrial function in endothelial cells, consistent in both -omics data sets.

    “treatment with semaglutide results in enriched pathways related to cytoskeleton organization and mitochondrial function in endothelial cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Semaglutide had no effect on sarcomere stiffness (Fpassive) but resulted in enrichment of actin-myosin and muscle contraction pathways.

    “semaglutide had no effect on sarcomere stiffness (Fpassive) but resulted in enrichment of actin-myosin and muscle contraction pathways.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In our experimental study, we observed a reduction in fat mass (>15%) but not in lean mass.

    “we also observed a reduction in fat mass (>15%) but not in lean mass.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Semaglutide improved several hallmarks of HFpEF (reduced LV hypertrophy and fibrosis, improved diastolic dysfunction, reduced lung congestion, and improved exercise capacity), whereas pair feeding only tended to influence some parameters.

    “However, whereas PF only tended to influence some parameters of HFpEF, semaglutide improved several hallmarks of HFpEF, including reduced LV hypertrophy and fibrosis, improved diastolic dysfunction, reduced lung congestion, and improved exercise capacity.”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF

    EMPEROR-Preserved was the first study to show a significant reduction on a combined hard end point of HF hospitalizations and cardiovascular mortality in patients with HFpEF.

    “EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), evaluating the effects of the sodium glucose co-transporter 2 inhibitor empagliflozin, was the first study to show a significant reduction on a combined “hard” end point of HF hospitalizations and cardiovascular mortality in patients with HFpEF.10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Anker, 2021, Empagliflozin in heart failure with a preserved ejection fraction, N Engl J Med source

      Not checked in the free run.

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

    Premisecitation

    Increased Fpassive has been observed in HFpEF patient biopsies, and increased cardiac stiffening is associated with aging.

    “Increased Fpassive has been observed in HFpEF patient biopsies, and increased cardiac stiffening is associated with aging.38,39”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [38] Nance, 2015, Attenuated sarcomere lengthening of the aged murine left ventricle observed using two-photon fluorescence microscopy, Am J Physiol Heart Circ Physiol source

      Not checked in the free run.

    • cites [39] Borbély, 2005, Cardiomyocyte stiffness in diastolic heart failure, Circulation source

      Not checked in the free run.

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

    Premisecitation
    § The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF

    Bariatric surgery results in very substantial weight loss, but ancillary effects such as incretin response and changes of the gut microbiome have also been described, and some refer to bariatric surgery as metabolic surgery.

    “Clearly, bariatric surgery results in very substantial weight loss, but ancillary effects also have been described, such as incretin response and changes of the gut microbiome, and some refer to bariatric surgery as metabolic surgery.17”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Aminian, 2020, How much weight loss is required for cardiovascular benefits? Insights from a metabolic surgery matched-cohort study, Ann Surg source

      Not checked in the free run.

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

    Premisecitation
    § The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF

    Several GLP-1RAs are approved for effective glucose lowering in patients with T2DM and improve cardiovascular outcomes.

    “In addition, several GLP-1RAs are approved for effective glucose lowering in patients with T2DM and improve cardiovascular outcomes.20,21”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Husain, 2019, Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes, N Engl J Med source

      Not checked in the free run.

    • cites [21] Holman, 2017, Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes, N Engl J Med source

      Not checked in the free run.

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

    Premisecitation
    § The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF

    Long-acting GLP-1RAs exert substantial and sustained body weight losses.

    “Long-acting GLP-1RAs exert substantial and sustained body weight losses,18”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Wilding, 2021, Once-weekly semaglutide in adults with overweight or obesity, N Engl J Med source

      Not checked in the free run.

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

    Premisecitation
    § The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF

    Possible mechanisms of action on the cardiovascular system of GLP-1RAs include anti-inflammatory, antiatherosclerotic, vasodilatory, and other hemodynamic effects, and life-long exposure of GLP-1 is associated with prevention of HF.

    “Possible mechanisms of action on the cardiovascular system of GLP-1RAs include anti-inflammatory, antiatherosclerotic, vasodilatory, and other hemodynamic effects, and life-long exposure of GLP-1 is associated with prevention of HF.22, 23, 24”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22] Daghlas, 2021, Genetic evidence for repurposing of GLP1R (glucagon-like peptide-1 receptor) agonists to prevent heart failure, J Am Heart Assoc

      Not checked in the free run.

    • cites [23] Marso, 2016, Liraglutide and cardiovascular outcomes in type 2 diabetes, N Engl J Med source

      Not checked in the free run.

    • cites [24] Knudsen, 2019, The discovery and development of liraglutide and semaglutide, Front Endocrinol (Lausanne) source

      Not checked in the free run.

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

    Premisecitation
    § The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF

    Marked weight loss achieved through bariatric surgery is associated with improvements in glucose levels and cardiac structure and function in patients with obesity and T2DM.

    “Indeed, marked weight loss achieved through bariatric surgery is associated with improvements in glucose levels and cardiac structure and function in patients with obesity and T2DM.14, 15, 16”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [14] Aminian, 2019, Association of metabolic surgery with major adverse cardiovascular outcomes in patients with type 2 diabetes and obesity, JAMA source

      Not checked in the free run.

    • cites [15] Fakhry, 2019, Bariatric surgery improves nonalcoholic fatty liver disease: a contemporary systematic review and meta-analysis, Surg Obes Relat Dis source

      Not checked in the free run.

    • cites [16] Aldoheyan, 2017, The effects of bariatric surgeries on nonalcoholic fatty liver disease, Surg Endosc source

      Not checked in the free run.

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

    Premisecitation
    § The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF

    SGLT2 inhibitors have metabolic effects, including lowering plasma glucose, and modest effects on body weight and blood pressure.

    “Sodium glucose co-transporter 2 inhibitors have metabolic effects, including lowering of plasma glucose levels, and (modest) effects on body weight and blood pressure.11”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Neeland, 2016, Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus, Diab Vasc Dis Res source

      Not checked in the free run.

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

    Premisecitation
    § The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF

    It remains elusive what proportion of the cardiometabolic effects of GLP-1RAs result from improved glycemic control and significant weight loss and to what extent additional metabolic and cardiovascular effects contribute, transcending reduction in weight.

    “However, it remains elusive what proportion of these effects result from improved glycemic control and significant weight loss and to what extent additional metabolic and cardiovascular effects contribute, transcending reduction in weight.26”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Rakipovski, 2018, The GLP-1 analogs liraglutide and semaglutide reduce atherosclerosis in ApoE −/− and LDLr −/− mice by a mechanism that includes inflammatory pathways, J Am Coll Cardiol Basic Trans Science

      Not checked in the free run.

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

    Premisecitation
    § The Cardioprotective Effects of Semaglutide Exceed Those of Dietary Weight Loss in Mice With HFpEF

    Semaglutide treatment results in significant reductions in levels of the inflammatory marker C-reactive protein.

    “Semaglutide treatment results in significant reductions in levels of the inflammatory marker C-reactive protein.25”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Wilding, 2022, Weight regain and cardiometabolic effects after withdrawal of semaglutide: the STEP 1 trial extension, Diabetes Obes Metab source

      Not checked in the free run.

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

    Premisecitation

    HFpEF is a major and growing public health problem.

    “HFpEF is a major and growing public health problem.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Groenewegen, 2020, Epidemiology of heart failure, Eur J Heart Fail source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Prolonged fasting of 10 months resulted in caloric restriction-mediated increase in insulin sensitivity.

    “prolonged fasting of 10 months resulted in caloric restriction–mediated increase in insulin sensitivity.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Pak, 2021, Fasting drives the metabolic, molecular and geroprotective effects of a calorie-restricted diet in mice, Nat Metab source

      Not checked in the free run.

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

    Premisecitation

    GLP-1RAs improve cardiac function in patients with T2DM.

    “In mechanistic studies, GLP-1RAs were shown to improve cardiac function in patients with T2DM.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] Holman, 2017, Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes, N Engl J Med source

      Not checked in the free run.

    • cites [46] Lambadiari, 2018, Effects of 6-month treatment with the glucagon like peptide-1 analogue liraglutide on arterial stiffness, left ventricular myocardial deformation and oxidative stress in subjects with newly diagnosed type 2 diabetes, Cardiovasc Diabetol source

      Not checked in the free run.

    • cites [47] Saponaria, 2016, Improved diastolic function in type 2 diabetes after a six month liraglutide treatment, Diabetes Res Clin Pract source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The amount of food consumed by the semaglutide groups is exactly matched to that consumed by the pair-fed group on a daily basis.

    “With this technique, the amount of food consumed by the semaglutide groups (grams of chow per day) is exactly matched to that consumed by the pair-fed group on a daily basis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Modest weight loss caused by lifestyle interventions in obesity-related HFpEF patients improved exercise capacity but had no effect on cardiac structure or function.

    “Several studies reported that (modest) weight loss caused by lifestyle interventions in obesity-related HFpEF patients improved exercise capacity but had no effect on cardiac structure or function.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [54] Kitzman, 2016, Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: a randomized clinical trial, J Am Med Assoc source

      Not checked in the free run.

    • cites [55] El Hajj, 2021, Pragmatic weight management program for patients with obesity and heart failure with preserved ejection fraction, J Am Heart Assoc

      Not checked in the free run.

    • cites [56] Kitzman, 2013, Effect of endurance exercise training on endothelial function and arterial stiffness in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial, J Am Coll Cardiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Long term >40% caloric restriction recovered insulin sensitivity, fasting glucose, and insulin levels.

    “long term >40% caloric restriction recovered insulin sensitivity, fasting glucose, and insulin levels”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [61] do Amaral, 2020, Caloric restriction recovers impaired β-cell-β-cell gap junction coupling, calcium oscillation coordination, and insulin secretion in prediabetic mice, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

    • cites [62] Wei, 2019, Comparison of glycemic improvement between intermittent calorie restriction and continuous calorie restriction in diabetic mice, Nutr Metab (Lond) source

      Not checked in the free run.

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

    Premisecitation

    GLP-1RAs induce meaningful weight loss in patients with obesity with or without T2DM.

    “GLP-1RAs are known to induce meaningful weight loss in patients with obesity with or without T2DM.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] Kadowaki, 2022, Semaglutide once a week in adults with overweight or obesity, with or without type 2 diabetes in an east Asian population (STEP 6): a randomised, double-blind, double-dummy, placebo-controlled, phase 3a trial, Lancet Diabetes Endocrinol source

      Not checked in the free run.

    • cites [43] Davies, 2021, Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial, Lancet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Obesity indirectly promotes insulin resistance and hyperglycemia and has additional direct deleterious effect via a systemic proinflammatory state.

    “Obesity indirectly promotes insulin resistance and hyperglycemia and has additional direct deleterious effect, given that adipose tissue is highly metabolically active and involved in promoting a systemic proinflammatory state.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Schiattarella, 2020, Metabolic inflammation in heart failure with preserved ejection fraction, Cardiovasc Res source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Semaglutide was administered after 8 weeks of HFD and at the start of ANGII infusion.

    “Semaglutide was administered in a phase where the HFpEF in part developed, namely after 8 weeks of HFD and at the start of ANGII infusion.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    GLP-1RAs improve major adverse cardiovascular outcomes including cardiovascular death, myocardial infarction, and stroke in patients with T2DM.

    “GLP-1RAs improve major adverse cardiovascular outcomes including cardiovascular death, myocardial infarction, and stroke in patients with T2DM.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Kristensen, 2019, Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials, Lancet Diabetes Endocrinol source

      Not checked in the free run.

    • cites [45] Sattar, 2021, Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials, Lancet Diabetes Endocrinol source

      Not checked in the free run.

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

    Premisecitation

    Treatment with GLP-1RAs activates several cardioprotective pathways, prevents HFD-induced insulin resistance and inflammation, improves endothelial function, and ameliorates cardiac function in obese mice.

    “treatment with GLP-1RAs activates several cardioprotective pathways, prevents HFD-induced insulin resistance and inflammation, improves endothelial function, and ameliorates cardiac function in obese mice.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Noyan-Ashraf, 2013, A glucagon-like peptide-1 analog reverses the molecular pathology and cardiac dysfunction of a mouse model of obesity, Circulation source

      Not checked in the free run.

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

    Study design and conductnone given

    We only used aged female mice with HFpEF.

    “we only used aged female mice with HFpEF.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Study design and conductnone given

    The multifactorial preclinical HFpEF model resembles the cardiometabolic human HFpEF phenotype to a large extent.

    “we used a multifactorial preclinical HFpEF model that resembles the cardiometabolic human HFpEF phenotype to a large extent.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The model is still not representative of the entire spectrum of HFpEF.

    “the model is still not representative of the entire spectrum of HFpEF.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: A distinct feature of HFpEF is the presence of multiple comorbidities and together with hypertension and aging, obesity is a main risk factor for HFpEF.

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

    Interpretationreasoning

    Our timing does not allow us to fully dissect whether semaglutide would prevent incident HFpEF or rather would attenuate prevalent HFpEF or both.

    “our timing does not allow us to fully dissect whether semaglutide would prevent incident HFpEF or rather would attenuate prevalent HFpEF or both.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    Direct translation of our findings into clinical practice must be done cautiously.

    “direct translation of our findings into clinical practice must be done cautiously.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: A distinct feature of HFpEF is the presence of multiple comorbidities and together with hypertension and aging, obesity is a main risk factor for HFpEF.

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

    Premisecitation

    In humans, the HFpEF phenotype is more prevalent in aging women and less common in aging men.

    “In humans, the HFpEF phenotype is more prevalent in aging women and less common in aging men”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Brouwers, 2013, Incidence and epidemiology of new onset heart failure with preserved vs. reduced ejection fraction in a community-based cohort: 11-year follow-up of PREVEND, Eur Heart J source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GLP-1RAs have anti-inflammatory and antioxidant properties.

    “GLP-1RAs have anti-inflammatory and antioxidant properties”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [26] Rakipovski, 2018, The GLP-1 analogs liraglutide and semaglutide reduce atherosclerosis in ApoE −/− and LDLr −/− mice by a mechanism that includes inflammatory pathways, J Am Coll Cardiol Basic Trans Science

      Not checked in the free run.

    • cites [67] Zobel, 2021, Effect of liraglutide on expression of inflammatory genes in type 2 diabetes, Sci Rep source

      Not checked in the free run.

    • cites [68] Bray, 2021, Glucagon-like peptide-1 receptor agonists improve biomarkers of inflammation and oxidative stress: a systematic review and meta-analysis of randomised controlled trials, Diabetes Obes Metab source

      Not checked in the free run.

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

    Premisecitation

    Other vitro studies observed a beneficial effect of GLP-1RAs on ANGII-induced cardiac fibrosis.

    “Other vitro studies observed a beneficial effect of GLP-1RAs on ANGII-induced cardiac fibrosis as well.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [53] Noyan-Ashraf, 2013, A glucagon-like peptide-1 analog reverses the molecular pathology and cardiac dysfunction of a mouse model of obesity, Circulation source

      Not checked in the free run.

    • cites [74] Helmstädter, 2020, Endothelial GLP-1 (glucagon-like peptide-1) receptor mediates cardiovascular protection by liraglutide in mice with experimental arterial hypertension, Arterioscler Thromb Vasc Biol source

      Not checked in the free run.

    • cites [76] Kim, 2013, GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure, Nat Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effects of GLP-1RAs are not organ-specific and a reduction in fibrosis and improved outcome have also been seen in patients with diabetic kidney disease.

    “The effects of GLP-1RAs are not organ-specific and a reduction in fibrosis and improved outcome have also been seen in patients with diabetic kidney disease.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Kawanami, 2020, GLP-1 receptor agonists in diabetic kidney disease: from clinical outcomes to mechanisms, Front Pharmacol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Inhibition of systemic metabolic inflammation with glucose-lowering drugs is thought to enhance endothelial and cardiomyocyte function.

    “Inhibition of systemic metabolic inflammation with glucose-lowering drugs is thought to enhance endothelial and cardiomyocyte function”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [70] Paulus, 2013, A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation, J Am Coll Cardiol source

      Not checked in the free run.

    • cites [71] Lam, 2016, Microvascular endothelial dysfunction in heart failure with preserved ejection fraction, Heart source

      Not checked in the free run.

    • cites [72] Shah, 2018, Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF, Eur Heart J source

      Not checked in the free run.

50 of 50

  • The paper relies on this without support.

    Weight loss by lifestyle interventions is notoriously difficult to achieve and rarely sustained for a longer period.

    “weight loss by lifestyle interventions is notoriously difficult to achieve and rarely sustained for a longer period.”

  • The paper relies on this without support.

    Extreme measures such as bariatric surgery come with considerable risks and side effects such as infections, bleeding, and absorption problems.

    “Extreme measures such as bariatric surgery come with considerable risks and side effects such as infections, bleeding, and absorption problems.”

  • The paper relies on this without support.

    A distinct feature of HFpEF is the presence of multiple comorbidities and together with hypertension and aging, obesity is a main risk factor for HFpEF.

    “A distinct feature of HFpEF is the presence of multiple comorbidities and together with hypertension and aging, obesity is a main risk factor for HFpEF.”

  • The paper relies on this without support.

    Myocardial diastolic stiffness is among the hallmarks of HFpEF and results from both myocardial fibrosis and increased cardiomyocyte stiffness.

    “Myocardial diastolic stiffness is among the hallmarks of HFpEF and results from both myocardial fibrosis and increased cardiomyocyte stiffness.”

  • The paper relies on this without support.

    To date, treatment options for HFpEF are limited and novel treatment options are eagerly awaited.

    “To date, treatment options for HFpEF are limited and novel treatment options are eagerly awaited.”
5 of 5

Claims other papers make about this one

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

Self-check

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

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

  • STEP 1 results are cited to an unrelated reference

    Minor

    The discussion attributes the stated STEP 1 result to reference 7, but reference 7 is the I-PRESERVE trial of irbesartan in heart failure.

  • Echocardiography timing differs between methods and figure caption

    Minor

    The methods place echocardiography three days before sacrifice, whereas the Figure 1 caption places it one day before sacrifice.

  • STEP-HFpEF studies are cited to the SELECT reference

    Minor

    The conclusions attach reference 83 to the STEP-HFpEF studies, but reference 83 is explicitly about SELECT.

3 of 3

Cites

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Cited by

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Related

Authors
Withaar, C., Meems, L. M. G., Nollet, E. E., Schouten, E. M., Schroeder, M. A., Knudsen, L. B., Niss, K., Madsen, C. T., Hoegl, A., Mazzoni, G., van der Velden, J., Lam, C. S. P., Silljé, H. H. W., & de Boer, R. A.
Affiliations
  • University Medical Center Groningen (NL)
  • Amsterdam Cardiovascular Sciences (NL)
  • Novo Nordisk (Denmark) (DK)
ORCID
Venue
JACC: Basic to Translational Science
Publisher
Elsevier BV
Published
2023-10
Volume
8
Issue
10
Pages
1298-1314
ISSN
2452-302X (ISSN-L)
DOI
10.1016/j.jacbts.2023.05.012
PMC
PMC10714176
OpenAlex
W4385310086
Semantic Scholar
c1e4c55ab5bcb7a755ef9aa3c10507dbff1c8701
Cited by
74
References
84
Citations by year
2026: 20 · 2025: 31 · 2024: 22 · 2023: 1
FWCI
14.50
Type
journal article
Language
en
Open access
Licence
Locations
  • JACC Basic to Translational Science (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
  • Pure Amsterdam UMC (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion, other-oa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
Funders
  • Netherlands Heart Foundation
  • Novo Nordisk AS
  • European Research Council
  • University of Groningen
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
Keywords
semaglutide, heart failure with preserved ejection fraction, obesity, type 2 diabetes, GLP-1 receptor agonists, cardioprotection, pair feeding, weight loss, endothelial function, visceral adipose tissue, cardiometabolic profile, aging, female sex, cardiac function

About these checks

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

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

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

Statistics and arithmetic are recomputed, not judged.

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