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Evidence weighs against a primary role for hyperglycemia, as glucose-lowering with insulin or multiple diabetes drug classes has not reduced HF risk. In contrast, studies and models link diabetes to excess visceral adiposity, where altered adipocyte biology, insulin resistance, inflammation, and cardiac lipid overload promote HFpEF. The diabetes-HFpEF link appears modifiable via adiposity-targeted interventions.",{"@graph":69,"@context":126},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/is-type-2-diabetes-a-modifiable-risk-factor-for-the-evolution-and-progression-of-heart-failure-with-a-preserved-ejection-fraction-abstract/435024/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/is-type-2-diabetes-a-modifiable-risk-factor-for-the-evolution-and-progression-of-heart-failure-with-a-preserved-ejection-fraction-abstract/435024.png","ImageObject",300,407,{"name":92,"@type":93},"Aran","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118,122],{"name":109,"@type":110,"acceptedAnswer":111},"Why does type 2 diabetes increase the risk of HFpEF?","Question",{"text":112,"@type":113},"Type 2 diabetes is associated with higher HFpEF risk. The document argues the relationship is mediated primarily through excess visceral adiposity rather than direct hyperglycemia effects.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What evidence argues against hyperglycemia as the main cause?",{"text":117,"@type":113},"Experimental models of hyperglycemia resemble type 1 diabetes, and clinical lowering of blood glucose with insulin or several drug classes has not reduced heart failure risk.",{"name":119,"@type":110,"acceptedAnswer":120},"How does visceral adiposity mediate diabetes-related HFpEF?",{"text":121,"@type":113},"Visceral fat and adipocyte biology changes can drive systemic insulin resistance, promote inflammation, sodium retention, and cardiac steatosis and fibrosis, and may enhance sensitivity to advanced glycation end products.",{"name":123,"@type":110,"acceptedAnswer":124},"Are diabetes and HFpEF risk modifiable, and how?",{"text":125,"@type":113},"The document concludes diabetes is a modifiable risk factor if treatment targets adiposity instead of hyperglycemia. Approaches discussed include GLP-1 receptor agonists, SGLT2 inhibitors, and bariatric surgery.","https://schema.org",{"og:url":83,"og:type":128,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":130,"canonical":83},"index,follow",{"doc_id":132,"site_id":62},435024,1790717386,{"code":4,"msg":5,"data":135},{"doc_id":132,"user_id":136,"nickname":92,"user_avatar":137,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":138,"file_id":139,"file_url":140,"file_type":141,"file_size":142,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":143,"language":144,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":145,"faqs":146,"seo_title":147,"seo_description":67,"update_tm":148,"read_time":149,"preview_page_count":4},137455076865,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","Author Manuscr ipt Author Manuscr ipt Author Manuscr ipt Author Manuscript  \n\n| | HHS Public Access\u003Cbr>Author manuscript\u003Cbr>J Am Coll Cardiol. Author manuscript; available in PMC 2026 January 05. |\n| --- | --- |\n\nPublished in final edited form as:  \nJ Am Coll Cardiol. 2025 November 18; 86(20): 1917–1931. doi:10.1016/j.jacc.2025.07.052 .  \nIs Type 2 Diabetes a Modifiable Risk Factor for the Evolution and Progression of Heart Failure With a Preserved Ejection Fraction?  \nMilton Packer, MDa,b, Carolyn S. P. Lam, MD, PhDc,d,e, Javed Butler, MD, MPHd,e, Faiez Zannad, MD, PhDf, Muthiah Vaduganathan, MDg, Barry A. Borlaug, MDh  \naBaylor Heart and Vascular Institute, Dallas, Texas, USA;  \nb Imperial College, London, United Kingdom;  \ncCardiovascular and Metabolic Disorders Programme, Duke-National University of Singapore Medical School, and the National Heart Centre Singapore, Singapore;  \ndBaylor Scott and White Research Institute, Dallas Texas, USA;  \ne University of Mississippi School of Medicine, Jackson, Mississippi, USA;  \nfUniversité de Lorraine, Centres d’Investigation Clinique, INSERM, Centre Hospitalier Régional Universitaire de Nancy, Nancy, France;  \ng Division of Cardiovascular Medicine Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA;  \nh Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.  \nAbstract  \nBACKGROUND: Type 2 diabetes is associated with an increased risk of heart failure with a preserved ejection fraction (HFpEF), but it is not clear whether this metabolic disorder is causal or represents a modifiable risk factor. Mechanisms by which diabetes may be associated with HFpEF can be grouped into the following: 1) those related to hyperglycemia and amenable to antihyperglycemic drugs; and 2) those related to the association of type 2 diabetes with obesity and visceral adiposity, and thus, treatable with interventions that reduce adipose tissue mass or improve adipocyte biology.  \nEVIDENCE AGAINST A ROLE FOR HYPERGLYCEMIA: Experimentally, acute and chronic hyperglycemia caused by islet cell destruction can lead to cardiac dysfunction, but these models resemble type 1 (not type 2) diabetes. Heightened levels of environmental glucose can cause enzymatic or nonenzymatic modification of proteins and signaling through the polyol pathway, but interference with these mechanisms has not produce clinical benefits in patients with heart disease and type 2 diabetes. Furthermore, lowering of blood glucose in type 2 diabetes with insulin,  \nThis is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)).  \nADDRESS FOR CORRESPONDENCE: Dr Milton Packer, Baylor Heart and Vascular Institute, Baylor University Medical Center, 621 North Hall Street, Dallas, Texas 75226, [USA. milton.packer@baylorhealth.edu](USA. milton.packer@baylorhealth.edu).  \nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.  \nAuthor Manuscr ipt Author Manuscr ipt Author Manuscr ipt Author Manuscript  \nPacker et al. Page 2  \nsulfonylureas, dipeptidyl peptidase-4 inhibitors and thiazolidinediones has not reduced the risk of heart failure.  \nEVIDENCE FOR A MEDIATING ROLE FOR ADIPOSITY: In marked contrast, experimental models that link type 2 diabetes to HFpEF are typically accompanied by excess adiposity.  \nEpidemiological studies demonstrate that the association between type 2 diabetes and HFpEFis mediated primarily through a common link with central obesity and an expanded visceral fat mass. Changes in the biology of adipocytes as a result of visceral adiposity are sufficient to cause systemic insulin resistance and diabetes. Interestingly, the primary metabolic defect in the diabetic heart ","cbCaip6KXsvoKIps","https://ap.wps.com/l/cbCaip6KXsvoKIps","pdf",553645,27,"English","# Abstract\n## Background\n## Evidence against a role for hyperglycemia\n## Evidence for a mediating role for adiposity\n## Conclusions\n## Keywords","[{\"question\":\"Why does type 2 diabetes increase the risk of HFpEF?\",\"answer\":\"Type 2 diabetes is associated with higher HFpEF risk. The document argues the relationship is mediated primarily through excess visceral adiposity rather than direct hyperglycemia effects.\"},{\"question\":\"What evidence argues against hyperglycemia as the main cause?\",\"answer\":\"Experimental models of hyperglycemia resemble type 1 diabetes, and clinical lowering of blood glucose with insulin or several drug classes has not reduced heart failure risk.\"},{\"question\":\"How does visceral adiposity mediate diabetes-related HFpEF?\",\"answer\":\"Visceral fat and adipocyte biology changes can drive systemic insulin resistance, promote inflammation, sodium retention, and cardiac steatosis and fibrosis, and may enhance sensitivity to advanced glycation end products.\"},{\"question\":\"Are diabetes and HFpEF risk modifiable, and how?\",\"answer\":\"The document concludes diabetes is a modifiable risk factor if treatment targets adiposity instead of hyperglycemia. Approaches discussed include GLP-1 receptor agonists, SGLT2 inhibitors, and bariatric surgery.\"}]","Is Type 2 Diabetes a Modifiable Risk Factor for the Evolution and Progression of Heart Failure With a Preserved Ejection Fraction - Abstract | PDF",1790671484,68]