Beyond Glycemic Control: Vascular Biologic Effects of Antidiabetic Drugs and Their Cardiovascular Promise

Ischemic heart disease (IHD) remains a leading cause of morbidity and mortality worldwide. Despite major advances in revascularization and pharmacotherapy, numerous patients are left with residual disease or symptoms [1, 2]. Coronary angiogenesis and microvascular function are critical determinants of myocardial perfusion yet they remain insufficiently investigated. In recent years, antidiabetic drugs, including sodium-glucose cotransporter (SGLT) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists, have demonstrated cardiovascular benefits that extend beyond glycemic control. While their benefit in heart failure and cardiovascular outcomes are well established [3, 4, 5, 6, 7], their direct vascular and angiogenic effects are less defined. Preclinical and translational evidence suggests these agents influence endothelial function, collateral vessel formation, and maladaptive remodeling. The evidence underscores the need for future clinical investigations to clarify their vascular effects and define the ideal patient that will most benefit from them.

The myocardium adapts to ischemia through angiogenesis, collateral vessel formation, and microvascular vasoreactivity, all of which determine perfusion. Therapeutic angiogenesis (TA) has emerged as a potential solution; however, it has not been adopted clinically, due to issues with patient selection, trial design, and reproducibility of biologic effects [8, 9, 10, 11]. Angiogenesis is manifested by endothelial proliferation, migration, and survival, stabilization and maturation of nascent vessels, and complex interactions between growth factors, extracellular matrix, and inflammatory mediators [12]. On the other hand, maladaptive angiogenesis, characterized by disorganized or inadequate vessel formation, fails to restore perfusion or may worsen myocardial injury. More sophisticated strategies, including combined protein and stem cell delivery or engineered extracellular vesicles, are under investigation [9]. Collectively, these interventions emphasize that restoring coronary microvascular environment requires an integrated and multifaceted approach rather than delivery of a single factor. Against this backdrop, the vascular effects of novel antidiabetic drugs warrant close consideration.

Large cardiovascular outcome trials (CVOTs), such as SELECT or EMPA-REG OUTCOME [4, 7], demonstrated reduced major cardiovascular events in patients with diabetes or obesity. Growing evidence suggests these benefits extend beyond their glycemic control and involve direct effects on vascular biology. For example, in a swine model of chronic myocardial ischemia, the SGLT2 inhibitor canagliflozin improved perfusion, attenuated fibrosis, and enhanced ventricular function, even without overt angiogenesis [13]. Complementary work in rodent models showed canagliflozin improved absolute myocardial blood flow through enhanced microvascular vasodilation, highlighting its ability to restore microvascular reactivity independent of angiogenesis [14]. In swine with diet-induced metabolic syndrome, canagliflozin demonstrated increased capillary density in ischemic myocardium, demonstrating angiogenic potential under metabolic stress [15]. Importantly, human studies have shown that SGLT2 inhibition enhances coronary microcirculation, endothelial homeostasis, and contractile performance [16, 17]. Similarly, GLP-1 receptor agonists and DPP-4 inhibitors appear to modulate vascular biology. In our swine model of IHD, semaglutide improved perfusion and ventricular function, with reduced fibrosis and enhanced endothelial signaling [18]. These findings highlight the multifaceted mechanisms by which GLP-1 agonists may protect the ischemic myocardium. Linagliptin, a DPP-4 inhibitor, reduced fibrosis and apoptosis while improving overall cardiac performance, illustrating its favorable vascular effects [19]. Human data remains limited but shows promise. A pilot trial of liraglutide in 24 patients with type 2 diabetes, although underpowered, suggested increased coronary microvascular function [20]. Another recent study showed dulaglutide enhanced endothelial function and indices of arterial stiffness [21]. Collectively, these findings suggest SGLT2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors exert cardiovascular benefits in part by modulating microvascular reactivity, endothelial homeostasis, and angiogenesis. Their utility appears most relevant in patients with diffuse coronary disease or microvascular angina, where impaired angiogenesis and vascular reactivity sustain ischemic burden. Additionally, patients with diabetes or metabolic syndrome, who often exhibit marked impairment in endothelial function and vascular reactivity, may especially benefit from these therapies [22].

Combination therapy with traditional antidiabetic medications, such as metformin, may augment these effects. In our swine model of IHD, metformin alone improved cardiac function by improving perfusion and reducing apoptosis, independent of glycemic control [23]. These findings align with historical evidence linking metformin to improved cardiovascular outcomes, and more recent studies demonstrating enhanced microvascular and endothelial function [24, 25, 26, 27, 28]. Notably, most participants in CVOTs of SGLT2 inhibitors and GLP-1 agonists were receiving metformin (67–82%), suggesting it may contribute to the cardiovascular benefits of these newer drugs [29]. Therefore, delineating how these mechanistic pathways interact across various drug classes will be critical to guide their role in IHD.

The vascular and angiogenic effects of these drugs raise an important question: in which patients will cardiovascular benefits be most meaningful? To date, CVOTs have focused on heart failure and atherosclerotic events, but patients with diffuse coronary disease or microvascular angina, conditions where ischemia persists without discrete lesions amenable to revascularization, may represent a particularly important target population. Future trials should move beyond broad outcomes to incorporate mechanistic endpoints, including myocardial perfusion imaging, endothelial function testing, and circulating angiogenic biomarkers. Crucial endpoints can be assessed using invasive techniques, such as quantitative coronary angiography with infusion of vasoactive agents to directly measure endothelial function, intravascular ultrasound to characterize lumen morphology following vasoactive challenges, or fractional flow reserve [30, 31]. Additional secondary endpoints may also be captured through non-invasive techniques, including positron emission tomography and single-photon emission computed tomography (PET/SPECT), cardiac magnetic resonance, or non-invasive assessment of myocardial function [32]. Extended follow up will be essential to monitor the durability of collateral formation and endothelial function, as well as to evaluate for possible adverse effects, such as maladaptive angiogenesis. By integrating a range of these mechanistic endpoints, future trials can more precisely define how these antidiabetic drugs influence coronary vascular biology and myocardial perfusion, ultimately guiding their use in IHD. SGLT2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors represent a new frontier in vascular therapeutics. Defining the clinical conditions for their application will be essential to realizing their full potential.

Availability of Data and Materials

The data supporting the findings and conclusions are available in online publications and are available upon reasonable request. There are no confidentiality or sensitivity concerns regarding the data. Please contact the corresponding author for further details on data access.

References

[1] Khan MA, Hashim MJ, Mustafa H, Baniyas MY, Al Suwaidi SKBM, AlKatheeri R, et al. Global Epidemiology of Ischemic Heart Disease: Results from the Global Burden of Disease Study. Cureus. 2020; 12: e9349. https://doi.org/10.7759/cureus.9349.

[2] Yang L, Zheng B, Gong Y. Global, regional and national burden of ischemic heart disease and its attributable risk factors from 1990 to 2021: a systematic analysis of the Global Burden of Disease study 2021. BMC Cardiovascular Disorders. 2025; 25: 625. https://doi.org/10.1186/s12872-025-05022-x.

[3] Fernández Balsells MM, Sojo-Vega L, Ricart-Engel W. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. The New England Journal of Medicine. 2017; 377: 2098. https://doi.org/10.1056/NEJMc1712572.

[4] Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. The New England Journal of Medicine. 2023; 389: 2221–2232. https://doi.org/10.1056/NEJMoa2307563.

[5] Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. The New England Journal of Medicine. 2016; 375: 1834–1844. https://doi.org/10.1056/NEJMoa1607141.

[6] Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N, et al. Effect of Linagliptin vs Placebo on Major Cardiovascular Events in Adults With Type 2 Diabetes and High Cardiovascular and Renal Risk: The CARMELINA Randomized Clinical Trial. JAMA. 2019; 321: 69–79. https://doi.org/10.1001/jama.2018.18269.

[7] Sarafidis PA, Tsapas A. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. The New England Journal of Medicine. 2016; 374: 1092. https://doi.org/10.1056/NEJMc1600827.

[8] Simons M, Bonow RO, Chronos NA, Cohen DJ, Giordano FJ, Hammond HK, et al. Clinical trials in coronary angiogenesis: issues, problems, consensus: An expert panel summary. Circulation. 2000; 102: E73–E86. https://doi.org/10.1161/01.cir.102.11.e73.

[9] Johnson T, Zhao L, Manuel G, Taylor H, Liu D. Approaches to therapeutic angiogenesis for ischemic heart disease. Journal of Molecular Medicine (Berlin, Germany). 2019; 97: 141–151. https://doi.org/10.1007/s00109-018-1729-3.

[10] Rubanyi GM. Mechanistic, technical, and clinical perspectives in therapeutic stimulation of coronary collateral development by angiogenic growth factors. Molecular Therapy: the Journal of the American Society of Gene Therapy. 2013; 21: 725–738. https://doi.org/10.1038/mt.2013.13.

[11] Tanaka E, Hattan N, Ando K, Ueno H, Sugio Y, Mohammed MU, et al. Amelioration of microvascular myocardial ischemia by gene transfer of vascular endothelial growth factor in rabbits. The Journal of Thoracic and Cardiovascular Surgery. 2000; 120: 720–728. https://doi.org/10.1067/mtc.2000.109536.

[12] Khurana R, Simons M, Martin JF, Zachary IC. Role of angiogenesis in cardiovascular disease: a critical appraisal. Circulation. 2005; 112: 1813–1824. https://doi.org/10.1161/CIRCULATIONAHA.105.535294.

[13] Sabe SA, Xu CM, Sabra M, Harris DD, Malhotra A, Aboulgheit A, et al. Canagliflozin Improves Myocardial Perfusion, Fibrosis, and Function in a Swine Model of Chronic Myocardial Ischemia. Journal of the American Heart Association. 2023; 12: e028623. https://doi.org/10.1161/JAHA.122.028623.

[14] Banerjee D, Sabe SA, Xing H, Xu C, Sabra M, Harris DD, et al. Canagliflozin improves coronary microvascular vasodilation and increases absolute blood flow to the myocardium independent of angiogenesis. The Journal of Thoracic and Cardiovascular Surgery. 2023; 166: e535–e550. https://doi.org/10.1016/j.jtcvs.2023.08.017.

[15] Harris DD, Broadwin M, Sabe SA, Stone C, Kanuparthy M, Nho JW, et al. Effects of diet-induced metabolic syndrome on cardiac function and angiogenesis in response to the sodium-glucose cotransporter-2 inhibitor canagliflozin. The Journal of Thoracic and Cardiovascular Surgery. 2024; 168: e183–e199. https://doi.org/10.1016/j.jtcvs.2024.06.004.

[16] Chen S, Ou W, Gan S, Chen L, Liu B, Zhang Z. Effect of sodium-glucose Co-transporter 2 inhibitors on coronary microcirculation. Frontiers in Pharmacology. 2025; 16: 1523727. https://doi.org/10.3389/fphar.2025.1523727.

[17] Göpel SO, Adingupu D, Wang J, Semenova E, Behrendt M, Jansson-Löfmark R, et al. SGLT2 inhibition improves coronary flow velocity reserve and contractility: role of glucagon signaling. Cardiovascular Diabetology. 2024; 23: 408. https://doi.org/10.1186/s12933-024-02491-w.

[18] Stone C, Harris DD, Broadwin M, Kanuparthy M, Nho JW, Yalamanchili K, et al. Semaglutide Improves Myocardial Perfusion and Performance in a Large Animal Model of Coronary Artery Disease. Arteriosclerosis, Thrombosis, and Vascular Biology. 2025; 45: 285–297. https://doi.org/10.1161/ATVBAHA.124.321850.

[19] Harris DD, 2nd, Stone C, Broadwin M, Kanuparthy M, Sabe SA, Nho JW, et al. Dipeptidyl peptidase-4 inhibitor linagliptin improves fibrosis, apoptosis, and cardiac function in a large animal model of chronic myocardial ischemia. The Journal of Pharmacology and Experimental Therapeutics. 2025; 392: 100532. https://doi.org/10.1016/j.jpet.2024.100532.

[20] Faber R, Zander M, Pena A, Michelsen MM, Mygind ND, Prescott E. Effect of the glucagon-like peptide-1 analogue liraglutide on coronary microvascular function in patients with type 2 diabetes - a randomized, single-blinded, cross-over pilot study. Cardiovascular Diabetology. 2015; 14: 41. https://doi.org/10.1186/s12933-015-0206-3.

[21] Tuttolomondo A, Cirrincione A, Casuccio A, Del Cuore A, Daidone M, Di Chiara T, et al. Efficacy of dulaglutide on vascular health indexes in subjects with type 2 diabetes: a randomized trial. Cardiovascular Diabetology. 2021; 20: 1. https://doi.org/10.1186/s12933-020-01183-5.

[22] Tran V, De Silva TM, Sobey CG, Lim K, Drummond GR, Vinh A, et al. The Vascular Consequences of Metabolic Syndrome: Rodent Models, Endothelial Dysfunction, and Current Therapies. Frontiers in Pharmacology. 2020; 11: 148. https://doi.org/10.3389/fphar.2020.00148.

[23] Stone C, Sabe SA, Harris DD, Broadwin M, Kant RJ, Kanuparthy M, et al. Metformin Preconditioning Augments Cardiac Perfusion and Performance in a Large Animal Model of Chronic Coronary Artery Disease. Annals of Surgery. 2024; 280: 547–556. https://doi.org/10.1097/SLA.0000000000006437.

[24] Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet (London, England). 1998; 352: 837–853.

[25] Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet (London, England). 1998; 352: 854–865.

[26] Jadhav S, Ferrell W, Greer IA, Petrie JR, Cobbe SM, Sattar N. Effects of metformin on microvascular function and exercise tolerance in women with angina and normal coronary arteries: a randomized, double-blind, placebo-controlled study. Journal of the American College of Cardiology. 2006; 48: 956–963. https://doi.org/10.1016/j.jacc.2006.04.088.

[27] Kinaan M, Ding H, Triggle CR. Metformin: An Old Drug for the Treatment of Diabetes but a New Drug for the Protection of the Endothelium. Medical Principles and Practice: International Journal of the Kuwait University, Health Science Centre. 2015; 24: 401–415. https://doi.org/10.1159/000381643.

[28] Sardu C, Paolisso P, Sacra C, Mauro C, Minicucci F, Portoghese M, et al. Effects of Metformin Therapy on Coronary Endothelial Dysfunction in Patients With Prediabetes With Stable Angina and Nonobstructive Coronary Artery Stenosis: The CODYCE Multicenter Prospective Study. Diabetes Care. 2019; 42: 1946–1955. https://doi.org/10.2337/dc18-2356.

[29] Schernthaner G, Brand K, Bailey CJ. Metformin and the heart: Update on mechanisms of cardiovascular protection with special reference to comorbid type 2 diabetes and heart failure. Metabolism: Clinical and Experimental. 2022; 130: 155160. https://doi.org/10.1016/j.metabol.2022.155160.

[30] Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007; 115: 1285–1295. https://doi.org/10.1161/CIRCULATIONAHA.106.652859.

[31] Sena CM, Gonçalves L, Seiça R. Methods to evaluate vascular function: a crucial approach towards predictive, preventive, and personalised medicine. The EPMA Journal. 2022; 13: 209–235. https://doi.org/10.1007/s13167-022-00280-7.

[32] Dewey M, Siebes M, Kachelrieß M, Kofoed KF, Maurovich-Horvat P, Nikolaou K, et al. Clinical quantitative cardiac imaging for the assessment of myocardial ischaemia. Nature Reviews. Cardiology. 2020; 17: 427–450. https://doi.org/10.1038/s41569-020-0341-8.

Funding

National Institute of Health(T32HL160517)

National Institute of Health(R01HL46716)

National Institute of Health(R01HL128831)