Endothelial Function and Dysfunction: Impact of Metformin

Nafisa, Asma; Gray, Susan G.; Cao, Yingnan; Wang, Tinghuai; Xu, Suowen; Wattoo, Feroza H.; Barras, Michael; Cohen, Neale; Kamato, Danielle; Little, Peter J.

doi:10.1016/j.pharmthera.2018.07.007

Cited by 128Nitric Oxide and Endothelin EffectsMetabolism, Diabetes, and CancerDiabetes Treatment and Management

Endothelial Function and Dysfunction: Impact of Metformin

Nafisa, Asma, Gray, Susan G., Cao, Yingnan, Wang, Tinghuai, Xu, Suowen, Wattoo, Feroza H., Barras, Michael, Cohen, Neale +2 more·2018·Pharmacology & Therapeutics

DOI 10.1016/j.pharmthera.2018.07.007

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Abstract

Cardiovascular and metabolic diseases remain the leading cause of morbidity and mortality worldwide. Endothelial dysfunction is a key player in the initiation and progression of cardiovascular and metabolic diseases. Current evidence suggests that the anti-diabetic drug metformin improves insulin resistance and protects against endothelial dysfunction in the vasculature. Hereby, we provide a timely review on the protective effects and molecular mechanisms of metformin in preventing endothelial dysfunction and cardiovascular and metabolic diseases.

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Based on evidence from both clinical and pre-clinical studies, metformin, independent of its anti-hyperglycemic actions, directly protects the endothelium.
“Based on evidence from both clinical and pre-clinical studies metformin, independent of its anti-hyperglycemic actions, directly protects the endothelium (33–35).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [33]
There is an extensive literature based on data from preclinical and clinical studies that indicates metformin protects endothelial function from the effects of diabetes.
“There is an extensive literature based on data from pre-clinical and clinical studies that indicates metformin protects endothelial function from the effects of diabetes (33).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [33]

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Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies
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Cognitive Impairment in Frail Hypertensive Elderly Patients: Role of Hyperglycemia
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Metformin regulates inflammation and fibrosis in diabetic kidney disease through TNC/TLR4/NF-κB/miR-155-5p inflammatory loop
Zhou, Y., Ma, X., Han, J., Yang, M. H., Lv, C., Shao, Y., Wang, Y., Kang, J.-Y., & Wang, Q. (2021) · World Journal of Diabetes · doi:10.4239/wjd.v12.i1.19 · Cited by 65 · see citing works
Metformin Alleviates LPS-Induced Acute Lung Injury by Regulating the SIRT1/NF-κB/NLRP3 Pathway and Inhibiting Endothelial Cell Pyroptosis
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Metformin as a Potential Agent in the Treatment of Multiple Sclerosis
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Metformin: A Dual-Role Player in Cancer Treatment and Prevention
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Metformin and Vascular Diseases: A Focused Review on Smooth Muscle Cell Function
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Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation
Kuchler, T., Günthner, R., Ribeiro, A., Hausinger, R. I., Streese, L., Wöhnl, A., Kesseler, V., Negele, J., Assali, T., Carbajo-Lozoya, J., et al. (2023) · Angiogenesis · doi:10.1007/s10456-023-09885-6 · Cited by 60 · see citing works
Endothelial Dysfunction and Cardiovascular Risk in Obstructive Sleep Apnea: A Review Article
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Metformin decreases bacterial trimethylamine production and trimethylamine N-oxide levels in db/db mice
Kuka, J., Ozola, M., Makrecka‐Kuka, M., Liepinsh, E., Grı̄nberga, S., Sevostjanovs, E., Vilks, K., Liepinsh, E., & Dambrova, M. (2020) · Scientific Reports · doi:10.1038/s41598-020-71470-4 · Cited by 52 · see citing works
Targeting mitochondrial fitness as a strategy for healthy vascular aging
Rossman, M. J., Gioscia‐Ryan, R. A., Clayton, Z. S., Murphy, M. P., & Seals, D. R. (2020) · Clinical Science · doi:10.1042/cs20190559 · Cited by 50 · see citing works
Why the endothelium? The endothelium as a target to reduce diabetes-associated vascular disease
Triggle, C. R., Ding, H., Marei, I., Anderson, T. J., & Hollenberg, M. D. (2020) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2019-0677 · Cited by 49 · see citing works
Cardiovascular effects of non-insulin glucose-lowering agents: a comprehensive review of trial evidence and potential cardioprotective mechanisms
Savarese, G., Butler, J., Lund, L. H., Bhatt, D. L., & Anker, S. D. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab271 · Cited by 43 · see citing works
Targeting oxidative stress in preeclampsia
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Utility of the cold pressor test to predict future cardiovascular events
Pouwels, S., van Genderen, M. E., Kreeftenberg, H. G., Ribeiro, R. J. D. S., Parmar, C. D., Topal, B., Çelik, A., & Ugale, S. M. (2019) · Expert Review of Cardiovascular Therapy · doi:10.1080/14779072.2019.1598262 · Cited by 37 · see citing works
Metabolic adaptations of cells at the vascular-immune interface during atherosclerosis
Bonacina, F., Dalt, L. D., Catapano, A. L., & Norata, G. D. (2020) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2020.100918 · Cited by 37 · see citing works
Enhancing immunity during ageing by targeting interactions within the tissue environment
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Sirtuins family as a target in endothelial cell dysfunction: implications for vascular ageing
Zhang, H., Dai, Y., Zhang, C., Alfred, M. O., Ghosh, A., Khanra, I., Chakraborty, M., Yu, X., & Liang, J. L. (2020) · Biogerontology · doi:10.1007/s10522-020-09873-z · Cited by 35 · see citing works
Endothelial dysfunction in the kidney transplant population: Current evidence and management strategies
Prabhahar, A., Batta, A., Hatwal, J., Kumar, V., Ramachandran, R., & Batta, A. (2025) · World journal of transplantation · doi:10.5500/wjt.v15.i1.97458 · Cited by 33 · see citing works
Metformin in Antiviral Therapy: Evidence and Perspectives
Halabitska, I., Petakh, P., Lushchak, O. V., Kamyshna, I. I., Oksenych, V., & Kamyshnyi, O. (2024) · Viruses · doi:10.3390/v16121938 · Cited by 33 · see citing works
Metformin Protects against Diabetic Cardiomyopathy: An Association between Desmin–Sarcomere Injury and the iNOS/mTOR/TIMP-1 Fibrosis Axis
Dawood, A. F., AlZamil, N. M., Hewett, P. W., Momenah, M. A., Dallak, M. A., Kamar, S. S., Kader, D. H. A., Yassin, H. Z., Haidara, M. A., Maarouf, A., et al. (2022) · Biomedicines · doi:10.3390/biomedicines10050984 · Cited by 33 · see citing works
Ginsenoside Rh1 Protects Human Endothelial Cells Against Lipopolysaccharide-Induced Inflammatory Injury Through Inhibiting TLR2/4-Mediated STAT3, NF-κB, and ER Stress Signaling Pathways
Jin, Y., Nguyen, T. L. L., Myung, C., & Heo, K. (2022) · Life Sciences · doi:10.1016/j.lfs.2022.120973 · Cited by 34 · see citing works
Minimizing Hyperglycemia-Induced Vascular Endothelial Dysfunction by Inhibiting Endothelial Sodium-Glucose Cotransporter 2 and Attenuating Oxidative Stress: Implications for Treating Individuals With Type 2 Diabetes
Venu, V. K. P., El‐Daly, M., Saifeddine, M., Hirota, S. A., Ding, H., Triggle, C. R., & Hollenberg, M. D. (2019) · Canadian Journal of Diabetes · doi:10.1016/j.jcjd.2019.01.005 · Cited by 30 · see citing works
Effect of Metformin on Cardiac Metabolism and Longevity in Aged Female Mice
Zhu, X., Shen, W., Liu, Z., Sheng, S., Xiong, W., He, R., Zhang, X., Ma, L., & Ju, Z. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.626011 · Cited by 30 · see citing works
Metformin alleviates monoamine oxidase-related vascular oxidative stress and endothelial dysfunction in rats with diet-induced obesity
Ionică, L. N., Gaiţă, L., Bînă, A. M., Șoșdean, R., Lighezan, R., Sima, A. C., Malita, D. C., Cretu, O. M., Burlacu, O. N., Muntean, D. M., et al. (2021) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-021-04194-2 · Cited by 30 · see citing works
A Clinical Perspective of the Multifaceted Mechanism of Metformin in Diabetes, Infections, Cognitive Dysfunction, and Cancer
Chow, E., Yang, A., Chung, C. H. L., & Chan, J. C. N. (2022) · Pharmaceuticals · doi:10.3390/ph15040442 · Cited by 30 · see citing works
Targeting Peptide, Fluorescent Reagent Modified Magnetic Liposomes Coated with Rapamycin Target Early Atherosclerotic Plaque and Therapy
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An investigation into the pleiotropic activity of metformin. A glimpse of haemostasis
Markowicz-Piasecka, M., Sadkowska, A., Huttunen, K. M., Podsiedlik, M., Mikiciuk‐Olasik, E., & Sikora, J. (2020) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2020.172984 · Cited by 29 · see citing works
Metformin Prevents Hyperglycemia-Associated, Oxidative Stress-Induced Vascular Endothelial Dysfunction: Essential Role for the Orphan Nuclear Receptor Human Nuclear Receptor 4A1 (Nur77)
Venu, V. K. P., Saifeddine, M., Mihara, K., Faiza, M., Gorobets, E., Flewelling, A. J., Derksen, D. J., Hirota, S. A., Marei, I., Al-Majid, D., et al. (2021) · Molecular Pharmacology · doi:10.1124/molpharm.120.000148 · Cited by 29 · see citing works
Renal Delivery of Pharmacologic Agents During Machine Perfusion to Prevent Ischaemia-Reperfusion Injury: From Murine Model to Clinical Trials
Franzin, R., Stasi, A., Fiorentino, M., Simone, S., Oberbauer, R. W., Castellano, G., & Gesualdo, L. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.673562 · Cited by 28 · see citing works
The Hormetic Effect of Metformin: “Less Is More”?
Panfoli, I., Puddu, A., Bertola, N., Ravera, S., & Maggi, D. C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126297 · Cited by 27 · see citing works
Metformin-mediated epigenetic modifications in diabetes and associated conditions: Biological and clinical relevance
Giordo, R., Posadino, A. M., Mangoni, A. A., & Pintus, G. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115732 · Cited by 27 · see citing works
Salvianolic Acid B Attenuates Apoptosis of HUVEC Cells Treated with High Glucose or High Fat via Sirt1 Activation
Zhai, J., Tao, L., Zhang, Y., Gao, H., Qu, X., Song, Y., & Zhang, S. (2019) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2019/9846325 · Cited by 25 · see citing works
Metformin Reverses Hashimoto's Thyroiditis by Regulating Key Immune Events
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Authors: Nafisa, A., Gray, S. G., Cao, Y., Wang, T., Xu, S., Wattoo, F. H., Barras, M., Cohen, N., Kamato, D., & Little, P. J.
Affiliations: The University of Queensland (AU)
Sun Yat-sen University (CN)
University of Rochester Medicine (US)
Pir Mehr Ali Shah Arid Agriculture University (PK)
Princess Alexandra Hospital (AU)
Baker Heart and Diabetes Institute (AU)
Corresponding author: Little, Peter J.
ORCID: Nafisa, Asma
Gray, Susan G.
Cao, Yingnan
Wang, Tinghuai
Xu, Suowen
Wattoo, Feroza H.
Cohen, Neale
Kamato, Danielle
Little, Peter J.
Venue: Pharmacology & Therapeutics
Publisher: Elsevier BV
Published: 2018-12
Volume: 192
Pages: 150-162
ISSN: 0163-7258 (ISSN-L)
DOI: 10.1016/j.pharmthera.2018.07.007
OpenAlex: W2884428355
Cited by: 128
References: 222
Citations by year: 2026: 8 · 2025: 9 · 2024: 22 · 2023: 15 · 2022: 19 · 2021: 25 · 2020: 19 · 2019: 10 · 2018: 1
FWCI: 1.81
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Pharmacology & Therapeutics (publishedVersion)
PubMed (publishedVersion)
Funders: National Health and Medical Research Council of Australia (#1022800)
National Heart Foundation of Australia (G09M4385)
Diabetes Australia Research Trust
RMIT University
University of Queensland
Australian Government Scholarships
American Heart Association (18CDA34110359)
Topics: Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords: metformin, endothelial dysfunction, endothelial function, insulin resistance, cardiovascular disease, metabolic disorders, molecular mechanisms
MeSH terms: Animals, Cardiovascular Diseases, Endothelium, Vascular, Humans, Hypoglycemic Agents, Metabolic Diseases, Metformin

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Endothelial Function and Dysfunction: Impact of Metformin

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