The DOI matches its Crossref record; 149 of the 151 references it cites were found in a registry or an index.
Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data
Abstract
Background Metformin, the eldest and most widely used glucose lowering drug, is likely to be effective also on cardiac and vascular disease prevention. Nonetheless, uncertainty still exists with regard to its effects on the cardiovascular system as a whole and specifically on the myocardium, both at the organ and cellular levels.Methods We reviewed the available data on the cardiac and vascular effects of metformin, encompassing both in vitro, either tissue or isolated organ, and in vivo studies in experimental animals and humans, as well as the evidence generated by major clinical trials.Results At the cellular level metformin's produces both AMP-activated kinase (AMPK) dependent and independent effects. At the systemic level, possibly also through other pathways, this drug improves endothelial function, protects from oxidative stress and inflammation, and from the negative effects of angiotensin II. On the myocardium it attenuates ischemia-reperfusion injury and prevents adverse remodeling induced by humoral and hemodynamic factors. The effects on myocardial cell metabolism and contractile function being not evident at rest or in more advanced stages of cardiac dysfunction, could be relevant during transient ischemia, during an acute increase in workload and in the early stages of diabetic/hypertensive cardiomyopathy as confirmed by few small clinical trials and some observational studies. The overall evidence emerging from both clinical trials and real world registry is in favor of a protective effect of metformin with respect to both coronary events and progression to heart failure.Conclusions Given this potential, its efficacy and its safety (and also its low cost) metformin remains the central pillar of the therapy of diabetes.
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“Metformin and other drugs used for T2DM, like the SGLT2 inhibitors, may also reduce hyperglycemia-induced elevated endothelial ROS, independent of negative effects on complex 1, such as via inhibition of NADPH oxidase or blocking the entry of glucose into the endothelium (32, 107–109, 187, 188)”
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 [32]
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Favorable outcomes of metformin on coronary microvasculature in experimental diabetic cardiomyopathy
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“AMPK activation by metformin, melatonin, and Tanshinone IIA could improve ischemia-induced cardiac dysfunction by inhibiting cardiomyocyte apoptosis and blocking the expression of key apoptotic proteins, including B cell lymphoma-2 associated X (BAX) and cleaved caspase-3 (c-caspase 3) (Nesti and Natali, 2017; Yu et a…”
BackgroundAssociation of Metformin and Abdominal Aortic Aneurysm Repair Outcomes
Turowicz, A., Kobecki, J., Laskowska, A., Wojciechowski, J., Świątkowski, F., & Chabowski, M. (2021) · Annals of Vascular Surgery · doi:10.1016/j.avsg.2021.02.048 · Cited by 16
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Metformin reduces risk of varicose veins in patients with type 2 diabetes
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Metformin Decreases Hyaluronan Synthesis by Vascular Smooth Muscle Cells
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“The CV effects of metformin are limited, but it is known to reduce oxidative stress and inflammation and improve endothelial function [10].”
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“Previous studies suggested that metformin not only reduced blood glucose but also had anti-inflammatory, antioxidative stress, and cardioprotective properties (27).”
BackgroundShaheed, C. A., Carland, J. E., Graham, G. G., STOCKER, S. L., Smith, G., Hicks, M., Williams, K. M., Furlong, T. J., Macdonald, P. S., Greenfield, J. R., et al. (2019) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.14107 · Cited by 14
Impaired end joining induces cardiac atrophy in a Hutchinson–Gilford progeria mouse model
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Gastrointestinal Mechanisms Underlying the Cardiovascular Effect of Metformin
Borg, M. J., Rayner, C. K., Jones, K. L., Horowitz, M., Xie, C., & Wu, T. (2020) · Pharmaceuticals · doi:10.3390/ph13110410 · Cited by 15
“Not surprisingly, the mechanisms accounting for cardiovascular benefit with metformin therapy remain contentious [16].”
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“Metformin also has favorable effects on cardiovascular disease; metformin treatment decreases infarct size during I/R injuries in rats [10].”
BackgroundNovel halogenated sulfonamide biguanides with anti-coagulation properties
Markowicz-Piasecka, M., Sikora, J., Zajda, A., & Huttunen, K. M. (2019) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2019.103444 · Cited by 13
Metformin Inhibits Autophagy, Mitophagy and Antagonizes Doxorubicin-Induced Cardiomyocyte Death
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“The best well-proven effect on inflammation and oxidative stress is attributed to metformin and pioglitazone, but reports on anti-inflammatory effect of the newer class of incretins are also available.(37,38) In the present study we did not account for all possible factors mentioned above that might have interfered in…”
Metformin Attenuates Early-Stage Atherosclerosis in Mildly Hyperglycemic Oikawa-Nagao Mice
Asai, A., Shuto, Y., Nagao, M., Kawahara, M., Miyazawa, T., Sugihara, H., & Oikawa, S. (2019) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.48223 · Cited by 12
Zhang, L., Zhang, X., Guan, L., Daxin, Z., & Ge, J. (2022) · Acta cardiologica. Supplementum · doi:10.1080/00015385.2021.2024701 · Cited by 13
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“Metformin produces both AMP-activated kinase (AMPK) dependent and independent effects [69].”
Xu, M., Li, L., He, X., Lu, X., Bi, X., Li, Q., & Xue, X. (2024) · The FASEB Journal · doi:10.1096/fj.202400070r · Cited by 11
“13 Cittadini et al. 14 recently found that the use of metformin improved cardiac function and prevented structural heart abnormalities in spontaneously hypertensive rats (SHRs) and insulin-resistant rats.”
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Yang, D., Yan, J., Deng, H., Yang, X., Luo, S., Zheng, X., Lv, J., Liang, W., Hong, M., Wu, Z., et al. (2020) · Journal of Diabetes Research · doi:10.1155/2020/7419345 · Cited by 10
“Metformin’s effects on the heart and the cardiovascular system have been shown in many conditions [39].”
BackgroundKifle, Z. D., Woldeyohanins, A. E., & Demeke, C. A. (2021) · Metabolism Open · doi:10.1016/j.metop.2021.100137 · Cited by 10
“…Sirt1/FoxO1 and decrease GBM thickness [104] Decrease reactive oxygen species production [105 – 107] Reduce inflammatory marker release [51] Protective arm of the renin-angiotensin-aldosterone system (RAAS) [62,63, 108] GBM: Glioblastoma; FoxO1: Forkhead Box O1; NCC: Sodium-Chloride Cotransporter.”
Uwimana, A., Ma, C., Chen, S., & Ma, X. (2022) · Medicine · doi:10.1097/md.0000000000031266 · Cited by 10
“However, its beneficial effects on ocular-related diabetic complications are still poorly understood.[40] Retinal researchers have recently focused on ameliorating DME management through anti-VEGF, steroids, laser, and surgical approaches.”
BackgroundParween, S., Rihs, S., & Flück, C. E. (2020) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2020.105684 · Cited by 10
Du, F., Cao, Y., Ran, Y., Wu, Q., & Chen, B. (2021) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2021.10665 · Cited by 9
“The beneficial effects of metformin on cardiac function have been attributed to direct actions on cell metabolism, endothelial function, platelet reactivity and calcium homeostasis (25).”
BackgroundZajda, A., Sikora, J., Huttunen, K. M., & Markowicz-Piasecka, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084132 · Cited by 10
Interactions between antidiabetes medications and heart–brain axis
Ong, L. T., & Sia, C. (2024) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000896 · Cited by 8
Sulong, N. A., Lee, V. S., Fei, C. C., & Johan, M. R. (2025) · Drug Delivery and Translational Research · doi:10.1007/s13346-025-01903-y · Cited by 9
“Beyond glycemic control, metformin’s pleiotropic effects, ranging from anti-inflammatory and antioxidant actions to endothelial protection, have laid the groundwork for its integration into personalized, multimodal treatment regimens [44, 56].”
Yen, F., Wei, J. C., Shih, Y., Hsu, C. Y., Hsu, C., & Hwu, C. (2022) · Vaccines · doi:10.3390/vaccines10101752 · Cited by 8
“Third, metformin use in patients with dialysis or hepatic failure showed increased susceptibility to lactic acidosis; therefore, we excluded these patients to decrease confounding bias by indications [36].”
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“Metformin (dimethylbiguanide) is derived from a guanidine drug, the hypoglycaemic active compound of Galega officinalis (French lilac), used for the treatment of diabetes mellitus since 1957 in Europe and since 1995 in the USA (Nesti & Natali, 2017).”
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Drug Repositioning in Doxorubicin-Induced Cardiotoxicity Protection
Kosić, M., Pajović, V., Jovanović, M., & Japundžić‐Žigon, N. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262010130 · Cited by 7
“In various preclinical models of cardiac disease, metformin has been shown to lower the risk of HF and reduce cardiovascular mortality, independent of its glucose-lowering effects [113,114].”
Metformin’s dual impact on Gut microbiota and cardiovascular health: A comprehensive analysis
Asar, T. O., Al-Abbasi, F. A., Sheikh, R. A., Zeyadi, M., Nadeem, M. S., Naqvi, S., Kumar, V., & Anwar, F. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.117128 · Cited by 7
Novel Targets of Metformin in Cardioprotection: Beyond the Effects Mediated by AMPK
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The effect of metformin on cardiovascular markers in female mice consuming a high fat diet
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Ren, J., Chen, X., Wang, T., Liu, C.-Y., & Wang, K. (2025) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2025.1533105 · Cited by 8
“In addition, metformin promotes mitochondrial β -oxidation of fatty acids by enhancing the expression of carnitine palmitoyltransferase 1, reducing apoptosis in cardiomyocytes, and decreasing the formation of myocardial mid-and late-phase glycosylation end products (AGEs) (128).”
Васильевна, Ц. О., Evdokimova, N. E., Васильевна, В. В., Latyntseva, L. D., & As, A. (2022) · Diabetes Mellitus · doi:10.14341/dm12916 · Cited by 8
Fawzi, H. A., Sabbar, R., Kadhim, S. A. A., Flayih, A., Mohammad, B. I., & Swadi, A. A. (2023) · Journal of Medicine and Life · doi:10.25122/jml-2023-0253 · Cited by 7
“Metformin may increase mitochondrial oxidation of fatty acids by lowering the synthesis of the cardiac advanced glycated end product and decreasing cardiomyocyte apoptosis through activation of adenosine monophosphate-activated protein kinase (AMPK) [17].”
BackgroundYen, F., Wei, J. C., Chiu, L., Hsu, C., & Hwu, C. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.919881 · Cited by 6
“, 2019), attenuate cardiac ischemia reperfusion injury, and positively affect cardiac performance during acute heart stress (Bhatt and Dransfield, 2013; Nesti and Natali, 2017).”
BackgroundInfluentialRegression therapy for cardiovascular disease
Rajagopalan, S., & Rashid, I. (2019) · European Heart Journal · doi:10.1093/eurheartj/ehz481 · Cited by 6
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“Although metformin is generally recommended and widely used as a first-line therapy due to its cardioprotective effects, selection of a subsequent antidiabetic agent among type 2 diabetic patients who failed to reach their glycemic goal has been debated [3, 4].”
BackgroundMohri, T., Okamoto, S., Nishioka, Y., Myojin, T., Kubo, S., Higashino, T., Okada, S., Akai, Y., Noda, T., Ishii, H., et al. (2023) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph20075300 · Cited by 5
“However, metformin is inexpensive, has a low risk of hypoglycemia, and can suppress cardiovascular events regardless of blood glucose levels [4].”
BackgroundShu, Y., Li, W., Hu, Q., & Xiong, D. (2023) · Medicine · doi:10.1097/md.0000000000036478 · Cited by 5
“…of T2DM, [46,50] not only has hypoglycemic effects, but also has the effects of anti-aging, [51] weight loss, [52] cardiovascular protection, [53] improvement of polycystic ovary syndrome, [54] tumor inhibition, [55,56] anti-inflammation, [57] reversal of pulmonary fibrosis [58] and reversal…”
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Metformin Use Beyond Diabetes: Reducing Cardiovascular Events In The Healthy Elderly
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“The anti-inflammatory and antioxidative properties of metformin might also indirectly improve endothelial function in the cardiovascular system [47].”
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“tective effects reducing the incidence and mortality for cardiovascular events [9,51,52].”
BackgroundImpact of metformin on hypertension; current knowledge
Bakhshaei, S., Bakhshaei, B., Korani, S. S., Alamouti-fard, E., Allamiaghmiouni, L., & Neshat, S. (2022) · Journal of Renal Endocrinology · doi:10.34172/jre.2022.25067 · Cited by 3
Biochemical bases of the organoprotective properties of metformin
Teplova, A. S., Titova, V. V., & Tenchurina, A. I. (2024) · FOCUS Endocrinology · doi:10.15829/2713-0177-2024-5-1-08 · Cited by 3
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“Despite pathophysiological mechanisms underlying the cardio-protective role of metformin in T2DM remaining controversial, a recent meta-analysis [33,34] confirms: (i) the anti-inflammatory and antioxidative properties of metformin might also indirectly improve endothelial function; (ii) experimental and clinical data…”
ResultFalode, J. A., Ajayi, O. I., Isinkaye, T. V., Adeoye, A. O., Ajiboye, B. O., & Brai, B. I. C. (2022) · Biomarkers · doi:10.1080/1354750x.2022.2157487 · Cited by 3
“ARTICLE HISTORY Received 3 October 2022 Accepted 4 December 2022 KEYWORDS Justicia carnea; type-1 diabetes; oxidative stress; inflammation; cytokines; hepato-protection stress (Nesti and Natali 2017; Loi et al.”
BackgroundType 2 diabetes: evidence-based medicine approach to glucose-lowering therapy
Biryukova, E. V., Morozova, I. A., & Родионова, С. В. (2021) · Meditsinskiy sovet = Medical Council · doi:10.21518/2079-701x-2020-21-160-168 · Cited by 3
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Fawzi, H. A., Sabbar, R., Kadhim, S. A. A., Flayih, A., Mohammad, B. I., & Swadi, A. A. (2024) · Journal of Medicine and Life · doi:10.25122/jml-2023-0340 · Cited by 2
“Metformin is believed to exert its effects by enhancing mi - tochondrial FFA oxidation, which reduces the heart's production of advanced glycation end-products and minimizes cardiac cell apoptosis by activating adenosine monophosphate-activated pro - tein kinase [20].”
BackgroundMetformin and Risks of Aortic Aneurysm and Aortic Dissection: A Mendelian Randomization Study
Wang, L., Lin, Z., Lin, Y., Wu, Q., Zhong, G., & Chen, L. (2025) · Reviews in Cardiovascular Medicine · doi:10.31083/rcm27734 · Cited by 2
“Clinical studies suggest that metformin may have the potential to reduce cardiovascular events in diabetic patients; this effect may be attributed to its influence on weight reduction [7,8].”
Su, H., Lu, D., Shen, M., Li, F., & Xu, C. (2022) · BMC Cardiovascular Disorders · doi:10.1186/s12872-022-02750-2 · Cited by 2
Metabolic and Metabolomic Effects of Metformin in Murine Model of Pulmonary Adenoma Formation
Elton, A. C., Cedarstrom, V., Quraishi, A., Wuertz, B. R. K., Murray, K. J., Markowski, T. W., Seabloom, D. E., & Ondrey, F. G. (2023) · Nutrition and Cancer · doi:10.1080/01635581.2023.2165692 · Cited by 2
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AMP ‐dependent kinase stimulates the expression of αKlotho
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Metadata
- Authors
- Nesti, L., & Natali, A.
- Affiliations
- University of Pisa (IT)
- Corresponding author
- Natali, A.
- ORCID
- Venue
- Nutrition Metabolism and Cardiovascular Diseases
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 27
- Issue
- 8
- Pages
- 657-669
- ISSN
- 0939-4753 (ISSN-L)
- OpenAlex
- W2612188869
- Cited by
- 211
- References
- 151
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 15 · 2023: 21 · 2022: 32 · 2021: 35 · 2020: 32 · 2019: 31 · 2018: 25 · 2017: 4
- FWCI
- 3.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nutrition Metabolism and Cardiovascular Diseases (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
- Keywords
- metformin, cardiovascular effects, myocardium, AMPK, endothelial function, oxidative stress, inflammation, angiotensin II, ischemia-reperfusion injury, cardiac remodeling, diabetic cardiomyopathy, hypertensive cardiomyopathy, heart failure, coronary events, diabetes treatment
- MeSH terms
- Animals, Anti-Inflammatory Agents, Antioxidants, Cardiovascular Diseases, Diabetes Mellitus, Endothelium, Vascular, Energy Metabolism, Fibrosis, Heart, Humans, Hypoglycemic Agents, Metformin, Myocardium, Disease Progression, Ventricular Remodeling
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