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 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 entry of glucose into the endothelium.
“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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Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach
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“In this respect, metformin has been shown to reduce cardiac hypertrophy in different animal models of hypertrophy.(18) Observational studies have also reported CV benefits in metformin users(19) especially in patients with type 2 diabetes mellitus (T2DM) and heart failure.”
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BackgroundCellular senescence and cardiovascular diseases: moving to the “heart” of the problem
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“Inclusion criteria were (1) type 2 diabetes and a first pharmacy-dispensing event for second-line ADMs, occurring on the index date; (2) at least 12 months of enrollment before the index date; (3) no ADM prescription fills other than metformin before the index date; and (4) at least 2 prescription fills of the index A…”
BackgroundMetformin as a geroprotector: experimental and clinical evidence
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“Metformin has protective effect on vasculature by improving endothelial function and smooth muscle relaxation (Nesti & Natali, 2017).”
BackgroundMetformin and the Risk of Dementia in Type 2 Diabetes Patients
Chin-Hsiao, T. (2018) · Aging and Disease · doi:10.14336/ad.2017.1202 · Cited by 98 · see citing works
“Aging and Disease • Volume 10, Number 1, February 2019 44 that metformin may protect the cardiac and vascular system from oxidative stress and inflammation via AMPK-dependent and -independent pathways [26].”
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“Systemic effects include inhibition of the renin‐angiotensin system, while cellular effects include AMPK (AMP‐activated kinase)‐dependent improvement in cellular respiration (Nesti & Natali, 2017).”
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“The most important of them is increasing the blood lactate levels, its use has been limited in people with chronic kidney disease (CKH), liver and heart failure (HF) (1).”
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“In recent years, it demonstrated that metformin and sodium-dependent glucose transporters 2 (SGLT2) inhibitors are also benefit for DCM (19).”
BackgroundEffect of Metformin on Microvascular Endothelial Function in Polycystic Ovary Syndrome
Heidari, B., Lerman, A., Lalia, A. Z., Lerman, L. O., & Chang, A. Y. (2019) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2019.06.015 · Cited by 57 · see citing works
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The Use of Metformin to Increase the Human Healthspan
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“Because none of the standardized differences had a value >10% in the matched cohorts (Table 3), a Tertile cutoffs are <29.5, 29.5 to 61.6, and >61.6 in the matched cohort I; and are <29.3, 29.3 to 61.3, and >61.3 in the matched cohort II.”
BackgroundInfluentialDludla, P. V., Nyambuya, T. M., Johnson, R., Silvestri, S., Orlando, P., Mazibuko-Mbeje, S. E., Gabuza, K., Mxinwa, V., Mokgalaboni, K., Tiano, L., et al. (2020) · Heart Failure Reviews · doi:10.1007/s10741-020-09942-y · Cited by 48 · see citing works
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“Nevertheless, if metformin is able to upregulate GDF-15 circulating levels independently of other factors, this might represent a mechanism through which the drug exerts its effect in terms of CVD protection.(10) For this reason, we sought to identify the major determinants of plasma levels of GDF-15 separately in peo…”
BackgroundHardy, E., & Fernández-Patrón, C. (2021) · Biomolecules · doi:10.3390/biom11030390 · Cited by 44 · see citing works
“In mice, a high dose of metformin (200 mg/kg/day) seems necessary to prevent agonist-induced LV hypertrophy [61,123].”
BackgroundElksnis, A., Martinell, M., Eriksson, O., & Espes, D. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00107 · Cited by 44 · see citing works
“, 2018), cardiovascular disease (Diaz-Morales et al., 2017; Nesti and Natali, 2017), skin disorders (Wang et al.”
BackgroundEmerging Trends in Metformin Prescribing in the United States from 2000 to 2015
Le, S., & Lee, G. C. (2019) · Clinical Drug Investigation · doi:10.1007/s40261-019-00799-0 · Cited by 42 · see citing works
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“Metformin is likely to be also effective for cardiac and vascular disease prevention, as this drug improves endothelial function and provides protection from oxidative stress and inflammation [44, 45].”
BackgroundPractical Insights Into Improving Adherence to Metformin Therapy in Patients With Type 2 Diabetes
Christofides, E. A. (2019) · Clinical Diabetes · doi:10.2337/cd18-0063 · Cited by 40 · see citing works
“It also has benefits beyond glucose control, including a protective effect on cardiac and vascular metabolism and function (11), an effect shown to result in a clinically significant reduction in the risk of cardiovascular events and cardiovascular mortality (9,12).”
BackgroundUngurianu, A., Șeremet, O. C., Gagniuc, E., Olaru, O. T., Guțu, C. M., Grădinaru, D., Ionescu-Tirgoviste, C., Margina, D. M., & Dănciulescu-Miulescu, R. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104522 · Cited by 39 · see citing works
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Effect of metformin on exercise capacity: A meta-analysis
Das, S., Behera, S. K., Srinivasan, A., Xavier, A. S., Selvarajan, S., Kamalanathan, S., Sahoo, J. P., & Nair, N. S. (2018) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2018.08.022 · Cited by 37 · see citing works
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Metformin Attenuates Cyclosporine A-induced Renal Fibrosis in Rats
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“Experimental studies have shown that metformin favorably affects cardiac energetic metabolism, structure and function by decreasing inflammation as well as oxidative and dicarbonyl stress and improving endothelial function [15,16].”
BackgroundInfluentialThe Function of Metformin in Aging-Related Musculoskeletal Disorders
Song, Y., Wu, Z., & Zhao, P. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.865524 · Cited by 32 · see citing works
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“Moreover, it showed tremendous application in many diseases (Lv and Guo 2020), including cancers (Mallik and Chowdhury 2018), obesity (Yerevanian and Soukas 2019), cardiovascular diseases (Nesti and Natali 2017), liver diseases (Li et al.”
BackgroundIonică, 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
Metformin Attenuates Postinfarction Myocardial Fibrosis and Inflammation in Mice
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Cardioprotective effects of a ruthenium (II) Schiff base complex in diet-induced prediabetic rats
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“On the myocardium, MTF attenuates ischemia-reperfusion injury and prevents adverse remodeling induced by humoral and hemodynamic factors as further observed in the current study.(46)”
BackgroundAn 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
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“Consistent with previous reports showing that cardiovascular protection of metformin is through blockade of the RAS [31], we observed that prenatal metformin therapy restored the increases of RAS components induced by HFR/HFA exposure in the kidney.”
ResultMetformin ameliorates bladder dysfunction in a rat model of partial bladder outlet obstruction
Chen, L., Lv, L., Zhang, L., Gao, Z., Liu, Y., Wang, S., Zhou, N., Xia, Y., Cui, J., Jiang, X., et al. (2021) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00625.2020 · Cited by 26 · see citing works
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“In addition to its hypoglycemic effect, Met is also effective in reducing the risk of cardiovascular disease, protecting nerve cells, improving immunity, and inhibiting the development of tumor cells [1,31-34].”
BackgroundNaghdi, A., Goodarzi, M. T., Karimi, J., Hashemnia, M., & Khodadadi, I. (2022) · Journal of Cardiovascular and Thoracic Research · doi:10.34172/jcvtr.2022.23 · Cited by 26 · see citing works
Metformin and risk of chronic obstructive pulmonary disease in diabetes patients
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mTORC1 and SGLT2 Inhibitors—A Therapeutic Perspective for Diabetic Cardiomyopathy
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“…in fl ammation [57] in diabetic animal models but earlier clinical trials with metformin, as an overall cardioprotective drug in diabetic patients, are incon-spicuous [19]. by regulating ionic homeostasis, specifically by regulating the activity and expression of various Ca 2+ channels [61–63].”
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Xu, T., Wu, X., Lu, X., Liang, Y., Mao, Y., Loor, J. J., & Yang, Z. (2021) · BMC Veterinary Research · doi:10.1186/s12917-021-02797-x · Cited by 24 · see citing works
Is metformin beneficial for heart failure in patients with type 2 diabetes?
Packer, M. (2017) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2017.12.011 · Cited by 23 · see citing works
Demystifying the Relationship Between Metformin, AMPK, and Doxorubicin Cardiotoxicity
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Kamel, A. M., Sabry, N. A., & Farid, S. F. (2022) · BMC Cardiovascular Disorders · doi:10.1186/s12872-022-02845-w · Cited by 23 · see citing works
“Metformin has also been shown to reduce LVH in animal models [12].”
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“There is also a growing body of evidence that metformin attenuates ischemia-reperfusion injury in myocardium and prevents remodelling induced by humoral and hemodynamic factors [14,15].”
BackgroundInfluentialStevenson‐Hoare, J. O., Leonenko, G., & Escott‐Price, V. (2023) · BMC Public Health · doi:10.1186/s12889-023-15764-y · Cited by 23 · see citing works
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“This result is clearly contradictory to the view that “metformin has a protective effect on the heart”, which is supported by many scholars [38].”
ResultDrug repurposing in cardiovascular diseases: Opportunity or hopeless dream?
Gelosa, P., Castiglioni, L., Camera, M., & Sironi, L. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.113894 · Cited by 20 · see citing works
“Furthermore, metformin attenuates mitochondrial dysfunction, through the eNOS/SIRT1/p53 and SIRT1/FOXO pathway, the degradation of CHOP and the closure of mitochondrial permeability transition pore (mPTP), and increases mitochondrial biogenesis by enhancing PGC1-α [90,91].”
BackgroundInfluentialEffect of metformin on 18F-fluorodeoxyglucose uptake and positron emission tomographic imaging
Zhang, X., Ogihara, T., Zhu, M., Gantumur, D., Li, Y., Mizoi, K., Kamioka, H., & Tsushima, Y. (2021) · British Journal of Radiology · doi:10.1259/bjr.20200810 · Cited by 20 · see citing works
Markowicz-Piasecka, M., Huttunen, K. M., Mateusiak, Ł., Mikiciuk‐Olasik, E., & Sikora, J. (2018) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2018.02.012 · Cited by 20 · see citing works
Metformin and Risk of Hypertension in Taiwanese Patients With Type 2 Diabetes Mellitus
Tseng, C. (2018) · Journal of the American Heart Association · doi:10.1161/jaha.118.008860 · Cited by 20 · see citing works
Metformin Prevents H₂O₂-Induced Senescence in Human Lens Epithelial B3 Cells
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“Metformin (Met), a first-line drug used to treat diabetes mellitus, has recently been shown to protect against cancer [19,20], cardiovascular disease and aging-related diseases [21,22] and has become the first anti-aging drug in clinical trials.”
BackgroundCharacterizing Effects of Antidiabetic Drugs on Heart Rate, Systolic and Diastolic Blood Pressure
Maringwa, J. T., Sardu, M. L., Hang, Y., Czerniak, R., Vishnubhotla, M., Vakilynejad, M., & Pfister, M. (2020) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.2130 · Cited by 20 · see citing works
“Nesti et al.16 reported a protective effect of metformin with respect to both coronary events and progression to heart failure.”
BackgroundJanjusevic, M., Fluca, A. L., Gagno, G., Pierri, A., Padoan, L., Sorrentino, A., Beltrami, A. P., Sinagra, G., & Aleksova, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23042336 · Cited by 21 · see citing works
“Moreover, metformin treatment, compared to other hypoglycemic drugs, resulted associated to a better outcome after myocardial infarction in patients with T2DM [55].”
BackgroundResultMetformin reverses the schizophrenia-like behaviors induced by MK-801 in rats
Wang, X., Luo, C., Mao, X., Li, X., Yin, J., Zhang, W., Zhou, H., & Liu, Z. (2019) · Brain Research · doi:10.1016/j.brainres.2019.05.023 · Cited by 19 · see citing works
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Metabolomics applications in coronary artery disease personalized medicine
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In Vitro Alpha-Amylase Inhibitory Activity of Microencapsulated Cosmos caudatus Kunth Extracts
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Tseng, C. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.578831 · Cited by 18 · see citing works
“Results from in vitro and in vivo studies suggested that metformin may exert cardiac and vascular protective effects via 5′-adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways (Nesti and Natali, 2017).”
BackgroundAmin, A. M. (2021) · Lifestyle Medicine · doi:10.1002/lim2.25 · Cited by 17 · see citing works
Poly, T. N., Islam, M. M., Li, Y., Lin, M., Hsu, M., & Wang, Y. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10163507 · Cited by 17 · see citing works
- 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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