Cited by 211Diabetes Treatment and ManagementMetabolism, Diabetes, and CancerCardiovascular Function and Risk Factors

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Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data

Nesti, L., Natali, A.·2017·Nutrition Metabolism and Cardiovascular Diseases

DOI 10.1016/j.numecd.2017.04.009

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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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Balliu, B., Carcamo‐Orive, I., Gloudemans, M. J., Nachun, D. C., Durrant, M. G., Gazal, S., Park, C. Y., Knowles, D. A., Wabitsch, M., Quertermous, T., et al. (2021) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2021.08.014 · Cited by 35
Research progress on the effects of novel hypoglycemic drugs in diabetes combined with myocardial ischemia/reperfusion injury
Yang, T., & Zhang, D. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101884 · Cited by 30
Cardioprotective effects of a ruthenium (II) Schiff base complex in diet-induced prediabetic rats
Mabuza, L. P., Gamede, M. W., Maikoo, S., Booysen, I. N., Ngubane, P. S., & Khathi, A. (2019) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s183811 · Cited by 29
“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)”
Background
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 31
Association of metformin and development of dry age-related macular degeneration in a U.S. insurance claims database
Eton, E. A., Wubben, T. J., Besirli, C. G., Hua, P., McGeehan, B., & VanderBeek, B. L. (2021) · European Journal of Ophthalmology · doi:10.1177/1120672121997288 · Cited by 30
Sulfenamide and Sulfonamide Derivatives of Metformin – A New Option to Improve Endothelial Function and Plasma Haemostasis
Markowicz-Piasecka, M., Huttunen, K. M., Broncel, M., & Sikora, J. (2019) · Scientific Reports · doi:10.1038/s41598-019-43083-z · Cited by 27
Prenatal Metformin Therapy Attenuates Hypertension of Developmental Origin in Male Adult Offspring Exposed to Maternal High-Fructose and Post-Weaning High-Fat Diets
Tain, Y., Wu, K. L. H., Lee, W., Leu, S., & Chan, J. Y. H. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19041066 · Cited by 30
“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.”
Result
Metformin 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 27
Metformin and arsenic trioxide synergize to trigger Parkin/pink1-dependent mitophagic cell death in human cervical cancer HeLa cells
Chen, J., Zhou, C., Yi, J., Sun, J., Xie, B., Zhang, Z., Wang, Q., Chen, G., Jin, S., Hou, J., et al. (2021) · Journal of Cancer · doi:10.7150/jca.61299 · Cited by 27
“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].”
Background
Effects of curcumin and metformin on oxidative stress and apoptosis in heart tissue of type 1 diabetic rats
Naghdi, 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 30
Metformin and risk of chronic obstructive pulmonary disease in diabetes patients
Tseng, C. (2018) · Diabetes & Metabolism · doi:10.1016/j.diabet.2018.05.001 · Cited by 26
mTORC1 and SGLT2 Inhibitors—A Therapeutic Perspective for Diabetic Cardiomyopathy
Saha, S., Fang, X., Green, C. D., & Das, A. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242015078 · Cited by 25
“…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].”
Result
Effects of metformin on the heart with ischaemia-reperfusion injury: Evidence of its benefits from in vitro, in vivo and clinical reports
Higgins, L., Palee, S., Chattipakorn, S. C., & Chattipakorn, N. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172489 · Cited by 24
Metformin activated AMPK signaling contributes to the alleviation of LPS-induced inflammatory responses in bovine mammary epithelial cells
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
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
Demystifying the Relationship Between Metformin, AMPK, and Doxorubicin Cardiotoxicity
Singh, M., Nicol, A. T., DelPozzo, J., Wei, J., Singh, M., Nguyen, T., Kobayashi, S., & Liang, Q. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.839644 · Cited by 24
Effect of metformin on left ventricular mass and functional parameters in non-diabetic patients: a meta-analysis of randomized clinical trials
Kamel, A. M., Sabry, N. A., & Farid, S. F. (2022) · BMC Cardiovascular Disorders · doi:10.1186/s12872-022-02845-w · Cited by 26
“Metformin has also been shown to reduce LVH in animal models [12].”
Background
Pleiotropic Activity of Metformin and Its Sulfonamide Derivatives on Vascular and Platelet Haemostasis
Markowicz-Piasecka, M., Huttunen, K. M., Sadkowska, A., & Sikora, J. (2019) · Molecules · doi:10.3390/molecules25010125 · Cited by 23
“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].”
BackgroundInfluential
Comparison of long-term effects of metformin on longevity between people with type 2 diabetes and matched non-diabetic controls
Stevenson‐Hoare, J. O., Leonenko, G., & Escott‐Price, V. (2023) · BMC Public Health · doi:10.1186/s12889-023-15764-y · Cited by 25
Morphological and functional characterization of diabetic cardiomyopathy in db/db mice following exercise, metformin alone, or combination treatments
Lu, J., Liu, J., Zhang, L., Wang, X., Zhang, Y., & Tang, Q. (2021) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2021.11.018 · Cited by 22
Novel Sulfonamide-Based Analogs of Metformin Exert Promising Anti-Coagulant Effects without Compromising Glucose-Lowering Activity
Markowicz-Piasecka, M., Sadkowska, A., Sikora, J., Broncel, M., & Huttunen, K. M. (2020) · Pharmaceuticals · doi:10.3390/ph13100323 · Cited by 21
Kolaviron attenuates cardiovascular injury in fructose-streptozotocin induced type-2 diabetic male rats by reducing oxidative stress, inflammation, and improving cardiovascular risk markers
Adoga, J. O., Channa, M. L., & Nadar, A. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112323 · Cited by 21
Effect of metformin (vs. placebo or sulfonylurea) on all-cause and cardiovascular mortality and incident cardiovascular events in patients with diabetes: an umbrella review of systematic reviews with meta-analysis
Bahardoust, M., Mousavi, S., Yariali, M., Haghmoradi, M., Hadaegh, F., Khalili, D., & Delpisheh, A. (2023) · Journal of Diabetes & Metabolic Disorders · doi:10.1007/s40200-023-01309-y · Cited by 21
Metformin Increases Cardiac Rupture After Myocardial Infarction via the AMPK-MTOR/PGC-1α Signaling Pathway in Rats with Acute Myocardial Infarction
Hua, J., Liu, Z., Liu, Z., An, D., Lai, W., Zhan, Q., Zeng, Q., Ren, H., & Xu, D. (2018) · Medical Science Monitor · doi:10.12659/msm.910930 · Cited by 21
“This result is clearly contradictory to the view that “metformin has a protective effect on the heart”, which is supported by many scholars [38].”
Result
Drug 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 19
“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].”
BackgroundInfluential
Effect 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 21
Sulfenamide and sulfonamide derivatives of metformin can exert anticoagulant and profibrinolytic properties
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
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
Metformin Prevents H₂O₂-Induced Senescence in Human Lens Epithelial B3 Cells
Zhang, C., Chen, M., Zhou, N., & Qi, Y. (2020) · Medical science monitor basic research/Medical science monitor. Basic research · doi:10.12659/msmbr.923391 · Cited by 23
“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.”
Background
Characterizing 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
“Nesti et al.16 reported a protective effect of metformin with respect to both coronary events and progression to heart failure.”
Background
Old and Novel Therapeutic Approaches in the Management of Hyperglycemia, an Important Risk Factor for Atherosclerosis
Janjusevic, 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
“Moreover, metformin treatment, compared to other hypoglycemic drugs, resulted associated to a better outcome after myocardial infarction in patients with T2DM [55].”
BackgroundResult
Metformin 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
Metformin attenuates TGF-β1-induced pulmonary fibrosis through inhibition of transglutaminase 2 and subsequent TGF-β pathways
Wang, Y., Lin, C., Han, R., Lu, C., Li, L., Hu, C., Feng, M., Chen, H., & He, Y. (2020) · 3 Biotech · doi:10.1007/s13205-020-02278-2 · Cited by 19
Metabolomics applications in coronary artery disease personalized medicine
Amin, A. M. (2020) · Advances in clinical chemistry · doi:10.1016/bs.acc.2020.08.003 · Cited by 18
In Vitro Alpha-Amylase Inhibitory Activity of Microencapsulated Cosmos caudatus Kunth Extracts
Safitri, A., Roosdiana, A., Hitdatania, E., & Damayanti, S. A. (2021) · Indonesian Journal of Chemistry · doi:10.22146/ijc.68844 · Cited by 18
Chronic Intracerebroventricular Infusion of Metformin Inhibits Salt-Sensitive Hypertension via Attenuation of Oxidative Stress and Neurohormonal Excitation in Rat Paraventricular Nucleus
Yu, X., Zhao, Y., Hou, Y.-K., Li, H., Xia, W., Gao, H., Liu, K., Su, Q., Yang, H., Liang, B., et al. (2018) · Neuroscience Bulletin · doi:10.1007/s12264-018-0308-5 · Cited by 19
Metformin relieves H/R-induced cardiomyocyte injury through miR-19a/ACSL axis - possible therapeutic target for myocardial I/R injury
Peng, C., Jiang, N., Zhao, J.-F., Liu, K., Jiang, W., & Cao, P. (2021) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2021.115408 · Cited by 18
Chronic Metformin Therapy is Associated with a Lower Risk of Hemorrhoid in Patients with Type 2 Diabetes Mellitus
Tseng, C. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.578831 · Cited by 18
“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).”
Background
The metabolic signatures of cardiometabolic diseases: Does the shared metabotype offer new therapeutic targets?
Amin, A. M. (2021) · Lifestyle Medicine · doi:10.1002/lim2.25 · Cited by 18
Metformin Use Is Associated with Decreased Mortality in COVID-19 Patients with Diabetes: Evidence from Retrospective Studies and Biological Mechanism
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 18

Authors: Nesti, L., & Natali, A.
Affiliations: University of Pisa (IT)
Corresponding author: Natali, A.
ORCID: Nesti, L.
Natali, A.
Venue: Nutrition Metabolism and Cardiovascular Diseases
Publisher: Elsevier BV
Published: 2017-08
Volume: 27
Issue: 8
Pages: 657-669
ISSN: 0939-4753 (ISSN-L)
DOI: 10.1016/j.numecd.2017.04.009
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
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
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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Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data

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