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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1 retracted
Bułdak, Ł., Łabuzek, K., Bułdak, R. J., Machnik, G., Bołdys, A., Basiak, M., & Okopień, B. (2016) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2016.2977 · Cited by 19
Retracted10-year follow-up of intensive glucose control in type 2 diabetes
Holman, R. R., Paul, S. K., Bethel, M. A., Matthews, D. R., & Neil, H. A. W. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0806470 · Cited by 7,751
Metabolic Endotoxemia Initiates Obesity and Insulin Resistance
Cani, P. D., Amar, J., Iglesias, M. A., Poggi, M., Knauf, C., Bastelica, D., Neyrinck, A. M., Fava, F., Tuohy, K. M., Chabo, C., et al. (2007) · Diabetes · doi:10.2337/db06-1491 · Cited by 6,638
Role of AMP-Activated Protein Kinase in Mechanism of Metformin Action
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., Wu, M., Ventre, J., Doebber, T., Fujii, N., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci13505 · Cited by 5,652
The AMPK signalling pathway coordinates cell growth, autophagy and metabolism
Mihaylova, M. M., & Shaw, R. J. (2011) · Nature Cell Biology · doi:10.1038/ncb2329 · Cited by 2,923
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The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin
Shaw, R. J., Lamia, K. A., Vasquez, D., Koo, S.-H., Bardeesy, N., DePinho, R. A., Montminy, M., & Cantley, L. C. (2005) · Science · doi:10.1126/science.1120781 · Cited by 1,950
A Randomized Trial of Therapies for Type 2 Diabetes and Coronary Artery Disease
(2009) · New England Journal of Medicine · doi:10.1056/nejmoa0805796 · Cited by 1,939
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Cuadrado, A., Manda, G., Hassan, A., Alcaraz, M. J., Barbas, C., Daiber, A., Ghezzi, P., León, R., López, M. G., Oliva, B., et al. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014753 · Cited by 632
Mohammed, I., Hollenberg, M. D., Ding, H., & Triggle, C. R. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.718942 · Cited by 278
“Additional supportive pre-clinical and clinical evidence has been provided by Nesti and Natali (32).”
BackgroundApostolova, N., Iannantuoni, F., Gruevska, A., Muntané, J., Rocha, M., & Víctor, V. M. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101517 · Cited by 206
“Despite its presence on the market for six decades now, this compound continues to intrigue researchers, especially due to mounting evidence of its effectiveness in other metabolic pathologies, such as obesity, PCOS [71], CVD [72], non-alcoholic fatty liver disease [73], premature puberty [74], kidney disease [75], T1…”
BackgroundInfluentialFeng, J., Wang, X., Ye, X., Arés, I., López-Torres, B., Martínez, M., Martínez‐Larrañaga, M., Wang, X., Anadón, A., & Martínez, M. (2022) · Pharmacological Research · doi:10.1016/j.phrs.2022.106114 · Cited by 201
Oxidative Stress and Antioxidant Treatments in Cardiovascular Diseases
Wang, W., & Kang, P. M. (2020) · Antioxidants · doi:10.3390/antiox9121292 · Cited by 199
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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