Metformin: A Narrative Review of Its Potential Benefits for Cardiovascular Disease, Cancer and Dementia

Overview

Journal Pharmaceuticals (Basel)

Publisher MDPI

Specialty Chemistry

Date 2022 Mar 26

PMID 35337110

Authors

Wiebe M C Top

Adriaan Kooy

Coen D A Stehouwer

Affiliations

Soon will be listed here.

Abstract

The biguanide metformin has been used as first-line therapy in type 2 diabetes mellitus (T2DM) treatment for several decades. In addition to its glucose-lowering properties and its prevention of weight gain, the landmark UK Prospective Diabetes Study (UKPDS) demonstrated cardioprotective properties in obese T2DM patients. Coupled with a favorable side effect profile and low cost, metformin has become the cornerstone in the treatment of T2DM worldwide. In addition, metformin is increasingly being investigated for its potential anticancer and neuroprotective properties both in T2DM patients and non-diabetic individuals. In the meantime, new drugs with powerful cardioprotective properties have been introduced and compete with metformin for its place in the treatment of T2DM. In this review we will discuss actual insights in the various working mechanisms of metformin and the evidence for its beneficial effects on (the prevention of) cardiovascular disease, cancer and dementia. In addition to observational evidence, emphasis is placed on randomized trials and recent meta-analyses to obtain an up-to-date overview of the use of metformin in clinical practice.

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References

Skinner H, Crane C, Garrett C, Eng C, Chang G, Skibber J . Metformin use and improved response to therapy in rectal cancer. Cancer Med. 2013; 2(1):99-107. PMC: 3797563. DOI: 10.1002/cam4.54. View

Arrieta O, Barron F, Padilla M, Aviles-Salas A, Ramirez-Tirado L, Arguelles Jimenez M . Effect of Metformin Plus Tyrosine Kinase Inhibitors Compared With Tyrosine Kinase Inhibitors Alone in Patients With Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019; 5(11):e192553. PMC: 6735425. DOI: 10.1001/jamaoncol.2019.2553. View

de Jager J, Kooy A, Lehert P, Wulffele M, van der Kolk J, Bets D . Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010; 340:c2181. PMC: 2874129. DOI: 10.1136/bmj.c2181. View

Ng C, Jiang A, Toh E, Ng C, Ong Z, Peng S . Metformin and colorectal cancer: a systematic review, meta-analysis and meta-regression. Int J Colorectal Dis. 2020; 35(8):1501-1512. DOI: 10.1007/s00384-020-03676-x. View

Higurashi T, Hosono K, Takahashi H, Komiya Y, Umezawa S, Sakai E . Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial. Lancet Oncol. 2016; 17(4):475-483. DOI: 10.1016/S1470-2045(15)00565-3. View

Li T, Providencia R, Mu N, Yin Y, Chen M, Wang Y . Association of metformin monotherapy or combined therapy with cardiovascular risks in patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2021; 20(1):30. PMC: 7847575. DOI: 10.1186/s12933-020-01202-5. View

Tsilidis K, Kasimis J, Lopez D, Ntzani E, Ioannidis J . Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ. 2015; 350:g7607. DOI: 10.1136/bmj.g7607. View

Lamanna C, Monami M, Marchionni N, Mannucci E . Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2011; 13(3):221-8. DOI: 10.1111/j.1463-1326.2010.01349.x. View

Hui T, Shang C, Yang L, Wang M, Li R, Song Z . Metformin improves the outcomes in Chinese invasive breast cancer patients with type 2 diabetes mellitus. Sci Rep. 2021; 11(1):10034. PMC: 8113316. DOI: 10.1038/s41598-021-89475-y. View

10.

Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G . Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010; 120(7):2355-69. PMC: 2898585. DOI: 10.1172/JCI40671. View

11.

Muller S, Versini A, Sindikubwabo F, Belthier G, Niyomchon S, Pannequin J . Metformin reveals a mitochondrial copper addiction of mesenchymal cancer cells. PLoS One. 2018; 13(11):e0206764. PMC: 6219783. DOI: 10.1371/journal.pone.0206764. View

12.

Gupta A, Bisht B, Dey C . Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer's-like changes. Neuropharmacology. 2011; 60(6):910-20. DOI: 10.1016/j.neuropharm.2011.01.033. View

13.

Zhang K, Yang W, Dai H, Deng Z . Cardiovascular risk following metformin treatment in patients with type 2 diabetes mellitus: Results from meta-analysis. Diabetes Res Clin Pract. 2020; 160:108001. DOI: 10.1016/j.diabres.2020.108001. View

14.

El-Mir M, Detaille D, R-Villanueva G, Delgado-Esteban M, Guigas B, Attia S . Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J Mol Neurosci. 2007; 34(1):77-87. DOI: 10.1007/s12031-007-9002-1. View

15.

Yang W, Yang H, Zhou J, Liu J . Relationship between metformin therapy and risk of colorectal cancer in patients with diabetes mellitus: a meta-analysis. Int J Colorectal Dis. 2020; 35(11):2117-2131. DOI: 10.1007/s00384-020-03704-w. View

16.

Poor S, Ettcheto M, Cano A, Sanchez-Lopez E, Manzine P, Olloquequi J . Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer's Disease Treatment. Pharmaceuticals (Basel). 2021; 14(9). PMC: 8465337. DOI: 10.3390/ph14090890. View

17.

Hong J, Zhang Y, Lai S, Lv A, Su Q, Dong Y . Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care. 2012; 36(5):1304-11. PMC: 3631843. DOI: 10.2337/dc12-0719. View

18.

Moiseeva O, Deschenes-Simard X, St-Germain E, Igelmann S, Huot G, Cadar A . Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell. 2013; 12(3):489-98. DOI: 10.1111/acel.12075. View

19.

Hu Y, Lei M, Ke G, Huang X, Peng X, Zhong L . Metformin Use and Risk of All-Cause Mortality and Cardiovascular Events in Patients With Chronic Kidney Disease-A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne). 2020; 11:559446. PMC: 7575818. DOI: 10.3389/fendo.2020.559446. View

20.

Gormsen L, Sondergaard E, Christensen N, Brosen K, Jessen N, Nielsen S . Metformin increases endogenous glucose production in non-diabetic individuals and individuals with recent-onset type 2 diabetes. Diabetologia. 2019; 62(7):1251-1256. DOI: 10.1007/s00125-019-4872-7. View