Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity

Abstract

Metformin is everywhere. Originally introduced in clinical practice as an anti-diabetic agent, its role as a therapeutic agent is expanding to include treatment of pre-diabetes, gestational diabetes, polycystic ovarian disease, and more recently, experimental studies, as well as observations in randomized clinical trials, suggest that metformin could have a place in the treatment or prevention of preeclampsia. This article provides a brief overview of the history of metformin in the treatment of diabetes, reviews the results of meta-analyses of metformin in gestational diabetes, and the treatment of obese non-diabetic pregnant women to prevent macrosomia. We highlight the results of a randomized clinical trial in which metformin administration in early pregnancy did not reduce the frequency of large-for-gestational-age infants (primary endpoint), but did decrease the frequency of preeclampsia (a secondary endpoint). The mechanisms by which metformin may prevent preeclampsia include a reduction in the production of anti-angiogenic factors (soluble vascular endothelial growth factor receptor-1 and soluble endoglin), and improving endothelial dysfunction, probably through an effect on the mitochondria. Another potential mechanism whereby metformin may play a role in the prevention of preeclampsia is its ability to modify cellular homeostasis and energy disposition, mediated by mTOR. Metformin has a molecular weight of 129 Dalton, and therefore, readily crosses the placenta. There is considerable evidence suggesting that this agent is safe during pregnancy. New literature on the role of metformin in the prevention of cancer, a chemotherapeutic adjuvant, and in prolonging life and protecting against aging, is briefly reviewed. Herein we discuss the mechanisms of action and potential benefits of metformin.

Metformin for prevention of hypertensive disorders of pregnancy in women with gestational diabetes or obesity: systematic review and meta‐analysis of randomized trials

“…Metformin is a biguanide that prevents gluconeogenesis in the liver and increases the sensitivity of the peripheral tissue to insulin. The use of metformin in obstetrics is gaining pace as it has been shown to be efficacious in the treatment of gestational diabetes mellitus (GDM) and possibly in the prevention of pre-eclampsia [8][9][10] . A plausible mechanism by which metformin, an anti-diabetic agent, might prevent pre-eclampsia is suggested in an in-vivo study by Brownfoot et al 11 , which demonstrated that metformin reduces soluble fms-like tyrosine kinase-1 levels, which correlate significantly with gestational age at onset of pre-eclampsia and severity 12 .…”

Anticancer Activities of the Quinone-Methide Triterpenes Maytenin and 22-β-hydroxymaytenin Obtained from Cultivated Maytenus ilicifolia Roots Associated with Down-Regulation of miRNA-27a and miR-20a/miR-17-5p

“…Compounds studied as cancer chemopreventive agents, such as the antidiabetic drug metformin, curcumin, and also triterpenoid natural products, such as celastrol and its analogs [21][22][23] exhibit, besides exclusive activities, a common effect: they down regulate specific protein (Sp) transcription factors (TFs) Sp1, Sp3 and Sp4 and, consequently, pro-oncogenic Sp-regulated genes [24][25][26][27]. Some miRNAs over expressed in cancer, such as members of the miR-17-92 (miR-20a/miR-17-5p) and miR-27a clusters indirectly maintain high expression of Sp1, Sp3 and Sp4 [28,29].…”

Metformin reduces maternal weight gain in obese pregnant women: A systematic review and meta‐analysis of two randomized controlled trials

“…36,37 Metformin may improve this outcome by acting on pathophysiological mechanisms similar to those explored in women with PCOS. In addition, it has also been suggested that metformin may prevent PE through its effect on the antiangiogenic state, 38 with a decrease in the production of soluble vascular endothelial growth factor receptor-1 and soluble endoglin. 39 Unfortunately, to date, no RCT has been published on this topic, so we cannot assume that a lower risk of PE is a consequence of a decrease in MWG.…”