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

Am J Obstet Gynecol. 2017 Sep;217(3):282-302. doi: 10.1016/j.ajog.2017.06.003. Epub 2017 Jun 12.

Abstract

Metformin is everywhere. Originally introduced in clinical practice as an antidiabetic agent, its role as a therapeutic agent is expanding to include treatment of prediabetes mellitus, gestational diabetes mellitus, and polycystic ovarian disease; more recently, experimental studies and 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 mellitus and reviews the results of metaanalyses of metformin in gestational diabetes mellitus as well as 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 (the 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 antiangiogenic factors (soluble vascular endothelial growth factor receptor-1 and soluble endoglin) and the improvement of 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 rapamycin, a mechanistic target. Metformin has a molecular weight of 129 Daltons and therefore readily crosses the placenta. There is considerable evidence to suggest that this agent is safe during pregnancy. New literature on the role of metformin as a chemotherapeutic adjuvant in the prevention of cancer and in prolonging life and protecting against aging is reviewed briefly. Herein, we discuss the mechanisms of action and potential benefits of metformin.

Keywords: fms-like tyrosine kinase-1 (sFlt-1); insulin resistance; large for gestational age (LGA); mTOR; macrosomia; mitochondria; nutritional sensing; obesity; placental growth factor (PlGF); soluble endoglin (sEng); soluble vascular endothelial growth factor receptor-1 (sVEGFR-1).

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Diabetes, Gestational / drug therapy
  • Female
  • Fetal Development
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Hypoglycemic Agents / therapeutic use*
  • Longevity
  • Maternal Nutritional Physiological Phenomena
  • Maternal-Fetal Exchange
  • Metformin / pharmacology
  • Metformin / therapeutic use*
  • Neoplasms / prevention & control
  • Pre-Eclampsia / prevention & control
  • Pregnancy
  • Randomized Controlled Trials as Topic
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Hypoglycemic Agents
  • Metformin
  • MTOR protein, human
  • TOR Serine-Threonine Kinases