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

https://doi.org/10.1016/j.ajog.2017.06.003Get rights and content

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.

Section snippets

Metformin: from the pharaohs to the present

Metformin (dimethylbiguanide hydrochloride) is a constituent of many herbal remedies, and the Ebers Papyrus, written in 1500 BCE,22 records its use in Egypt since the time of the Pharaohs (Figure 2). In Europe, herbal remedies derived from the plant Galega officinalis (Figure 3) containing metformin have been prescribed to treat polyuria and other symptoms of diabetes mellitus since the Middle Ages,22, 23, 24 but it was not until the early 1900s that guanidine was identified as the organic base

The role of angiogenic and antiangiogenic factors in the genesis of preeclampsia

For more than 100 years, preeclampsia was thought to be caused by the release of “toxic factors” from an ischemic placenta, hence, the name “toxemia.”102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117 The most widely known “toxins” at this time are soluble fms-like tyrosine kinase-1 (sFlt-1 or soluble vascular endothelial growth factor receptor 1 [sVEGFR-1]) and soluble endoglin.118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135,

Nutrient sensing: key for the survival of all living forms

“Cell growth and division are the two most fundamental features of life.”220 All organisms must be able to detect nutrient levels in their environment to coordinate growth and development. This is true of bacteria that must choose whether to grow or to remain stationary, and, in the case of motile bacteria, to determine in which direction to move, depending on the availability of nutrients. Bacteria evolved specific chemoreceptors for this purpose that coordinate information received from the

Safety of metformin during pregnancy

Metformin has a molecular weight of 129 Daltons and crosses the placenta by direct diffusion without affecting the facilitated transfer of glucose.242 Indeed, an ex vivo dually perfused human placental lobule demonstrated the rapid transfer of metformin from maternal to fetal circulation with a lag time of 1.7±0.28 minutes, similarly observed in women with normal pregnancies and those diagnosed with gestational diabetes mellitus.242 In vivo studies reported the detection of metformin in the

A role for metformin in cancer and aging

Originally introduced for the treatment of diabetes mellitus, metformin is now gaining attention as a potential anticancer agent (Figure 1).7, 8, 9, 10 The first observation that metformin might reduce the risk of cancer was made in a population-based case-control study of patients with type 2 diabetes who were treated with metformin.253 A cohort study of type 2 diabetic patients, newly treated with metformin and later followed, reported that the frequency of cancer was significantly lower in

Conclusion

Metformin, long known to be an herbal medicine, has evolved from its use as a popular treatment for diabetes mellitus into a drug with a significantly wider array of beneficial effects that range from cancer treatment to extending longevity and, in our field, gestational hypertension and preeclampsia in obese women. Current evidence suggests that metformin’s wide-ranging beneficial effects are mediated by at least 2 primary mechanisms: suppression of intracellular metabolic activity of

References (278)

  • S. Niromanesh et al.

    Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trial

    Diabetes Res Clin Pract

    (2012)
  • C.P. Spaulonci et al.

    Randomized trial of metformin vs insulin in the management of gestational diabetes

    Am J Obstet Gynecol

    (2013)
  • J. Ainuddin et al.

    Metformin versus insulin treatment in gestational diabetes in pregnancy in a developing country: a randomized control trial

    Diabetes Res Clin Pract

    (2015)
  • G.M. Rodgers et al.

    Preeclampsia is associated with a serum factor cytotoxic to human endothelial cells

    Am J Obstet Gynecol

    (1988)
  • J.M. Roberts et al.

    Preeclampsia: an endothelial cell disorder

    Am J Obstet Gynecol

    (1989)
  • L. Myatt et al.

    Vascular biology of preeclampsia

    J Thromb Haemost

    (2009)
  • A. Many et al.

    Hyperuricemia and xanthine oxidase in preeclampsia, revisited

    Am J Obstet Gynecol

    (1996)
  • L. Myatt

    Review: reactive oxygen and nitrogen species and functional adaptation of the placenta

    Placenta

    (2010)
  • G.J. Burton et al.

    Oxidative stress

    Best Pract Res Clin Obstet Gynaecol

    (2011)
  • J.V. Ilekis et al.

    Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development

    Am J Obstet Gynecol

    (2016)
  • C. Chiswick et al.

    Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial

    Lancet Diabetes Endocrinol

    (2015)
  • J. Cramer et al.

    Medication compliance feedback and monitoring in a clinical trial: predictors and outcomes

    Value Health

    (2003)
  • J.A. Cramer et al.

    Medication compliance and persistence: terminology and definitions

    Value Health

    (2008)
  • B. Onken et al.

    Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1

    PloS One

    (2010)
  • A. Martin-Montalvo et al.

    Metformin improves healthspan and lifespan in mice

    Nat Commun

    (2013)
  • W. De Haes et al.

    Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2

    Proc Natl Acad Sci U S A

    (2014)
  • Crandall J. Metformin in Longevity Study (MILES). Clinical Trial.gov., 2015. Available at:...
  • Z.J. Zhang et al.

    Reduced risk of lung cancer with metformin therapy in diabetic patients: a systematic review and meta-analysis

    Am J Epidemiol

    (2014)
  • M. Franciosi et al.

    Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review

    PloS One

    (2013)
  • L. Wu et al.

    Pharmacologic therapy of diabetes and overall cancer risk and mortality: a meta-analysis of 265 studies

    Scientific Rep

    (2015)
  • X. Tan et al.

    Effect of metformin treatment during pregnancy on women with PCOS: a systematic review and meta-analysis

    Clin Invest Med

    (2016)
  • L. Feng et al.

    Efficacy of metformin on pregnancy complications in women with polycystic ovary syndrome: a meta-analysis

    Gynecol Endocrinol

    (2015)
  • B. Brock et al.

    Is metformin therapy for polycystic ovary syndrome safe during pregnancy?

    Basic Clin Pharmacol toxicol

    (2005)
  • M.J. Crowley et al.

    Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: a systematic review

    Ann Intern Med

    (2017)
  • N. Nath et al.

    Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis

    J Immunol

    (2009)
  • L. Negrotto et al.

    Immunologic effects of metformin and pioglitazone treatment on metabolic syndrome and multiple sclerosis

    JAMA Neurol

    (2016)
  • Y. Takiyama et al.

    Tubular injury in a rat model of type 2 diabetes is prevented by metformin: a possible role of HIF-1alpha expression and oxygen metabolism

    Diabetes

    (2011)
  • A. Bhat et al.

    Systematic review: preventive and therapeutic applications of metformin in liver disease

    World J Hepatol

    (2015)
  • Hypertension in Pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy

    Obstet Gynecol

    (2013)
  • L.A. Witters

    The blooming of the French lilac

    J Clin Invest

    (2001)
  • C.J. Bailey et al.

    Metformin

    N Engl J Med

    (1996)
  • C.J. Bailey et al.

    Metformin: its botanical background

    Pract Diabetes Int

    (2004)
  • J. Sterne

    Pharmacology and mode of action of the hypoglycaemic guanidine derivatives

  • H. Muller et al.

    Pharmacology of galegin

    Arch Expll Path Pharm

    (1927)
  • H. Simonnet et al.

    [Sur les propietes hypoglycemiantes du sulfate de galegine.]

    Bull Soc Chim Biol Paris

    (1927)
  • M. Nattrass et al.

    Biguanides

    Diabetologia

    (1978)
  • N. Paulesco

    [Recherches sur le role du pancreas dans l’assimilation nutritive.]

    Arch Int Physiol

    (1921)
  • F.G. Banting et al.

    Pancreatic extracts in the treatment of diabetes mellitus

    Can Med Assoc J

    (1922)
  • J. Sterne

    [Treatment of diabetes mellitus with N,N-dimethylguanylguanidine (LA. 6023, glucophage)]

    Therapie

    (1959)
  • G.M. Bernier et al.

    Lactic acidosis and phenformin hydrochloride

    JAMA

    (1963)
  • Cited by (188)

    • Nutritional aspects

      2023, Ketogenic: The Science of Therapeutic Carbohydrate Restriction in Human Health
    View all citing articles on Scopus

    This work was supported, in part, by the Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS); and, in part, with Federal funds from NICHD/NIH/DHHS under Contract No. HHSN275201300006C.

    The authors report no conflict of interest.

    View full text