Is Metformin the Aspirin of the 21st Century?

During the latter half of the 20th century, a cheap, readily available drug used by millions of people as a fast-acting and reliable pain reliever began to be revealed as something more. 1-5

Little by little, studies uncovered associations between aspirin use and a lower risk of cardiovascular events (including ischemic stroke and heart attack), preeclampsia, cognitive decline, an array of cancers, and even premature mortality from all causes in a number of patient populations.

Meanwhile, a drug introduced in 1957 in France became available for the first time in the U.S., in 1995, for the treatment of type 2 diabetes. An analog of biguanide drugs that have their origin in French lilac (Galega officinalis), metformin increases insulin sensitivity and lowers the liver’s production of glucose, making it a popular and effective antidiabetic drug that was incorporated into the World Health Organization’s list of essential medicines.

Metformin, an ancient herbal remedy derived from the French lilac, appears in herbal guides dating back to the 17th century. French scientist Jean Sterne published about the properties of metformin, and he named the compound Glucophage, which means glucose eater.6

Modern Day Usage of Metformin

Metformin is widely used and that its potential clinical applications continue to expand. For example, metformin is currently being studied as a treatment to promote longevity, and this suggests that its future applications are broad.6

“Metformin is everywhere,” observed Roberto Romero and colleagues in a 2017 review. While originally introduced into clinical practice as an antidiabetic agent, the roles of metformin as a therapeutic agent are expanding; they include prediabetes, gestational diabetes, and polycystic ovarian disease. Also, several experimental studies and observations from randomized clinical trials indicated that metformin could be useful for preventing or treating preeclampsia.7

Calorie restriction is a well-studied approach that has resulted in an extension of life span in nearly every species tested. Calorie restriction down-regulates the secretion of insulin and insulin-like growth factor 1 activity. Metformin, by activating AMP-activated kinase (AMPK), may elicit similar effects, making it a calorie restriction mimetic.8 Interestingly, AMPK is also activated by salicylate, aspirin’s major breakdown product.9 Both compounds have been associated with protection against cancer.

In the worm C. elegans, metformin extended median life span and prolonged the ability to move around in a youthful way.10 In mice bred to develop mammary tumors, metformin decelerated the age-related increase in blood glucose and prolonged the mean life span by 8% and the maximum life span by a month in comparison with control mice.11 A comparison of the effects of metformin and aspirin on the longevity of crickets resulted in a maximum life span of 194 days in association with aspirin, 188 days with metformin, and 136 days for unsupplemented controls. While aspirin was associated with a greater life extension benefit, metformin was associated with a greater delay in maturation age and reduced growth rate in both sexes.12

Review of Literature: Health Effects of Metformin

In a review article that analyzed 53 studies, J. M. Campbell and colleagues reported that diabetics taking metformin, compared to nondiabetics, had a 7% lower risk of all-cause mortality over followup. Diabetics who used metformin had a 28% lower mortality risk than diabetics who used non-metformin therapies. Metformin users also had a reduced risk of cancer compared to nondiabetics and less cardiovascular disease in comparison with diabetics who received treatments other than metformin. “The apparent reductions in all-cause mortality and diseases of aging associated with metformin use suggest that metformin could be extending life and healthspans by acting as a geroprotective agent,” the authors concluded.13

In a study that included a large group of male, type-2-diabetic veterans aged 65 years and older who were free of age-related comorbidities between 2002 and 2003, the use of metformin reduced the risk of cardiovascular diseases (CVD), cancer, depression, dementia, and frailty-related diseases, together as well as individually.14 Another study of older, type-2-diabetic veterans found an 8% lower risk of death during an average period of 5.6 years among frail subjects treated with metformin compared to those treated with sulfonylurea drugs.15 However, when those without frailty were examined, the use of metformin was associated with a 31% lower risk of death, suggesting that metformin could promote longevity by preventing frailty in older diabetics.

Looking Forward: Benefits of Metformin

What’s in the future for metformin? The Targeting Aging with Metformin (TAME) randomized trial, which plans to enroll 3,000 subjects between the ages of 65 and 79 years at 14 U.S. centers, will assess the time to a new occurrence of a composite outcome that includes cardiovascular events, cancer, dementia, and mortality over followup, as well as other end points, in metformin users and nonusers.16

“If successful, TAME will mark a paradigm shift, moving from treating each medical condition to targeting aging per se,” remarked Nir Barzilai and colleagues in an essay. “We expect this to facilitate the development of even better pharmacologic approaches that will ultimately reduce healthcare costs related to aging,” the authors wrote.16

Like aspirin, metformin may be a wonder drug, aiding in the prevention or treatment of a number of serious diseases and helping protect against premature mortality. While aspirin is easily purchased over-the-counter, metformin requires a prescription. As with any drug, there are possible side effects and conditions under which metformin should not be used. Ask your physician if metformin is right for you.

References

  1. Xie M et al. PLoS One. 2014 Oct 31;9(10):e90286.
  2. Chan AT et al. Arch Intern Med. 2007 Mar 26;167(6):562-72.
  3. Zhou CK et al. Cancer Prev Res (Phila). 2017 Jul;10(7):410-420.
  4. Razzouk L et al. Clin Cardiol. 2010 Sep;33(9):553-8.
  5. Ong G et al. Diabetes Care. 2010 Feb;33(2):317-21.
  6. Thomas I et al. Pediatr Diabetes. 2017 Feb;18(1):10-16.
  7. Romero B et al. Am J Obstet Gynecol. 2017 Sep;217(3):282-302.
  8. McCarty MF et al. Med Hypotheses. 2004;63(2):334-9.
  9. Hardie DG et al. Chem Biol. 2012 Oct 26;19(10):1222-36.
  10. Onken B et al. PLoS One. 2010 Jan 18;5(1):e8758.
  11. Anisimov VN et al. Exp Gerontol. 2005 Aug-Sep;40(8-9):685-93.
  12. Hans H et al. Age (Dordr). 2015;37(2):31.
  13. Campbell JM et al. Ageing Res Rev. 2017 Nov;40:31-44.
  14. Wang CP et al. J Diabetes Complications. 2017 Apr;31(4):679-686.
  15. Wang CP et al. J Endocrinol Diabetes Obes. 2014;2(2).
  16. Barzilai Nir et al. Cell Metab. 2016 Jun 14;23(6):1060-1065.

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