Metformin (Glucophage®)

Metformin in Brief
  • Generic name: Metformin
  • Brand names: Glucophage®, Glucophage XR®, Riomet®, Fortamet®, Glumetza®, Obimet®, Dianben®, Diabex®, and Diaformin®
  • Therapeutic class: Antihyperglycemic agent
  • Pharmacologic class: Biguanide
  • FDA Approved: 1995
  • Pregnancy Category: B
  • Originally discovered: France France

History

Metformin has a really interesting story. Structurally metformin is a biguanide and its chemical structure is related to guanidine. Guanidine-like compounds are extracted from the medicinal herb Galega officinalis (Goat’s rue).

The glucose-lowering properties of guanidine where recognized early in the 20th century. Galega officinalis extracts were used to treat diabetes in the 1920s but had prohibitive gastrointestinal side effects.

Metformin itself was first prepared in 1922 by the Dublin chemists Emil A. Werner and James Bell. In 1929, Slotta and Tschesche discovered its sugar-lowering action was the most potent of the biguanide analogs they studied. However, the discovery of the action of metformin was soon overshadowed by insulin.

Under the suggestive name of flumamine, the guanidine analogue was used by Eusebio Y. Garcia (an eminent Philippine specialist in infectious diseases) for the treatment of viral influenza in 1949 1, 2. He noted sugar-lowering properties of the drug.

The publication 1 from the Philippines, mentioning glucose lowering effects of biguanidines, stimulated Jean Stern, a French researcher and diabetologist, in 1957 to try "flumamine" for diabetics. Thus Jean Sterne was the first to try metformin on humans for the treatment of diabetes. He coined the name "Glucophage" (glucose eater) for the drug and published his results in 1957.

The drug, soon renamed metformin, demonstrated a significant advantage over insulin, at least for treating type 2 diabetes.

Metformin was introduced to the United Kingdom in 1958, and Canada in 1972.

In the United States broad interest in metformin began to rise only after the other biguanides (phenformin and buformin) were withdrawn in the 1970s. Only in 1995 metformin received FDA approval.

FDA approved uses
  • Improve glycemic control in adults and children with type 2 diabetes mellitus. Metformin is considered the most efficient and inexpensive first line of treatment for type 2 diabetes. However, its effectiveness often diminishes after a few years of treatment5. Worsening in glycemic control over time can be attenuated by increasing the dose of metformin or addition of other medications.
Off-label uses & Therapeutic perspectives
  • Gestational diabetes during pregnancy 8, 9
  • Polycystic ovary syndrome (PCOS) - metformin increases the likelihood of ovulation 10, reduces hyperinsulinemia and hyperandrogenemia 11
  • Prediabetes17
  • Adjunct therapy in type 1 diabetes18
  • Drug-induced weight gain 6

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Metformin "pros" and "cons"

Advantages:

  • Highly effective. Metformin is a first-line oral therapy for type 2 diabetes mellitus.
  • Does NOT cause hypoglycemia. Metformin does not increase the concentration of insulin in the blood and, therefore, does not cause hypoglycemia (excessively low blood glucose levels)35. However, hypoglycemia may be induced by simultaneous strenuous physical activity or fasting.
  • Does NOT cause weight gain. Unlike the sulphonylureas and insulin, metformin therapy is not associated with increased body weight.
  • Good choice for people who skip meals.
  • Vascular protection. Metformin provides greater protection against the development of macrovascular complications19 than would be expected from its effects upon glycemic control alone.
  • Cardioprotective effect: reduced risk of myocardial infarction 20-21. Metformin is the only antidiabetic medication to show the benefit of reduced risk for myocardial infarction.
  • Stimulates fibrinolysis and decreases plasminogen activator inhibitor -1 (PAI-1), an antithrombolytic protein 28-29.
  • Anti-inflammatory effect 22 Metformin can act as an inhibitor of pro-inflammatory responses through direct inhibition of Nuclear factor-kappaB by blocking the PI3K–Akt pathway23.
  • Decreases oxidative stress24.
  • Favorable effects on serum lipoproteins25. Lowers blood cholesterol, triglycerides, and beta-lipoproteins.
  • Reduces risk of development of atherosclerosis26.
  • Metformin may help delay the onset of diabetes and prevent progression to diabetes in patients with impaired glucose tolerance. The results of the Diabetes Prevention Program show that in persons with impaired glucose tolerance, metformin treatment delays the progression to diabetes 27.
  • Metformin helps to counteract the weight gain caused by insulin, sulfonylureas, thiazolidinediones30. Also, metformin is effective for weight loss in patients treated with weight-promoting antipsychotic and mood-stabilizing drugs31.
  • Very low risk of lactic acidosis33.
  • Lifespan-extending properties32.
  • Neuroprotective activity 12-13. Experimental studies have demonstrated that metformin rescues neuronal insulin resistance 7.
  • Potential geroprotector - slows down the rate of aging and increases lifespan 14-15.
  • Reduced risk of open-angle glaucoma16.

Disadvantages:

  • Multiple contraindications. Contraindicated in patients with congestive heart failure, hepatic impairment (lactate accumulation), and acute or chronic metabolic acidosis.
  • Metformin is contraindicated with glomerular filtration rate <30mL min −1 per 1.73m2, when the clearance of metformin drops precipitously .
  • Frequent gastrointestinal side effects in the form of diarrhea, nausea, bloating and flatulence, cramping and abdominal pain.
  • Prolonged use may cause malabsorption of vitamin B1234.
  • Lactic acidosis (a build-up of lactic acid in the blood) is the feared adverse effect of the biguanide drugs. However the incidence of elevated lactate levels is very low with metformin37. There is a theoretical problem of lactic acidosis in patients with impaired kidney function. Therefore patients with severely impaired kidney function and other risk factors for metformin-associated lactic acidosis (e.g. hypoxemia, alcohol abuse, liver failure, myocardial infarction) should take metformin only under the doctor's care, and should have blood levels of lactic acid checked periodically.
  • Possible worsening in glycemic control over long-term use5.

Mode of action

Metformin does NOT stimulate the release of insulin. However, the therapeutic effect of metformin requires the presence of insulin.

Metformin mechanism of action:

  • Decreases hepatic gluconeogenesis: metformin reduces glucose production by 25–40%.
  • Improves peripheral insulin sensitivity thus improving glucose utilization. Metformin increases insulin-mediated glucose uptake into muscle cells and glucose utilization by 20–50%. Skeletal muscle accounts for 75% of glucose uptake and utilization, so improvements in glucose disposal are expected to involve this important metabolic tissue.
  • Decreases intestinal absorption of glucose.
  • Metformin has tissue-specific effects on circadian clocks36.

Time to clear out of the system

The plasma half- life is approximately 6.2 hours.

Further reading
References
  • 1. Garcia EY. Flumamine, a new synthetic analgesic and anti-flu drug. J Philipp Med Assoc. 1950;26:287–93.
  • 2. Dronsfield A, Ellis P. Drug discovery: metformin and the control of diabetes. Education in Chemistry. 2011;185–7.
  • 3. Hesse G, Taubmann G. Die Wirkung des Biguanids und seiner Dervate auf den Zuckerstoffwechsel. Naunyn-Schmiedebergs Arch Exp Path Pharmacol. 1929;(142):290–308.
  • 4. Werner E, Bell J. The preparation of methylguanidine, and of ββ-dimethylguanidine by the interaction of dicyanodiamide, and methylammonium and dimethylammonium chlorides respectively. Journal of the Chemical Society, Transactions. 1921;121:1790–5.
  • 5. Ito H, Ishida H, Takeuchi Y, Antoku S, Abe M, Mifune M, Togane M. Long-term effect of metformin on blood glucose control in non-obese patients with type 2 diabetes mellitus. Nutr Metab (Lond). 2010 Nov 12;7:83. PubMed
  • 6. Zheng W, Li XB, Tang YL, Xiang YQ, Wang CY, de Leon J. Metformin for Weight Gain and Metabolic Abnormalities Associated With Antipsychotic Treatment: Meta-Analysis of Randomized Placebo-Controlled Trials. J Clin Psychopharmacol. 2015 Oct;35(5):499-509. PubMed
  • 7. Gupta A, Bisht B, Dey CS. Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer's-like changes. Neuropharmacology. 2011 May;60(6):910-20. PubMed
  • 8. Kitwitee P, Limwattananon S, Limwattananon C, et al. Metformin for the treatment of gestational diabetes: An updated meta-analysis. Diabetes Res Clin Pract. 2015 Sep;109(3):521-32. PubMed
  • 9. Ainuddin J, Karim N, Hasan AA, Naqvi SA. Metformin versus insulin treatment in gestational diabetes in pregnancy in a developing country: a randomized control trial. Diabetes Res Clin Pract. 2015 Feb;107(2):290-9. PubMed
  • 10. Creanga AA, Bradley HM, McCormick C, Witkop CT. Use of metformin in polycystic ovary syndrome: a meta-analysis. Obstet Gynecol. 2008 Apr;111(4):959-68.
  • 11. Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, Zanolin E, Muggeo M. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab. 2000 Jan;85(1):139-46. PubMed
  • 12. Patil SP, Jain PD, Ghumatkar PJ, Tambe R, Sathaye S. Neuroprotective effect of metformin in MPTP-induced Parkinson's disease in mice. Neuroscience. 2014 Sep 26;277:747-54. PubMed
  • 13. Wahlqvist ML, Lee MS, Hsu CC, Chuang SY, Lee JT, Tsai HN. Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson's disease occurring with Type 2 diabetes in a Taiwanese population cohort. Parkinsonism Relat Disord. 2012 Jul;18(6):753-8. PubMed
  • 14. De Haes W, Frooninckx L, Van Assche R, Smolders A, Depuydt G, Billen J, Braeckman BP, Schoofs L, Temmerman L. Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2. Proc Natl Acad Sci U S A. 2014 Jun 17;111(24):E2501-9. PubMed
  • 15. Miles JM, Rule AD, Borlaug BA. Use of metformin in diseases of aging. Curr Diab Rep. 2014 Jun;14(6):490.
  • 16. Lin HC, Stein JD, Nan B, Childers D, Newman-Casey PA, Thompson DA, Richards JE. Association of Geroprotective Effects of Metformin and Risk of Open-Angle Glaucoma in Persons With Diabetes Mellitus. JAMA Ophthalmol. 2015 Aug;133(8):915-23. PubMed
  • 17. Lily M, Godwin M. Treating prediabetes with metformin: systematic review and meta-analysis. Can Fam Physician. 2009 Apr;55(4):363-9. PubMed
  • 18. Moon RJ, Bascombe LA, Holt RI. The addition of metformin in type 1 diabetes improves insulin sensitivity, diabetic control, body composition and patient well-being. Diabetes Obes Metab. 2007 Jan;9(1):143-5. PubMed
  • 19. Kooy A, de Jager J, Lehert P, Bets D, Wulffelé MG, Donker AJ, Stehouwer CD. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. 2009 Mar 23;169(6):616-25 PubMed
  • 20. Lexis CP, Wieringa WG, Hiemstra B, van Deursen VM, Lipsic E, van der Harst P, van Veldhuisen DJ, van der Horst IC. Chronic metformin treatment is associated with reduced myocardial infarct size in diabetic patients with ST-segment elevation myocardial infarction. Cardiovasc Drugs Ther. 2014 Apr;28(2):163-71. PubMed
  • 21. Lexis CP, van der Horst-Schrivers AN, Lipsic E, et al. The effect of metformin on cardiovascular risk profile in patients without diabetes presenting with acute myocardial infarction: data from the Glycometabolic Intervention as adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III) trial. BMJ Open Diabetes Res Care. 2015 Dec 11;3(1):e000090. PubMed
  • 22. Krysiak R, Okopien B. Lymphocyte-suppressing and systemic anti-inflammatory effects of high-dose metformin in simvastatin-treated patients with impaired fasting glucose. Atherosclerosis. 2012 Dec;225(2):403-7. PubMed
  • 23. Huang NL, Chiang SH, Hsueh CH, Liang YJ, Chen YJ, Lai LP. Metformin inhibits TNF-alpha-induced IkappaB kinase phosphorylation, IkappaB-alpha degradation and IL-6 production in endothelial cells through PI3K-dependent AMPK phosphorylation. Int J Cardiol. 2009 May 15;134(2):169-75.
  • 24. Esteghamati A, Eskandari D, Mirmiranpour H, Noshad S, Mousavizadeh M, Hedayati M, Nakhjavani M. Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: a randomized clinical trial. Clin Nutr. 2013 Apr;32(2):179-85. PubMed
  • 25. Mughal MA, Jan M, Maheri WM, Memon MY, Ali M. The effect of metformin on glycemic control, serum lipids and lipoproteins in diet alone and sulfonylurea-treated type 2 diabetic patients with sub-optimal metabolic control. J Pak Med Assoc. 2000 Nov;50(11):381-6. PubMed
  • 26. Forouzandeh F, Salazar G, Patrushev N, Xiong S, Hilenski L, Fei B, Alexander RW. Metformin beyond diabetes: pleiotropic benefits of metformin in attenuation of atherosclerosis. J Am Heart Assoc. 2014 Dec;3(6):e001202. PubMed
  • 27. Diabetes Prevention Program Research Group: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002, 346: 393-403.
  • 28. Vague P, Juhan-Vague I, Alessi MC, Badier C, Valadier J. Metformin decreases the high plasminogen activator inhibition capacity, plasma insulin and triglyceride levels in non-diabetic obese subjects. Thromb Haemost. 1987 Jun 3;57(3):326-8. PubMed
  • 29. Grant PJ. The effects of metformin on the fibrinolytic system in diabetic and non-diabetic subjects. Diabete Metab. 1991 May;17(1 Pt 2):168-73.
  • 30. Bell DS, Mayo MS. Weight loss in patients with diabetes treated with a metformin-sulfonylurea combination in comparison with twice-daily mixed insulin. Endocr Pract. 1998 Nov-Dec;4(6):360-4. PubMed
  • 31. Wang M, Tong JH, Zhu G, Liang GM, Yan HF, Wang XZ. Metformin for treatment of antipsychotic-induced weight gain: a randomized, placebo-controlled study. Schizophr Res. 2012 Jun;138(1):54-7 PubMed
  • 32. De Haes W, Frooninckx L, Van Assche R, et. al. Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2. Proc Natl Acad Sci U S A. 2014 Jun 17;111(24):E2501-9. PubMed
  • 33. DeFronzo R, Fleming GA, Chen K, Bicsak TA. Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism. 2016 Feb;65(2):20-9. PubMed
  • 34. Singh AK, Kumar A, Karmakar D, Jha RK. Association of B12 deficiency and clinical neuropathy with metformin use in type 2 diabetes patients. J Postgrad Med. 2013 Oct-Dec;59(4):253-7. PubMed
  • 35. Bodmer M, Meier C, Krähenbühl S, Jick SS, Meier CR. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis. Diabetes Care. 2008 Nov;31(11):2086-91. PubMed
  • 36. Barnea M, Haviv L, Gutman R, Chapnik N, Madar Z, Froy O. Metformin affects the circadian clock and metabolic rhythms in a tissue-specific manner. Biochim Biophys Acta. 2012 Nov;1822(11):1796-806 PubMed
  • 37. Lee EY, Hwang S, Lee YH, et al. Association between Metformin Use and Risk of Lactic Acidosis or Elevated Lactate Concentration in Type 2 Diabetes. Yonsei Med J. 2017 Mar;58(2):312-318. PubMed

Published: May 07, 2016
Last updated: January 30, 2017

Interesting facts
metformin facts
  • Metformin should not be taken for 24 hours before a radiologic contrast exam and for 48 hours after the contrast exam.
  • Available data suggests that lactic acidosis may be coincidental rather than causally associated with metformin treatment35.
  • In comparison with multiple benefits of metformin, the risk of serious side effects is very low.
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