Skip to main content

Advertisement

Log in

Metformin: New Preparations and Nonglycemic Benefits

  • Pharmacologic Treatment of Type 2 Diabetes (HE Lebovitz and G Bahtiyar, Section Editors)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Metformin has been widely used for over 5 decades. New preparations have been developed for possible enhancement of efficiency, tolerability, and pleiotropic nonglycemic effects. Extended-release metformin has contributed to adherence and improved gastrointestinal tolerability. Delayed-release metformin acts in the lower gastrointestinal tract and exerts glucose-lowering effects at lower plasma metformin levels, which might suggest use of this biguanide in patients with chronic kidney disease. Metformin is also known to have numerous nonglycemic effects. Results of the UK Prospective Diabetes Study indicate improvements in cardiovascular outcome and reduced total mortality independent of glycemic control. Anticancer effects of metformin have been discussed and many clinical trials are on-going. Metformin is noted for its beneficial effects on lifespan extension and on disorders due to increased insulin resistance. Further investigations, including randomized control trials in nondiabetic individuals, are required to demonstrate the nonglycemic effects of metformin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38:140–9.

    Article  PubMed  Google Scholar 

  2. UKPDS Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854–65.

    Article  Google Scholar 

  3. Holman R, Paul S, Bethel M, Matthews D, Neil H. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–89.

    Article  CAS  PubMed  Google Scholar 

  4. Godarzi MO, Brier-Ash M. Metformin revisited: re-evaluation of its properties and role in the pharmacopoeia of modern antidiabetic agents. Diabetes Obes Metab. 2005;5:654–65.

    Article  Google Scholar 

  5. Rojas LB, Gomes MB. Metformin: an old but still the best treatment for type 2 diabetes. Diabetol Metab Syndr. 2013;5:6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Campbell IW, Bailey C, Bailey CJ, et al. Metformin: The Gold Standard: A Scientific Handbook. John Wiley & Sons Inc; 2008.

  7. Pryor R, Cabreiro F. Repurposing metformin: an old drug with new tricks in its binding pockets. Biochem J. 2015;471:307–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. El-Mir MY, Nogueira V, Fontaine E, et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000;275:223–8.

    Article  CAS  PubMed  Google Scholar 

  9. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its antidiabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348:607–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hardie DG. The AMP-activated protein kinase pathway: new players upstream and downstream. J Cell Sci. 2004;117:5479–87.

    Article  CAS  PubMed  Google Scholar 

  11. Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shaw RJ, Lamia KA, Vasquez D, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310:1642–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Miller RA, Chu Q, Xie J, et al. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013;494:256–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Madiraju AK, Erion DM, Rahimi Y, et al. Metforminsuppresses gluconeogenesis by inhibiting mitochondrial glycerophosphatedehydrogenase. Nature. 2014;510:542–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Anabtawi A, Miles JM. Metformin: nonglycemic effects and potential novel indications. Endocr Pract. In press.

  16. Wheaton WW, Weinberg SE, Hamanaka RB, et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife. 2014;13, e02242.

    Google Scholar 

  17. Davis BJ, Xie Z, Viollet B, et al. Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes. 2006;55:496–505.

    Article  CAS  PubMed  Google Scholar 

  18. Kalender A, Selvaraj A, Kim SY, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 2010;11:390–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Pala L, Rotella CM. The "slower" the better. J Endocrinol Investig. 2014;37:497–8.

    Article  CAS  Google Scholar 

  20. •• Scheen AJ. Will delayed release metformin provide better management of diabetes type 2? Expert Opin Pharmacother. 2016;17:627–30. A useful review describing the characteristics of the different formulations of metformin: delayed release compared with extended release and immediate release.

    Article  PubMed  Google Scholar 

  21. DeFronzo R, Fleming GA, Chen K, et al. Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism. 2016;65:20–9.

    Article  CAS  PubMed  Google Scholar 

  22. • McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016;59:426–35. A important review which focuses on the effects of metformin on the gut and introduces the many defferent mechanisms of those effects.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Stepensky D, Friedman M, Raz I, et al. Pharmacokinetic-pharmacodynamic analysis of the glucose-lowering effect of metformin in diabetic rats reveals first-pass pharmacodynamic effect. Drug Metab Dispos. 2002;30:861–8.

    Article  CAS  PubMed  Google Scholar 

  24. Bonora E, Cigolini M, Bosello O, et al. Lack of effect of intravenous metformin on plasma concentrations of glucose, insulin, C-peptide, glucagon and growth hormone in nondiabetic subjects. Curr Med Res Opin. 1984;9:47–51.

    Article  CAS  PubMed  Google Scholar 

  25. Napolitano A, Miller S, Nicholls AW, et al. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS One. 2014;9, e100778.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica. 1994;241:49–57.

    Article  Google Scholar 

  27. Bailey CJ, Wilcock C, Scarpello JH. Metformin and the intestine. Diabetologia. 2008;51:1552–3.

    Article  CAS  PubMed  Google Scholar 

  28. Duca FA, Côté CD, Rasmussen BA, et al. Metformin activates a duodenal AMPK-dependent pathway to lower hepatic glucose production in rats. Nat Med. 2015;21:506–11.

    Article  CAS  PubMed  Google Scholar 

  29. Forslund K, Hildebrand F, Nielsen T, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528:262–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fujioka K, Brazg RL, Raz I, et al. Efficacy, dose-response relationship and safety of once-daily extended-release metformin (Glucophage XR) in type 2 diabetic patients with inadequate glycaemic control despite prior treatment with diet and exercise: results from two double-blind, placebo-controlled studies. Diabetes Obes Metab. 2005;7:28–39.

    Article  CAS  PubMed  Google Scholar 

  31. Fujioka K, Pans M, Joyal S. Glycemic control in patients with type 2 diabetes mellitus switched from twice-daily immediate-release metformin to a once-daily extended-release formulation. Clin Ther. 2003;25:515–29.

    Article  CAS  PubMed  Google Scholar 

  32. Timmins P, Donahue S, Meeker J, et al. Steady-state pharmacokinetics of a novel extended-release metformin formulation. Clin Pharmacokinet. 2005;44:721–9.

    Article  CAS  PubMed  Google Scholar 

  33. Dohahue S, Marathe P, Guld T, et al. The pharmacokinetics and pharmacodynamics of extended-release metformin tablets vs immediate-release metformin in subjects with type 2 diabetes. Diabetes. 2002;51 Suppl 2:A468.

    Google Scholar 

  34. Blonde L, Dailey GE, Jabbour SA, et al. Gastrointestinal tolerability of extended-release metformin tablets compared to immediate-release metformin tablets: results of a retrospective cohort study. Curr Med Res Opin. 2004;20:565–72.

    Article  CAS  PubMed  Google Scholar 

  35. Levy J, Cobas RA, Gomes MB. Assessment of efficacy and tolerability of oncedaily extended release metformin in patients with type 2 diabetes mellitus. Diabetol Metab Syndr. 2010;2:16.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Guo L, Guo X, Li Y, et al. Effects of body mass index or dosage on gastrointestinal disorders associated with extended-release metformin in type 2 diabetes: Sub-analysis of a Phase IV open-label trial in Chinese patients. Diabetes Metab Syndr. In press.

  37. Yoon KH, Lee JH, Kim JW, et al. Epidemic obesity and type 2 diabetes in Asia. Lancet. 2006;368:1681–8.

    Article  PubMed  Google Scholar 

  38. Yabe D, Seino Y, Fukushima M, et al. B-cell dysfunction versus insulin resistance in the pathogenesis of type 2 diabetes in East Asians. Curr Diab Rep. 2015;15:602.

    Article  PubMed  Google Scholar 

  39. Donnelly LA, Morris AD, Pearson ER. Adherence in patients transferred from immediate release metformin to a sustained release formulation: a population-based study. Diabetes Obes Metab. 2009;11:338–42.

    Article  CAS  PubMed  Google Scholar 

  40. Schwartz S, Fonseca V, Berner B, et al. Efficacy, tolerability, and safety of a novel once-daily extended-release metformin in patients with type 2 diabetes. Diabetes Care. 2006;29:759–64.

    Article  CAS  PubMed  Google Scholar 

  41. Boulton DW, Smith CH, Li L, et al. Bioequivalence of saxagliptin/metformin extended-release (XR) fixed-dose combination tablets and single-component saxagliptin and metformin XR tablets in healthy adult subjects. Clin Drug Investig. 2011;31:619–30.

    Article  CAS  PubMed  Google Scholar 

  42. •• Buse JB, DeFronzo RA, Rosenstock J, et al. The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care. 2016;39:198–205. An original article which provides the action of the new preparation form of metformin, metformin DR, is mediated through predominantly lower bowel.

    Article  CAS  PubMed  Google Scholar 

  43. •• DeFronzo RA, Buse JB, Kim T, et al. Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. Diabetologia. 2016;59:1645–54. An original article which providing the characteridtics of the new preparation form of metformin, metformin DR.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rachmani R, Slavachevski I, Levi Z, et al. Metformin in patients with type 2 diabetes mellitus: reconsideration of traditional contraindications. Eur J Intern Med. 2002;13:428.

    Article  CAS  PubMed  Google Scholar 

  45. Kamber N, Davis WA, Bruce DG, et al. Metformin and lactic acidosis in an Australian community setting: the Fremantle Diabetes Study. Med J Aust. 2008;188:446–9.

    PubMed  Google Scholar 

  46. Roussel R, Travert F, Pasquet B, et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Arch Intern Med. 2010;170:1892–9.

    Article  CAS  PubMed  Google Scholar 

  47. Ekström N, Schiöler L, Svensson AM, et al. Effectiveness and safety of metformin in 51 675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open. 2012;2.pii:e001076.

  48. FDA Drug Safety Communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. http://www.fda.gov/Drugs/DrugSafety/ucm493244.htm Accessed April 8, 2016

  49. Bakris GL, Mudaliar S, Kim T, et al. Effects of new metformin formulation in stage 3 and 4 CKD: a pilot study. J Am Soc Nephrol. 2014;25:549A.

    Google Scholar 

  50. Kao J, Tobis J, Mc Clelland RL, et al. Relation of metformin treatment to clinical events in diabetic patients undergoing percutaneous intervention. Am J Cardiol. 2004;93:1347–50.

    Article  CAS  PubMed  Google Scholar 

  51. Isoda K, Young J, Zirlik A, et al. Metformin inhibits proinflammatory responses and nuclear factor ĸß in human vascular wall cells. Arterioscler Thromb Vasc Biol. 2006;26:611–7.

    Article  CAS  PubMed  Google Scholar 

  52. The Diabetes Prevention Program Research Group Intensive. Lifestyle Intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes. 2005;54:1566–72.

    Article  Google Scholar 

  53. De Jager J, Kooy A, Lehert P, et al. Effects of short-term treatment with metformin on markers of endothelial function and inflammatory activity in type 2 diabetes mellitus: a randomized, placebo-controlled trial. J Intern Med. 2004;256:1–14.

    Article  Google Scholar 

  54. Grant PJ. Beneficial effects of metformin on haemostasis and vascular function in man. Diabetes Metab. 2003;29:44–52.

    Article  Google Scholar 

  55. Standeven KF, Ariens RA, Whitaker P, et al. The effect of dimethylbiguanide on thrombin activity, FXIII activation, fibrin polymerization, and fibrin clot formation. Diabetes. 2002;51:189–97.

    Article  CAS  PubMed  Google Scholar 

  56. Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol. 2001;37:1344–50.

    Article  CAS  PubMed  Google Scholar 

  57. Anfosso F, Chomiki N, Alessi MC, et al. Plasminogen activator inhibitor-1 synthesis in the human hepatoma cell line Hep G2. Metformin inhibits the stimulating effect of insulin. J Clin Invest. 1993;91:2185–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bhamra GS, Hausenloy DJ, Davidson SM, et al. Metformin protects the ischemic heart by the Akt-mediated inhibition of mitochondrial permeability transition pore opening. Basic Res Cardiol. 2008;103:274–84.

    Article  CAS  PubMed  Google Scholar 

  59. Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33:1674–85.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Noto H, Tsujimoto T, Noda M. Significantly increased risk of cancer in diabetes mellitus patients: a meta-analysis of epidemiological evidence in Asians and non-Asians. J Diabetes Investig. 2012;3:24–33.

    Article  PubMed  Google Scholar 

  61. Evans JM, Donnelly LA, Emslie-Smith AM, et al. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330:1304–5.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Franciosi M, Lucisano G, Lapice E, et al. Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review. PLoS One. 2013;8:1–12.

    Article  Google Scholar 

  63. Stevens RJ, Ali R, Bankhead CR, et al. Cancer outcomes and all-cause mortality in adults allocated to metformin: systematic review and collaborative meta-analysis of randomised clinical trials. Diabetologia. 2012;55:2593–603.

    Article  CAS  PubMed  Google Scholar 

  64. Bodmer M, Becker C, Jick S, et al. Metformin does not alter the risk of lung cancer: a case-control analysis. Lung Cancer. 2012;78:133–7.

    Article  PubMed  Google Scholar 

  65. Bodmer M, Becker C, Meier C, et al. Use of metformin is not associated with a decreased risk of colorectal cancer: a case-control analysis. Cancer Epidemiol Biomarkers Prev. 2012;21:280–6.

    Article  CAS  PubMed  Google Scholar 

  66. • Golozar A, Liu S, Lin JA, et al. Does metformin reduce cancer risks? Methodologic Considerations. Curr Diab Rep. 2016;16:4. This review describes methods used to assess the effect of metformin on cancer risk, outline the major methodological challenges in assessing the metformin-cancer association, and summarize the evidence on the effect of metformin on cancer risk.

    Article  PubMed  Google Scholar 

  67. Kim J, Lim W, Kim EK, et al. Phase II randomized trial of neoadjuvant metformin plus letrozole versus placebo plus letrozole for estrogen receptor positive postmenopausal breast cancer (METEOR). BMC Cancer. 2014;14:170.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Rothermundt C, Hayoz S, Templeton AJ, Winterhalder R, Strebel RT, Bärtschi D, et al. Metformin in chemotherapy-naive castration-resistant prostate cancer: a multicenter phase 2 trial (SAKK 08/09). Eur Urol. 2014;66:468–74.

  69. • Chae YK, Arya A, Malecek MK, et al. Repurposing metformin for cancer treatment: current clinical studies. Oncotarget. In press. Recent ongoing clinical trials of metformin for anticancer effects are summarized in this review.

  70. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008;8:915–28.

    Article  CAS  PubMed  Google Scholar 

  71. Moiseeva O, Deschênes-Simard X, St-Germain E, et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell. 2013;12:489–98.

    Article  CAS  PubMed  Google Scholar 

  72. Eikawa S, Nishida M, Mizukami S, et al. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci U S A. 2015;112:1809–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Zakikhani M, Dowling R, Fantus IG, et al. Metformin is an AMP kinase–dependent growth inhibitor for breast cancer cells. Cancer Res. 2006;66:10269–73.

    Article  CAS  PubMed  Google Scholar 

  74. Dowling RJ, Zakikhani M, Fantus IG, et al. Metformin inhibits mammalian target of rapamycin–dependent translation initiation in breast cancer cells. Cancer Res. 2007;67:10804–12.

    Article  CAS  PubMed  Google Scholar 

  75. Ben Sahra I, Regazzetti C, Robert G, et al. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res. 2011;71:4366–72.

    Article  CAS  PubMed  Google Scholar 

  76. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell. 2007;12:9–22.

    Article  CAS  PubMed  Google Scholar 

  77. Peterson TR, Laplante M, Thoreen CC, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137:873–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. • Obara A, Fujita Y, Abudukadier A, et al. DEPTOR-related mTOR suppression is involved in metformin's anti-cancer action in human liver cancer cells. Biochem Biophys Res Commun. 2015;460:1047–52. This original article provides a novel pathway of metformin's anti-cancer actions in liver using human liver cancer cells.

    Article  CAS  PubMed  Google Scholar 

  79. Bakaev V. Effect of 1-butylbiguanide hydrochloride on the longevity in the nematoda Caenorhabditis elegans. Biogerontology. 2002;3 Suppl 1:23–4.

    Google Scholar 

  80. Onken B, Driscoll M. 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;5, e8758.

    Article  PubMed  PubMed Central  Google Scholar 

  81. • Cabreiro F, Au C, Leung KY, et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013;153:228–39. This original article provides the unique mechanism which metformin entends the longevity in C. Elegans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Anisimov VN. Metformin: do we finally have an anti-aging drug? Cell Cycle. 2013;12:3483–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Mair W, Dillin A. Aging and survival: the genetics of life span extension by dietary restriction. Annu Rev Biochem. 2008;77:727–54.

    Article  CAS  PubMed  Google Scholar 

  84. Masoro EJ, Yu BP, Bertrand HA. Action of food restriction in delaying the aging process. Proc Natl Acad Sci U S A. 1982;79:4239–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Walker G, Houthoofd K, Vanfleteren JR, et al. Dietary restriction in C. elegans: from rate-of-living effects to nutrient sensing pathways. Mech Ageing Dev. 2005;126:929–37.

    Article  CAS  PubMed  Google Scholar 

  86. •• Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192. This original article provides the molecular mechanisms of beneficial effects of metformin on healthspan and lifespan in mice.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Aguilar D, Chan W, Bozkurt B, et al. Metformin use and mortality in ambulatory patients with diabetes and heart failure. Circ Heart Fail. 2011;4:53–8.

    Article  CAS  PubMed  Google Scholar 

  88. Misbin RI, Green L, Stadel BV, et al. Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med. 1998;338:265–6.

    Article  CAS  PubMed  Google Scholar 

  89. Masoudi FA, Wang Y, Inzucchi SE, et al. Metformin and thiazolidinedione use in Medicare patients with heart failure. JAMA. 2003;290:81–5.

    Article  CAS  PubMed  Google Scholar 

  90. Inzucchi SE, Masoudi FA, McGuire DK. Metformin in heart failure. Diabetes Care. 2007;30, e129.

    Article  PubMed  Google Scholar 

  91. Johnson NP. Metformin use in women with polycystic ovary syndrome. Ann Transl Med. 2014;2:56.

    PubMed  PubMed Central  Google Scholar 

  92. Misso ML, Teede HJ. Metformin in women with PCOS, cons. Endocrine. 2015;48:428–33.

    Article  CAS  PubMed  Google Scholar 

  93. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551–66.

    Article  CAS  PubMed  Google Scholar 

  94. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod. 2008;23:462–77.

    Article  Google Scholar 

  95. Palomba S, Pasquali R, Orio Jr F, et al. Clomiphene citrate, metformin or both as first-step approach in treating anovulatory infertility in patients with polycystic ovary syndrome (PCOS): a systematic review of head-to-head randomized controlled studies and meta-analysis. Clin Endocrinol (Oxf). 2009;70:311–21.

    Article  CAS  Google Scholar 

  96. Mazza A, Fruci B, Garinis GA, et al. The role of metformin in the management of NAFLD. Exp Diabetes Res. 2012;2012:716404.

    Article  PubMed  Google Scholar 

  97. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology. 2012;142:1592–609.

    Article  PubMed  Google Scholar 

  98. Bhat A, Sebastiani G, Bhat M. Systematic review: preventive and therapeutic applications of metformin in liver disease. World J Hepatol. 2015;28:1652–9.

    Article  Google Scholar 

  99. 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.

    Article  PubMed Central  Google Scholar 

  100. Diabetes Prevention Program Research Group. Effects of withdrawal from metformin on the development of diabetes in the diabetes prevention program. Diabetes Care. 2003;26:977–80.

    Article  Google Scholar 

  101. Diabetes Prevention Program Research Group. Ten-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374:1677–86.

    Article  PubMed Central  Google Scholar 

  102. Yang W, Lin L, Qi J, et al. The preventive effect of acarbose and metformin on the IGT population from becoming diabetes mellitus: a 3- year multicentral prospective study. Chin J Endocrinol Metab. 2001;17:131–4.

    CAS  Google Scholar 

  103. Cusi K, DeFronzo RA. Metformin: a review of its metabolic effects. Diabetes Rev. 1998;6:89–131.

    Google Scholar 

  104. Filioussi K, Bonovas S, Katsaros T. Should we screen diabetic patients using biguanides for megaloblastic anaemia? Aust Fam Phys. 2003;32:383–4.

    Google Scholar 

  105. Wei Ting RZ, Szeto CC, Chan MH, et al. Risk factors of vitamin B12 deficiency in patients receiving metformin. Arch Intern Med. 2006;166:1975–9.

    Article  Google Scholar 

  106. Liu Q, Li S, Heng Quan H, et al. Vitamin B12 status in metformin treated patients: systematic review. PLoS One. 2014;9, e100379.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by Scientific Research Grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nobuya Inagaki.

Ethics declarations

Conflict of Interest

Nobuya Inagaki received research grants from Astellas Pharma Inc., Taisho Toyama Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Company Ltd., Daiichi Sankyo Company, Ltd., MSD, Sanofi, Dainippon Sumitomo Pharma Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Eli Lilly Japan K.K., Shiratori Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., JT, Pfizer, Nippon Boehringer Ingelheim Co., Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Kissei Pharmaceutical Co., Ltd., and Japan Diabetes Foundation. Yoshihito Fujita declares no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Pharmacologic Treatment of Type 2 Diabetes

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fujita, Y., Inagaki, N. Metformin: New Preparations and Nonglycemic Benefits. Curr Diab Rep 17, 5 (2017). https://doi.org/10.1007/s11892-017-0829-8

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11892-017-0829-8

Keywords

Navigation