Metformin: Mechanisms in Human Obesity and Weight Loss

  • Armen Yerevanian
  • Alexander A. SoukasEmail author
Obesity Treatment (CM Apovian, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Obesity Treatment


Purpose of Review

Metformin has multiple benefits for health beyond its anti-hyperglycemic properties. The purpose of this manuscript is to review the mechanisms that underlie metformin’s effects on obesity.

Recent Findings

Metformin is a first-line therapy for type 2 diabetes. Large cohort studies have shown weight loss benefits associated with metformin therapy. Metabolic consequences were traditionally thought to underlie this effect, including reduction in hepatic gluconeogenesis and reduction in insulin production. Emerging evidence suggests that metformin-associated weight loss is due to modulation of hypothalamic appetite regulatory centers, alteration in the gut microbiome, and reversal of consequences of aging. Metformin is also being explored in the management of obesity’s sequelae such as hepatic steatosis, obstructive sleep apnea, and osteoarthritis.


Multiple mechanisms underlie the weight loss–inducing and health-promoting effects of metformin. Further exploration of these pathways may be important in identifying new pharmacologic targets for obesity and other aging-associated metabolic diseases.


Metformin Obesity Weight loss Appetite regulation Type 2 diabetes Aging 



We wish to acknowledge Scott Leighton for creating the figure for this review.


This work was supported by NIH R01AG058256, R01DK101522, and R01DK072041, the Weissman Family MGH Research Scholar Award, and a Glenn Award for Research in the Biological Mechanisms of Aging (to AS). AY is supported by the NIH-NIDDK funded MGH Endocrinology training grant T32DK007028.

Compliance with Ethical Standards

Conflict of Interest

Armen Yerevanian and Alexander A. Soukas M.D., Ph.D. declare they have 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.


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

  1. 1.
    Witters LA. The blooming of the French lilac. J Clin Invest. 2001;108(8):1105–7.Google Scholar
  2. 2.
    Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60(9):1566–76.Google Scholar
  3. 3.
    Werner EA, Bell J. The preparation of methylguanidine, and of ββ-dimethylguanidine by the interaction of dicyandiamide, and methylammonium and dimethylammonium chlorides respectively. J Chem Soc Trans. 1922;121:1790–4.Google Scholar
  4. 4.
    DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995;333(9):541–9.Google Scholar
  5. 5.
    American Diabetes A. Standards of medical care in diabetes-2019 abridged for primary care providers. Clin Diabetes. 2019;37(1):11–34.Google Scholar
  6. 6.
    Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333(9):550–4.Google Scholar
  7. 7.
    Holman RR, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577–89.Google Scholar
  8. 8.
    Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355(23):2427–43.Google Scholar
  9. 9.
    Saenz A, et al. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005;(3):CD002966.Google Scholar
  10. 10.
    Golay A. Metformin and body weight. Int J Obes. 2008;32(1):61–72.Google Scholar
  11. 11.
    Fontbonne A, Charles MA, Juhan-Vague I, Bard JM, Andre P, Isnard F, et al. The effect of metformin on the metabolic abnormalities associated with upper-body fat distribution. BIGPRO Study Group. Diabetes Care. 1996;19(9):920–6.Google Scholar
  12. 12.
    Paolisso G, et al. Effect of metformin on food intake in obese subjects. Eur J Clin Investig. 1998;28(6):441–6.Google Scholar
  13. 13.
    Glueck CJ, Fontaine RN, Wang P, Subbiah MTR, Weber K, Illig E, et al. Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30. Metabolism. 2001;50(7):856–61.Google Scholar
  14. 14.
    Levri KM, et al. Metformin as treatment for overweight and obese adults: a systematic review. Ann Fam Med. 2005;3(5):457–61.Google Scholar
  15. 15.
    •• Diabetes Prevention Program Research, G. Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care. 2012;35(4):731–7. Largest and most comprehensive study that identified persistent weight loss with metformin treatment. Google Scholar
  16. 16.
    • Apovian CM, et al. Pharmacological management of obesity: an endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(2):342–62 Provides the most recent guidelines on pharmacotherapy for obesity. Google Scholar
  17. 17.
    Garvey WT, Mechanick JI, Brett EM, Garber AJ, Hurley DL, Jastreboff AM, et al. American Association of Clinical Endocrinologists and American College of Endocrinology Comprehensive Clinical Practice Guidelines for Medical Care of Patients with Obesity. Endocr Pract. 2016;22(Suppl 3):1–203.Google Scholar
  18. 18.
    de Silva VA, Suraweera C, Ratnatunga SS, Dayabandara M, Wanniarachchi N, Hanwella R. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry. 2016;16(1):341.Google Scholar
  19. 19.
    Makimattila S, Nikkila K, Yki-Jarvinen H. Causes of weight gain during insulin therapy with and without metformin in patients with type II diabetes mellitus. Diabetologia. 1999;42(4):406–12.Google Scholar
  20. 20.
    Kooy A, de Jager J, Lehert P, Bets D, Wulffelé MG, Donker AJM, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch Intern Med. 2009;169(6):616–25.Google Scholar
  21. 21.
    Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000;49(12):2063–9.Google Scholar
  22. 22.
    Inzucchi SE, Maggs DG, Spollett GR, Page SL, Rife FS, Walton V, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med. 1998;338(13):867–72.Google Scholar
  23. 23.
    El-Mir MY, et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000;275(1):223–8.Google Scholar
  24. 24.
    He L, Wondisford FE. Metformin action: concentrations matter. Cell Metab. 2015;21(2):159–62.Google Scholar
  25. 25.
    Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–74.Google Scholar
  26. 26.
    Shaw RJ, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310(5754):1642–6.Google Scholar
  27. 27.
    Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010;120(7):2355–69.Google Scholar
  28. 28.
    Miller RA, Birnbaum MJ. An energetic tale of AMPK-independent effects of metformin. J Clin Invest. 2010;120(7):2267–70.Google Scholar
  29. 29.
    Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013;494(7436):256–60.Google Scholar
  30. 30.
    • Madiraju AK, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014;510(7506):542–6. A novel mechanism by which metformin reduces hepatic glucose output by inhibiting the mitochondrial glycerol-phosphate shuttle, altering hepatocellular redox potential. Google Scholar
  31. 31.
    Madiraju AK, Qiu Y, Perry RJ, Rahimi Y, Zhang XM, Zhang D, et al. Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo. Nat Med. 2018;24(9):1384–94.Google Scholar
  32. 32.
    Lee A, Morley JE. Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. Obes Res. 1998;6(1):47–53.Google Scholar
  33. 33.
    Yki-Jarvinen H, Nikkila K, Makimattila S. Metformin prevents weight gain by reducing dietary intake during insulin therapy in patients with type 2 diabetes mellitus. Drugs. 1999;58(Suppl 1):53–4 discussion 75-82.Google Scholar
  34. 34.
    Kalantar-Zadeh K, Mehrotra R, Fouque D, Kopple JD. Metabolic acidosis and malnutrition-inflammation complex syndrome in chronic renal failure. Semin Dial. 2004;17(6):455–65.Google Scholar
  35. 35.
    Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348(Pt 3):607–14.Google Scholar
  36. 36.
    Tokubuchi I, et al. Beneficial effects of metformin on energy metabolism and visceral fat volume through a possible mechanism of fatty acid oxidation in human subjects and rats. PLoS One. 2017;12(2):e0171293.Google Scholar
  37. 37.
    Islam H, Townsend LK, McKie GL, Medeiros PJ, Gurd BJ, Hazell TJ. Potential involvement of lactate and interleukin-6 in the appetite-regulatory hormonal response to an acute exercise bout. J Appl Physiol (1985). 2017;123(3):614–23.Google Scholar
  38. 38.
    Lam CK, et al. Central lactate metabolism regulates food intake. Am J Physiol Endocrinol Metab. 2008;295(2):E491–6.Google Scholar
  39. 39.
    Chari M, Lam CKL, Wang PYT, Lam TKT. Activation of central lactate metabolism lowers glucose production in uncontrolled diabetes and diet-induced insulin resistance. Diabetes. 2008;57(4):836–40.Google Scholar
  40. 40.
    Mulherin AJ, Oh AH, Kim H, Grieco A, Lauffer LM, Brubaker PL. Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell. Endocrinology. 2011;152(12):4610–9.Google Scholar
  41. 41.
    Napolitano A, et al. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS One. 2014;9(7):e100778.Google Scholar
  42. 42.
    DeFronzo RA, Buse JB, Kim T, Burns C, Skare S, Baron A, 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(8):1645–54.Google Scholar
  43. 43.
    • Buse JB, 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(2):198–205. Identified the importance of gut-specific effects of metformin. Metformin’s effects were present even when serum levels were minimal. Google Scholar
  44. 44.
    Lien F, Berthier A, Bouchaert E, Gheeraert C, Alexandre J, Porez G, et al. Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk. J Clin Invest. 2014;124(3):1037–51.Google Scholar
  45. 45.
    Kuhre RE, Wewer Albrechtsen NJ, Larsen O, Jepsen SL, Balk-Møller E, Andersen DB, et al. Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas. Mol Metab. 2018;11:84–95.Google Scholar
  46. 46.
    Duca FA, Côté CD, Rasmussen BA, Zadeh-Tahmasebi M, Rutter GA, Filippi BM, et al. Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats. Nat Med. 2015;21(5):506–11.Google Scholar
  47. 47.
    Huang YC, et al. Effects of metformin on the cerebral metabolic changes in type 2 diabetic patients. ScientificWorldJournal. 2014;2014:694326.Google Scholar
  48. 48.
    de Wit S, Corlett PR, Aitken MR, Dickinson A, Fletcher PC. Differential engagement of the ventromedial prefrontal cortex by goal-directed and habitual behavior toward food pictures in humans. J Neurosci. 2009;29(36):11330–8.Google Scholar
  49. 49.
    Huerta CI, Sarkar PR, Duong TQ, Laird AR, Fox PT. Neural bases of food perception: coordinate-based meta-analyses of neuroimaging studies in multiple modalities. Obesity (Silver Spring). 2014;22(6):1439–46.Google Scholar
  50. 50.
    • Duan Y, et al. Metformin inhibits food intake and neuropeptide Y gene expression in the hypothalamus. Neural Regen Res. 2013;8(25):2379–88. Identified hypothalamic mechanism by which metformin could inhibit appetite. Google Scholar
  51. 51.
    Stevanovic D, Janjetovic K, Misirkic M, Vucicevic L, Sumarac-Dumanovic M, Micic D, et al. Intracerebroventricular administration of metformin inhibits ghrelin-induced hypothalamic AMP-kinase signalling and food intake. Neuroendocrinology. 2012;96(1):24–31.Google Scholar
  52. 52.
    Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica. 1994;24(1):49–57.Google Scholar
  53. 53.
    Labuzek K, et al. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol Rep. 2010;62(5):956–65.Google Scholar
  54. 54.
    Vaisse C, Halaas JL, Horvath CM, Darnell JE, Stoffel M, Friedman JM. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice. Nat Genet. 1996;14(1):95–7.Google Scholar
  55. 55.
    Lv WS, Wen JP, Li L, Sun RX, Wang J, Xian YX, et al. The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats. Brain Res. 2012;1444:11–9.Google Scholar
  56. 56.
    Aubert G, Mansuy V, Voirol MJ, Pellerin L, Pralong FP. The anorexigenic effects of metformin involve increases in hypothalamic leptin receptor expression. Metabolism. 2011;60(3):327–34.Google Scholar
  57. 57.
    Kim YW, Kim JY, Park YH, Park SY, Won KC, Choi KH, et al. Metformin restores leptin sensitivity in high-fat-fed obese rats with leptin resistance. Diabetes. 2006;55(3):716–24.Google Scholar
  58. 58.
    Stark R, Ashley SE, Andrews ZB. AMPK and the neuroendocrine regulation of appetite and energy expenditure. Mol Cell Endocrinol. 2013;366(2):215–23.Google Scholar
  59. 59.
    Claret M, Smith MA, Batterham RL, Selman C, Choudhury AI, Fryer LGD, et al. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J Clin Invest. 2007;117(8):2325–36.Google Scholar
  60. 60.
    • Chau-Van C, et al. Metformin inhibits adenosine 5′-monophosphate-activated kinase activation and prevents increases in neuropeptide Y expression in cultured hypothalamic neurons. Endocrinology. 2007;148(2):507–11. Explored mechanism of metformin’s effects on hypothalamic neurons. It showed that unlike peripheral AMPK, neuronal AMPK is suppressed by metformin. Google Scholar
  61. 61.
    McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016;59(3):426–35.Google Scholar
  62. 62.
    Gontier E, Fourme E, Wartski M, Blondet C, Bonardel G, le Stanc E, et al. High and typical 18F-FDG bowel uptake in patients treated with metformin. Eur J Nucl Med Mol Imaging. 2008;35(1):95–9.Google Scholar
  63. 63.
    Bailey CJ, Wilcock C, Day C. Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol. 1992;105(4):1009–13.Google Scholar
  64. 64.
    • Dujic T, et al. Organic cation transporter 1 variants and gastrointestinal side effects of metformin in patients with type 2 diabetes. Diabet Med. 2016;33(4):511–4. Population study that suggested that concentrations of metformin in the gut lumen affects risk of experiencing GI side effects from metformin. Google Scholar
  65. 65.
    Dujic T, Zhou K, Donnelly LA, Tavendale R, Palmer CNA, Pearson ER. Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: a GoDARTS study. Diabetes. 2015;64(5):1786–93.Google Scholar
  66. 66.
    Cubeddu LX, Bönisch H, Göthert M, Molderings G, Racké K, Ramadori G, et al. Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors. Naunyn Schmiedeberg's Arch Pharmacol. 2000;361(1):85–91.Google Scholar
  67. 67.
    Schiffman SS. Influence of medications on taste and smell. World J Otorhinolaryngol Head Neck Surg. 2018;4(1):84–91.Google Scholar
  68. 68.
    Lee N, Duan H, Hebert MF, Liang CJ, Rice KM, Wang J. Taste of a pill: organic cation transporter-3 (OCT3) mediates metformin accumulation and secretion in salivary glands. J Biol Chem. 2014;289(39):27055–64.Google Scholar
  69. 69.
    Maruvada P, Leone V, Kaplan LM, Chang EB. The human microbiome and obesity: moving beyond associations. Cell Host Microbe. 2017;22(5):589–99.Google Scholar
  70. 70.
    Karlsson FH, Tremaroli V, Nookaew I, Bergström G, Behre CJ, Fagerberg B, et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature. 2013;498(7452):99–103.Google Scholar
  71. 71.
    Shin NR, Lee JC, Lee HY, Kim MS, Whon TW, Lee MS, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut. 2014;63(5):727–35.Google Scholar
  72. 72.
    Cani PD, de Vos WM. Next-generation beneficial microbes: the case of Akkermansia muciniphila. Front Microbiol. 2017;8:1765.Google Scholar
  73. 73.
    Morrison DJ, Preston T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes. 2016;7(3):189–200.Google Scholar
  74. 74.
    Zhang X, Zhao Y, Xu J, Xue Z, Zhang M, Pang X, et al. Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats. Sci Rep. 2015;5:14405.Google Scholar
  75. 75.
    Bauer PV, et al. Metformin alters upper small intestinal microbiota that impact a glucose-SGLT1-sensing glucoregulatory pathway. Cell Metab. 2018;27(1):101–117 e5.Google Scholar
  76. 76.
    • Wu H, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017;23(7):850–8. Explored impacts of metformin with the microbiome. It showed through transplantation studies that metformin alters microbiome composition that is associated with improved metabolic status. Google Scholar
  77. 77.
    Collaborators GBDO, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017;377(1):13–27.Google Scholar
  78. 78.
    Bouchard DR, Dionne IJ, Brochu M. Sarcopenic/obesity and physical capacity in older men and women: data from the Nutrition as a Determinant of Successful Aging (NuAge)-the Quebec longitudinal Study. Obesity (Silver Spring). 2009;17(11):2082–8.Google Scholar
  79. 79.
    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(1):e8758.Google Scholar
  80. 80.
    Kim HJ, Lee SJ, Chun KH, Jeon JY, Han SJ, Kim DJ, et al. Metformin reduces the risk of cancer in patients with type 2 diabetes: an analysis based on the Korean National Diabetes Program Cohort. Medicine (Baltimore). 2018;97(8):e0036.Google Scholar
  81. 81.
    Johnson SC, Rabinovitch PS, Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature. 2013;493(7432):338–45.Google Scholar
  82. 82.
    Kalender A, Selvaraj A, Kim SY, Gulati P, Brûlé S, Viollet B, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 2010;11(5):390–401.Google Scholar
  83. 83.
    • Wu L, et al. An ancient, unified mechanism for metformin growth inhibition in C elegans and cancer. Cell. 2016;167(7):1705–1718 e13. Mechanistic paper showing that metformin extends lifespan and inhibits growth of cancer cells by altering mitochondrial function, mTOR, and nucleocytoplasmic transport through the nuclear pore complex. Google Scholar
  84. 84.
    Castillo-Quan JI, Blackwell TK. Metformin: restraining nucleocytoplasmic shuttling to fight cancer and aging. Cell. 2016;167(7):1670–1.Google Scholar
  85. 85.
    D'Angelo MA, Raices M, Panowski SH, Hetzer MW. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell. 2009;136(2):284–95.Google Scholar
  86. 86.
    Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cochemé HM, Noori T, et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013;153(1):228–39.Google Scholar
  87. 87.
    Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a tool to target aging. Cell Metab. 2016;23(6):1060–5.Google Scholar
  88. 88.
    Long DE, Peck BD, Martz JL, Tuggle SC, Bush HM, McGwin G, et al. Metformin to Augment Strength Training Effective Response in Seniors (MASTERS): study protocol for a randomized controlled trial. Trials. 2017;18(1):192.Google Scholar
  89. 89.
    Li Y, et al. Metformin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Biomed Rep. 2013;1(1):57–64.Google Scholar
  90. 90.
    • Chalasani N, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–57. Guideline paper from the American Association for the Study of Liver Disease (AASLD) on the management of nonalcoholic fatty liver disease. Google Scholar
  91. 91.
    Lavrentaki A, et al. Mechanisms of disease: the endocrinology of obstructive sleep apnoea. Eur J Endocrinol. 2018.Google Scholar
  92. 92.
    Lin D, et al. The relationship between metformin and obstructive sleep apnea. J Sleep Med Disord. 2015;2(4).Google Scholar
  93. 93.
    Bonds DE, Larson JC, Schwartz AV, Strotmeyer ES, Robbins J, Rodriguez BL, et al. Risk of fracture in women with type 2 diabetes: the Women’s Health Initiative Observational Study. J Clin Endocrinol Metab. 2006;91(9):3404–10.Google Scholar
  94. 94.
    de Liefde II, et al. Bone mineral density and fracture risk in type-2 diabetes mellitus: the Rotterdam Study. Osteoporos Int. 2005;16(12):1713–20.Google Scholar
  95. 95.
    Jeyabalan J, Viollet B, Smitham P, Ellis SA, Zaman G, Bardin C, et al. The anti-diabetic drug metformin does not affect bone mass in vivo or fracture healing. Osteoporos Int. 2013;24(10):2659–70.Google Scholar
  96. 96.
    Nordklint AK, Almdal TP, Vestergaard P, Lundby-Christensen L, Boesgaard TW, Breum L, et al. The effect of metformin versus placebo in combination with insulin analogues on bone mineral density and trabecular bone score in patients with type 2 diabetes mellitus: a randomized placebo-controlled trial. Osteoporos Int. 2018;29(11):2517–26.Google Scholar
  97. 97.
    Schwartz AV. Diabetes, bone and glucose-lowering agents: clinical outcomes. Diabetologia. 2017;60(7):1170–9.Google Scholar
  98. 98.
    Bliddal H, Leeds AR, Christensen R. Osteoarthritis, obesity and weight loss: evidence, hypotheses and horizons - a scoping review. Obes Rev. 2014;15(7):578–86.Google Scholar
  99. 99.
    Lu CH, et al. Combination COX-2 inhibitor and metformin attenuate rate of joint replacement in osteoarthritis with diabetes: a nationwide, retrospective, matched-cohort study in Taiwan. PLoS One. 2018;13(1):e0191242.Google Scholar
  100. 100.
    Chen D, Xia D, Pan Z, Xu D, Zhou Y, Wu Y, et al. Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo. Cell Death Dis. 2016;7(10):e2441.Google Scholar
  101. 101.
    Blokhin IO, Lentz SR. Mechanisms of thrombosis in obesity. Curr Opin Hematol. 2013;20(5):437–44.Google Scholar
  102. 102.
    Lu DY, Huang CC, Huang PH, Chung CM, Lin SJ, Chen JW, et al. Metformin use in patients with type 2 diabetes mellitus is associated with reduced risk of deep vein thrombosis: a non-randomized, pair-matched cohort study. BMC Cardiovasc Disord. 2014;14:187.Google Scholar
  103. 103.
    Xin G, Wei Z, Ji C, Zheng H, Gu J, Ma L, et al. Metformin uniquely prevents thrombosis by inhibiting platelet activation and mtDNA release. Sci Rep. 2016;6:36222.Google Scholar

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Authors and Affiliations

  1. 1.Department of Medicine, Diabetes Unit, Endocrine Division, and Center for Genomic MedicineMassachusetts General HospitalBostonUSA
  2. 2.Department of MedicineHarvard Medical SchoolBostonUSA
  3. 3.Broad Institute of Harvard and MITCambridgeUSA

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