Home Metformin: new applications for an old drug
Article
Licensed
Unlicensed Requires Authentication

Metformin: new applications for an old drug

  • Amirreza Naseri ORCID logo , Sarvin Sanaie ORCID logo , Sina Hamzehzadeh ORCID logo , Sepideh Seyedi-Sahebari ORCID logo , Mohammad-Salar Hosseini ORCID logo , Elnaz Gholipour-khalili ORCID logo , Ehsan Rezazadeh-Gavgani ORCID logo , Reza Majidazar ORCID logo , Parya Seraji ORCID logo , Sara Daneshvar ORCID logo and Erfan Rezazadeh-Gavgani ORCID logo EMAIL logo
Published/Copyright: December 7, 2022
Journal of Basic and Clinical Physiology and Pharmacology
From the journal Journal of Basic and Clinical Physiology and Pharmacology Volume 34 Issue 2

Abstract

Metformin is a biguanide, evolved as one of the most widely used medicines. The applications of this component include but are not limited to reducing blood glucose, weight loss, and polycystic ovary syndrome. Studies about other probable indications have emerged, indicating that this agent can also be utilized for other purposes. In this review, applications of metformin are noticed based on the current evidence. Metformin commonly is used as an off-label drug in non-alcoholic fatty liver disease (NAFLD), but it worsens inflammation and should not be used for this purpose, according to the latest research. Metformin decreased the risk of death in patients with liver cirrhosis. It is an effective agent in the prevention and improvement of survival in patients suffering hepatocellular carcinoma. There is evidence of the beneficial effects of metformin in colorectal cancer, early-stage prostate cancer, breast cancer, urothelial cancer, blood cancer, melanoma, and bone cancer, suggesting metformin as a potent anti-tumor agent. Metformin shows neuroprotective effects and provides a potential therapeutic benefit for mild cognitive impairment and Alzheimer’s disease (AD). It also has been shown to improve mental function and reduce the incidence of dementia. Another condition that metformin has been shown to slow the progression of is Duchenne muscular dystrophy. Regarding infectious diseases, tuberculosis (TB) and coronavirus disease (COVID-19) are among the conditions suggested to be affected by metformin. The beneficial effects of metformin in cardiovascular diseases were also reported in the literature. Concerning renal function, studies showed that daily oral administration of metformin could ameliorate kidney fibrosis and normalize kidney structure and function. This study reviewed the clinical and preclinical evidence about the possible benefits of metformin based on recent studies. Numerous questions like whether these probable indications of metformin can be observed in non-diabetics, need to be described by future basic experiments and clinical studies.

Keywords: biguanides; central nervous system diseases; communicable diseases; liver diseases; metformin; neoplasms
Corresponding author: Erfan Rezazadeh-Gavgani, Student Research Committee, Tabriz University of Medical Sciences, Golgasht Street, Tabriz, East Azerbaijan, 5166/15731, Iran, E-mail:

Funding source: Tabriz University of Medical Sciences

Award Identifier / Grant number: Unassigned

Acknowledgments

The research protocol was approved and supported by Student Research Committee, Tabriz University of Medical Sciences (grant number: 69820).

  1. Research funding: This study was supported by the Deputy for Research of Tabriz University of Medical Sciences.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: Not applicable.

References

1. Lv, Z, Guo, Y. Metformin and its benefits for various diseases. Front Endocrinol 2020;11:191. https://doi.org/10.3389/fendo.2020.00191.Search in Google Scholar PubMed PubMed Central

2. Triggle, CR, Mohammed, I, Bshesh, K, Marei, I, Ye, K, Ding, H, et al.. Metformin: is it a drug for all reasons and diseases? Metabolism 2022;133:155223. https://doi.org/10.1016/j.metabol.2022.155223.Search in Google Scholar PubMed

3. Mohammed, I, Hollenberg, MD, Ding, H, Triggle, CR. A critical review of the evidence that metformin is a putative anti-aging drug that enhances healthspan and extends lifespan. Front Endocrinol 2021;12:718942. https://doi.org/10.3389/fendo.2021.718942.Search in Google Scholar PubMed PubMed Central

4. Wang, Y-W, He, S-J, Feng, X, Cheng, J, Luo, Y-T, Tian, L, et al.. Metformin: a review of its potential indications. Drug Des Dev Ther 2017;11:2421–9. https://doi.org/10.2147/dddt.s141675.Search in Google Scholar PubMed PubMed Central

5. Association, AD. Standards of medical care in diabetes—2019 abridged for primary care providers. Clin Diabetes 2019;37:11. https://doi.org/10.2337/cd18-0105.Search in Google Scholar PubMed PubMed Central

6. Saudek, CD, Brick, JC. The clinical use of hemoglobin A1c. J Diabetes Sci Technol 2009;3:629–34. https://doi.org/10.1177/193229680900300402.Search in Google Scholar PubMed PubMed Central

7. Amin, SV, Khanna, S, Parvar, SP, Shaw, LT, Dao, D, Hariprasad, SM, et al.. Metformin and retinal diseases in preclinical and clinical studies: insights and review of literature. Exp Biol Med 2022;247:317–29. https://doi.org/10.1177/15353702211069986.Search in Google Scholar PubMed PubMed Central

8. Lentferink, Y, Knibbe, C, Van Der Vorst, M. Efficacy of metformin treatment with respect to weight reduction in children and adults with obesity: a systematic review. Drugs 2018;78:1887–901. https://doi.org/10.1007/s40265-018-1025-0.Search in Google Scholar PubMed

9. 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 Psychiatr 2016;16:1–10. https://doi.org/10.1186/s12888-016-1049-5.Search in Google Scholar PubMed PubMed Central

10. Astiz, S, Gonzalez-Bulnes, A, Astiz, I, Barbero, A, Pesantez-Pacheco, JL, Garcia-Contreras, C, et al.. Metformin alleviates obesity and systemic oxidative stress in obese young swine. Pharmaceuticals 2020;13:142. https://doi.org/10.3390/ph13070142.Search in Google Scholar PubMed PubMed Central

11. Association, AD. 13. Management of diabetes in pregnancy: standards of medical care in diabetes-2018. Diabetes Care 2018;41(1 suppl):S137–43.10.2337/dc18-S013Search in Google Scholar PubMed

12. Brown, J, Martis, R, Hughes, B, Rowan, J, Crowther, CA. Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes. Cochrane Database Syst Rev 2017;1:CD011967. https://doi.org/10.1002/14651858.CD011967.pub2.Search in Google Scholar PubMed PubMed Central

13. Apampa, B. Pharmacology and safe prescribing of metformin. NursePrescribing 2012;10:597–602. https://doi.org/10.12968/npre.2012.10.12.597.Search in Google Scholar

14. Gong, L, Goswami, S, Giacomini, KM, Altman, RB, Klein, TE. Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenetics Genom 2012;22:820. https://doi.org/10.1097/fpc.0b013e3283559b22.Search in Google Scholar

15. Inzucchi, SE, Lipska, KJ, Mayo, H, Bailey, CJ, McGuire, DK. Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA 2014;312:2668–75. https://doi.org/10.1001/jama.2014.15298.Search in Google Scholar PubMed PubMed Central

16. Graham, GG, Punt, J, Arora, M, Day, RO, Doogue, MP, Duong, J, et al.. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011;50:81–98. https://doi.org/10.2165/11534750-000000000-00000.Search in Google Scholar PubMed

17. Wooley, AC, Kerr, JL. Monitoring patients on metformin: recent changes and rationales. J Pharm Technol 2018;34:28–36. https://doi.org/10.1177/8755122517747295.Search in Google Scholar PubMed PubMed Central

18. Leoni, S, Tovoli, F, Napoli, L, Serio, I, Ferri, S, Bolondi, L. Current guidelines for the management of non-alcoholic fatty liver disease: a systematic review with comparative analysis. World J Gastroenterol 2018;24:3361. https://doi.org/10.3748/wjg.v24.i30.3361.Search in Google Scholar PubMed PubMed Central

19. Said, A, Akhter, A. Meta-analysis of randomized controlled trials of pharmacologic agents in non-alcoholic steatohepatitis. Ann Hepatol 2017;16:538–47. https://doi.org/10.5604/01.3001.0010.0284.Search in Google Scholar PubMed

20. Liang, H, Song, H, Zhang, X, Song, G, Wang, Y, Ding, X, et al.. Metformin attenuated sepsis-related liver injury by modulating gut microbiota. Emerg Microb Infect 2022;11:815–28. https://doi.org/10.1080/22221751.2022.2045876.Search in Google Scholar PubMed PubMed Central

21. Witchel, SF, Oberfield, SE, Peña, AS. Polycystic ovary syndrome: pathophysiology, presentation, and treatment with emphasis on adolescent girls. J Endocr Soc 2019;3:1545–73. https://doi.org/10.1210/js.2019-00078.Search in Google Scholar PubMed PubMed Central

22. Tang, T, Lord, JM, Norman, RJ, Yasmin, E, Balen, AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev 2012;11:CD003053.10.1002/14651858.CD003053.pub5Search in Google Scholar PubMed

23. Medicine PCotASfR, Electronic address: ASRM@ asrm. org, Practice Committee of the American Society for Reproductive Medicine. Role of metformin for ovulation induction in infertile patients with polycystic ovary syndrome (PCOS): a guideline. Fertil Steril 2017;108:426–41. https://doi.org/10.1016/j.fertnstert.2017.06.026.Search in Google Scholar PubMed

24. Abdalla, MA, Deshmukh, H, Atkin, S, Sathyapalan, T. A review of therapeutic options for managing the metabolic aspects of polycystic ovary syndrome. Ther Adv Endocrinol Metabol 2020;11:2042018820938305. https://doi.org/10.1177/2042018820938305.Search in Google Scholar PubMed PubMed Central

25. Bordewijk, EM, Nahuis, M, Costello, MF, Van der Veen, F, Tso, LO, Mol, BWJ, et al.. Metformin during ovulation induction with gonadotrophins followed by timed intercourse or intrauterine insemination for subfertility associated with polycystic ovary syndrome. Cochrane Database Syst Rev 2017;1:CD009090. https://doi.org/10.1002/14651858.CD009090.pub2.Search in Google Scholar PubMed PubMed Central

26. Sharpe, A, Morley, LC, Tang, T, Norman, RJ, Balen, AH. Metformin for ovulation induction (excluding gonadotrophins) in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2019;12:CD013505. https://doi.org/10.1002/14651858.CD013505.Search in Google Scholar PubMed PubMed Central

27. Zadehmodares, S, Niyakan, M, Sharafy, SA, Yazdi, MH, Jahed, F. Comparison of treatment outcomes of infertile women by clomiphene citrate and letrozole with gonadotropins underwent intrauterine insemination. Acta Med Iran 2012;50:18–20.Search in Google Scholar

28. Wu, Y, Tu, M, Huang, Y, Liu, Y, Zhang, D. Association of metformin with pregnancy outcomes in women with polycystic ovarian syndrome undergoing in vitro fertilization: a systematic review and meta-analysis. JAMA Netw Open 2020;3:e2011995–e. https://doi.org/10.1001/jamanetworkopen.2020.11995.Search in Google Scholar PubMed PubMed Central

29. Rojas, J, Chávez-Castillo, M, Bermúdez, V. The role of metformin in metabolic disturbances during pregnancy: polycystic ovary syndrome and gestational diabetes mellitus. Int J Reprod Med 2014;2014:797681. https://doi.org/10.1155/2014/797681.Search in Google Scholar PubMed PubMed Central

30. MF THMMC, Dokras, A, Laven, J, Moran, T, Norman, RJ, International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril 2018;110:364–79. https://doi.org/10.1016/j.fertnstert.2018.04.006.Search in Google Scholar PubMed

31. ESHRE, TT, Group A-SPCW. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril 2008;89:505–22. https://doi.org/10.1093/humrep/dem426.Search in Google Scholar PubMed

32. Lautatzis, M-E, Goulis, DG, Vrontakis, M. Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: a systematic review. Metabolism 2013;62:1522–34. https://doi.org/10.1016/j.metabol.2013.06.006.Search in Google Scholar PubMed

33. Sivalingam, VN, Myers, J, Nicholas, S, Balen, AH, Crosbie, EJ. Metformin in reproductive health, pregnancy and gynaecological cancer: established and emerging indications. Hum Reprod Update 2014;20:853–68. https://doi.org/10.1093/humupd/dmu037.Search in Google Scholar PubMed

34. Feng, L, Lin, X-F, Wan, Z-H, Hu, D, Du, Y-K. Efficacy of metformin on pregnancy complications in women with polycystic ovary syndrome: a meta-analysis. Gynecol Endocrinol 2015;31:833–9. https://doi.org/10.3109/09513590.2015.1041906.Search in Google Scholar PubMed

35. Talaulikar, VS, Tang, T, Yasmin, E. Role of metformin in women’s health: review of its current place in clinical practice and emerging indications for future. Obstet Gynecol Surv 2016;71:307–17.10.1097/OGX.0000000000000312Search in Google Scholar PubMed

36. Tan, X, Li, S, Chang, Y, Fang, C, Liu, H, Zhang, X, et al.. Effect of metformin treatment during pregnancy on women with PCOS: a systematic review and meta-analysis. Clin Invest Med 2016;39:E120–31. https://doi.org/10.25011/cim.v39i4.27091.Search in Google Scholar PubMed

37. Zeng, X-L, Zhang, Y-F, Tian, Q, Xue, Y, An, R-F. Effects of metformin on pregnancy outcomes in women with polycystic ovary syndrome: a meta-analysis. Medicine 2016;95:e4526. https://doi.org/10.1097/MD.0000000000004526.Search in Google Scholar PubMed PubMed Central

38. Løvvik, TS, Carlsen, SM, Salvesen, Ø, Steffensen, B, Bixo, M, Gómez-Real, F, et al.. Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2019;7:256–66. https://doi.org/10.1016/S2213-8587(19)30002-6.Search in Google Scholar PubMed

39. Baillargeon, J-P, Jakubowicz, DJ, Iuorno, MJ, Jakubowicz, S, Nestler, JE. Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertil Steril 2004;82:893–902. https://doi.org/10.1016/j.fertnstert.2004.02.127.Search in Google Scholar PubMed

40. Carmina, E, Lobo, RA. Does metformin induce ovulation in normoandrogenic anovulatory women? Am J Obstet Gynecol 2004;191:1580–4. https://doi.org/10.1016/j.ajog.2004.05.030.Search in Google Scholar PubMed

41. Kollmann, M, Martins, W, Lima, M, Craciunas, L, Nastri, C, Richardson, A, et al.. Strategies for improving outcome of assisted reproduction in women with polycystic ovary syndrome: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2016;48:709–18. https://doi.org/10.1002/uog.15898.Search in Google Scholar PubMed

42. Palomba, S, Falbo, A, Di Cello, A, Cappiello, F, Tolino, A, Zullo, F. Does metformin affect the ovarian response to gonadotropins for in vitro fertilization treatment in patients with polycystic ovary syndrome and reduced ovarian reserve? A randomized controlled trial. Fertil Steril 2011;96:1128–33. https://doi.org/10.1016/j.fertnstert.2011.08.020.Search in Google Scholar PubMed

43. Tso, LO, Costello, MF, Albuquerque, LET, Andriolo, RB, Macedo, CR. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome. Cochrane Database Syst Rev 2020;12:CD006105. https://doi.org/10.1002/14651858.CD006105.pub4.Search in Google Scholar PubMed PubMed Central

44. Palomba, S, Falbo, A, La Sala, GB. Effects of metformin in women with polycystic ovary syndrome treated with gonadotrophins for in vitro fertilisation and intracytoplasmic sperm injection cycles: a systematic review and meta-analysis of randomised controlled trials. BJOG An Int J Obstet Gynaecol 2013;120:267–76. https://doi.org/10.1111/1471-0528.12070.Search in Google Scholar PubMed

45. Costello, MF, Chapman, M, Conway, U. A systematic review and meta-analysis of randomized controlled trials on metformin co-administration during gonadotrophin ovulation induction or IVF in women with polycystic ovary syndrome. Hum Reprod 2006;21:1387–99. https://doi.org/10.1093/humrep/dei501.Search in Google Scholar PubMed

46. Abdalmageed, OS, Farghaly, TA, Abdelaleem, AA, Abdelmagied, AE, Ali, MK, Abbas, AM. Impact of metformin on IVF outcomes in overweight and obese women with polycystic ovary syndrome: a randomized double-blind controlled trial. Reprod Sci 2019;26:1336–42. https://doi.org/10.1177/1933719118765985.Search in Google Scholar PubMed

47. Kimber-Trojnar, Ż, Dłuski, DF, Wierzchowska-Opoka, M, Ruszała, M, Leszczyńska-Gorzelak, B. Metformin as a potential treatment option for endometriosis. Cancers 2022;14:577.10.3390/cancers14030577Search in Google Scholar PubMed PubMed Central

48. Bai, B, Chen, H. Metformin: a novel weapon against inflammation. Front Pharmacol 2021;12:622262. https://doi.org/10.3389/fphar.2021.622262.Search in Google Scholar PubMed PubMed Central

49. Schneider, MB, Matsuzaki, H, Haorah, J, Ulrich, A, Standop, J, Ding, XZ, et al.. Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology 2001;120:1263–70. https://doi.org/10.1053/gast.2001.23258.Search in Google Scholar PubMed

50. Coyle, C, Cafferty, F, Vale, C, Langley, R. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Ann Oncol 2016;27:2184–95. https://doi.org/10.1093/annonc/mdw410.Search in Google Scholar PubMed PubMed Central

51. Aljofan, M, Riethmacher, D. Anticancer activity of metformin: a systematic review of the literature. Future Science OA 2019;5:FSO410. https://doi.org/10.2144/fsoa-2019-0053.Search in Google Scholar PubMed PubMed Central

52. Clement, NS, Oliver, TR, Shiwani, H, Sanner, JR, Mulvaney, CA, Atiomo, W. Metformin for endometrial hyperplasia. Cochrane Database Syst Rev 2017. https://doi.org/10.1002/14651858.CD012214.pub2.Search in Google Scholar PubMed PubMed Central

53. Cunha Júnior, AD, Pericole, FV, Carvalheira, JBC. Metformin and blood cancers. Clinics 2018;73(1 Suppl):e412s. https://doi.org/10.6061/clinics/2018/e412s.Search in Google Scholar PubMed PubMed Central

54. De, A, Kuppusamy, G. Metformin in breast cancer: preclinical and clinical evidence. Curr Probl Cancer 2020;44:100488. https://doi.org/10.1016/j.currproblcancer.2019.06.003.Search in Google Scholar PubMed

55. Jaune, E, Rocchi, S. Metformin: focus on melanoma. Front Endocrinol 2018;9:472. https://doi.org/10.3389/fendo.2018.00472.Search in Google Scholar PubMed PubMed Central

56. Yu, X, Mao, W, Zhai, Y, Tong, C, Liu, M, Ma, L, et al.. Anti-tumor activity of metformin: from metabolic and epigenetic perspectives. Oncotarget 2017;8:5619. https://doi.org/10.18632/oncotarget.13639.Search in Google Scholar PubMed PubMed Central

57. Li, D. Metformin as an antitumor agent in cancer prevention and treatment. J Diabetes 2011;3:320–7. https://doi.org/10.1111/j.1753-0407.2011.00119.x.Search in Google Scholar PubMed

58. Jauvain, M, Courtois, S, Lehours, P, Bessède, E. Metformin modifies the gut microbiota of mice infected with Helicobacter pylori. Pharmaceuticals 2021;14:329. https://doi.org/10.3390/ph14040329.Search in Google Scholar PubMed PubMed Central

59. Tsou, Y-A, Chang, W-C, Lin, C-D, Chang, R-L, Tsai, M-H, Shih, L-C, et al.. Metformin increases survival in hypopharyngeal cancer patients with diabetes mellitus: retrospective cohort study and cell-based analysis. Pharmaceuticals 2021;14:191. https://doi.org/10.3390/ph14030191.Search in Google Scholar PubMed PubMed Central

60. Garrido, MP, Salvatierra, R, Valenzuela-Valderrama, M, Vallejos, C, Bruneau, N, Hernández, A, et al.. Metformin reduces NGF-induced tumour promoter effects in epithelial ovarian cancer cells. Pharmaceuticals 2020;13:315. https://doi.org/10.3390/ph13100315.Search in Google Scholar PubMed PubMed Central

61. Sorokin, D, Shchegolev, Y, Scherbakov, A, Ryabaya, O, Gudkova, M, Berstein, L, et al.. Metformin restores the drug sensitivity of MCF-7 cells resistant derivates via the cooperative modulation of growth and apoptotic-related pathways. Pharmaceuticals 2020;13:206. https://doi.org/10.3390/ph13090206.Search in Google Scholar PubMed PubMed Central

62. Tao, L, Li, D, Liu, H, Jiang, F, Xu, Y, Cao, Y, et al.. Neuroprotective effects of metformin on traumatic brain injury in rats associated with NF-κB and MAPK signaling pathway. Brain Res Bull 2018;140:154–61. https://doi.org/10.1016/j.brainresbull.2018.04.008.Search in Google Scholar PubMed

63. Ng, TP, Feng, L, Yap, KB, Lee, TS, Tan, CH, Winblad, B. Long-term metformin usage and cognitive function among older adults with diabetes. J Alzheimers Dis 2014;41:61–8. https://doi.org/10.3233/jad-131901.Search in Google Scholar

64. Luchsinger, JA, Perez, T, Chang, H, Mehta, P, Steffener, J, Pradabhan, G, et al.. Metformin in amnestic mild cognitive impairment: results of a pilot randomized placebo controlled clinical trial. J Alzheim Dis JAD 2016;51:501–14. https://doi.org/10.3233/jad-150493.Search in Google Scholar PubMed PubMed Central

65. Campbell, JM, Stephenson, MD, De Courten, B, Chapman, I, Bellman, SM, Aromataris, E. Metformin use associated with reduced risk of dementia in patients with diabetes: a systematic review and meta-analysis. J Alzheim Dis 2018;65:1225–36. https://doi.org/10.3233/jad-180263.Search in Google Scholar PubMed PubMed Central

66. Poels, J, Spasić, MR, Callaerts, P, Norga, KK. Expanding roles for AMP-activated protein kinase in neuronal survival and autophagy. Bioessays 2009;31:944–52. https://doi.org/10.1002/bies.200900003.Search in Google Scholar PubMed

67. Marinangeli, C, Didier, S, Vingtdeux, V. AMPK in neurodegenerative diseases: implications and therapeutic perspectives. Curr Drug Targets 2016;17:890–907. https://doi.org/10.2174/1389450117666160201105645.Search in Google Scholar PubMed

68. Zemgulyte, G, Tanaka, S, Hide, I, Sakai, N, Pampuscenko, K, Borutaite, V, et al.. Evaluation of the effectiveness of post-stroke metformin treatment using permanent middle cerebral artery occlusion in rats. Pharmaceuticals 2021;14:312. https://doi.org/10.3390/ph14040312.Search in Google Scholar PubMed PubMed Central

69. Hafner, P, Bonati, U, Erne, B, Schmid, M, Rubino, D, Pohlman, U, et al.. Improved muscle function in Duchenne muscular dystrophy through L-arginine and metformin: an investigator-initiated, open-label, single-center, proof-of-concept-study. PLoS One 2016;11:e0147634. https://doi.org/10.1371/journal.pone.0147634.Search in Google Scholar PubMed PubMed Central

70. Dong, X, Hui, T, Chen, J, Yu, Z, Ren, D, Zou, S, et al.. Metformin increases sarcolemma integrity and ameliorates neuromuscular deficits in a murine model of Duchenne muscular dystrophy. Front Physiol 2021;12. https://doi.org/10.3389/fphys.2021.642908.Search in Google Scholar PubMed PubMed Central

71. Yu, X, Li, L, Xia, L, Feng, X, Chen, F, Cao, S, et al.. Impact of metformin on the risk and treatment outcomes of tuberculosis in diabetics: a systematic review. BMC Infect Dis 2019;19:1–11. https://doi.org/10.1186/s12879-019-4548-4.Search in Google Scholar PubMed PubMed Central

72. Ibrahim, S, Lowe, JR, Bramante, CT, Shah, S, Klatt, NR, Sherwood, N, et al.. Metformin and covid-19: focused review of mechanisms and current literature suggesting benefit. Front Endocrinol 2021;12. https://doi.org/10.3389/fendo.2021.587801.Search in Google Scholar PubMed PubMed Central

73. Misbin, RI. The phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care 2004;27:1791–3. https://doi.org/10.2337/diacare.27.7.1791.Search in Google Scholar PubMed

74. Masoudi, FA, Inzucchi, SE, Wang, Y, Havranek, EP, Foody, JM, Krumholz, HM. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 2005;111:583–90. https://doi.org/10.1161/01.cir.0000154542.13412.b1.Search in Google Scholar PubMed

75. Eurich, DT, Majumdar, SR, McAlister, FA, Tsuyuki, RT, Johnson, JA. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care 2005;28:2345–51. https://doi.org/10.2337/diacare.28.10.2345.Search in Google Scholar PubMed

76. Eurich, DT, McAlister, FA, Blackburn, DF, Majumdar, SR, Tsuyuki, RT, Varney, J, et al.. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ 2007;335:497. https://doi.org/10.1136/bmj.39314.620174.80.Search in Google Scholar PubMed PubMed Central

77. Kristensen, SL, Rørth, R, Jhund, PS, Docherty, KF, Sattar, N, Preiss, D, et al.. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7:776–85. https://doi.org/10.1016/s2213-8587(19)30249-9.Search in Google Scholar PubMed

78. Kluger, AY, Tecson, KM, Lee, AY, Lerma, EV, Rangaswami, J, Lepor, NE, et al.. Class effects of SGLT2 inhibitors on cardiorenal outcomes. Cardiovasc Diabetol 2019;18:99. https://doi.org/10.1186/s12933-019-0903-4.Search in Google Scholar PubMed PubMed Central

79. De Luca, M, Bosso, G, Valvano, A, Guardasole, V, Botta, A, Carbone, V, et al.. Management of patients with chronic heart failure and type 2 diabetes mellitus: the SCODIAC-II study. Intern Emerg Med 2021;16:895–903. https://doi.org/10.1007/s11739-020-02528-4.Search in Google Scholar PubMed

80. Ghosh-Swaby, OR, Goodman, SG, Leiter, LA, Cheng, A, Connelly, KA, Fitchett, D, et al.. Glucose-lowering drugs or strategies, atherosclerotic cardiovascular events, and heart failure in people with or at risk of type 2 diabetes: an updated systematic review and meta-analysis of randomised cardiovascular outcome trials. Lancet Diabetes Endocrinol 2020;8:418–35. https://doi.org/10.1016/s2213-8587(20)30038-3.Search in Google Scholar

81. Han, Y, Xie, H, Liu, Y, Gao, P, Yang, X, Shen, Z. Effect of metformin on all-cause and cardiovascular mortality in patients with coronary artery diseases: a systematic review and an updated meta-analysis. Cardiovasc Diabetol 2019;18:1–16. https://doi.org/10.1186/s12933-019-0900-7.Search in Google Scholar PubMed PubMed Central

82. Braunwald, E. Diabetes, heart failure, and renal dysfunction: the vicious circles. Prog Cardiovasc Dis 2019;62:298–302. https://doi.org/10.1016/j.pcad.2019.07.003.Search in Google Scholar PubMed

83. Pan, Q, Lu, X, Zhao, C, Liao, S, Chen, X, Guo, F, et al.. Metformin: the updated protective property in kidney disease. Aging (Albany NY) 2020;12:8742–59. https://doi.org/10.18632/aging.103095.Search in Google Scholar PubMed PubMed Central

84. Song, A, Zhang, C, Meng, X. Mechanism and application of metformin in kidney diseases: an update. Biomed Pharmacother 2021;138:111454. https://doi.org/10.1016/j.biopha.2021.111454.Search in Google Scholar PubMed

85. Zhai, L, Gu, J, Yang, D, Hu, W, Wang, W, Ye, S. Metformin ameliorates podocyte damage by restoring renal tissue nephrin expression in type 2 diabetic rats: 二甲双胍通过调节 2 型糖尿病模型大鼠足细胞 nephrin 的表达减轻足细胞损伤. J Diabetes 2017;9:510–7. https://doi.org/10.1111/1753-0407.12437.Search in Google Scholar PubMed

86. Zhang, S, Xu, H, Yu, X, Wu, Y, Sui, D. Metformin ameliorates diabetic nephropathy in a rat model of low-dose streptozotocin-induced diabetes. Exp Ther Med 2017;14:383–90. https://doi.org/10.3892/etm.2017.4475.Search in Google Scholar PubMed PubMed Central

87. Kang, KY, Kim, Y-K, Yi, H, Kim, J, Jung, H-R, Kim, IJ, et al.. Metformin downregulates Th17 cells differentiation and attenuates murine autoimmune arthritis. Int Immunopharm 2013;16:85–92. https://doi.org/10.1016/j.intimp.2013.03.020.Search in Google Scholar PubMed

88. Kim, JW, Choe, JY, Park, SH. Metformin and its therapeutic applications in autoimmune inflammatory rheumatic disease. Korean J Intern Med 2022;37:13–26. https://doi.org/10.3904/kjim.2021.363.Search in Google Scholar PubMed PubMed Central

89. Naffaa, M, Rosenberg, V, Watad, A, Tiosano, S, Yavne, Y, Chodick, G, et al.. Adherence to metformin and the onset of rheumatoid arthritis: a population-based cohort study. Scand J Rheumatol 2020;49:173–80. https://doi.org/10.1080/03009742.2019.1695928.Search in Google Scholar PubMed

90. Lu, C-H, Chung, C-H, Lee, C-H, Su, S-C, Liu, J-S, Lin, F-H, et al.. Combination of COX-2 inhibitor and metformin attenuates rate of admission in patients with rheumatoid arthritis and diabetes in Taiwan. Medicine 2019;98:e17371. https://doi.org/10.1097/MD.0000000000017371.Search in Google Scholar PubMed PubMed Central

91. Robinson, WH, Lepus, CM, Wang, Q, Raghu, H, Mao, R, Lindstrom, TM, et al.. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol 2016;12:580–92. https://doi.org/10.1038/nrrheum.2016.136.Search in Google Scholar PubMed PubMed Central

92. Liu-Bryan, R, Terkeltaub, R. Emerging regulators of the inflammatory process in osteoarthritis. Nat Rev Rheumatol 2015;11:35–44. https://doi.org/10.1038/nrrheum.2014.162.Search in Google Scholar PubMed PubMed Central

93. Zhou, S, Lu, W, Chen, L, Ge, Q, Chen, D, Xu, Z, et al.. AMPK deficiency in chondrocytes accelerated the progression of instability-induced and ageing-associated osteoarthritis in adult mice. Sci Rep 2017;7:43245. https://doi.org/10.1038/srep43245.Search in Google Scholar PubMed PubMed Central

94. Barnett, LA, Jordan, KP, Edwards, JJ, van der Windt, DA. Does metformin protect against osteoarthritis? An electronic health record cohort study. Prim Health Care Res Dev 2017;18:623–8. https://doi.org/10.1017/S1463423617000287.Search in Google Scholar PubMed

95. Lu, C-H, Chung, C-H, Lee, C-H, Hsieh, C-H, Hung, Y-J, Lin, F-H, 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:e0191242. https://doi.org/10.1371/journal.pone.0191242.Search in Google Scholar PubMed PubMed Central

96. Price, T J, Das, V, Dussor, G. Adenosine monophosphate-activated protein kinase (AMPK) activators for the prevention, treatment and potential reversal of pathological pain. Curr Drug Targets 2016;17:908–20. https://doi.org/10.2174/1389450116666151102095046.Search in Google Scholar PubMed PubMed Central

97. Li, H, Ding, X, Terkeltaub, R, Lin, H, Zhang, Y, Zhou, B, et al.. Exploration of metformin as novel therapy for osteoarthritis: preventing cartilage degeneration and reducing pain behavior. Arthritis Res Ther 2020;22:34. https://doi.org/10.1186/s13075-020-2129-y.Search in Google Scholar PubMed PubMed Central

98. Bruderer, SG, Bodmer, M, Jick, SS, Meier, CR. Poorly controlled type 2 diabetes mellitus is associated with a decreased risk of incident gout: a population-based case-control study. Ann Rheum Dis 2015;74:1651. https://doi.org/10.1136/annrheumdis-2014-205337.Search in Google Scholar PubMed

99. Barskova, VG, Eliseev, MS, Nasonov, EL, Volkov, AV, Tsapina, TN, Zilov, AV, et al.. [Use of metformin (siofor) in patients with gout and insulin resistance (pilot 6-month results)]. Ter Arkh 2005;77:44–9.Search in Google Scholar

100. Singh, JA, Gaffo, A. Gout epidemiology and comorbidities. Semin Arthritis Rheum 2020;50(3 Suppl):S11–6. https://doi.org/10.1016/j.semarthrit.2020.04.008.Search in Google Scholar PubMed

101. Romero, R, Erez, O, Hüttemann, M, Maymon, E, Panaitescu, B, Conde-Agudelo, A, et al.. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol 2017;217:282–302. https://doi.org/10.1016/j.ajog.2017.06.003.Search in Google Scholar PubMed PubMed Central

102. Bonnet, F, Scheen, A. Understanding and overcoming metformin gastrointestinal intolerance. Diabetes Obes Metabol 2017;19:473–81. https://doi.org/10.1111/dom.12854.Search in Google Scholar PubMed

103. Crowley, MJ, Diamantidis, CJ, McDuffie, JR, et al.. Metformin use in patients with historical contraindications or precautions [Internet]. Washington (DC): Department of Veterans Affairs (US); 2016. Available from: https://www.ncbi.nlm.nih.gov/books/NBK409379/.Search in Google Scholar

104. Baerlocher, MO, Asch, M, Myers, A. Five things to know about…metformin and intravenous contrast. Can Med Assoc J 2013;185:E78. https://doi.org/10.1503/cmaj.090550.Search in Google Scholar PubMed PubMed Central

105. Christensen, K, Doblhammer, G, Rau, R, Vaupel, JW. Ageing populations: the challenges ahead. Lancet 2009;374:1196–208. https://doi.org/10.1016/s0140-6736(09)61460-4.Search in Google Scholar

106. Thomas, I, Gregg, B. Metformin; a review of its history and future: from lilac to longevity. Pediatr Diabetes 2017;18:10–6. https://doi.org/10.1111/pedi.12473.Search in Google Scholar PubMed

Received: 2022-09-22
Accepted: 2022-11-17
Published Online: 2022-12-07

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. The clinical potential of flavonoids in Peyronie’s disease
  4. Reviews
  5. Emphasizing roles of BDNF promoters and inducers in Alzheimer's disease for improving impaired cognition and memory
  6. Diabetic wound healing approaches: an update
  7. Metformin: new applications for an old drug
  8. Bispecific antibodies and its applications: a novel approach for targeting SARS-Cov-2
  9. A review on pulmonary and mediastinal synovial sarcoma
  10. Original Articles
  11. Cytokine release by human bone marrow stromal cells isolated from osteoarthritic and diabetic osteoarthritic patients in vitro
  12. Antioxidant and anti-inflammatory effect of olive leaf extract treatment in diabetic rat brain
  13. Implication of nitrergic system in the anticonvulsant effects of ferulic acid in pentylenetetrazole-induced seizures in male mice
  14. The effects of G protein-coupled receptor 30 (GPR30) on cardiac glucose metabolism in diabetic ovariectomized female rats
  15. Effects of weight-bearing vs. non-weight-bearing endurance exercise on reducing body fat and inflammatory markers in obese females
  16. [Lys5,MeLeu9,Nle10]-NKA(4–10) induces neurokinin 2 receptor mediated urination and defecation and neurokinin 1 receptor mediated flushing in rats: measured using the rapid detection voiding assay
  17. Single 30 min treadmill exercise session suppresses the production of pro-inflammatory cytokines and oxidative stress in obese female adolescents
  18. Letter to the Editor
  19. Effect of tirzepatide on prediabetics and blood pressure with implications for future research
https://doi.org/10.1515/jbcpp-2022-0252
Keywords for this article
biguanides; central nervous system diseases; communicable diseases; liver diseases; metformin; neoplasms

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. The clinical potential of flavonoids in Peyronie’s disease
  4. Reviews
  5. Emphasizing roles of BDNF promoters and inducers in Alzheimer's disease for improving impaired cognition and memory
  6. Diabetic wound healing approaches: an update
  7. Metformin: new applications for an old drug
  8. Bispecific antibodies and its applications: a novel approach for targeting SARS-Cov-2
  9. A review on pulmonary and mediastinal synovial sarcoma
  10. Original Articles
  11. Cytokine release by human bone marrow stromal cells isolated from osteoarthritic and diabetic osteoarthritic patients in vitro
  12. Antioxidant and anti-inflammatory effect of olive leaf extract treatment in diabetic rat brain
  13. Implication of nitrergic system in the anticonvulsant effects of ferulic acid in pentylenetetrazole-induced seizures in male mice
  14. The effects of G protein-coupled receptor 30 (GPR30) on cardiac glucose metabolism in diabetic ovariectomized female rats
  15. Effects of weight-bearing vs. non-weight-bearing endurance exercise on reducing body fat and inflammatory markers in obese females
  16. [Lys5,MeLeu9,Nle10]-NKA(4–10) induces neurokinin 2 receptor mediated urination and defecation and neurokinin 1 receptor mediated flushing in rats: measured using the rapid detection voiding assay
  17. Single 30 min treadmill exercise session suppresses the production of pro-inflammatory cytokines and oxidative stress in obese female adolescents
  18. Letter to the Editor
  19. Effect of tirzepatide on prediabetics and blood pressure with implications for future research
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 24.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/jbcpp-2022-0252/html
Scroll to top button