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Metformin - A Helping Hand

Updated: Jan 7

Metformin almost seems too good to be true but a robust body of research indicates it has many health benefits with few side effects. It’s the third most prescribed medication in the world and the drug of choice for the prevention and treatment of type 2 diabetes [1] due to its excellent safety record [2]. Metformin was originally developed from a traditional herbal medicine and has been used to treat diabetes for over 60 years [1]. Now, studies are showing metformin has health benefits that go far beyond its ability to regulate blood sugar [3], including for people who are not diabetic [1, 3, 4].


The reported benefits of metformin include reducing oxidative stress, inflammation, infection, cancer and fibrosis as well as delaying aging and reducing all-cause mortality.

The reported benefits of metformin include reducing oxidative stress, inflammation, infection, cancer and fibrosis [2, 3, 5] as well as delaying aging and reducing all-cause mortality [5]. Metformin also reduces heart attacks, heart disease and stroke [6]. Further benefits derive from metformin’s ability to reduce cell death [3], while increasing autophagy, the process by which cells clean out the rubbish, such as damaged proteins and organelles [1]. It’s not surprising that metformin is increasingly being used off-label to treat medical conditions in non-diabetics, including polycystic ovary syndrome (fibrosis of the ovaries) and cancer [6]. My view is that metformin should be given both as a preventative and a treatment for arthrofibrosis, and thankfully surgeons are starting to prescribe it off-label this way.



In people with diabetes, adding metformin to their medications significantly reduced the need for joint replacement surgery [7]. Clinical trials of metformin for treating arthrofibrosis are lacking, however animal studies indicate the drug significantly reduces arthrofibrosis from immobilisation [8]. Other research in rats suggests that injections of metformin into the joints reduced arthrofibrosis and improved range of motion [9]. Although injected metformin is not a typical application, oral metformin has been shown to reduce tendon fibrosis and adhesions in rats following tendon injury, in contrast to celecoxib, which impaired tendon healing [10]. Based on the scientific literature I expect metformin research will continue to demonstrate significant benefits for arthrofibrosis.


It may be beneficial to take metformin before, and for a period after, joint surgery to promote healthier wound healing.

Metformin has demonstrated efficacy for treating organ fibrosis in human clinical trials, as well as in numerous animal [2] and cell culture studies [11] including for lung, kidney, liver, skin and heart fibrosis [2, 12]. It does this by suppressing multiple pro-fibrotic factors [3, 13] and beneficially altering many different biological pathways [2]. It has been suggested that this ability of metformin to target multiple pathways provides a unique anti-fibrotic benefit compared to other drugs [3]. Metformin downregulates TGF-β1 (the key fibrotic signalling protein) and directly binds to it [2, 10]. Interestingly, COVID research indicates that metformin reduces the expression of HIF-1 genes in response to hypoxia (lack of oxygen), with some suggesting this may be an important pathway by which metformin reduces fibrosis [3]. Since surgery creates hypoxia it may be beneficial to take metformin before, and for a period after, joint surgery to promote healthier wound healing. This is supported by animal studies showing the effects of metformin were stronger when taken immediately after surgery, compared to delaying the medication [8]. And, even although the majority of metformin research has been conducted in animals [1], clinical trials in humans and epidemiological research show that metformin is useful as an anti-fibrotic medication that also reduces the risk of cancer.


Other anti-fibrotic effects of metformin include reduced adhesions, scar tissue and activation of myofibroblasts (the cells that cause fibrosis) [3, 14]. Fewer cells become transformed into myofibroblasts and it’s thought that lower blood sugar reduces myofibroblast production of scar tissue [10] as well as their adhesions [2]. These anti-fibrotic effects of metformin are reinforced by the reduction in reactive oxygen species and inflammation (including the cytokines IL-1, IL-6 and TNF-α [3, 13]) and inhibition of macrophages, one of the key immune system cells involved in fibrosis [1, 12]. Oxidative stress is reduced because metformin scavenges free radicals and causes the production of anti-oxidant enzymes [13]. Metformin also reduces fibrosis by downregulating other essential components of metabolism and inflammation that influence healing such as complement C3 [12], sirtuins [5] and Nrf [2] signalling [1].


Yet more benefits of metformin include its anti-aging effects. These have been extensively studied with evidence indicating the drug extends life and health span in both diabetic and non-diabetic people [5]. Even more astonishing, a recent observational study found that metformin improves the survival of older diabetic patients compared to people without diabetes (and not taking metformin), and several large studies are underway to further investigate its anti-aging properties [5]. One study showed that women taking metformin had an amazing 88% reduction in ovarian cancer incidence, and its ability to reverse or prevent ovarian fibrosis in postmenopausal women was recently demonstrated [12]. Metformin is also known for its ability to fight infections and has proven its worth for fighting flu and preventing long COVID [3].


Metformin’s excellent safety, low cost and wide-ranging health benefits makes it an attractive medication for fighting fibrosis. Starting on a low dose and slowly increasing it is recommended to allow gut microbes time to adapt without causing digestive effects. Slow release metformin (XR) appears to have benefits over the immediate release form with typical daily doses between 1 000 mg to 2000 mg often split over the day. As with all medications and supplements, don’t overdose.


A couple of things are worth bearing in mind if you’re taking metformin. Metformin binds metals, potentially reducing the efficacy of both metformin and mineral supplements. So, if you take metal supplements like iron and magnesium it might be best to take them at a separate time. Some research suggests that long-term use of metformin can reduce absorption of vitamins B12 and B6, however more recent research contradicts this, so ask your doctor if you should supplement with these vitamins. If you also take losartan as an anti-fibrotic, or to lower blood pressure, it might be best to take low-dose metformin (500 mg), rather than higher metformin doses. This is because losartan appears to increase the amount of metformin in the blood, however, the combination of losartan and low-dose metformin appears to be beneficial, at least in animals [4].


Please keep in mind that metformin is not a cure for arthrofibrosis and is not a guarantee you won’t get it; there are currently no medications that can do these things. However, metformin will alter many biological pathways and should help both recovery in the early post-op period and for managing chronic arthrofibrosis. Despite the extensive research, non-diabetes research in humans is in the early days and some scepticism remains around this use [15].


References

  1. Li, J. Z. & Li, Y. R. Cardiovascular Protection by Metformin: Latest Advances in Basic and Clinical Research. Cardiology 148, 374-384 (2023). https://doi.org/10.1159/000531432

  2. Wu, M. et al. Metformin and Fibrosis: A Review of Existing Evidence and Mechanisms. J Diabetes Res 2021, 6673525 (2021). https://doi.org/10.1155/2021/6673525

  3. Wiernsperger, N., Al-Salameh, A., Cariou, B. & Lalau, J. D. Protection by metformin against severe Covid-19: An in-depth mechanistic analysis. Diabetes Metab 48, 101359 (2022). https://doi.org/10.1016/j.diabet.2022.101359

  4. Omachi, K. et al. Metformin ameliorates the severity of experimental Alport syndrome. Sci Rep 11, 7053 (2021). https://doi.org/10.1038/s41598-021-86109-1

  5. Du, Y., Zhu, Y. J., Zhou, Y. X., Ding, J. & Liu, J. Y. Metformin in therapeutic applications in human diseases: its mechanism of action and clinical study. Mol Biomed 3, 41 (2022). https://doi.org/10.1186/s43556-022-00108-w

  6. Rusanov, D. A., Zou, J. & Babak, M. V. Biological Properties of Transition Metal Complexes with Metformin and Its Analogues. Pharmaceuticals 15, 453 (2022). https://doi.org/10.3390/ph15040453

  7. Lu, C. 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 13, e0191242 (2018). https://doi.org/10.1371/journal.pone.0191242

  8. Tokuda, K. et al. Effect of metformin treatment and its time of administration on joint capsular fibrosis induced by mouse knee immobilization. Sci Rep 11, 17978 (2021). https://doi.org/10.1038/s41598-021-97445-7

  9. Zhu, Z. et al. Metformin improves fibroblast metabolism and ameliorates arthrofibrosis in rats. Journal of Orthopaedic Translation 40, 92-103 (2023). https://doi.org/10.1016/j.jot.2023.05.011

  10. Zheng, W. et al. Metformin prevents peritendinous fibrosis by inhibiting transforming growth factor-β signaling. Oncotarget 8, 101784-101794 (2017). https://doi.org/10.18632/oncotarget.21695

  11. Usher, K. M. et al. Pathological mechanisms and therapeutic outlooks for arthrofibrosis. Bone Research 7 (2019). https://doi.org/10.1038/s41413-019-0047-x

  12. McCloskey, C. W. et al. Metformin Abrogates Age-Associated Ovarian Fibrosis. Clin Cancer Res 26, 632-642 (2020). https://doi.org/10.1158/1078-0432.CCR-19-0603

  13. Mummidi, S. et al. Metformin inhibits aldosterone-induced cardiac fibroblast activation, migration and proliferation in vitro, and reverses aldosterone+salt-induced cardiac fibrosis in vivo. J Mol Cell Cardiol 98, 95-102 (2016). https://doi.org/10.1016/j.yjmcc.2016.07.006

  14. Salminen, A. AMPK signaling inhibits the differentiation of myofibroblasts: impact on age-related tissue fibrosis and degeneration. Biogerontology (2023). https://doi.org/10.1007/s10522-023-10072-9

  15. Glossmann, H. H. & Lutz, O. M. D. Metformin and Aging: A Review. Gerontology, 1-10 (2019). https://doi.org/10.1159/000502257

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