Metformin and increased cancer survival; a Review

Metformin and increased cancer survival; a Review

Metformin may reduce the risk of certain cancers, especially in patients with type-2 diabetes; it may also increase survival times with some cancers; but it is inconsistent in performance and has known side-effects such as increasing homocysteine. An updated Research Review

What is Metformin?

Metformin, or Glucophage, is an anti-hyperglycemic drug, which lowers blood glucose levels because it reduces glucose production in the liver and also improves uptake of blood glucose by cells; however it does not increase insulin production, nor does it promote weight gain. It is a widely used medication for the treatment of Type-2 diabetes, especially in overweight people (this is the 5th update on this article by Chris Woollams MA (Oxon), Biochemistry.)

Metformin decreases fasting and post-fasting blood sugar levels and insulin resistance. It also seems to exert a sugar-control effect through the gut microbiome (see below). When using this 'licensed for diabetes' drug but repurposed as a drug for cancer, the use is termed "Off-label" and metformin in this context may be referred to as a 'repurposed' or 'off-label drug'.

Metformin - cancer prevention and survival in people with type-2 diabetes

Diabetes can increase the likelihood of various types of cancer such as lung cancer, colorectal cancer, liver cancer and pancreatic cancer. Incidence of cancer is higher in type-2 diabetes patients because of insulin resistance and through mitogenic activity (where poor sugar control and hyperglycemia increase cell proliferation and division with decreased apoptosis). For example, a meta-analysis published in Frontiers in Oncology in 2019, showed there was strong evidence in diabetics that Metformin could prevent pancreatic cancer in people with diabetes(12). 

In an NIH February 2021 study (13) of 44,541 women, those with diabetes who took Metformin for 10 or more years had a 38% lowered risk of developing ER+ve breast cancer. 

In a meta-review of cancer and metformin, the drug was 'reported to have reduced the risk of cancer since 2005 by 23% worldwide', but this seemed rather a wooly finding with poor support (14).

Indeed, much of the research involves observational studies, looking back on people with diabetes, who were taking metformin. As long ago as 2013, we published three studies on metformin's use in patients with type-2 diabetes - one on endometrial and another general study, plus one on ovarian which didn't specify that people who were on the metformin had diabetes (but why else would they have been using it prior to 2012).

Metformin - inconsistency of findings 

So, people known to have poor sugar control have a lowered risk of cancer and a greater survival, if they take metformin. This brings three big questions, which we have tried to answer in this review:

i) Is this true for all cancers? The answer to this is 'No'

ii) Is there a benefit if you don't have diabetes? The answer to this is 'there can be significant benefit but certainly not always"'.

III) Are there any risks in taking metformin? The answer to this is 'Yes'.

A study with cervical cancer showed no increase in survival in people taking Metformin (30). This looked at cases prior to 2012 and people taking metformin (presumably for diabetes).

In a study from the Institute of Cancer Research in London (presented later) on melanoma with BRAF mutation, Metformin was shown to actually accelerate growth. Of course, some colorectal cancers are also BRAF- mutated.

In another study (17) there was a confusing finding on lung cancer - those taking metformin before diagnosis (presumably because of type-2 diabetes) had no benefit at all; but where it was added after diagnosis, it did increase survival.

As we will see later, findings of no-benefit occurred in breast cancer patients who were already taking metformin (presumably for type-2 diabetes) but this was explained away by suggesting that those taking metformin already had a chronic illness and this would ultimately determine the results. So, the diabetes determines the results, not the metformin?

Importantly, one study, on Triple Negative Breast Cancer, using post-diagnostic metformin concluded worse results.

While the review (30) on ovarian cancer patients already on metformin showed benefit, later we will show that there are two meta-analyses showing no benefit with ovarian cancer patients.

A 2023 Oxford University review of metformin and cancer in the journal Nature went further, asking the question: "Is it still worth pursuing the repurposing of metformin as a cancer therapeutic?" (31). Although the title is somewhat negative, their answer went on to show how it worked.

Metformin potential benefits and actions for cancer patients 

Metformin seems to have several potential ways of acting against cancer: 

  1. Metformin has proven action in lowering blood sugar. The Official view is that it does this by reducing the ability of the liver to release glucose (1). Metformin actually accumulates in the liver. There can only be a few remaining quacks who deny that cancer tumours need sugar; leukaemia cells even rob healthy cells of theirs and change the insulin production system in the body to keep blood sugar higher and available for their avarice - there was a study from Colorado Cancer Center on exactly this in leukaemia. There is now too much research on sugar promoting cancer to argue against.

Go to: 20 research links between sugar and cancer

  1. Metformin also lowers circulating levels of insulin (2), which has proven links to inflammation in the body via the COX-2 pathway. And inflammation aids metastases. Metformin lowers circulating levels of Insulin-like Growth Factor or IGF-1 (1) which can play a part in cancer development.
  2. The 2023 review from Lord and Harris (31) above stated that metformin causes the up-regulation of several pathways linked to mitochondrial metabolism and changes in the levels of a number of mitochondrial metabolites. This suggests that metformin disrupts cancer mitochondrial metabolism at clinical dosing. A reactive increase in mitochondrial oxidative phosphorylation gene transcription linked to metformin resistance and two distinct metabolic responses in breast cancer were observed. Furthermore, in primary breast cancer they showed an increased expression of multiple genes regulating glycolysis, glucose transport and glutamine metabolism. 
  3. Metformin indirectly inhibits m-TOR. Eating a big meal leads to increased plasma levels of insulin and IGF-1. In turn these stimulate phosphoinositide 3-kinase (PI3K) and Akt and protein kinase B (PKB), which stimulate m-TOR, an important signaling pathway in cancer such as melanoma (4). Indeed, inhibiting m-TOR may be the crucial factor as it appears to play a pivotal role in the metabolism, growth and proliferation of cancer cells.
  4. Metformin may also reduce fatty liver and lowers blood cholesterol levels (3). Heightened levels of blood cholesterol are linked to greater metastases in cancer patients.
  5. In an Oxford University review (7) of research on metformin with prostate cancer, metformin appeared to help Androgen Deprivation Therapy work better. This may be due to its secondary cholesterol-lowering abilities rather than its sugar-lowering ones.
  6. Research (19) from MD Anderson suggests metformin seems to possess antitumour activity and promote cytotoxic T-lymphocyte levels and can block the same PD-L1 protein immune system 'brake' as some new immunotherapy drugs target. This seems to occur via the AMPK pathway. Researchers are suggesting metformin should be used with PD-L1 immunotherapy drugs, although there is little evidence overall.

Critics argue that the effect in people with Diabetes is that metformin helps them regulate their poor sugar control, and this is less true for people with cancer without diabetes. But according to MD Anderson, metformin affects multiple signaling processes to do with cancer growth, proliferation and cell death in laboratory experiments so it is not only concerned with glucose control. And you should know that 70% of people have some degree of insulin resistance and poor sugar control and metformin should potentially help all these people fight cancer. 

Metformin potential benefits and actions for cancer patients 

Let's look at some of the positive studies:

Metformin has been used by a number of oncologists in London as an off-label drug to fight cancer since 2005, but since 2012 has been promoted by Care Oncology as one of four drugs in the Care Oncology Protocol, (an anti-cancer, increased cancer survival protocol) with the claim that 'these medicines target cholesterol, glucose and the glycolysis process, which impact on the metabolism of cancer cells and the immune cells around them”

As you have seen, in many of the early studies on metformin's benefits, patients were already taking metformin because they had Type-2 diabetes. One study (12) of women having Breast cancer chemotherapy showed 24% of Type-2 diabetes patients taking metformin having complete remission, vs 16% non-diabetic patients vs 8% Type-2 diabetes patients not taking metformin.

In HER2 positive cancer, patients taking metformin because of diabetes had a 40% lower progression and death after 4.5 years than those not taking metformin.

The same meta-analysis as above published in Frontiers in Oncology, showed that Metformin could increase overall survival in Colorectal cancer in people taking it for Diabetes (12). 

Dr Pamela Soliman was treating Endometrial cancer patients with an m-Tor inhibitor Everolimus, and Letrozole. m-Tor inhibition can reduce insulin secretion, so some patients were also prescribed metformin. The metformin addition resulted in patients responding far better to the drugs and a full clinical trial is now underway. Another trial is studying Paclitaxel and Carboplatin with and without metformin.

A colleague, Dr. Heath Skinner is conducting a trial using metformin or a placebo with people having radiotherapy for NSCLC.

A 2012 study by the Mayo Clinic involving women with Ovarian cancer followed 61 patients with diabetes and 178 patients without. Comparing two matched samples, 67% of women taking metformin survived 5 years, compared to only 47% of those not taking the drug.  Dr William Cliby, Director of the Department of Gynecology said, "Whichever way you looked at the figures, the women on metformin always did better."  However, this finding has been countered by two more recent ovarian cancer studies (see below).

In 2016, researchers from the Perelman School of Medicine, Pennsylvania showed that Breast cancer patients who started taking metformin after their diagnosis were almost 50% more likely to survive than non-users. Lead Author Yun Rose said that they also looked at people who were already on metformin at the time of diagnosis but those people tended to be poor survivors possibly because they had chronic illness prior to diagnosis.

In a 2019 meta-study on prostate cancer (8), researchers concluded that there were clear survival benefits due to the multiple action of metformin - "Evidence has shown that metformin has multiple anti-neoplastic effects through AMPK-dependent and independent mechanisms, an alteration of IGF-1 signaling, suppression of androgen receptor pathway, inhibition of m-Tor pathway, and lipogenesis". 

After concerns were expressed that metformin given to Type-2 Diabetes patients could increase kidney cancer risk, a 2016 Taiwanese study (18) of 2000 people followed up a decade later showed that users had a lowered incidence of Kidney cancer.

Metformin influences the gut microbiome, but effects are inconsistent

In a four-month double-blind study, randomised individuals with type 2 diabetes were shown to have significant changes to their microbiome. In a second part of the study, transfer of fecal samples (obtained either before or 4 months after treatment) to germ-free mice showed that glucose tolerance was improved in mice that received metformin-altered microbiota.  The action of metformin may not simply be due to liver effects but possibly more to do with microbiome changes (27). A 2023 meta-anaylsis of 13 studies however showed that metformin altered the abundance of certain families and types of bacteria in the gut, putting some up, and others down, and causing dysbiosis - but these changes were totally inconsistent (32). 

Some Metformin studies show no anti-cancer benefit, some even show it making the cancer worse 

Let's look at some studies where it didn't work -

  • A 2015 randomised controlled trial (11) of metformin with advanced pancreatic cancer, showed no impact on survival.
  • A 2017 study (9) on the use of platinum-based drugs with Lung cancer (NSCLC) showed no survival benefit in adding metformin.
  • In a study on AML leukemia by McMaster University, metformin showed no benefit in reducing the cancer cells' avarice for sugar, but surprisingly altered the composition of the bone marrow fat for the better (21). 
  • In the 2021 meta-analysis above (12) whilst increasing Er+ve breast cancer survival, metformin increased the risk of developing TNBC. 
  • Metformin also has been shown to accelerate the growth of BRAF Melanoma (22). 2012 research (20) shows that while metformin can inhibit most cancer cells by inhibiting TORC1, in the case of BRAF-mutant melanoma, metformin accelerates their growth in vivo by upregulating VEGF, which can increase angiogenesisHowever, VEGF inhibitors work in synergy with metformin against BRAF mutations. BRAF mutations are found in approximately 70% of melanoma cases and in some colorectal cancers. It would be wiser not to use metformin unless your oncologist agrees.
  • In studies with PD-1 immunotherapy drug Nivolumab and colorectal cancer, metformin was shown to have no real immunomodulatory benefit on its own, but appeared to help Nivolumab a little (26).
  • A 2021 study on ovarian cancer showed no increased cancer survival benefit when taking metformin (28).
  • A 2020 Finnish review showed that preclinical laboratory research was not born out in real life epidemiology studies (29)
  • As we said above, a study with cervical cancer patients shows no survival benefit with people taking metformin (30)

Metformin use complex and variable 

Chris Woollams, former Oxford University Biochemist and a founder of CANCERactive added, "Almost all of the early studies on metformin have been with patients who have type-2 diabetes and these studies largely concerned prevention and a reduced risk of cancer. Even newer studies confirm prevention benefits; for example, a 2018 study that Type-2 diabetes patients who took metformin had a lower risk of colorectal cancer (5). A previous study on CRC had shown a decreased risk of 54% in those taking metformin vs those not taking it.

There is also research showing improved drug effectiveness when using metformin - for example, Metformin increases the performance of Temozolomide in GBM and reduces the expression of Glioma stem cells (15). However, as shown above, metformin works well in some situations, gives mixed results in others, doesn't work with certain drugs or certain cancers, and can act in different ways. It is very complex and metformin cannot simply be used in every situation with or without drugs. It is not a universal panacea for all cancers and all situations - that just is not what the results show."

Metformin warnings

1). Metformin appears to contain N-Nitrosodimethylamine, or NDMA. This is the chemical that caused the recall of drugs such as Zantac. The FDA has stated that levels above 96 nannograms a day could be unsafe. The FDA even asked manufacturers to recall the drug.  

2). Metformin can increase liver problems and even cause spread of cancer to the liver. CANCERactive witnessed two patients where Metformin was blamed for worsening liver metastases by the oncologist. Part of this issue may be the purity of the drug as some supplies of metformin come from cheaper laboratories in third world countries and the quality is not rigorously checked. 

3) Metformin is known to increase homocysteine, a key driver of histone formation in cancer and other chronic illnesses. It is also known to increase the risk of neuropathy (23).

4) Metformin has also been shown to cause vitamin B-12 deficiency (24). In research, this was linked to the dose of metformin used.

Patients need to understand that Metformin is a drug. Care Oncology recommend four drugs and sometimes five, but drugs can have strong interactions with other drugs. Patients should not simply construct their own protocols, nor should they use any off-label drugs without the approval of their primary oncologist.

Dose of metformin in cancer

Professional expertise must be sought. Metformin usually comes in 500 mg pills and patients take 2-4 per day on the Care Oncology Protocol. 

Is Berberine the natural anti-cancer alternative to Metformin?

Side by side research has shown that the herbal ingredient Berberine may reduce fasting blood sugar more than metformin in type-2 diabetes patients. Berberine has also been shown in several studies to attack the cancer cell's energy production pathway, correct AMPK and inhibit m-TOR (10); and berberine has the added benefits of being anti-microbial (reducing E coli, for example) and anti-inflammatory. Berberine also has positive effects on the microbiome and the microbiome aids its absorption. There is no reported issue with Berberine on contamination and liver problems, and berberine cuts homocysteine levels, rather than increasing them as Metformin unfortunately does.

Research with brain cancer, pancreatic cancer and others shows that you can use both simultaneously (25)..

Chris Woollams added, "The fact is that berberine and metformin, although they both lower blood sugar, have quite different properties. For example, in Pancreatic cancers. Berberine and Metformin both activate AMP-activated protein Kinase (AMPK) which is a key regulator of glucose metabolism. Berberine is much more consistent across different cancers and its absorption is positively aided by the gut microbiome. Berberine also has several important studies on its effects against TNBC, where Metformin does not. Berberine is also a proven chemo-sensitiser and helps overcome chemo-resistance. Another major difference is that Berberine also has antibacterial and anti-inflammatory benefits. Finally, in cancer, it is important to reduce homocysteine levels (Berberine does) and this, for me, is a significant concern with homocysteine-promoting metformin.

However, one study did call them two very similar and versatile drugs in the management of metabolic diseases" (16).

Go to: A review on Berberine as a cancer treatment 

Go to: Care Oncology Protocol

                                                                                                             *************************************

References

  1. J Clin Endocrinol Metab. 2003 Mar;88(3):1323-32.
  2. Nat Med. 2000 Sep;6(9):998-1003.
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398862/
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291999/
  5. https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=29716927
  6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395104/
  7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405102/
  8. https://pubmed.ncbi.nlm.nih.gov/30651580/
  9. https://pubmed.ncbi.nlm.nih.gov/30572481/
  10. https://pubmed.ncbi.nlm.nih.gov/23974852/
  11. Lancet Oncol 2015, 16:839–847
  12. https://www.frontiersin.org/articles/10.3389/fendo.2019.00617/full
  13. https://www.esmo.org/newsroom/press-office/metformin-may-affect-risk-of-breast-cancer-in-women-with-type-2-diabetes
  14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497052/
  15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762574/
  16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839379/
  17. https://www.nature.com/articles/s41416-020-01186-9
  18. Use of metformin and risk of kidney cancer in patients with type 2 diabetes; Eur J Canc; 2016 Jan;52:19-25.
  19. Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1; Jong Ho Cha et al; MD Anderson.
  20. https://aacrjournals.org/cancerdiscovery/article/2/4/344/3247/Metformin-Accelerates-the-Growth-of-BRAFV600E'; Cancer Discov (2012) 2 (4): 344–355.
  21. Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow nicheAllison L. Boyd, .Nature Cell Biology, 2017
  22. Metformin accelerates the growth of BRAF V600E-driven melanoma by upregulating VEGF-A; Mathew J Martin et al; Cancer Discov. 2012 Apr;2(4):344-55.
  23. Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy; Daryl J Wile, Cory Toth; Diabetes Care 2010
  24. Risk Factors of Vitamin B12 Deficiency in Patients Receiving Metformin; Rose Zhao-Wei Ting et al; Arch Intern Med. 2006;166(18):1975-1979.
  25. Metformin and berberine, two versatile drugs in treatment of common metabolic diseases; Oncotarget. 2018; 9:10135-10146
  26. Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer Mehmet Akce et al; https://jitc.bmj.com/content/11/10/e007235
  27. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug; Hao Wu et al; Nature Medicine volume 23, pages 850–858 (2017)
  28. Impact of metformin on survival outcome in ovarian cancer: a nationwide population-based cohort study; Jeong-Yeol Park et al; J Gynecol Oncol. 2021 Jul; 32(4): e65.
  29. Metformin and ovarian cancer: the evidence; Elina Urpilainen et al; Review  Ann Transl Med. 2020 Dec;8(24):1711.  
  30. Association of Metformin Use and Survival Outcome in Women With Cervical Cancer; Tsuyoshi Takiuchi et al; Int J Gynecol Cancer. 2017 Sep; 27(7): 1455–1463.
  31. Is it still worth pursuing the repurposing of metformin as a cancer therapeutic? Simon R. Lord, Adrian L. Harris; British Journal of Cancer volume 128, pages 958–966 (2023)
  32. Effects of metformin on the gut microbiota: A systematic review; Pavlo Petakh et al; Mol Metab. 2023 Nov; 77: 101805.

 


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