Metformin and increased cancer survival

Metformin and increased cancer survival

Metformin appears capable of increasing survival in patients with a wide variety of cancers - breast, prostate, ovarian, colorectal, NSCLC and more because it has multiple actions against cancer; it reduces blood glucose, inhibits insulin and IGF-1 production, reduces cholesterol and has an indirect effect on reducing m-TOR levels.

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.

Metformin decreases fasting and post-fasting blood sugar levels and insulin resistance.

Metformin and cancer prevention

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 diabetics 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 that it could prevent Pancreatic cancer (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. However, Metformin increased the risk of developing TNBC.

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

Indeed, a 2020 study in Nature from Norway on Lung cancer showed no increased survival in people taking Metformin (17). As we will see later, similar non-findings occurred in breast cancer and it was felt that those taking metformin already had a chronic illness and this would ultimmately determine the results.

Metormin and increased cancer survival

Metformin was originally used by a number of oncologists in London as an off-label drug to fight cancer from 2005 onwards, 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”

In many of the early studies, patients were already taking metformin because they had Type-2 diabetes. One study 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). 

But you don't have to have diabetes to benefit. According to MD Anderson, metformin affects multiple signaling processes to do with cancer growth, proliferation and cell death. 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 the 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."

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 and 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 Taiwanese study of 2000 people followed up a decade later showed that users had a lowered incidence of Kidney cancer.

Some Metformin studies show no anti-cancer benefit 

  • 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.

Seven ways Metformin might help fight cancer

When using this licenced for diabetes drug as a drug for cancer the use is termed "Off-label" and metformin in this context may be referred to as a 'repurposed' drug. 

How might work in cancer:

  1. Metformin has proven action in lowering blood sugar. 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 thrive on sugar; leukemia cells even rob healthy cells of theirs and change the insulin production system in the body to keep blood sugar 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.
  2. Metformin lowers circulating levels of Insulin-like Growth Factor 1. Or IGF1, which plays a part in cancer development
  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 cholesterol-lowering abilities rather than its sugar-lowering ones.
  6. Research suggests Metformin seems to possess anti-tumour activity and promote cytoxic T-lymphocyte levels and can block the same PD-L1 protein immune system 'brake' as some new immunotherapy drugs target. These seems to occur via the AMPK pathway. Researchers are suggesting metformin should be used with PD-L1 immunotherapy drugs.

Go to: Fat and cancer spread

Chris Woollams, former Oxford University Biochemist and a founder of CANCERactive added, "Many of the early studies on metformin have been with patients who have type-2 diabetes, and concern prevention and a reduced risk of cancer. For example, a 2018 study that Type-2 diabetes patients who took metformin had a lower risk of colorectal cancer (5). A previous study had shown a decreased risk of 54% in those taking metformin vs those not taking it. But there is increasing research showing improved drug effectiveness - for example Metformin increases the performance of Temozolomide in GBM and reduces the expression of Glioma stem cells (15)."

Metformin warnings

1). New research shows that while metformin can inhibit most cancer cells by inhibiting TORC1, in the case of BRAF-mutant melanoma, melatonin accelerates their growth in vivo. However, VEGF inhibitors work in synergy with metformin against BRAF mutations.

BRAF mutations are found in approximately 70% of melanoma cancers. It would be wiser not to use metformin unless your oncologist agrees.

2). 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.  

3). 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 mets, 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. 

Patients need to understand that Metformin is a drug. Care Oncology recommend four drugs in total 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.

Go to: Concerns on Metformin

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. 

Go to: Care Oncology Protocol

Is Berberine a natural alternative?

Side by side research has shown that the herbal ingredient Berberine may reduce fasting blood sugar more than metformin in type-2 diabetes. Berberine has also been shown in several studies to attack the cancer cell's energy production pathway, and also to inhibit m-TOR (10); and berberine has the added benefits of being anti-microbial and anti-inflammatory. There is no issue with Berberine and liver problems.

Chris Woollams added, "The fact is that berberine and metformin, although they both lower blood sugar, can have slightly 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. However, Berberine also has several important studies on its effects against TNBC, where Metformin does not. Perhaps the major difference is that Berberine also has anti-inflammatory benefits not just similar glucose-lowering benefits to metformin. In fact one study called 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

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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
2019 Research
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