Metformin double hit lymphoma

I was looking at clinical trials for double hit lymphoma and I came across this trial including Metformin in DA-EPOCH-Rituximab for Double Hit Lymphoma (DA-EPOCH-Rituximab/Metformin (RM) for Double Hit Lymphoma (DLBCL)https://clinicaltrials.gov/ct2/show/NCT02815397).

Reading further on the activity of Metformin on AMPK shows that there are currently 310 studies found for metformin and cancer on clinicaltrials.gov which have been spurred by the possibility this has for slowing cancer growth by inhibiting mTOR enzyme and the further possibility to inhibit mTOR directly (independent of AMPK activation), along with its potential action on cancer stem cells (Shi, W. Y., et al. "Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy." Cell death & disease 3.3 (2012): e275.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317343/Hirsch, H. A., Iliopoulos, D., Tsichlis, P. N., & Struhl, K. (2009). Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer research, 69(19), 7507-7511https://www.ncbi.nlm.nih.gov/pubmed/19752085, Del Barco, Sonia, et al. "Metformin: multi-faceted protection against cancer." Oncotarget 2.12 (2011): 896-917.https://www.ncbi.nlm.nih.gov/pubmed/22203527Libby, Gillian, et al. "New users of metformin are at low risk of incident cancer." Diabetes care 32.9 (2009): 1620-1625.https://www.ncbi.nlm.nih.gov/pubmed/19564453).

I am aware that there is concern that biguanides may cause lactic acidosis, however, Salpeter et al., recently conducted a Cochrane Systematic Review of over 200 trials in order to evaluate the incidence of lactic acidosis among patients prescribed metformin vs non-metformin antidiabetes medications. Of 100,000 people, the incidence of lactic acidosis was 5.1 cases in the metformin group and 5.8 cases in the non-metformin group. Hence the authors concluded that metformin is not associated with an increased risk for lactic acidosis. (Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus, Cochrane Database Syst Rev , 2010, vol. 4 pg. CD002967https://www.ncbi.nlm.nih.gov/pubmed/20091535)

Similarly, recent reports suggest that although metformin use has increased over the years, observational studies have not been able to demonstrate an increased incidence of lactic acidosis in metformin-treated patients, even when it is used in populations with relative contraindications (Hamnvik OP, McMahon GT. Balancing risk and benefit with oral hypoglycemic drugs. Mt Sinai J Med. 2009;76:234-243.https://www.ncbi.nlm.nih.gov/pubmed/19421967)

Further, a recent study reports that the anticancer activity of metformin is strongly potentiated by syrosingopine and that combination therapy is particularly effective against different types of cancer cells without harming normal cells, with syrosingopine strongly sensitizing cancer cells to killing by metformin in vitro and in vivo, particularly in blood cancers.  (Benjamin, Don, et al. "Syrosingopine sensitizes cancer cells to killing by metformin." Science Advances 2.12 (2016): e1601756.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5182053/)

Finally, some studies suggest that lymphoma cell response to chemotherapeutic agents (such as doxorubicin) and mTOR inhibitors (i.e. temsirolimus) is significantly enhanced when co-treated with metformin. (Shi, W. Y., et al. "Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy." Cell death & disease 3.3 (2012): e275.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317343/)

Metformin seems to be a drug with pretty low associated risk so in the situation we are in there seems very little harm in making use of it, in fact, the only negative effects on mortality I have observed were for those individuals taking metformin and sulfonylurea drugs concurrently. (Olsson J, Lindberg G, Gottsäter M, et al. Increased mortality in Type II diabetic patients using sulphonylurea and metformin in combination: a population-based observational study. Diabetologia. 2000 May;43(5):558-60https://link.springer.com/article/10.1007%2Fs001250051343?LI=true)

On clinicaltrials.gov alone there are currently 310 clinical trials investigating the activity of Metformin on cancers. The importance of Metformin in cancers is something that MD Anderson are currently investigating across a wide variety of disease subtypes, including blood cancers. Although I have not spoken to them personally Dr. Aung Naing at 713-563-0181, Dr. Heath Skinner at 713-563-3508, or Dr. Pamela Soliman at 713-745-2352 at MD Anderson may be able to provide information on their experiences with, and treatment approaches to, using this drug at the clinic.

http://reference.medscape.com/drug-interactionchecker

IS VITAMIN B SUPPLEMENTATION SAFE:

As vitamin B12 expert Professor Allen explains, vitamin B12 deficiency is found throughout the world and contributes to a preventable cause of illness for millions of people.https://www.ncbi.nlm.nih.gov/pubmed/19116323

DOSING:

https://integrativeoncology-essentials.com/2013/02/metformin-supplementation-and-cancer-treatment-more-highlights-from-naturopathic-cancer-conference-oncanp/

http://www.lifeextension.com/Magazine/2012/11/Metformin-Makes-Headline-News/Page-02

CLINICAL TRIAL WITH DOSING:

https://clinicaltrials.gov/ct2/show/NCT02815397

https://www.clinicaltrials.gov/ct2/show/results/NCT02531308?term=metformin+and+cancer&cond=%22Lymphoma%2C+Large+B-Cell%2C+Diffuse%22&rank=3&sect=X5437016 - limit

MD ANDERSON CONTACT PEOPLE:

https://www.mdanderson.org/publications/oncolog/november-december-2014/beyond-diabetes-metformin-may-have-broad-utility-in-cancer.html

The below comes from the life extension article I cited above:

Metformin reduces triglycerides,62-64 glucose,32,65,66 insulin,67-69 and hemoglobin A1C (a marker of long term glucose control).32,70 These blood markers are all proven heart attack risk factors. Yet not all studies show metformin reduces heart attack incidence.

Furthermore, not all studies show that metformin reduces cardiovascular risk or improves overall survival in type II diabetic patients. There are several reasons to explain these discrepancies.

Metformin is known to cause vitamin B12 deficiency which translates into higher levels of artery-clogging homocysteine.72-74 The tiny amount of vitamin B12 and other B-vitamins found in commercial supplements is not always sufficient to offset this problem. Those who take metformin should ensure they are taking higher doses of B-vitamins (at least 300 mcg of vitamin B12) and check their homocysteine levels to make sure it stays in the safer ranges.75 One study showed that the addition of 5,000 mcg of folic acid to patients taking metformin reduced their homocysteine from 15.1 µmol/L to 12.1 µmol/L.76 Optimal homocysteine levels are probably under 8 µmol/L, but any reduction is helpful. Sadly, most diabetics prescribed metformin don't check their homocysteine levels and don't take enough B-vitamins to prevent a deficiency.

Some studies show that metformin reduces free testosterone and total testosterone levels in men.77 Testosterone is especially important in male diabetics as it significantly enhances insulin sensitivity.78 Life Extension has previously published clinical data showing the critical importance of diabetic men to maintain youthful testosterone levels in order to improve glucose utilization.79

The greatest challenge in evaluating clinical data on metformin is that it is often prescribed to debilitated patients who have undergone severe arterial attack for many decades. These diabetic patients are at significant risk of cardiovascular disease from a number of underlying causes. They need to take aggressive steps to correct all independent risk factors for vascular disease, something that is never done in clinical studies.

It turned out that only patients with severe kidney, liver, pulmonary, or cardiac impairment had to avoid metformin because of lactic acidosis concerns, and even these worries were overblown.

The regrettable fact is that doctors in the United States were taught to avoid drugs in the class of metformin, even though metformin itself was being safely used throughout the world. If only the medical establishment in the United States had looked across the border as close as Canada, they would have seen metformin being liberally prescribed with nowhere near the incidences of lactic acidosis they feared.

 In the early years, when I was taking metformin for anti-aging purposes, most doctors warned me about lactic acidosis risk. I always asked where in the scientific literature does it show a healthy person is at risk for lactic acidosis when taking metformin? They could never cite a reference, so I continued taking my metformin.



also prevent precancerous cells from evolving into cancer cells.



Metformin reduces the amount of circulating estrogen and testosterone, both of which can stimulate the growth of hormone-dependant tumors (i.e. breast cancer, prostate cancer)



Human Studies Show Improved Outcomes On Metformin:

Metformin Supplementation and Cancer Treatmenthttps://integrativeoncology-essentials.com/2013/02/metformin-supplementation-and-cancer-treatment-more-highlights-from-naturopathic-cancer-conference-oncanp/



Our interest is blood cancer and particularly:



Revlimid (Lenalidomide) in combination with Rituximab:

Similarly, a recent phase 2, single-arm, single-center trial evaluating the safety and efficacy of lenalidomide plus rituximab in elderly patients with relapsed or refractory DLBCL found that oral lenalidomide in combination with rituximab was active in elderly patients with relapsed/refractory DLBCL with a high percentage of patients achieving a continuous CR. This is supported by the effect lenalidomide has been shown to have in enhancing the natural killer cell–mediated antibody-dependent cellular cytotoxicity of rituximab. (Combination of Lenalidomide and Rituximab in Elderly Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma: A Phase 2 Trialwww.sciencedirect.com.ucd.idm.oclc.org/science/article/pii/S2152265011000231)



Hope this is of some help,



John