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Advanced Prostate Cancer
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The impact of metformin use on survival in prostate cancer: a systematic review and meta-analysis

New meta-analysis below.

This analysis of published PCa-Metformin studies is specifically to survival (which is why I began using Metformin >5 years ago).

I am not aware of statistics, but I expect that most Metformin users with PCa are diabetic. I know of a number of non-diabetic men with PCa (including myself) who were initially turned down by their GPs.

A few years ago, Life Extension suggest that Metformin might be a drug that everyone should be on as they age. LEF members received considerable resistance from their doctors, so LEF began pushing an over-the-counter AMPK activator [2] as an alternative. See also Swanson's AMPK Stimulator [3]. {AMPK = 5' adenosine monophosphate-activated protein kinase [4]}

{The role of AMPK in PCa is too big a topic to cover here.}

It might be a long while before we see a PCa survival study that reports on non-diabetic Metformin users, & also AMPK activator users.

...

"DISCUSSION

Principal findings of this study

This present systematic review and meta-analysis

represents the most comprehensive review to date on the association between metformin use and PCa prognosis by

including 13 cohort studies enrolling 177,490 individuals.

Overall, we find that metformin intake has a trend to

improve survival for patients with PCa in terms of OS {overall survival},

CSS {cancer-specific

survival} and RFS {recurrence-free survival}. Significant CSS benefits were noted in

studies conducted in USA/Canada with prospective, large

sample size, multiple-centered study design."

...

For those interested in potential mechanisms, the following is included (without helpful comments):

"Potential mechanisms

Several potential mechanisms for the antineoplastic

action of metformin have been noted.

Metformin, as an activator of AMP-activated protein

kinase (AMPK), may play an important role in cancer

metabolism. AMPK pathway is reported to inhibit mTOR

signaling and result in fatty acid synthesis, inhibition of

protein synthesis, and cell proliferation [26]. It has been

reported that fatty acid synthase is overexpressed in PCa,

breast cancer and pancreatic cancer, which is necessary for de novo fatty acid biosynthesis and malignant

phenotype. AMPK activation can reduce the expression

of fatty acid synthase and acetyl-CoA carboxylase, which

diminishes the metabolization and growth of PCa cells

[27]. Zadra et al [28] also suggested that suppression of

de novo lipogenesis affected AMPK-mediated inhibition

of PCa growth. In addition, metformin plays a role in

cyclin-dependent kinase (CDK) induction of autophagy,

cell cycle arrest, and apoptosis. Metformin can reduce

the activity of cyclin D1, leading to the inhibition of

PCa cell lines [29]. It has been verified that the cyclin

D1 pathway can serve as a regulator of androgen dependent

transcription and cell cycle progression in

PCa cells [30]."

...

{I came across the paper by chance - it hadn't appeared in my daily PubMed search for new PCa papers. Turns out that the journal OncoTarget has been delisted by MedLine. Papers going back to Vol. 1 (2010) are still available, but nothing since August.

OncoTarget is a peer-reviewed open-access publication, where authors pay to be published. Presumably, there is a question as to how much peer-reviewing occurs. The authors submitted the paper before the delisting & may now regret their choice of journal.}

-Patrick

[1] impactjournals.com/oncotarg...[]=22117

[2] lifeextension.com/Vitamins-...

[3] swansonvitamins.com/swanson...

[4] en.wikipedia.org/wiki/AMP-a...

31 Replies
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Patrick, thanks for all your great posts

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I am going to try again to get my husband's doctor to prescribe this. Thank you Patrick!

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Thanks, Patrick. I have a suggestion for other guys. I knew that my MO, along with the others at Kaiser, want proof in the form of a Phase 3 clinical trial. So I asked my PCP (primary care provider) who was satisfied with the research findings that Patrick has reported on our site. So ask the doctor you think might be more cooperative, & if one says no, try the other.

Neal

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Metformin is one of the least expensive generic drugs in the world, and there is little financial/research incentive for big pharma companies to fund expensive definitive trials for a new indication for localized or advanced prostate cancer.

(When I brought up the question with my local oncologist, he simply said "No" - it had no relevance. When I brought up the question with one of the top prostate cancer researchers, he advised caution for anything that had only shown benefit in studies involving mice or lab cultures as opposed to humans (regardless of retrospective correlations from human clinical records). Finally, when my own blood glucose went a little bit into the marginal range, my newly established Primary Care Physician heard me out as I threw out some stuff about the possible relevance of the inhibition of the "mTOR" (mammalian Target of Rapamycin) pathway in prostate cancer, and had no problem prescribing me Metformin.)

In my case, I think it may have helped me some with the diet/weight/metabolism issues of being on Lupron for 4 years now, too. I am now a 195 pound Peter Pan instead of a 205 pound Peter Pan. (Oh, Lordy, I hope that cable doesn't snap as I swing out over the stage! Ha. Ha. Ha. Ha. Ha.)

Charles

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Funny, Charles!

Good for you for successfully making the mTOR argument to your new PCP. I hope you 2 will have a wonderful relationship, as I have with mine.

I've been on Lupron for 10 years, & have been trying to have a healthy diet for fighting PCa for even longer. I've gone down from 165, a healthy adult weight for me, to 155, my high school weight, to as low as 150, my junior high weight. I reached my full height of 5'11" in the 8th grade, & have shrunk to under 5'10" (I just turned 76.) I looked healthy at those weights as a youth, but I I look too thin now. I haven't found the answer to gaining some weight back without sacrificing my diet.

Neal

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I could not take metformin, for I have kidney disease.

Rich

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Arm K, of the Stampede trial in the UK, uses 2x850mg of Metformin per day. I am on the trial but do not know when a trial result is due to be published.

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I have a favorite article about natural AMPK activators. Many of them are supplements that we already take like resveratrol, quercetin, curcumin, green tea, fish oil, CoQ10, reishi, turkey tail and aspirin. Many more in the article.

link: selfhacked.com/blog/natural...

-Dave

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Dave,

Tried the link and was refused access as 'an unsupported protocol" Is there another url/ link for this article?

I tried reservatol and quercetin in early days before surgery and neither seemed to have any impact on PSA but everyone is different as both seem to work for some guys.

I am currently using Estrogen patches as ADT and reduced PSA from 12 to 1.4 in s9 weeks however for several weeks I added CoQ10 and K2 as daily supplements.

I have blood work done every three weeks and discovered my blood Estrogen level plummeted. Dropped both, did some reading and it seems one or both absorb Estrogen. Subsequent blood test showed Estrogen level returned to previous level of 900.

I want to continue with Estrogen as it works well for me and hoping fro a long time.

My experience and but may be relevant for others.

Peter

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Good Morning pjoshea13,

Thanks for the references! While under the care of Dr. Charles "Snuffy" Myers for 5 years, he regularly prescribed Metformin and believes that it will eventually be available over the counter for everyone because of its benefits, cost, and few side effects.

His dose for me reached 2000mg/day. Current Med Onc says go no higher than 1000/day, so I take 500mg am and 500mg pm.

Best wishes. Never Give In.

Mark

Atlanta

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Hi Vandy,

I remember Patrick increasing to 2000 mg/day because of new research. If your MO is your prescriber, I guess you're stuck, unless you can convince him that 2000 is more beneficial. I convinced my PCP, who is my prescriber, based on the research that Patrick reported here.

I guess you're lucky to have an MO who isn't too much to a stick-in-the-mud to prescribe it at all. If you want, you could check Patrick's posts & see if he'll ease up even more--or convince you there's a problem in going over 1000. I think quite a few of us are at 2000 now.

Best of luck,

Neal

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I was DX in March 2014 as stage 4 Gleason 9 with multiple mets to my bones and nodes. After reading Snuffys book I asked my GP for a prescription for Metformin back then and faced no resistance (he probably figured what have I got to lose?). I've been taking 2000 mg/day ever since. I later became a patient of Snuffy In 2015. Metformin is part of the arsenal I've used to reach a point where My PSA has been undetectable for 3 years and latest Axumin scan was clear. I've been able to lose about 30 lbs. and get to a normal BMI through diet and exercise and likely with the help of Metformin despite being on triple ADT since I was DX. I've had no SE's from Metformin and Publix supermarket fills scripts for free. What's not to like?

Ed

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Hi Ed,

That's impressive. Glad you were with a responsive GP.

-Patrick

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Been on metformin since 2015. Rx by my RO who is colleague of Snuffy’s.

Bob

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Patrick

Thank you for sharing this. Snuffy put me on this years ago, and I am constantly explaining to internists, etc. why I take it. One doctor did a literature such while I was sitting there.

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I was taking metformin because of my diabetes. I went on a ketogenic diet lost a ton of weight and in 9 months my A1C went from 7.8 down to 5.6. The diabetes is under control now but I still take the metformin because Dr. Dominick D'agostiino keto expert says it has a lot of benefits for those with cancer mainly keeping insulin spikes down. That was all I needed to hear so I am keeping up with the metformin.

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I got my family doc to prescribe about 2 years ago after hearing about metformin at the PCRI Conference in Los Angeles. He had no problem prescribing and told me he had his wife on it as well as she had pancreatic cancer. My MO concurs with my metformin use and the dosage, 500 mg twice a day. The interesting item is that I come across several physicians, without cancer or diabetes, who take metformin daily as they believe it is good for you. Having said this, I will note that I have no idea if it has helped to slow my rising PSA. But I see little downside from my limited research.

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I've heard good things about metformin. My wife takes it for diabetes. I haven't heard of any bad side effects. I'll research a bit and ask my doctor about it when I see him in a week or so.

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Always thank you Patrick for the scholarly work in helping us all.

I provided my new Clinical Oncologist with refs below and he immediately wrote the prescription. I'm on 2x 500mg/day no issues or adverse impacts.

My robotic surgeon at PMH Toronto is a co-author of article below in Journal of Clinical Oncology (read tab for Full Test).

Following my surgery my PSA was 3.3 and looking ominous. He said NOTHING about Metformin despite the explicit recommendation in the article that "metformin should be considered first-line therapy among patients with PC and diabetes, not only for diabetes control but possibly to improve cancer prognosis".

I left PMH and the condescending arrogance and found a Clinical Oncologist who allowed me to talk and he listened fro a collaborative strategy fro MPC.

PS: Albert Einstein Institute for Aging has applied to FDA fro approval of Metformin as a prescription anti-aging drug due to it's documented multi-faceted benefits

Peter

harvardprostateknowledge.or...

webmd.com/prostate-cancer/n...

integrativeoncology-essenti...

ascopubs.org/doi/abs/10.120...

mdanderson.org/publications...

dailymail.co.uk/health/arti...

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Thanks for the links Peter! -Patrick

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I am non-diabetic Patrick--I think you know that. Dr. Donaldson has been convinced by me---and he now prescribes, many of his patients with Metformin---I was his first.

Nalakrats

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Hi, Like doesn’t say it. You writers are our lifeline. Whoever Dr. Donaldson is, we thank him and are looking for someone like him. Maybe we have one already but don’t know it. There are so many of you to thank, I don’t know where to start.

Mrs. S

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There are papers you can find on Google, by just typing in the search bar----Metformin and Prostate Cancer---Print them off and take them to your Doctor---if you have positive papers, that can be impactful.

Nalakrats

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To Nalakrats, That is precisely what I did, and it was successful, i.e. we got the 5 mo prescription from our oncologist. I guess we will try again when we run out, this time asking our urologist who is in charge at the moment. You know the following source which I think is quite convincing. If I repeat the quote perhaps it will help someone.

urologytimes.modernmedicine...

"In men receiving ADT, diabetes agent linked with significantly prolonged survival"

August 01, 2017By Cheryl Guttman Krader

Boston—Metformin may act synergistically with androgen deprivation therapy (ADT) to improve outcomes for men with advanced prostate cancer, according to findings of an observational study presented at the AUA annual meeting in Boston.

The investigation included 87,344 patients identified from national Veterans Affairs databases who were diagnosed with prostate cancer between 2000 and 2008, received ADT for >6 months, and were not on concurrent radiotherapy. The men were categorized into three groups defined as non-diabetics (61%), diabetics on metformin (17%), and diabetics not on metformin (22%).

Metformin use and overall survival in advanced PCa With follow-up data through May 2016, median overall survival for the non-diabetics, diabetics on metformin, and diabetics not on metformin was 7.1, 9.1, and 7.4 years, respectively. A multivariable Cox proportional hazards analysis controlling for age, comorbidity, year of diagnosis, PSA, and Gleason score showed that both overall survival and cancer-specific survival were significantly prolonged among the diabetics on metformin compared with the non-diabetic controls (hazard ratio=0.79 and 0.72, respectively; p<.01 for both endpoints).

Cancer-specific survival was also significantly improved in the men with diabetes not on metformin compared with the referent group (hazard ratio=0.91; p=.026), but overall survival was not significantly different (hazard ratio=0.99). The risk of skeletal-related events, which was evaluated as a marker of disease progression, was not significantly different in either of the diabetic groups compared with the controls.

“Previous studies have investigated the effects of metformin treatment in men with prostate cancer, but to our knowledge, ours is one of the largest studies of prostate cancer patients to date and also uniquely evaluates the subset of men on ADT,” said Kyle A. Richards, MD, assistant professor of urology at the University of Wisconsin, Madison.

“We were interested in studying this patient population because residual cancer cells after ADT demonstrate metabolic susceptibilities that make them amenable to synergistic treatment. Our finding of improved survival among the metformin-treated patients suggests that a prospective clinical trial is warranted.”

Prospective clinical trial planned

Planning for a prospective clinical trial is in an early stage. In addition, in their research laboratory at the University of Wisconsin, David Jarrard, MD, and colleagues are trying to determine the mechanism(s) by which metformin may improve survival of prostate cancer patients on ADT.

“Basic science studies indicate that metformin has direct antineoplastic activity that may be mediated by mTOR inhibition, but its anticancer benefit may also be related to its effects on insulin and glucose,” Dr. Richards said.

“We are now analyzing data on metformin dose as well as HbA1c and blood glucose levels to try to better understand the mechanism for the benefit of metformin that we observed.”

Dr. Richards noted that the study has limitations related to its retrospective design. In particular, due to missing data in the VA database, it could not control for all prostate cancer-related prognostic variables.

The work is funded by DOD PCRP #150221. The contents do not represent the views of the U.S. Department of Veterans Affairs or the U.S. government.

These days I could be accused of having an affair with Google! Jan

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Good For You--glad to help.

Nalakrats

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Hi all,

Les has been on Lupron and now Vantas for sixteen months. After discussing with our oncologist the retrospective results at the U of WI, he permitted us a prescription for 500 mg of Metformin for 5 months, one daily. I wonder what happens when we run out? I want Les to have a refill and a 3 month supply for 2 tablets daily.

Now that we have been transferred back to the urologist from the oncologist, I wonder if a refill will be possible. We are paying $100 per month for Modified Citrus Pectin and don’t look forward to a $20 replacement for Metformin from LEF, an organization we were members of and buyers from for many years and still respect.

Les is still doing quite well in spite of his horrific initial diagnosis, i.e. reminder, 1500 PSA, 7 + 9 GS, by which I mean that at age 78 he is working hard, lifting loads of compost the past several days, and stays at 156-160 lbs even after having had my turkey dinner three days in a row. (Not that we both wouldn’t be doing better if we followed the Brady/Bundchen diet. NFL games kept us going on salad and squash until after Thanksgiving proper.)

I should quit. Even if I’m not always writing, know that you are in our minds daily.

We aren’t giving up. Best, Mr. and Mrs. S

P.S. to Patrick, We heard Martha Argerich twice, once when young in Rachmaninoff’s third with Riccardo Chailly and tonight, at age 69, playing Chopin’s No. 1 in e minor. High recommendation from us both. Les has new hearing aids! FYI, we purchased Costco’s Kirkland Signature 7s with 6 programs including two for music. So far I like the one for live music. Also he profits on the phone and TV from the inductive Telecoil. I add this information since his hearing became much worse after chemotherapy and ADT.

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P.S. Leswell is on Metformin and is not diabetic.

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Good evening, Patrick. This time my reply is in the form of a post. Very curious about AMPK. Are you going to take it? Jan and Les

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Thanks again, for your great work Patrick. I can't seem to find the Oncotarget article, could you reply with the full link? I just get directed to the front page. My MO said there was no evidence that taking Metformin after diagnosis made any difference. He also said it was a risk of causing acidosis, where your body's pH falls to dangerous levels. Is that a realistic concern?

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Paul,

The number of annual prescriptions suggests that Metformin is fairly safe:

"This statistic represents the top diabetes drugs in the United States, based on prescriptions dispensed between July 2011 and June 2012. In this period, prescriptions for diabetes drug Metformin hydrochloride were dispensed over 49 million times."

statista.com/statistics/242...

Acidosis might be a concern in diabetics with renal insufficiency.

Try this link:

researchgate.net/publicatio...

-Patrick

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I don’t claim to understand this data but I’ve taken one 500mg tab twice daily and I’ve had what I and my docs consider very mild PCa progression for my pathology.

Whatever works!

Bob

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