Metformin + ADT

[pjoshea13]

-Patrick

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.

[Neal-Snyder]

Hi Patrick,

Thank you for keeping us up to date with the research on metformin & PCa.

I used info that Chuck Maack provided to convince my primary care provider to start me on metformin, & then info you provided to convince him to double the dose to 1000 mg twice a day. Note to others considering approaching their doctor: I did not approach my med onc because at least at my Kaiser Hospital, they're wedded to waiting for a Phase 3 clinical trial report before they'll prescribe anything, whereas my PCP is more flexible. So think carefully about which of your doctors might be the least dogmatic or the most sympathetic.

Patrick, did they address the dosage of metformin the guys in this study were taking, or did any dose qualify? Is there a standard dose for Type 2 diabetics? Again, thank you.

Neal

[tonmead in reply to Neal-Snyder]

I am on the STAMPEDE trial in the UK, arm K, which means taking metformin. Dose is 850 mg twice a day. Been on this trial for about 3 months, no serious side effects ( some diarrhoea early on) hope this helps. Best wishes

Tony

[Neal-Snyder in reply to tonmead]

Extremely safe drug, Tony. Most commonly taken Type 2 diabetes drug.

Neal

[pjoshea13 in reply to Neal-Snyder]

Neal,

"Initial dose: 500 mg orally twice a day or 850 mg orally once a day

Dose titration: Increase in 500 mg weekly increments or 850 mg every 2 weeks as tolerated

Maintenance dose: 2000 mg daily in divided doses

Maximum dose: 2550 mg/day"

drugs.com/dosage/metformin....

So I would expect most were on 1,000-2,000mg/day.

It would be crazy to ignore dosage in this type of study. I expect there would be a dose-related benfit. Paper not yet published.

-Patrick

[Neal-Snyder in reply to pjoshea13]

Thanks Patrick. I wasn't aware of dose titration when I started or increased, & I had no SEs, but that doesn't mean anyone should follow my bad example. So it's good that you pointed it out. And you answered my question.

Neal

[Abouziz in reply to pjoshea13]

Hello,

My father was diagnosed with advanced pc and I was reading your post about adding metformin to his ADT treatment. I also saw this study which seemed to say no improvement from adding it.

jurology.com/article/S0022-...

I was wondering if anyone had any thought on this ?

Thank you all

[pjoshea13 in reply to Abouziz]

This was a study that looked at Metformin users. Typically, these would be diabetics. Diabetics have a poorer prognosis than non-diabetics. You can't logically compare diabetic Metformin users with non-users who would presumably be mostly non-diabetics.

Here is the intervention study (non-diabetics, 2,000 mg) that convinced Fr. Myers:

ncbi.nlm.nih.gov/pubmed/244...

-Patrick

[leswell in reply to Neal-Snyder]

Neal, If one has a selection of doctors, yours is excellent advice. Since we have just one, we’re counting on him to be flexible. He certainly has been thus far. We are keeping our fingers crossed for a prescription for Metformin. I’m still smiling about the hopeful news from Madison. Thanks to all those participating vets—and to you. (I’ve already thanked Patrick.) Mrs. S

[Neal-Snyder in reply to leswell]

Mrs. S, I'm glad to hear that your one doctor has been flexible so far, & I'm keeping my fingers crossed in support of you! Are you providing the doctor with Patrick's post, above? Please let us know how it goes.

Neal

[leswell in reply to Neal-Snyder]

Thank you, Neal, for your well wishes. I have printed Patrick’s post about the ADT and Metformin study results for Dr. H. What more could one want as proof of efficacy?

At our last appointment I requested a DHT reading. Will we get one? I have also put Mr. Maack’s article about that in Google Keep for us to study.

We appreciate every one of you.

Leswell and spouse.

[leswell]

Patrick, This is the most exciting study for us! I’ll pass this on to our family members who are in medicine. One niece (2 post doctorates, Harvard) is at Madison. Specialty? Fruit flies.

We’ll try to twist our oncologist’s arm this month to add Metformin, probably start with 500 mg twice daily. THANK YOU! - to Nal, too. Mrs. S

[Neal-Snyder in reply to leswell]

Is the oncologist more flexible & sympathetic, or the primary care physician? You don't want someone who goes by what has been established in Phase 3 double-blind clinical trials only. You want a doctor who will go along with your wishes based on the rather convincing available evidence.