Metformin

[pjoshea13]

New study below. 2,652 diabetics with PCa.

"A significantly lower percentage of metformin users were diagnosed with advanced prostate cancer as compared to nonusers (4.7% versus 6.7% ...)"

"After adjusting for the observed selection bias and other independent variables, metformin use was associated with a 32% reduction in the risk of advanced prostate cancer"

"This is the first epidemiological study to support the role of metformin in reducing the risk of advanced prostate cancer."

I suppose it will be a while before there is a study on non-diabetics.

I do have a question about the study. Metformin is now standard in the U.S. upon being diagnosed with diabetes. Metformin as monotherapy often fails in the first year, but is not discontinued. So, how did the diabetics not on Metformin differ from those on it? How might that have affected PCa risk?

-Patrick

ncbi.nlm.nih.gov/pubmed/275...

J Diabetes Res. 2016;2016:2656814. doi: 10.1155/2016/2656814. Epub 2016 Jul 31.

Association between Metformin Use and Cancer Stage at Diagnosis among Elderly Medicare Beneficiaries with Preexisting Type 2 Diabetes Mellitus and Incident Prostate Cancer.

Raval AD1, Mattes MD2, Madhavan S3, Pan X4, Wei W5, Sambamoorthi U3.

Author information

1Department of Pharmaceutical Systems and Policy, School of Pharmacy, West Virginia University, Morgantown, WV 26505, USA; Healthcore, Inc., Wilmington, DE 19801, USA.

2Department of Radiation Oncology, School of Medicine, West Virginia University, Morgantown, WV 26505, USA.

3Department of Pharmaceutical Systems and Policy, School of Pharmacy, West Virginia University, Morgantown, WV 26505, USA.

4Evidera, Lexington, MA 02420, USA.

5Sanofi U.S., Inc., Bridgewater, NJ 08807, USA.

Abstract

Objective. To examine the association between metformin use and cancer stage at diagnosis among elderly men with preexisting diabetes mellitus and incident prostate cancer. Methods. This study used a population-based observational cohort of elderly men (≥66 years) with preexisting diabetes and incident prostate cancer between 2008 and 2009 (N = 2,652). Cancer stage at diagnosis (localized versus advanced) was based on the American Joint Cancer Committee classification. Metformin use and other independent variables were measured during the one year before cancer diagnosis. Logistic regressions with inverse probability treatment weights were used to control for the observed selection bias. Results. A significantly lower percentage of metformin users were diagnosed with advanced prostate cancer as compared to nonusers (4.7% versus 6.7%, p < 0.03). After adjusting for the observed selection bias and other independent variables, metformin use was associated with a 32% reduction in the risk of advanced prostate cancer (adjusted odds ratio, AOR: 0.68, 95% confidence interval, CI: 0.48, 0.97). Conclusions. This is the first epidemiological study to support the role of metformin in reducing the risk of advanced prostate cancer. Randomized clinical trials are needed to confirm the causal link between metformin use and prostate cancer diagnosis stage.

PMID: 27547763 DOI: 10.1155/2016/2656814

[PubMed - in process]

[JoelT]

Patrick,

What are your conclusions from this abstract?

Joel

[pjoshea13 in reply to JoelT]

Joel.

The curious thing about diabetics is that they get more cancer of every type - except PCa. In fact, they get less PCa than non-diabetics. [1]

I tend to think of it differently - that non-diabetics who get PCa are likey to have some degree of insulin resistance - i.e. are producing greater levels of insulin: a known growth factor. Putting it another way: a loss of insulin sensitivity is a risk factor for PCa. & seemingly, uniquely so, for PCa. (& diabetes is a bad solution. LOL)

"Metformin may decrease prostate cancer (PCa) risk by reducing hyperinsulinemia-associated carcinogenesis {or through direct effects on cancer cells}." [2]

Diabetes occurs when pancreatic beta cells can no longer meet insulin demand (that's where the PCa protection starts to kick in, IMO.) If a diabetic can control glucose via Metformin alone, & reduce the need for insulin to what his pancreas can produce, it's a decent solution.

If Metformin isn't enough, the patient may remain on Metformin, but there will be an additional drug.

Those who were not on Metformin might not have been able to tolerate it, & be on an alternative drug, such as a thiazolidinedione (e.g. pioglitazone, rosiglitazone).

In either group, a patient might ultimately need insulin, which, depending on dosage, reintroduces the risk factor.

"The use of metformin or TZDs {thiazolidinediones} trended toward decreased odds of high-grade tumors and decreased risk of progression, while sulfonylureas and high-dose insulin tended toward an increased odds of high-grade tumors and increase the risk of progression compared to non-diabetics." [3]

However, in those who ultimately need insulin, Metformin seems able to moderate the increased risk (can't find the citation right now.)

Without knowing something about insulin use in Metformin users & non-users, one can't be clear about what is going on in the study.

It seems that Metformin had no effect on lesser cancer risk, which suggests that the benefit comes later. Perhaps a direct anti-cancer action. LEF seems to think that the most important thing about Metformin, is that it is an AMPK activator. Metformin also has a dampening effect on the insulin-like growth factor axis & down-regulates the IGF-I receptor. (There are over 500 PubMed hits for <prostate "igf-i" >.)

The apparent risk reduction for advanced PCa is consistent with reports on PCa mortality:

"Many site-specific cancers including breast, colorectal, lung, and prostate demonstrated reduced mortality with metformin use in at least one EHR {electronic health record}." [6]

"Our data demonstrate that metformin improves overall cancer survival compared to other hypoglycemic therapies in patients with DM2 and compared to patients without diabetes."

Those last 6 words are important, since while diabetics get less PCa, they have a poorer prognosis compared to non-diabetics.

I suppose that non-diabetics will be most interested in the direct anti-cancer effects, rather than its role in restoring insulin sensitivity, but I see insulin as a big threat. & ADT makes things worse: (new study [5]):

"Androgen deprivation therapy (ADT) is commonly used for treatment of prostate cancer, but is associated with side effects such as sarcopenia and insulin resistance." & there isn't a lot that can be done, but Metformin can help.

Having just upped my dose to 2,000 mg from 1,500 mg, I'm happy to see another pro-Metformin study, however opaque.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/245...

[2] ncbi.nlm.nih.gov/pubmed/248...

[3] sciencedirect.com/science/a...

[4] care.diabetesjournals.org/c...

[5] ncbi.nlm.nih.gov/pubmed/275...

[6] ncbi.nlm.nih.gov/pubmed/250...