U-Shaped PCa Risk - Metformin (& Warfarin & Vitamin D).

[pjoshea13]

A new Israeli Metformin study below [1]

"With 666,553 person-years follow-up, 1,592 men were diagnosed with prostate cancer. Metformin exposure in the previous year was positively associated with prostate cancer risk ..."

"However, exposure in the previous 2-7 years was negatively associated with risk ..."

There's an old Giovannucci study that added a wrinkle to the findings of other studies that reported that diabetics have a lower risk for PCa - risk reduction only kicks in after 12 months.

It's common for older men in the U.S. to have some degree of insulin resistance.

"In the United States, an estimated 60 to 70 million individuals are affected by insulin resistance. Statistics report that more than 40% of individuals older than 50 years may be at risk for insulin resistance ..." [2]

Insulin resistance is a pre-diabetic condtion, although most do not progress to diabetes. With insulin resistance, the pancreas secretes high levels of insulin, which might stimulate PCa growth. When diabetes occurs, it is because pancreatic beta cells have burned out and there is now inadequate insulin. A PCa risk factor has been removed. However, the PCa risk does not istantaneously change from elevated to negative.

The standard approach to new cases of diabetes is to prescribe Metformin & to try dietary changes to control glucose spikes. Insulin is generally not prescribed up front. Those who are new to Metformin appear to have increased risk of PCa, whereas long-term users appear to have protection.

Diabetics have a higher risk for all other cancers, which suggests that elevated insulin is a particular problem for PCa.

***

Something similar with Warfarin.

The first sign of PCa for some men is a DVT or a blood clot in the lungs. It is suggested that DVT cases be screened for cancer, since cancer alters coagulation factors.

& so, men who have begun to use Warfarin have an association with increased PCa risk.

It is thought that mico-clots have a role in metastasis. Circulating cancer cells that have docked on micro-clots are protected. Long-term Warfarin users have a lower risk of metastatic PCa.

***

In Nordic vitamin D studies, a U-shaped risk for PCa has been noted. Unless considerable 25-D reserves have been built up over the summer months, there will be deficiency by the end of the winter. Diet will not help much. Nor will cod liver oil, since there is an unfavorable vitamin A ratio, and vitamin A toxicity limits cod liver oil intake.

So who are these Nordic men with "high" vitamin D levels & excess PCa risk? It's well know in the PCa community that vitamin D is important. Dr. Myers was an early promoter. Nordic men who feel that that they are at high risk for PCa, will perhaps have the greatest incentive to use a vitamin D supplement. An association between high levels of vitamin D & increased PCa risk is to be expected.

One Swedish study that reported a U-shaped risk, went on to investigate survival in the same population. They reported that high levels of D were associated with greater survival.

***

Three examples of paradoxical findings, easily misunderstood but easily explained, IMO.

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/348...

Am J Epidemiol

. 2021 Dec 10;kwab287. doi: 10.1093/aje/kwab287. Online ahead of print.

Metformin Treatment Among Men With Diabetes and the Risk Of Prostate Cancer, a Population-Based Historical Cohort Study

Laurence S Freedman 1 2 , Nirit Agay 3 , Ruth Farmer 4 , Havi Murad 1 , Liraz Olmer 1 , Rachel Dankner 5 3

Affiliations collapse

Affiliations

1 Unit for Biostatistics and Biomathematics, Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Ramat Gan, Israel.

2 Department for Biostatistics, Tel Aviv University, Israel.

3 Unit for Cardiovascular Epidemiology, The Gertner Institute for Epidemiology and Health Policy Research, Sheba Medical Center, Ramat Gan, Israel.

4 Department for Non Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.

5 Department for Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Israel.

PMID: 34893792 DOI: 10.1093/aje/kwab287

Abstract

There is conflicting evidence regarding the association between metformin treatment and prostate cancer risk in diabetic men. We investigated this association in an Israeli population-based cohort of 145,617 diabetes-incident men, aged 21-90y, followed over 2002-2012. We implemented a time-dependent covariate Cox model, using weighted cumulative exposure to relate metformin history to prostate cancer risk, adjusting for other glucose-lowering medications, age, ethnicity and socioeconomic status. To adjust for time-varying glucose control variables, we used inverse probability weighting of a marginal structural model. With 666,553 person-years follow-up, 1,592 men were diagnosed with prostate cancer. Metformin exposure in the previous year was positively associated with prostate cancer risk (hazard ratio (HR) per defined daily dose without glucose control adjustment 1.53, 95%CI: 1.19, 1.96; with adjustment 1.42, 95%CI: 1.04, 1.94). However, exposure in the previous 2-7 years was negatively associated with risk (HR without glucose control adjustment 0.58, 95%CI: 0.37, 0.93; with adjustment 0.60, 95%CI: 0.33, 1.09). These positive and negative associations, with previous-year and earlier metformin exposure respectively, need to be confirmed and better understood.

Keywords: glucose-lowering medications; inverse probability weighting; marginal structural models; metformin; prostate cancer; time-dependent confounding; type 2 diabetes.

© The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.

[2] pharmacytimes.com/view/insu...

[Adam10]

Thanks for posting Patrick. When you say “An association between high levels of vitamin D & increased PCa risk is to be expected.” Should that be decreased PCA risk?Do vitamin D supplements decrease risk of PCA?

[pjoshea13 in reply to Adam10]

Adam,

The point is that insufficiency/deficiency is common at Nordic lattitudes. What would a man have to take to be in the "high" category? 10,000 IU/day? More? Some of those men - perhaps most will be taking super-high doses because they perceive themselves to be at risk for PCa. Perhaps due to familial risk; perhaps a high PSA but negative biopsy? Those men should have been excluded from a PCa study, since they could skew the numbers. Detection bias. One shouldn't be surprised to find a disproportionate number of cases in that group.

& in the study I mentioned, those men had better survival in spite of not being protected from incidence:

"In this study population, s-25(OH)D was inversely associated with total mortality during more than two decades of follow-up, despite, as previous reported, high s-25(OH)D was associated with increased risk of prostate cancer."

ncbi.nlm.nih.gov/pmc/articl...

You ask: "Do vitamin D supplements decrease risk of PCA?"

PCa cells down-regulate the enzyme needed to convert 25-D to 1,25-D, and up-regulate the enzyme that clears 1,25-D. This means that after diagnosis, (a) we have to rely on the kidneys for 1,25-D production & must avoid high levels of calcium & phosphorus, & (b) we must also maintain an adequate reservoir of 25-D.

The value of vitamin D for prevention is magnitudes smaller. However, there is some correlation of PCa with lattitude, and even the U- or J-shaped studies found greater risk with a poor vitamin D status.

-Patrick

[homer13]

I am a long time metformin user per Snuffy Myers. I am assuming from this Israeli study that nothing changes for me.......correct?

[pjoshea13 in reply to homer13]

Correct.

[Currumpaw]

Thank you pjoshea13,

I worked on the outside of my house for much of the summer usually wearing just shorts.

I still take D though.

Very interesting about the one year reversal of Metformin. Jekyll and Hyde comes to mind. Who would have thunk that?

Currumpaw

[6357axbz]

Are you modifying your metformin use based on this?

[pjoshea13 in reply to 6357axbz]

The association of increased risk with short-term use is simply detection bias. I think that doctors should give patients the opportunity to begin Metformin at diagnosis, if they have any degree of insulin resistance.

-Patrick

[GeorgeGlass in reply to pjoshea13]

What level constitutes insulin resistance? My blood glucose levels are usually around 96. My a1c was 5.1 recently.

[Bacana in reply to GeorgeGlass]

I would like to know this too as my hubby also has an A1C of 5.1

[GeorgeGlass in reply to Bacana]

probably when you get above 100 blood glucose is pre-diabetes, and A1C above 5.6 I think.

[GeorgeGlass]

I was reading about these topics yesterday. Good information!