PCa-specific Survival after Radical Prostatectomy Is Improved by Metformin but not other Antidiabetic Drugs

[pjoshea13]

New study from Finland below [1].

"Only postdiagnostic metformin use was associated with reduced risks of PCa death {53% reduction} and ADT initiation compared with nonusers."

While Metformin users would be predominantly diabetic, it looks as though "nonusers" inxlude non-diabetics.

"insulin and insulin secretagogues were associated with poor survival"

Old studies have associated diabetes with a reduced risk of PCa. I'm surprised that more hasn't been written about it, since diabetice have an increased risk for every other cancer type. A curious thing about PCa is that radio-labeled glucose PET is not a useful imaging tool, for the most part - unlike for other cancer types.

Many men at risk for PCa have some degree of insulin resistance. This causes the pancreas to secrete higher levels of insulin in an effort to overcome the resistance. If the beta cells burn out and there will no longer be enough insulin to cope with glucose spikes, and a diabetes diagnosis will be likely.

It seems obvious that, while glucose is not the preferred energy source for PCa, it may increase PCa risk via the elevation of insulin levels.

The initial treatment for diabetics involves dietary advice to control glucose spikes (the high-fat Mediterranean diet will do that), and the use of Metformin to inhibit glucose production. If this is enough to keep glucose low enough to be controled by available pancreatic insulin, the diabetic will not need to take insulin.

A diabetic who takes high levels of insulin, is back where he started before the beta cells began to fail.

The PCa literature is full of references to insulin-like growth factors (IGF-I & IGF-II) - 1,593 PubMed hits for <prostate " insulin-like growth factor">, but it is clear that the entire insulin axis is implicated. IMO

A surrogate for insulin resistance is the Triglycerides:HDL-cholesterol ratio. My rule of thumb is:

1:1 is exellent

2:1 is not good

3:1 is very bad.

Alas, a 1:1 ratio requires high-normal testosterone in my case. With ADT, I slip to 2:1. It would be far worse if I were not on 2,000 mg Metformin daily, IMO.

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/349...

Eur Urol Open Sci

. 2021 Nov 17;34:86-93. doi: 10.1016/j.euros.2021.10.002. eCollection 2021 Dec.

Prostate Cancer-specific Survival After Radical Prostatectomy Is Improved Among Metformin Users but Not Among Other Antidiabetic Drug Users

Roni M Joentausta 1 , Antti Rannikko 2 , Teemu J Murtola 1 3

Affiliations collapse

Affiliations

1 Tampere University, Faculty of Medicine and Health Technology, Tampere, Finland.

2 Department of Urology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

3 TAYS Cancer Center, Department of Urology, Tampere, Finland.

PMID: 34934970 PMCID: PMC8655383 DOI: 10.1016/j.euros.2021.10.002

Abstract

Background: Metformin has been linked to improved survival among diabetic prostate cancer (PCa) patients, while hyperinsulinemia and insulin usage has been related to worse prognosis.

Objective: To evaluate the association of metformin and other antidiabetic drugs with PCa death and androgen deprivation therapy (ADT).

Design setting and participants: The study cohort included 14 424 men who underwent radical prostatectomy in Finland during 1995-2013. Cases were identified, and clinical data were collected from patient files and national registries using personal identification numbers.

Intervention: Information on the use of each antidiabetic drug during 1995-2014 was collected from prescription registry of the Social Insurance Institution of Finland.

Outcome measurements and statistical analysis: The risks of PCa death and initiation of ADT were analyzed by antidiabetic drug use with the Cox regression method. Each antidiabetic drug group was analyzed separately to model simultaneous usage. Pre- and postdiagnostic uses were analyzed separately.

Results and limitations: Prediagnostic use of antidiabetic drugs in general had no association with the risk of PCa death. Prediagnostic use of metformin was related to a reduced risk of ADT initiation (hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.59-0.96), while high-dose insulin users had an increased risk. Overall, antidiabetic drug use after PCa diagnosis was associated with an elevated risk of PCa death. Only postdiagnostic metformin use was associated with reduced risks of PCa death (HR 0.47, 95% CI 0.30-0.76) and ADT initiation compared with nonusers. Study limitations are missing information on glycemic control, smoking, living or exercise habits, prostate-specific antigen, and Gleason score.

Conclusions: Among surgically treated PCa patients, use of metformin was associated with improved disease-specific survival, while insulin and insulin secretagogues were associated with poor survival. Metformin might be a favorable diabetes treatment among men with PCa.

Patient summary: In this Finnish nationwide study, we found that the risks of prostate cancer death and cancer progression are lowered among metformin users, but not among other antidiabetic drug users. Metformin might be a favorable treatment choice for diabetes in men with prostate cancer.

Keywords: Androgen deprivation therapy; Cohort; Diabetes mellitus; Metformin; Prostate cancer; Radical prostatectomy; Survival.

© 2021 The Author(s).

References

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[cesces]

"A surrogate for insulin resistance is the Triglycerides:HDL-cholesterol ratio. My rule of thumb is:

1:1 is exellent

2:1 is not good

3:1 is very bad."

Patrick

Do know what the cause and effect mechanism is?

If you use statins to alter that ratio, would it be reasonable to expect doing that to

a) improve insulin resistance, or

b) have no effect on insulin resistance

In your opinion.

[pjoshea13 in reply to cesces]

I may have come across the Triglycerides:HDL-cholesterol ratio as a stand-in for insulin resistance 30 years ago. Barry Sears of ZONE fame had a rule along the lines of triglycerides should be <100 & no more than twice HDL-C.

But this is from a paper published in April this year [2]:

"Type 2 diabetes mellitus (T2DM) is a worldwide growing health problem. IR and impaired β-cell function are considered as the primary defects in T2DM. Currently, the standard methods of measuring IR include the glucose clamp, the modified insulin suppression test, and the HOMA-IR, but these tests are not routinely measured in most clinical practices owing to the time and cost involved. Thus, early identification of IR by using simple and inexpensive method is essential for preventing T2DM.

"IR is characterized by a decrease in the ability of insulin to stimulate the use of glucose by muscles and adipose tissues and to suppress hepatic glucose production and output. It is worth noting that IR is often accompanied by dyslipidemia. Low-density lipoprotein (LDL), HDL, and cholesterol can regulate the function and survival of β-cells. HDL even improves insulin sensitivity of muscle and liver. Evidence suggested that dyslipidemias may not be only consequences but also contributors to the pathogenesis of T2DM. McLaughlin et al. first proposed that TG/HDL-C ratio could be used to identify overweight individuals who are insulin-resistant in 2003. Thereafter, several studies have reported that TG/HDL-C ratio could be a simple marker of IR"

...

"It is worth noting that TG/HDL-C has also been shown to predict cardiovascular events and nonalcoholic fatty liver disease (NAFLD) independently. In addition to being associated with IR, the lipoprotein phenotype is also associated with increased cardiovascular disease. A study of McLaughlin's group showed that TG/HDL ratio ≥3.5 predicts the presence of the small dense LDL phenotype (LDL phenotype B) with high sensitivity and specificity. Those insulin-resistant, dyslipidemic patients are at increased risk of cardiovascular disease. Cystatin C has been found to be closely related to T2DM and coronary heart disease. Recently, Klisic et al. reported that serum cystatin C levels were associated with TG/HDL-C ratio in adolescent girls, suggesting TG/HDL-C could be a surrogate marker of cardiometabolic disease. A cross-sectional study reported that a cut-off value of TG/HDL-C ratio of 0.9 in women (sensitivity = 78.8%, specificity = 77.3%) and 1.4 in men (sensitivity = 70.7%, specificity = 73.5%) could predict NAFLD.

"The mechanism of TG/HDL-C predicting IR is still unclear. When circulating TG persists at high levels, heparin activates lipoprotein lipase to increase intravascular lipolysis of TG, thus increasing the risk of tissue exposure to free fatty acids (FFAs). High FFAs may deteriorate insulin sensitivity via oxidative stress pathway. Previous studies have indicated that the TG/HDL-C ratio as a marker of lipotoxicity in β-cells results in impaired insulin secretion and increased β-cell apoptosis from high circulating TG levels. Shimabukuro et al. demonstrated that β-cell apoptosis is induced by increased FFA via de novo ceramide formation and increased nitric oxide (NO) production. Elevated levels of circulating FFA and lipoproteins transport to islets far more FFA than can be oxidized, leading to an increase in ceramide, inducible nitric oxide synthase (iNOS) expression, and NO production, which cause apoptosis."

...

Yes, I believe that anything you do to change the numbers for an improved ratio, is beneficial - even though we are talking about a surrogate, rather than IR itself.

-Patrick

[2] ncbi.nlm.nih.gov/pmc/articl...

[MateoBeach]

Just breaking out those who started metformin after diagnosis it might show two things: they became hyperglycemia and or insulin resistant after starting on ADT (not specified though). And those who did so were more likely proactive in their healthcare to do so. Hence better outcomes in their PC treatment. So metformin may be a concomitant marker for them.Still, I have normal glucose response, no pre diabetes, etc. an d choose to include metformin in my regimen. 1000 mg/day. Tummy doesn’t like more.

[Hidden in reply to MateoBeach]

I am up in the air for the reason you mention and some others. But, I still take 1000 mg per day a few days a week. I pick my drugs and supplements carefully to reduce burdening my liver and kidneys. I'm becoming particularly leery of supplements. A 3rd party lab tested psyllium from 8 different manufacturers. 5 failed their lead testing. 1 was so bad that a tsp of their psyllium husk bumped you up to the allowable lead limit for a full day.

[pjoshea13 in reply to Hidden]

One should be leery of supplements - or rather, leery of the supplier.

One example I can think of is zinc. Cadmium is usually found with zinc in nature. NutriCology is a respected company. Their zinc citrate is a few dollars more than many brands - but still inexpensive. They test each batch for cadmium.

-Patrick

[Hidden in reply to pjoshea13]

That is the main reason why I reduced my supplements. It isn't that I don't think that some nutraceuticals can help if I get 100% of the targeted dose. But some sups have 1% or less of the targeted dose and 25% or more toxins and heavy metals. If I want to utilize a substance I try to find an FDA-regulated version.

[CurrentSEO]

Patrick do you think berberine can have the same desired effect as Metformin or it have to be Metformin?

[pjoshea13 in reply to CurrentSEO]

Supposedly berberine is non-inferior. With Metformin you can be sure of the dose. If using berberine, go for a reliable brand with a standardized dose.

Just to confuse matters:

From 2019, a cell study [2]:

"In-vitro Synergistic Effect of Metformin and Berberine on High Glucose-induced Lipogenesis"

"The combination of Metformin and berberine exerted synergistic lipid-lowering effects on HepG2 cells by reducing total lipid content, triglyceride level, and the expression of the genes involved in lipogenesis."

This recent animal study used berberine with Metformin [1]:

"Berberine Improves the Protective Effects of Metformin on Diabetic Nephropathy in db/db Mice through Trib1-dependent Inhibiting Inflammation"

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/347...

[2] pubmed.ncbi.nlm.nih.gov/321...

[CurrentSEO in reply to pjoshea13]

Thank you Patrick, I'm taking Thorne berberine (approved by Consumers Lab) - 3 capsules a day, may consider adding Metformin later for synergy.

[Hidden in reply to pjoshea13]

So should we consider adding berberine to daily metformin intake?

[bean1008]

Thank you so much! My doctor just a few days ago added a new drug along with my Metformin… It is called glipizide and it is on the list of drugs mentioned in the study that you should not take along with your Metformin as it will potentially eliminate the benefit seen by Metformin in extending life.

[timotur]

I follow TG/HDL particularly close, having total cholesterol of 225. I've read that TG/HDL of < 2.0 means that your LDL is more of the large variety (good), than the small LDL-P variety (bad), which tends to form deposits on arteries.

I've been able to lower TG from about 130 to 45 over several years of improving my diet, particularly lowering fructose and simple-carbohydrate intake, avoiding high-glycemic foods, exercising and reaching caloric deficit at least once a day through delayed food intake. My TG/HDL ratio is 45/58 = 0.70

healthyeating.sfgate.com/ca...

[Hidden]

My MO said that while she can't recommend a nonuser take metformin if you are taking it and don't have side effects she recommends that you continue. She said that part of it is about insulin but that the main contributor is mTOR inhibition. I didn't ask her about a low dose of rapamycin so I'll bring it up next meeting.

pubmed.ncbi.nlm.nih.gov/302...