Simvastatin and Metformin?: Yesterday... - Advanced Prostate...

Advanced Prostate Cancer
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Simvastatin and Metformin?

Yesterday:

"Sanjay Gupta, PhD, of Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center will receive $962,000 over three years to investigate drug resistance mechanisms in prostate cancer. The funding is part of the Department of Defense's Idea Award program, that aims to improve quality of life by decreasing the impact of cancer on active duty service members and their communities." [1]

Something of a letdown to read that Gupta will be looking at Simvastatin and Metformin, two drugs I have been using for almost a decade.

"Gupta will study simvastatin and metformin--two drugs that appear promising in his preliminary studies. Together, the drugs weaken CRPC cells and halt metastasis. Simvastatin works by blocking the rate-limiting enzyme for cholesterol synthesis, called HMG-CoAR (3-hydroxy-3-methylglutaryl-Coenzyme A). Metformin activates AMP kinase (5'-adenosine monophosphate kinase), a so-called "master regulator" of androgen signaling in prostate cancer cells."

"Together with colleagues, Gupta will test whether the enzymes HMG-CoAR and AMP kinase represent novel therapeutic targets for CRPC--particularly CRPC that is already resistant to existing androgen inhibitor drugs. The researchers will transplant drug-resistant CRPC patient samples into mouse models and determine if changing the enzymes' levels via medications offers therapeutic benefits."

In 2014, Gupta published:

"Synergistic Simvastatin and Metformin Combination Chemotherapy for Osseous Metastatic Castration-Resistant Prostate Cancer" [5].

I have been looking through Gupta's papers on PubMed & came across a full-text 2017 review of Apigenin [2].

My own PCa-Apigenin review was posted two years before [3], so probably needs updating. It mentions a Gupta paper [4], but Gupta has a lot of apigenin papers - there are 23 PubMed hits for <Sanjay Gupta "Case Western" apigenin> [6].

-Patrick

[1] eurekalert.org/pub_releases...

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

[3] healthunlocked.com/advanced...

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

[5] mct.aacrjournals.org/conten...

[6] ncbi.nlm.nih.gov/pubmed/?te...

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something of a letdown? not sure if I understand you correctly.

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Meaning that if I thought Simvastatin + Metformin was a good idea ten years ago, based on what I was reading at the time, how does the DoD justify throwing a million dollars at it via their Idea Award program ten years later? What's suddenly new about it?

Of course, I was expecting additive benefit back then, not necessarily synergy, (from reducing cholesterol levels in PCa cells, & restoring insulin sensitivity). Well, I'm still here a decade later, but if there is synergy I'm not particularly impressed.

But I take my 2,000mg Metformin & 40mg Simvastatin without fail.

-Patrick

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Be careful, I was taken 2,000mg Metformin & 40mg Simvastatin and my total cholesterol dropped be low 100 and I had severe muscle weakness

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Is Simvastatin better than Atorvastatin for PCa? I was on Simvastatin but was changed to Atorvastatin after I had a kidney transplant. Supposedly better for the kidney.

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Graham,

Simvastatin & Atorvastatin are similarly placed in the lipophilic scale. We need a lipophilic statin for PCa cell uptake.

When comparing statins, there is the question of equivalent doses:

"Rosuvastatin appears to be at least 2 and 4 times as potent as atorvastatin and simvastatin, respectively, and at least 8 times as potent as pravastatin and lovastatin." [1]

However, relative potency can vary by medical situation:

"Our group has recently examined the effect of varying doses of statins on postoperative AF in 623 patients undergoing cardiac surgery.4 We concur with Lertsburapa and colleagues that statins significantly reduce AF and that this effect is dose-related. However, following propensity score analysis, we identified that the antifibrillatory effect of statins did not match their lipid-lowering capacity. More specifically, simvastatin 20 mg, which is an atorvastatin 10 mg equivalent based on lipid-lowering efficacy, demonstrated a statistically significant effect on postoperative AF when compared to no statins (OR 2.32, 95%CI 1.30-4.11), whereas atorvastatin 10 mg had no impact on AF (OR 1.05, 95%CI 0.55-1.99). In addition, the beneficial effect of simvastatin 40 mg (OR 3.89, 95%CI 2.03-7.45), which is an atorvastatin 20 mg equivalent, was significantly more pronounced than the effect conferred by atorvastatin 20 mg (OR 1.99, 95%CI 1.00-3.94) or atorvastatin 40 mg (OR 2.76, 95%CI 1.24-6.15) when compared to no statins." [2]

There are no PCa survival studies comparing Simvastatin with Atorvastatin.

As with Metformin, most statin users are treating a condition unrelated to PCa. We need studies on otherwise healthy men with PCa. We also need to know how statins might affect PCa treatment results.

My preference for Simvastatin at the time I asked my doctor for it, was due to the studies available at that time. Simvastatin continues to be popular with researchers, presumably because it has the biggest market share:

"Among available statins, atorvastatin remained the most commonly prescribed through 2006-2007, after which it was surpassed by simvastatin. In 2012-2013, simvastatin (41.4%) and atorvastatin (28.3%) were the most commonly used statins, followed by pravastatin (16.2%), rosuvastatin (11.2%), and lovastatin (7.0%)". [3]

-Patrick

[1] ncbi.nlm.nih.gov/pubmed?ter...

[2] jtcvs.org/article/S0022-522...

[3] jamanetwork.com/journals/ja...

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Thanks Patrick

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Also one more question if you will. Do Apigenins also have a J-curve with dosage and their effects?

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I am only aware of a dose-dependent suppression in the PCa studies.

-Patrick

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Just ahead of your time Patrick!

Nalakrats

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Mainstream is catching up ;)

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Thanks Patrick....great info....appreciate the posts...

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Thanks for posting this information! Happy Holidays!

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Thanks Patrick. Very interesting! Like you, I have been taking Simvastatin for over 10 years. It didn’t prevent me from getting Stage 4 prostate cancer 3 1/2 years ago, but maybe it, along with Metformin, will show synergistic benefits with ADT. I have also taken Metformin for about 2 years, and did a 6 cycle course of docetaxel last year. I would love to get 10 years (i.e. 7 more years) of hormone sensitivity before the ADT fails. By then we will hopefully have new second line therapies that will keep us alive even longer. It’s a crap shoot, but I like to have hope. Merry Christmas to you!

Mark

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I was taking simvastatin for around 20 yrs prior to dx with Stage 4 PCa. During my first visit with Dr. Myers he switched me to Crestor, if I recall correctly it was due to the way simvastatin reacts/interferes with the ADT drugs I am taking.

Ed

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I take Crestor and metformin as well. I think it’s helping.

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I read about Metformin being useful in delaying and even preventing prostate cancer. I asked a nurse practitioner about it at one of my doctors. They are husband and wife and very forward thinking. I have been taking 500 mg morning and night as well as 10 mg of Atorvastatin in the evening. In the evening I also take a Naltrexone capsule. It is formulated for me at a compounding center. This doctor suggested LDN, low dose Naltrexone. What it does according to the med sheet that comes with it is during the night it boosts the immune system. I was instructed to take it at night with my other supplements and medications as it wouldn't interfere with them.

Here is a link about LDN prescribed to help slow or prevent cancer. Copy the entire text to access it. Once you do there will be screens of info about LDN.

___________________________________________________________________________________________

Naltrexone: Immune Boost Fact or Wishful Thinking ...

sperlingprostatecenter.com/...

___________________________________________________________________________________________

Other supplements that work in a similar way to Metformin would be berberine and Life Extension's AMPK, both of which I take.

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You may already be aware of the (US) LDN site:

lowdosenaltrexone.org/ldn_a...

Best, -Patrick

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Thank you! Good info.

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rosuvastatin is primarily HYDROPHILIC,not lipophilic so even tho more potent w/r cholsterol lowering ,maybe < useful re cancer ?

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[1] "This is the first study to report the comparative effects of different statins on CaP cellular migration towards and within human BMS. The results demonstrate a clear effect on CaP migration towards and through BMS and on malignant PEC's ability to grow clonally in that location. However, this effect was limited to the lipophilic statins and was not seen with the hydrophilic statin, pravastatin. The differential effect of the two basic subtypes of this class of drug has been well described; lipophilic statins diffuse across cellular membranes and exert their metabolic effects in the liver and other tissues; hydrophilic statins require active transport across the cell membrane in order to exert their actions intracellularly. This action of hydrophilic agents is therefore predominantly hepatic and not peripheral (Stancu and Sima, 2001; Garwood, 2010) and this fact has significant consequences for the effects observed in neoplasms such as breast and other cancers (Campbell et al, 2006; Kotamraju et al, 2007; Koyuturk et al, 2007). This differential action was clearly evident in the results presented herein and may be an important consideration when interpreting data from population studies of the effect of statins or when planning statin-based prevention trials in CaP."

However, Rosuvastatin did show an effect - albeit at five times the concentration of Atorvastatin, Mevastatin & Simvastatin.

-Patrick

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

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Just change your name to Ramishohea and you'll be eligible for the $962K.

Good Luck, Good Health and Good Humor.

J-o-h-n Sunday 12/23/2018 7:49 PM EST

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See this old but interesting article which claims higher uptake in peripheral tissues and some glands by pravastatin vs. simvastatin: clincancerres.aacrjournals....

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In one of the cell studies [1]:

"Statins act directly on PC-3 cells with atorvastatin, mevastatin, simvastatin (1 μM) and rosuvastatin (5 μM), but not pravastatin, significantly reducing invasion towards BMS by an average of 66.68%"

"All statins, except pravastatin, induced a similar and marked reduction in PEC invasion towards BMS .., averaging 66.68% of control"

"Pravastatin, at doses up to 100 μℳ, had no effect on PC-3 colony formation or cellular proliferation in either clonogenic or BMS co-culture assays"

"... These morphological effects were not seen with pravastatin."

"... this effect was limited to the lipophilic statins and was not seen with the hydrophilic statin, pravastatin. "

See also [2].

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/225...

[2] ncbi.nlm.nih.gov/pubmed/222...

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Thank you Patrick! I am going to discuss with providers. Years ago had been on simvastatin but had some blood work issues with it. Time to revisit!

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Thanks for sharing. My husband's cholesterol is "borderline" and his PCP has mentioned a statin, and is considering Metformin as well to combat metabolic syndrome.

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Note this caution though - need to check our Tregs?

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

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Shouldnt you be glad that he can verify that these drugs may have helped you or are you saying you know they dont work? Or do you mean other drugs should researched?

Dominick

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Simply that the idea is an old one. Will the research turn up anything new? I think I have done well partly due the drugs, but I'm looking for new ideas.

-Patrick

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Patrick...hats off to you!!!!!!!!

I am sure that any statin drug is good overall. It has a great deal of bad press with th e homeopathic group.Metformin is not much better. These drugs may be worse than PCa.

I have to be the devils advocate here... I know metastasis must be stopped but maybe there is a safer way. I take 10mg of Crestor so I have skin in the game but I am fearful of Metformin. I would take a natural substitute and what about red yeast rice for Crestor.

BTW is DES a loser??????

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Further,we have to stop PSA from rising which is equivanent to saying I want to kill PCa cells.9 I am hormone sensitive so ADT will work fine.)My PSA rever goes down or stays the same yet I take everything in creation to halt its rise.I want to do the MRI multi parametric 3t blue laser. I dont know if medicare will approve it. It may be only for dx. or to supplement biopsy.

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