PCa Mortality & Statins

[pjoshea13]

New large study below [1]. U.S. study - Canadian data - European journal.

"A retrospective cohort study was conducted by abstracting prescription and health service records for 249,986 Saskatchewan men aged ≥40 years between January 1, 1990 and December 31, 2014 and comparing first-time statin and {non-statin lipid-lowering medications} users with age-matched non-users and glaucoma medication users for PC incidence, metastases at diagnosis and PC mortality ..."

"Substantial protective associations were observed between statin use and metastatic PC and PC mortality (HRs 0.69 ... and 0.73 .., respectively), which were stronger when compared with {glaucoma medication} use (HRs 0.52 ... and 0.51 .., respectively)."

"Similar associations were found for {non-statin lipid-lowering medications} versus {glaucoma medication} for metastatic PC (HR 0.57 ...) and PC mortality (HR 0.66 ...."

"Our analyses provide one of the more comprehensive findings to date that statins may reduce risk of metastatic PC and PC mortality, and the first to demonstrate that {non-statin lipid-lowering medications} have similar effects, supporting a cholesterol-based mechanism."

Two things jump out:

i) "supporting a cholesterol-based mechanism"

"Ample evidence exists in support of the potent anti-inflammatory properties of statins." [2] I have long wondered whether a significant part of the benefit of statins is due to this, rather than cholesterol inhibition. But since, both, inflammation & cholesterol are associated with aggressive disease, it hardly matters. I know nothing about anti-inflammatory properties of non-statin lipid-lowering medications.

ii) the inclusion of glaucoma medication use in the study. Anyone know why that might be?

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/308...

Eur J Cancer. 2019 Mar 5. pii: S0959-8049(19)30048-6. doi: 10.1016/j.ejca.2018.11.033. [Epub ahead of print]

Prostate cancer incidence and mortality among men using statins and non-statin lipid-lowering medications.

Van Rompay MI1, Solomon KR2, Nickel JC3, Ranganathan G4, Kantoff PW5, McKinlay JB6.

Author information

1

HealthCore-NERI, 480 Pleasant Street, Watertown, MA 02472, USA. Electronic address: [e-mail].

2

Department of Orthopaedic Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA 02115, USA; Department of Urology, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: [e-mail].

3

Department of Urology, Queen's University, Kingston, ON, Canada. Electronic address: [e-mail].

4

HealthCore-NERI, 480 Pleasant Street, Watertown, MA 02472, USA. Electronic address: [e-mail].

5

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: [e-mail].

6

HealthCore-NERI, 480 Pleasant Street, Watertown, MA 02472, USA; Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: [e-mail].

Abstract

BACKGROUND:

Statins have demonstrated protection against aggressive/late-stage and/or lethal prostate cancer (PC), but prior studies are limited by small populations, short follow-up and unequal health-care access. Research has not demonstrated that non-statin lipid-lowering medications (NSLLMs) provide a similar benefit, which would support a cholesterol-based mechanism. We sought to rigorously test the hypothesis that cholesterol-lowering drugs affect PC incidence and severity.

METHODS:

A retrospective cohort study was conducted by abstracting prescription and health service records for 249,986 Saskatchewan men aged ≥40 years between January 1, 1990 and December 31, 2014 and comparing first-time statin and NSLLM users with age-matched non-users and glaucoma medication (GM) users for PC incidence, metastases at diagnosis and PC mortality using Cox proportional hazards regression.

RESULTS:

In comparing statin users to non-users, a weak association was detected with increased PC incidence (hazard ratio [HR] 1.07, 95% confidence interval [CI]: 1.02-1.12) that disappeared when compared with GM users. Substantial protective associations were observed between statin use and metastatic PC and PC mortality (HRs 0.69, 95% CI: 0.61-0.79 and 0.73, 95% CI: 0.66-0.81, respectively), which were stronger when compared with GM use (HRs 0.52, 95% CI: 0.40-0.68 and 0.51, 95% CI: 0.41-0.63, respectively). Similar associations were found for NSLLM versus GM for metastatic PC (HR 0.57, 95% CI: 0.41-0.79) and PC mortality (HR 0.66, 95% CI: 0.51-0.85).

CONCLUSIONS:

Our analyses provide one of the more comprehensive findings to date that statins may reduce risk of metastatic PC and PC mortality, and the first to demonstrate that NSLLM have similar effects, supporting a cholesterol-based mechanism.

Copyright © 2019 Elsevier Ltd. All rights reserved.

KEYWORDS:

Hydroxymethylglutaryl-CoA reductase inhibitors; Pharmacoepidemiology; Prostatic neoplasms

PMID: 30850323 DOI: 10.1016/j.ejca.2018.11.033

***

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

[cesanon]

Patrick,

Do there exist any studies that differentiate between the various different types of stating, at least with respect to inflammation?

[pjoshea13 in reply to cesanon]

According to [2] in my post, the entire class can lower C-reactive protein, etc. I'm not aware of comparative studies.

-Patrick

[cesanon in reply to pjoshea13]

Myers told me that he preferred Crestor because it was stronger in some way relevant to prostate cancer. Unfortunately, I never followed that comment up for more detail.

[PhilipSZacarias in reply to cesanon]

My urologist/oncologist made a similar comment about Crestor when I suggested switching from Crestor to a lipophilic statin such as Lipitor. He strongly recommended that I stay on Crestor - it is more more efficacious than other statins at the same dosage. Cheers, Phil

[Abiathar in reply to cesanon]

Most of the experts feel that the more potent statins, rosuvastatin, atorvastatin and simvastatin in that order would probably have the most anti-inflammatory action (also called pleotropic effect)

[George71]

Patrick, which type of statin is best for PCa

[pjoshea13 in reply to George71]

George,

When I chose ten years ago, the best evidence was for Simvastatin, & I am still using it. However, it may not be the best - I can't really tell from the literature. But one thing is clear: it must be highly lipophilic or it will not be taken up by PCa cells.

"Atorvastatin, lovastatin, and simvastatin are lipophilic, whereas pravastatin, rosuvastatin, and fluvastatin are more hydrophilic."

-Patrick

[6357axbz in reply to pjoshea13]

I’m not sure if either lipophilic or hydrophilic is relavent if, as the study strongly suggests, it’s a cholesterol-based mechanism

[pjoshea13 in reply to 6357axbz]

You are probably thinking of liver production.

PCa cells will take up circulating cholesterol - VLDL-C will readily be taken up - but if they can't get as much as they want, the cells will make it. Hence the importance of the lipophilic form.

-Patrick

[6357axbz in reply to pjoshea13]

However, as stated in cesanon’s post above, Dr Myers thinks Crestor (rouvestatin) is one of the most effective for PCa, and

Abiathar’s post states that “most of the experts feel” that rouvastatin has most anti-inflammatory effect.

[pjoshea13 in reply to 6357axbz]

Good points.

Dr. Myers, in his vblog makes it clear that his interest in statins was due to most of his new patients being at risk of death from CVD. I can't recall him ever saying that he used statins to treat PCa itself.

Perhaps Myers noticed that Crestor was beneficial in a PCa context, & perhaps that was due to the anti-inflammatory effect? In any case, when PCa cells are starved, they will manufacture cholesterol, & I doubt that Crestor will prevent that.

You might be interested in:

"The differential effects of statins on the metastatic behaviour of prostate cancer"

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

"Lipophilic statins reduce the migration and colony formation of PC-3 cells in human BMS by inhibiting GGPP production, reducing the formation and the spread of metastatic prostate colonies."

"the lipophilic statins and rosuvastatin all had a significant effect on colony formation in both assays and cellular proliferation. Lipophilic statins and rosuvastatin significantly reduced the number of colonies to a similar degree in clonogenic assays and BMS co-culture (Table 1), with simvastatin being the most potent (reduction of 75.44% and 49.44%, respectively)."

However, the rosuvastatin dose was 5 times that of the other statins.

"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)."

-Patrick

[cesanon in reply to pjoshea13]

Hmm I wonder if it might make sense to to a combo of crestor and simvistatin?

[pjoshea13 in reply to cesanon]

I was thinking that too. Just enough Simvastatin to tame the PCa, & the difference made up with Crestor.

-Patrick

[6357axbz in reply to pjoshea13]

I may be mistaken but glaucoma medication (an eyedrop) in the study seemed to have the same positive effect on mPCa. Is glaucoma medication either lipophilic or hydrophilic or neither? My interest is that I recently switched from atorvastatin to Rosuvastatin (Crestor), which I take for CVD. I’m wondering if I should switch back for my mPCa.

[pjoshea13 in reply to 6357axbz]

If you are finding Atorvastatin & Rosuvastatin to be equivalent in terms of cholesterol levels, I'd opt for the lipophilic Atorvastatin. If not, or if there is a side-effect issue, the decision will be more difficult. But those two statins are not the only options.

-Patrick

[6357axbz in reply to pjoshea13]

Thanks Patrick. My dilemma is that I have found nothing in the medical literature regarding lipophilic versus hydrophilic with respect to statins and their positive effect on mPCa, only impressions from fellow posters to this site. Some are very articulate and state very technical reasons but things are not always what they seem. To that point the study you posted (many thanks to you for that) said men taking glaucoma meds get the same benefit for increased OS. Are these two medications equivalent when it comes to being either hydrophilic or lipophilic? If not then the mechanism that retards mPCa is something else.

[PhilipSZacarias in reply to pjoshea13]

Hello Patrick, please see my reply to cesanon. If the primary benefit of statins is the reduction in cholesterol (as per the Van Rompay, et al paper and others), which is a feedstock for steroid synthesis, then any statin will be beneficial providing the dosage is adjusted to achieve a significant reduction in cholesterol. Crestor remains the most effective on an equivalent dose (mg) basis. Cheers, Phil

[ITCandy]

So is a statin beneficial to someone that doesn't eat animal products or does it have more to do with stopping cancer cells from making their own cholesterol?

[pjoshea13 in reply to ITCandy]

IT,

Diet aside, solid tumors accumulate cholesterol. In PCa, this is a double issue, since cholesterol can convert to androgen.

Cholesterol circulates attached to lipoproteins. It is the smaller lipoproteins that can be taken up by PCa cells. You would need to test for VLDL-C to find out if circulating C favors PCa. Men on ADT tend to have more VLDL-C.

But the irony is that men with low LDL-C & very low VLDL-C are at greater risk of inducing PCa to make its own.

PCa wants cholesterol just like other solid cancers, so will make it if necessary even if not on ADT. If on ADT, PCa has a double need for cholesterol.

Personally, I am less concerned with circulating C than with the ability of PCa to make it. Hence my interest in lipophilic statins.

-Patrick

[ITCandy in reply to pjoshea13]

As always, much appreciated.

[6357axbz in reply to pjoshea13]

Patrick, I emailed one of the authors of the new study you presented regarding whether they considered the distinction between lipophilic versus hydrophilic statins in their study and here is their reply:

“I am so sorry to read about your present situation, and to be able to most thoughtfully and completely respond to your question, I consulted with our paper’s co-first author, Keith Solomon (cc’d), to draw on his extensive knowledge of the biochemistry of statins. Please note that while we attempt to offer any advice we can concerning the use of statins in the setting of aggressive prostate cancer, neither of us is an MD, and it is important to consult with your Oncologist, Urologist and PCP for a full understanding of the clinical application of statins. Please read below for Keith’s detailed thoughts.

We did not distinguish between hydrophobic and hydrophilic statins, as the information that we abstracted did not include these distinctions. I know that some investigators have found distinctions between hydrophobic and hydrophilic statins, and some of the differences between the structure of these drugs may be impactful, but I think not.

I’m going to assume that you are not a biochemist so I’ll try to explain my reasoning in a manner that someone without this expertise would be able to understand, so please excuse my use of analogy to help me get the salient points across, but otherwise the amount of a priori knowledge required would make understanding difficult.

When prostate cancer has spread (i.e. metastasized) the main and time-tested treatment is androgen ablation therapy (aka chemical castration). The reason that this is usually quite effective is that at all points the normal healthy prostate and the malignant cancerous prostate are completely dependent upon testosterone (and related molecules) for the growth of the prostate (the whole organ and its cellular components) i.e. testosterone is prostate fuel. Since nearly all the testosterone in your body is produced by the testes, stopping the ability of the testes to make testosterone cuts off the fuel supply and stops the growth of prostate tumors. For a while (and in some cases a very long time) this is a very effective treatment; tumors shrink to nearly nothing, pain dissipates, and things return to relative normalcy. A good way to think of it is to imagine the prostate tumors as cars –highly dependent on gasoline supplied by a service station—cut off that supply of gas and the car stops running.

But after a while a horrible insidious event occurs –getting back to the car analogy—the car starts to make its own gas (it no longer requires a gas station and cutting off that supply is no longer useful!). It is at this point that statins enter the picture. Testosterone and similar molecules (referred to as androgens) are made from cholesterol i.e. cholesterol is a building block for androgens.

Statins of all kinds target the liver (the major source of cholesterol) in which they interfere with cholesterol synthesis, reduce the level of cholesterol in your circulation, and thereby reduce the amount of cholesterol available to make androgen – this would occur whether the statins are lipophilic (hydrophobic) or hydrophilic. All that matters are the potency of the statin to reduce circulating cholesterol.

Lowing circulating cholesterol likely is insufficient to impact disease progression alone, but in conjunction with abiraterone may be more impactful than using abiraterone alone (what abiraterone is doing is blocking the use of cholesterol to make androgen). By lowering cholesterol and blocking the ability of cholesterol to be turned into androgen you may really lower the ability of the tumor to make its own fuel!

It may be that statins are working in other ways in which being lipophilic or hydrophilic matters, but I’m quite unsure of this and can think of no plausible reason why they should, but there are lots of things we do not fully understand and this, of course, may be one of them.”

[Ralph1966 in reply to pjoshea13]

Now I am really worry, because I asked my cardiologest to add simvastatin to the Zetia (non statin cholestrol lowering medication).

This dropped my LDL to 57!

Now the cancer cells will be non-sensitive to statins??

More over I asked him today to change Simvastatin to Rosuvastatin (Crestor).

Any one has an answer, please?

[6357axbz]

I was remiss in not reading your referenced article "The differential effects of statins on the metastatic behaviour of prostate cancer". Having done so I better understand the hydrophilic vs lipophilic properties of statins. It does seem that Rosuvastatin has the same benefits as more lipophilic statins, albeit, as you pointed out, when given in higher doses. Apparently it has both lipophilic and hydrophilic properties. My new Rosuvastatin script is 40mg/day replacing 40mg/day of atorvastatin. As I understand dosage equivalencies my new Rosuvastatin Rx is about a 3.0 to 3.5 x higher dose than the atorvastatin was. Hopefully that’s sufficient to get some mPCa benefits.

Thanks again!

[Advo__cate]

Do you supplement with CoQ10 while on statins? Is there a favorable dosage?

[pjoshea13 in reply to Advo__cate]

It is prudent to take CoQ10 while on statins, IMO.

However, from the Mayo [1]:

"At this time, coenzyme Q10 isn't universally recommended for preventing side effects from cholesterol-lowering drugs known as statins.

...

"Although statins are well-tolerated by most people, they can cause muscle and joint aches. Statins have been found to reduce the amount of naturally occurring coenzyme Q10 in the body.

"Because coenzyme Q10 plays a role in muscle cell energy production, some researchers have proposed that taking a coenzyme Q10 supplement might reduce the risk of muscle-related side effects.

"Scientific studies to determine the effectiveness of coenzyme Q10 in reducing statin-related muscle pain have had mixed results. Some studies show a benefit while other studies show no effect."

Harvard Health is much more negative [2]:

"MYTH 3 Taking CoQ10 prevents muscle aches caused by statins.

"Coenzyme Q10 (CoQ10) is a vitamin-like substance made naturally by the body that is involved in energy production in all your cells. It's also sold as a dietary supplement and touted as a way to boost energy and "support heart function," as the product labels assert. Taking a statin lowers CoQ10 levels, and scientists have wondered if raising blood levels of CoQ10 might help treat statin-related muscle aches. But so far, the results have been mixed, with no solid evidence to support that idea.

"Some physicians maintain that trying the supplements for a month or so is likely safe. However, research suggests that CoQ10 may reduce the effectiveness of warfarin (Coumadin). That could raise the risk of a dangerous blood clot, so don't try CoQ10 if you are taking that medication."

IMO, "mixed" results do not justify calling it a "myth". & there is a plausible biological basis for replacing the lost CoQ10 caused by the statin.

Having had muscle aches & finding that CoQ10 help, I do take CoQ10.

It is possible that there is A PCa benefit too. I don't know what the optimum dose is. I take CoQ10 at a low dose & I should make an effort to figure out what might be best for PCa. There are 10 papers on PubMed that may be helpful ... or not.

-Patrick

[1] mayoclinic.org/diseases-con...

[2] health.harvard.edu/heart-he...

[Advo__cate in reply to pjoshea13]

This is helpful. thank you.

[PhilipSZacarias]

Hello Patrick, I was able to obtain a copy of the paper. My understanding for comparing the populations of patients on statins and on non-statin lipid lowering drugs to a population on glaucoma medication was to reduce any potential bias caused by the selection process (selection bias). The assumption is that the glaucoma medication has no impact on prostate cancer occurrence or progression, but this was not discussed in depth. Nevertheless, I believe this further validates the usefulness of statins in slowing progression. I can forward the paper if you want a copy. Cheers, Phil

[6357axbz]

Patrick, regarding the anti-inflammatory versus cholesterol inhibiting properties of statins and their effect on mPCa wouldn’t the fact that statins don’t come close to eliminating cholesterol but only reduce the levels in our systems to get them into a suggested range to minimize CVD risk, would that not indicate it’s more the anti-inflammatory properties of statins that help with mPCa since the cholesterol is always there?

[pjoshea13 in reply to 6357axbz]

I was never interested in statins before I had PCa. More than half of the men who have heart attacks have normal cholesterol [C]. The drug companies say that lower C is always better, etc., but that seems crazy to me.

I think that eliminating inflammation and balancing hormone levels would have considerable impact on cardiovascular risk. Here's a recent Dutch paper [1]:

"In male patients with manifest atherosclerotic disease, low T/E2 ratio was associated with increased systemic inflammation, increased inflammatory plaque proteins, and an increased risk of future MACE as compared to men with normal T/E2 ratio. These effects are strongest in men with elevated BMI and are expected to be affected by aromatase activity in white fat tissues. Normalization of T/E2 ratio may be considered as target for the secondary prevention of CVD in men."

In other words, I think that most men should stop worrying about cholesterol & should tackle the underlying problems of the T:E2 ratio & inflammation.

But for cancer, cholesterol is a legitimate target (along with inflammation). The value of statins is dose dependent. We may think that by reducing circulating C, we are reducing PCa uptake & depriving the cells, but when PCa is thwarted, it starts to make its own C. Statins prevent this.

Having very low C is not protective in men with PCa. PCa manufacture of C must be inhibited.

ADT tends to increase the fraction of LDL-C that is VLDL-C, and that increases the availability of C to PCa cells. IMO, a statin will significantly slow progression only if it can slow C uptake. But to prove that, we would need to have a study on men with near-zero C-reactive protein levels.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/300...

[6357axbz in reply to pjoshea13]

Patrick,

I don’t mean to belabor this but as a final, unsolicited, comment I’ll offer the following from the primary investigator, who I’ve been cooresponding with, for the article you brought to us, “Prostate cancer incidence and mortality among men using statins and non-statin lipid-lowering medications.”

“There is good evidence that lipophilic statins will be taken up by cells more easily than hydrophilic statins and if true it certainly could be explained and would not be surprising. The problem is that under normal statin dosing regimens the the likelihood that sufficient statin ever gets to these cells is, I believe, quite remote. There are scenarios in which it might be possible to get statins at sufficient levels to directly affect prostate cancer cells--for example IV delivery or a very large oral dose might do the trick. Of course under those scenarios you would likely have off target effects as I've treated numerous cell types with statins and they are all killed by statins through a process referred to as apoptosis (there is nothing particularly special about prostate tumor cells with regards to being affected by statin treatment). If luck is on our side there might even be a dose of statins that affects prostate cancer cells that does not affect normal healthy cells (I have no idea if this is even possible). If a clinician were to propose using statins as a chemotherapeutic it might be something worth trying.

With regards to our recent publication--what we were able to show is that drugs that lower your cholesterol systemically (not just statins) reduce the incidence of late stage or aggressive fatal disease. Our interpretation is that taking statins over time lowers that chance of having aggressive fatal disease if you ever have prostate cancer.. There is no suggestion in our work that once you have prostate cancer that statins are a useful treatment for disease. Statins may be useful in combating extant disease (such as the scenarios indicated above, or as I indicated in a prior email in conjunction with abiraterone, and perhaps in other was as well) but our paper did not address that.”

[pjoshea13 in reply to 6357axbz]

Thanks for sharing. -Patrick