Dr. Mark A. Moyad presented “S.A.2M.2: The Best ‘Natural’ and Heart Healthy Pills for Patients Concerned About Prostate Cancer” at the 27th annual International Prostate Cancer Update meeting on Thursday, January 26, 2017.
Keywords: prostate cancer, metformin, cholesterol, cardiovascular, placebo, aspirin, meta-analysis, supplements
How to cite: Moyad, Mark A. “S.A.2M.2: The Best ‘Natural’ and Heart Healthy Pills for Patients Concerned About Prostate Cancer” January 26, 2017. Accessed Aug 2020. https://grandroundsinurology.com/s-2m-2-best-natural-researched-heart-healthy-pills-patients-concerned-prostate-cancer
S.A.2M.2 : The Best “Natural” and Researched Heart Healthy Pills for Patients Concerned About Prostate Cancer
I didn’t want to give the exact same talk. So now I’m going to call it S.A.M., but SA squared, M squared, the Best Natural and Research Heart Healthy Pills for Patients Concerned about Prostate Cancer. There was a quick reason why I came up with this acronym, Sam is a unisex name. It can be for a boy or a girl. This is the same advice we give to breast cancer patients, colon cancer patients, prostate cancer patients, there’s are thousands of over-the-counter pills and different pills patients can take, and you only have so much time to discuss them. So if you could just get in three to five pills on a discussion with a prostate cancer patient, you obviously can’t talk about the 100 different supplements. So which are the top ones to talk about to make sure the patients are working with their primary care to see if they qualify. And so my argument has been if you memorize the acronym SAM, S-A-M, that’s good enough to discuss the natural pills that patients should prioritize before they take other pills out there, over-the-counter, for example.
So the mantra in 2017 is the same. When I was 29 and I came here long ago, heart healthy is prostate healthy. First do no harm. So the idea here is can we recommend a pill that in the worst case scenario just reduces the risk of a cardiovascular event, and the best case scenario reduces the risk of a recurrence and a cardiovascular event, but ultimately first do no harm? The patient wins every time. And the reason why I think this is a good place to turn for the future is we’ve spent a lot of money on some important trials, but in the end they were all negative trials, so we’re not recommending any of these products. From SELECT we know that vitamin E and selenium was a problem. But earlier trials, ATBC carrots showed that betacarotene in smokers actually increases the risk of lung cancer. And then lycopene really didn’t go anywhere. And now people are really excited about vitamin D, and I think it’s interesting, but before I jump on that vitamin D bandwagon you’d like to see more information, because a lot of people thought a lot of other supplements were going to work and it ended actually doing harm.
And then the latest de jour from last year was pomegranate, so people were all excited about pomegranate and that’s kind of died down. What happened, what was the result? And I would argue I never jumped on the pomegranate bandwagon because I never saw anything heart healthy about it. It was just a lot of sugar and a lot of calories, but how is this going to work out in prostate cancer?
There you go, three randomized trials up against placebo. So people getting excited about pomegranate juice and pomegranate extract really got excited based on non-controlled trials, looking at historic controls. Then finally you throw a placebo in there, no difference is detected between groups with regard to PSA, kinetics, and pain scores. Then you’ve got one, pomegranate extract did not significantly prolong PSA doubling time (PSADT). We’ve been waiting in this one for about a decade. And then the surgical neoadjuvant trial, our primary endpoint in modest size short-term trial was negative.
Three placebo-controlled trials and three showing no better than placebo, so that’s why I continue to push the idea that if you can talk about just a few pills, talk S.A.M.. These are natural, they’re all generic, they’re dirt cheap, like me, they’re heart healthy, and I get more excited about supplements in cancer for side effects. So these are three drugs that all came from natural sources.
The first one is statins. And I’m not sure if you know, the latest meta-analysis just came out in the past few weeks in The Journal of the American Medical Association (JAMA). So show me another pill in all of the medicine that can make this statement for primary prevention. You have completely healthy individuals, they have a slightly higher risk for heart disease, they haven’t had a heart endpoint, they haven’t had a heart attack, they haven’t had a stroke, no clinical event, and you put them on a statin and what happens? In adults it increased cardiovascular risk but without prior CVD events. It was associated with a reduced risk of all-cause and cardiovascular mortality, and CVD events with greater absolute benefits in patients at greater baseline risk. What you tend to hear by the statin conspiracy theorist all the time is there’s not enough trials in healthy people. 19 randomized trials, 71,000 individuals, average age running 51 to 66, and then the trial is 28 to 97. And in this meta-analysis they couldn’t find a serious event overall greater than placebo. So statins tend to get criticized a lot, but in reality when you look at the data and sum total it’s quite impressive in terms of primary prevention. We have nothing better. But it does with a catch, which I’ll show you in a minute.
This trial just finished, so it added to the statin data, another primary prevention trial, but this is 21 countries showing benefit across the board of 10 mg rosuvastatin, which is Crestor, one of my favorites, versus placebo. And just within five years showing a significant difference. So the trial is essentially stopped. But here’s the criticism I just lay on statins, some people taking statins don’t need a dose that high, but they can go to a lower dosage, or go on no statin at all if they made moderate lifestyle changes. So when you look at a number needed to treat of 1 in 100, or 1 in 75, you just wonder if some of these patients at intermediate risk were more active and changed their diet slightly if they would do as well in this situation as a drug. And my guess is I think they would. But some people do everything right and still can’t get that number down, like my father, and I understand that, so they qualify for pill.
So I want you to remember only one web site from today’s talk, CV risk calculator.com. It’s a fabulous web site, the American Heart Association, the American College of Cardiology put together for men and women. It takes you 20 seconds. You type in your numbers and it spits out whether or not the benefits of a statin might outweigh the negatives. We’ve been waiting for an absolute risk calculator like this from a legitimate organization for a long time. So this takes pooled cohorts and establishes a risk, and based on that risk decides, and opens up the discussion with your primary care doctor, does benefit outweigh risk, or does risk outweigh benefit?
If you look at latest meta-analysis we’re also seeing enough benefit here, we’re seeing benefit especially in radiation therapy. Not enough data amongst radical prostatectomy patients. But you could argue there’s just not enough surgery data to really have a strong meta-analysis as of yet.
So if you start seeing some of the newer data coming out, 2014, 2015 presented at American Urological Association (AUA) and other meetings, you do see some surgical data that shows that post RP statin use is associated potentially with a lower risk of recurrence. Now, in the end people always say to me, but this, a lot of this retrospective, you don’t have that much prospective data. But all we’re doing is reducing the risk of a cardiovascular event in men, and it doesn’t reduce the risk of recurrence in prostate cancer, the patient still wins. That’s why I like this idea.
And this is a new stuff coming out, which is exciting. Whether it’s from Boston or from Canada, the new stuff being published shows that it might actually enhance the effects of ADT, and these are very large databases, or allow more off of ADT, and more off treatment intervals, longer off treatment on IAD, for example, intermittent androgen deprivation. So these are very large databases. These are next publications you’ll see. This is not going away any time.
If you look at the Boston group, they argued in this study, because they’ve done some basic science with it, that actually statins compete, the molecule competes with DHEA and some other precursors that could stimulate the growth of an existing tumor. But there’s probably many, many mechanisms. And so I just decided to list all the mechanisms that I have read about and followed over the past 25 years. You could give it a variety of reasons why it could be helpful against a variety of cancers, from reducing, inhibiting angiogenesis, possibly VEGF, for example, reducing inflammatory markers, like CRP, which is used prognostically in some cancers. There’s been some talk about using it in prostate cancer, just stabilizing plaques, or just simply lowering LDL reduces oxidative stress. The list goes on and on.
And then there’s a new pathway that I should have memorized long ago, but this is a new pathway. We learned that the liver makes cholesterol and that you need to block that cholesterol production from the liver, and that’s how statins primarily work, and that is interesting. But we all know in medicine now after all these years that it’s not black and white, things are very grey. What organ is second to the liver in terms of cholesterol production and uptake, it’s the prostate. So if you actually block that precursor then you also reduce the number of intermediates downstream. And as more basic science is being done, larger amounts of these intermediates downstream then are possible stimulants or stimulators of well-known oncogenes. So there’s a lot of pharmaceutical development in blocking some of these other pathways to see if then you could have an effect on the progression of the disease. Now, no one is saying that you should get rid of all cholesterol. In fact, some of the most concerning patients that I talk to are the ones that think they want to take their LDL down to 20 or 30, but you need cholesterol to make vitamin D, you need it to make testosterone, your steroids. So one of the concerns I see is some men get their LDL down to 20, 30, 35, and then you start seeing their testosterone low. So sometimes the explanation for a low testosterone, a minority of cases, is the LDL is far too low.
And then the question is, well, which one? Most of them are now generic, which is fabulous. So they’re now affordable. I talked yesterday about Jim Fixx, who had the number one selling book 40 years ago, the Complete Book of Running. We didn’t have statins that were that accessible. He had high cholesterol, and my understanding is he wasn’t on a statin. So exercise alone in someone like that is not going to help, you need something synergistic, a pill with exercise. If I had my druthers, which pill would I use for the next chemo prevention trial, or let’s say you wanted to reduce recurrence after radical prostatectomy, or you wanted to do a trial of ADT, which one would I use? I would use the ones with the longer half-life. And the reason for that is if you miss a dose or miss several days the drug still works just fine. So we exploit this all the time. Here’s rosuvastatin, which is Crestor. It has a 19-hour half-life. So now you’re starting to see publications in cardiology where patients that can’t tolerate statins will go on a Crestor one time a week, or Monday, Wednesday, Friday, and they still get 20% to 30% reduction in LDL. So when I hear patients tell me I can’t be on a statin, generally in my experience 9 out of 10 times it’s because they don’t understand this chart. They have a lot to play with, a lot of different half-lives, and most people can tolerate a statin one day a week, three times a week, but you’ve got to exploit the ones that have the longer half-life.
So in the Primary Prevention trials, again, rosuvastatin was used here, Crestor. These are people who are perfectly healthy but they have high inflammatory markers. And then when they got their statin they got their cholesterol down to 70 and their CRP low, then below that you saw these very large reductions. So this is a phase 3 trial of rosuvastatin that was actually stopped in healthy people in less than two years in a phase 3, can you imagine that, because it already reached its cardiovascular endpoints and they had to instruct the placebo group that, hey, even though your cholesterol is running about 100 to 110, taking it down a little bit below 100 actually seems to be beneficial. I think we should be copying this in the future, this model if we end up doing a statin trial in prostate cancer, because I hear all the time that there too many patients on statins and so you can’t do an objective trial. I don’t agree with that, because some of these numbers we’re talking about, I rarely see, unless a patient has already had a cardiovascular event. So I think there’s plenty of room to do such a trial if the funding is there.
I want you to also remember that anytime there’s a successful drug, most of the time, there’s going to be a supplement that rides the heels of it. There’s going to be a supplement that makes a claim that it’s just as good as the drug. In some rare cases it is, in most cases it’s just a copycat trying to copy on the profitability of a successful medication. So patients should be aware of that. Do we have a cholesterol lowering drug over the counter, of course we do, it’s called red yeast rice, and it has a bunch of different components. But one compound in there is called monacolin K. It’s identical to Lovastatin. It’s basically a natural statin. So a lot of patients like it. In the old days we used to recommend it a lot, but now it’s become more expensive than the statins, so this is generally something that people utilize if they’ve gone through every statin and they still have side effects, and they want to try something different. But it’s just a statin in disguise, diluted, but it has potential. And people don’t realize that outside of this country there’s been very large trials of supplements. Some of the most successful supplements in the United States are actually just prescription drugs in other countries. It’s all perception versus reality when it comes to the word natural. So let me repeat that, some of the most successful selling supplements in the United States that work are actually prescription drugs in other countries, so it’s all perception versus reality. A good supplements is actually just a drug in disguise.
Another option if you can tolerate any statins is actually Zetia. It’s a cholesterol absorption inhibitor. In Boston and other places they’ve done basic science work on it. It’s an FDA approved drug. It can be added to a statin. There’s a suggestion, at least basic science-wise, that by reducing cholesterol or the cholesterol from food you can impact microvessel density. But this hasn’t gone much outside of the basic science area, but is now becoming a more and more popular drug, because it’s an alternative statin use. You won’t get the statin reduction, but then again, the side effects has been the same as placebo in most clinical trials. Again, this works differently. This blocks the absorption of cholesterol from food. There’s one standard dose, 10 mg, and it’s always an option for people that can’t tolerate a statin.
The A in S.A.M. is aspirin. Aspirin is a natural drug. It comes from willow bark, and it is dirt cheap, and aspirin is having a couple of really good years here. So in colorectal cancer right now the US Preventative Services Task Force is saying there’s enough randomized data that it reduces the risk of the colorectal cancer, even baby aspirin, in men as well as women. They made the announcement in 2016. So in men as well as women. Does it reduce deaths, we don’t know. And there’s all these other trials being initiated of aspirin to not only prevent cancer, prevent the recurrence of cancer, even a baby aspirin.
So the meta-analysis in prostate cancer, people get all impressed about aspirin in colorectal cancer, but we fail to mention that, look, when you have 39 studies suggesting a benefit of aspirin in prostate cancer, that’s interesting. There’s serious toxicity though, so it’s not be first choice, but as much we’re excited about colorectal cancer we should be excited about trials in the area of breast and prostate cancer.
This is a study that you haven’t seen yet that was presented at meetings this year. Actually, last year, and this is most impressive data you’ll see on aspirin thus far in prostate cancer. This is the Physician’s Health Study-1. It’s one of the first studies to look at taking aspirin prophylactically to reduce heart attacks. Only physicians were in this study, healthy physicians, and essentially they have now followed these physicians after 27 years. This is the longest duration of following a patient population to see prostate cancer risk, and they’re going to report in their future publication a 27% reduction in mortality, taking a greater than 3 tablets a week. So it’s only going to up the interest in using aspirin in the future in some capacity.
But again, I want to warn the audience, anytime it’s natural does not mean it’s better. Poison ivy is natural. Arsenic is natural. That doesn’t mean I recommend it to patients.
So, if you look at some basic phase 3 data it’s chilling. These are completely healthy women taking a baby aspirin, and after ten years they have significant increases in major GI bleeds and peptic ulcers. We have to do a better job to see who qualifies for even a baby aspirin. And this was a baby aspirin. And in this study it was every other day, and you still saw that kind of toxicity. And people think the word baby, when you think baby you think soft and cuddly. It’s not going to do any damage. It did a lot of damage in this study, so we need better tools on how to predict who goes on aspirin. That’s why I go back to CV risk calculator.com. It helps predict whether or not the benefit outweighs the risk. And so all you have to in urology and oncology is send them back to their primary care, have them go to this web site. Have a discussion, and if they qualify, great. If they don’t, based on cardiac risk, I’m not excited about them taking it for prostate cancer. I think that gets a little reckless.
The last one—oh, I want to mention one more thing about, there’s a natural aspirin out there. Remember, aspirin came from willow bark, but the active anti-inflammatory in aspirin is salicylic acid. And for of those of you who really enjoy history, like I do, imagine that you’re Bayer in 1900 and people are complaining that when they take aspirin they vomit and it tastes horrible. So a couple of scientists get together and say, “I know who to actually take this molecule and we’ll add an acetyl group on there and we’ll reduce the bitter taste. And they add this acetyl group and low and behold, that’s the group that impacts the platelet that causes the blood thinning. So by pure serendipity it became a blood thinner. It’s naturally not a blood thinner in its natural state. It’s when we slightly manipulate it. The moment it’s digested in the GI tract you lose that acetyl group, but then the active anti-inflammatory salicylic acid. Interestingly enough, you find salicylic acid in many healthy foods. So most of the fruits and veggies out there, and spices, you see low quantities of sort of natural aspirin out there. And you also see it being sold in supplements as white willow bark.
My last pill to talk about it metformin. That’s the “M”. Here you have meta-analysis showing that it has a potential roles somewhere in prostate cancer. I want to reiterate though about these three pills, S.A.M.. I think people expect too much from them in later stage disease. I’m not as excited about using these in metastatic disease. I think we expect too much from a pill that has very little toxicity. The excitement here is I think to prevent disease or to prevent recurrence of high-grade disease. I think when you ask for it do some incredible job for metastatic patients I think most people would be disappointed. But in metformin, at least, it’s use has been for side effects in ADT.
Here is the trial always published a while ago. This is the Nobes study using 850 BID. And look at this. When is the last time you saw a group of patients on ADT actually lose weight and blood pressure comes down. No change in lipids, but they actually become more heart healthy with a generic pill like metformin.
There’s one small study at ten Swiss centers of CRPC. They’re claiming a potential benefit of metformin even in early stages of castrate-resistant prostate cancer. Again, I’m excited about this, but this is not the time I would ideally want to use it. I’d want to use it earlier on, especially potentially with androgen deprivation, because for metabolic syndrome it can reduce the risk of most of those things. Metformin is arguably the safest, greatest drug ever invented in the United States for weight loss that doesn’t have an indication for weight loss. Why is that? Because it’s generic now, and we’ve learned that one of the mechanisms of how it prevents type 2 diabetes is patients lose weight. So it’s one of my favorite weight loss agents because it’s a heart healthy weight loss agent, unlike most of the weigh loss drugs we’ve approved in the United States, which end up getting pulled from the market because it helps you lose weight, but it was heart unhealthy, like sibutramine or Meridia.
There’s a phase 3 breast cancer trial going on, and there’s a little glimpse of what’s going on in the trial. It’s metformin versus placebo to reduce the risk of recurrence and possibly death. And we’re probably going to get data on this trial in the next few years. If this trial is a failure who gives a damn? And what I mean by that is that patients were still winning. Within six months of those allocated to metformin the average insulin drop is 11%, CRP 7%, the average weight drop is already 4 pounds in the first 6 months versus the placebo group, which is gaining almost 2 pounds. So the patients are at least becoming heart healthy on this product in the phase 3 trial.
And I want to reiterate something, because last night at the midnight I was on the phone with an individual who had lung cancer. And she wanted to go on metformin. And the doctor said, “Don’t do that, it doesn’t change your glucose that much, and the body is still going to make glucose and feed the tumor.” That is a naïve answer. The truth of metformin is it reduces insulin to significant amounts, in many of the clinical trials by one-third. That’s the mitogen, that’s the signaling agent. The great thing about metformin is it puts your glucose in cruise control, it doesn’t let it go too high or too low. So in these trials they’re seeing maybe a 1 point drop in glucose. They’re seeing it basically stay at the same number. It’s the insulin that’s dropped significantly.
And here’s the new trial that got me really excited. Here’s the polyp prevention trial from Japan. Average glucose is 100. So they’re not even basically pre-diabetic. They have a normal glucose. And after one year they stopped the trial because it was a 40% reduction in polyps. And did anyone notice the dose? I don’t know if anyone knows this trial has now been published. Did anyone notice the dose in the material and methods section? Get ready for this, remember the average dose that used in primary care is anywhere from a 1,000 to about 2,000, but the average runs about 850 twice a day. In the Japanese trial for prevention they used 250. So I’m now telling patients to buy a pill splitter. And many patients since this trial has been published do very well on 250 in controlling their blood sugar and reducing insulin levels. So maybe we’re using a dose that’s too high, because as you go to higher dosages you go to a higher rate of side effects. But this is fascinating to me.
My final thoughts is now the dose range runs 250 to 2,000. This is the highest dose, this is the most common dose. It’s being used in a lot of cancer trials. Maybe it’s too high. You have to take it with a meal, otherwise you will run into GI symptoms, like diarrhea, soft stool. Weight loss is one of the side effects, but side benefits. You’re not supposed to use it at the time of contrast agents or if there’s renal or liver insufficiency. The biggest catch I actually see with metformin, besides using too high of dose, is it will in some patients significantly reduce B12 and magnesium levels. You have to monitor patient’s B12 and magnesium levels in clinical trials and in the clinic if they’re going to take metformin daily. It’s well published, it’s well put out in meta-analysis, and I have personally seen it so many times.
So with that, I have three minutes to go. And I just want you to remember what I said last time, which is—which I said yesterday, don’t get too excited about pills too often, because the trial that launched metformin had a third group in it where people just changed their lifestyle to lose weight, and they exercised more. And at the end of ten years the lifestyle changers still beat the drug. But you never hear about the lifestyle change group, which was the third arm of the trial. What happens if you combine lifestyle change with metformin? I think you see synergism. I get excited. But clearly there’s benefit to lifestyle in terms of losing weight that might be equal to the drug.
The copycat for metformin right now that’s selling over-the-counter in Canada and the United States is called Berberine. You may have never heard of it. It’s an herbal product. It mimics metformin. I’m nervous about it because it has huge quality control problems. So if a patients look, I want to take that metformin, natural metformin over-the-counter called Berberine, I’m excited about testing a high-quality product, but there’s been a lot of quality control issues, so we still are just kind of watching it.
I just want to mention one other drug, just for the next time I see all of you, or some educational session. The other “A” in S.A.M. should be acarbose. If you haven’t heard of this drug, this actually blocks the uptake of carbohydrates. So patients have to take it two or three times a day. So every time you take carbohydrates you take it with your meal. The first bite of your meal. This has been out for decades. It’s generic. And for those people who can’t do metformin, this has data that’s arguably as good as metformin, especially in the area of cardiovascular risk. So they’ve had large trials showing these potential benefits in terms of improving lipids, increasing weight loss, improves blood pressure. And again, this blocks the uptake of sugar from food. It’s a wonderful mechanism, but it’s more of a pain in the gluteus, because you have to take it multiple times a day, generally with each meal at the first bite. But this is something we should look into too. It’s more popular in Asia than metformin, which I think is interesting.
The last thing in “M” as I finish up is multivitamins. Right here is Centrum Silver. It’s the only multivitamin involved in a phase 3 trial that showed it was safe with prostate cancer. That’s my point here. And I find so interesting, I’ll travel, and I don’t want to mention any cities, Boston, but the reality is I went there, and the CME bozos there said to me, “You can’t mention Centrum in your slide, because that’s favoring a pill.” And I said, but it’s reckless if I don’t mention that Centrum was used in the only randomized trial, because then I’m endorsing generic multivitamins, which are all the place. There are some generic multivitamins that say six pills a day. So I’m not going to mention the generic, I’m going to mention the one that went through the randomized trial that had quality control. So in CME we have to understand that it’s not like pharmaceutical, you have to mention the actual product because not all products are the same over-the-counter.