Dr. Moyad presented at the 26th International Prostate Cancer Update on Friday, January 22, 2016 on “Statins, Aspirin, and Metformin (S.A.M.): The Best “Natural” Pills for Patients Concerned about Prostate Cancer.”
Keywords: prostate cancer,Â statins, aspirin, metformins, cholesterol
How to cite: Moyad, Mark A.”Statins, Aspirin, and Metformin (S.A.M.): The Best “Natural” Pills for Patients Concerned about Prostate Cancer” Grand Rounds in Urology. January 22, 2016. Jun 2019. https://grandroundsinurology.com/prostate-cancer-mark-moyad-SAM-best-natural-pills-for-patients-concerned-prostate-cancer/.
Statins, Aspirin, and Metformin (S.A.M.): The Best “Natural” Pills for Patients Concerned about Prostate Cancer
This is the simplest talk of the conference, but I think it’s going to drive home the point. We watched over 30 years now trials costing a lot of money. I appreciate those trials. I think Dr. Crawford remembers going back even 15, 20 years ago at this meeting. These costs have been very high, and we’ve learned something, but we still haven’t walked out with an agent to help patients either adjuvantly or in prevention. So, we had the select trial, that’s over $100-plus million U.S. dollars; that was taxpayer dollars. At least we learned that more is not better. We had the athatacopheral beta carotene trial and simultaneously a trial called CARET, because forever we thought that beta carotene could reduce the risk of a variety of cancers. It turned out in smokers and those people exposed to asbestos, essentially, that there was in increased risk of lung cancer. So, that was the first two trials to show clearly an increased risk of a cancer in smokers, and even in ex-smokers now, we believe, exposed to high doses of supplements. Over the past decade I watched the lycopene, I’ve watched the vitamin D; we’ll talk about that at lunch. I’ve watched people talk about all this data on what’s going to be added for prostate cancer, and we don’t have anything. One of my take-home points today and at noon will be this; I am still a huge fan of supplements under the right conditions. A good supplement’s like a good drug, but what we’re seeing in cancer is that if supplements really have a role, it’s for treating some side effects, not necessarily right now in the treatment of the disease. Patients want to know what I can take that’s natural? What can I take that’s low-cost? What might benefit me over everything else? So, that’s what we’re going to talk about. I came up with in publication about three years ago, because physicians always told me, and nurses told me, that they only have minutes to talk about nutrition and supplements, and there are hundreds of supplements that we address. What’s the top two or three pills that they could talk about that are natural, they come from a natural source, that you could discuss with patients after they’re diagnosed, or those at high risk. So, my argument has been that clinicians need to embrace the acronym S.A.M., not just in prostate cancer, but I just did a text in breast cancer and the same data exists there. I like to talk to patients and spouses, also, about what this data shows. Again, I remind you, this is a natural, generic, heart-healthy options, all three of these. So, what are they? Let’s start with S, that’s Statins. With as much criticism as statins get, this is something that urology never gets to see. One of the largest analysis in the Cochrane database ever done on statins, just published, didn’t make a single newspaper, and here’s the conclusion, and I challenge you to find me another pill in the history of medicine that can give you the same conclusion for primary prevention. When used for primary prevention, statins are associated with lower rates of all-cause mortality, major vascular events, and revascularizations compared to placebo. For the women in the audience, also remember the word revascularization. As much criticism as statins get, they don’t do anything; it’s a conspiracy. The reality is, when you look at the data, even with women, people never talk about revascularization procedures. Of course you don’t want someone get a CABG. Of course you don’t want to see them getting stented. The largest reductions we’re seeing in men and women are in those procedures; that’s where the real benefit of statin lies, in preventing having to go to an extensive surgical procedure. I wish people would talk about that data. 18 randomized trials, 56,000 individuals, and of course we have toxicity, which I’ll talk about. So, if a patient really needs it after diet and exercise, it makes sense, in the data there for women, to me, it’s just as good as we see for men. So, that’s all-cause mortality. What about prostate cancer? Here’s the latest meta-analysis suggesting a potential benefit of statins on prostate cancer treated with RT but not among radical prostatectomy. Not among radical prostatectomy because we just don’t have enough data yet. That’s my opinion. So, it’s significant in radiation enough, whether you look at Sloan Kettering data, MD Anderson data, what’s significant there to potentially act as a chemo sensitization agent–we talked about radiation patients–but now there’s new data coming in from all around the world, and it’s retrospective data for the most part. If you look at surgical series, patients were on statins might have actually had an improved prognosis, and the worst-case scenario, all you’re doing is reducing the risk of the number one cause of death in men, which is cardiovascular disease, so you’re still benefitting them if they qualify. I’ll get to if they qualify in a moment. These two papers just getting published; one from Mass General, one from Canada, showing statin use in the time of ADT was associated with significant increase in the type of progression on ADT, even after adjusting for established prognostic factors. That was just actually published; a nice series from Boston. ADT falling primary – – RT, statin use was associated with improved overall survival, and maybe more off-treatment intervals when you are on interventive androgen deprivation. They have done some recent lab work which was just published in there from Boston suggesting that one of the mechanism of action here is that it competes with DHEA receptor intake inside the tumor. But, here’s your pleiotropic properties of statins. It’s not just the fact that they lower cholesterol; if you look at tumor cell proliferation, most of this is in the laboratory, of course, angiogenesis reducing inflammation, it reduces CRP levels, a few phase reactants. You can provide a list that goes for slides and slides on potential mechanism of action. Here’s a new pathway that I think medical students need to memorize. This is how cholesterol is made from the liver. So, you have HMG-CoA, you block it with statins or diet. We don’t know if patients going on statins have been doing just fine on diet, they could still get these numbers. And then you also reduce all the precursors that you see down the chain that are needed to make cholesterol. If you can reduce the precursors, some of these precursors have been shunted off, and we believe can go stimulate oncogenes. So, this is a hot area of research right now in the pharmaceutical industry, is to cut off a number of these pathways here. We memorize that the liver is the greatest producer of cholesterol. Nobody ever said, well, who’s number two? Because all different organ systems produce cholesterol, and right now, arguably, the prostate is number two second to the liver. So, the prostate itself is a machine for cholesterol synthesis and uptake. But, of course we need a certain amount of cholesterol, so I’ll see patients who will go on too much Lipitor, or too much Crestor. They get their LDLs down to 30 and then suddenly they become hypogonadal. You got to be careful about trying to get your cholesterol too low because you need cholesterol to make testosterone and estrogen, vitamin D, bile acid, so on and so forth. What I also love about statins is that all of them are basically generic now but two. So, in the old days, which is only 15 years ago, it was very difficult to afford some of these, especially if you’re using them for prevention, or using them as adjuvant therapy. But now, even atorvastatin, there at the top, which is Lipitor, is generic. What you’re seeing is the newer statins that come out through the FDA have longer and longer half-lives. So, for a patient that’s not compliant every day with taking a statin, that’s okay. Let me focus your attention on the final one at the bottom, rosuvastatin. That’s the generic name for Crestor. There’s now data to suggest that patients can take that once a week, twice a week, and still get a 20% reduction in LDL. So, this idea that I have to take it every single day, that’s an archaic idea based on some of the new half-lives that we’re seeing with the newer statin drugs, which makes it ideal for a clinical trial. You don’t have to worry about compliance. We don’t get to see data like this. This is the only primary prevention, really pure primary prevention trial of people that have normal cholesterol, who are then put on statins, men and women. This is the Jupiter Trial. If you ever look up this trial, it was run by a friend called Paul Ridker from Harvard. He did this groundbreaking trial where it was supposed to go five years. People with an average LDL of about 105, they would never be put on a cholesterol lowering drug at 105. Then they’re put on Crestor versus placebo in 26 countries. It’s a Phase III trial, and the trial is stopped at 1.9 years because it reduces cardiovascular events in perfectly healthy people within two years of starting the trial. So, what you see here is, it was predictable that the lower your LDL, and the lower your inflammatory marker, the greater the reduction overall in cardiovascular events. This would be perfect for a prostate study. We also always have a supplement that mimics a drug. There’s a supplement called red yeast rice extract. One of the first statins actually came from it. So, there’s actually a statin compound in it, so patients will take an over-the-counter supplement and their cholesterol will drop 15-20%, and they’ll say, how’s that possible? I tell them their taking a natural statin. It’s alovastatin equivalent as one of the compounds. There actually has been very large clinical trials with this supplement throughout the world that have shown benefits like we see with statins because it’s a statin in its natural place. I tell patients I prefer the pharmaceutical over the supplement because today multiple pharmaceutical statins are dirt cheap, and the supplement now is extremely expensive. In the old days, 15 years ago, the supplement looked very cheap up against the drug. Now that situation is switched because we have so many generics. So, I rarely push red yeast rice anymore unless the patient can’t tolerate any of the statins or any of the dosages. We have a new player as of 2015, and it’s Ezetimbe. The trade name for it is Zetia, so you’ve probably heard that. 10 mg, watch GI cholesterol absorption, just for the first Phase III randomized trial with the statin. It’s called the Improva trial, and it did show that if you’re able to get another 10- to 20-point decrease in your LDL level it an actually also reduce cardiovascular dose. So, you’re going to be hearing more about not just statins but a cholesterol absorption inhibitor drug that a lot of people tolerate well called Zetia. Let’s now go to A in S.A.M. That was statins, now let’s talk about aspirin for a second. We have reached a point in 2015, as much of this conference and other places I hear people vilify the United States Preventative Services Task Force. They actually have done a few things right. The one thing they did right this year which I thought was groundbreaking, and you may have missed it, was they now recommend aspirin for men and women to reduce the risk of colon cancer. So, this is the first time we actually have a recommendation to reduce the risk of a cancer with a simple, generic, natural agent. Remember that aspirin comes from willow bark. Women and men benefit in reducing the risk of colorectal cancer even when they’re at average risk. Now it’s being studied in esophageal, lung, pancreas, and prostate. The Reduce Trial; everybody knows the Reduce Trial as being a pharmaceutical trial, but there’s always data in a good pharmaceutical trial that tells you something else beyond the pharmaceutical drug. They did a good job of monitoring supplement intake in this trial, and they found individuals on NSAIDs or aspirin, actually, it was a negative biopsy, was associated with significant decreased risk of prostate cancer, not just total prostate cancer, but also high-grade disease. What I love about S.A.M. is that if it shows any benefit at all, it’s potentially showing benefit in reducing the risk of our most aggressive tumor types, our Gleason 8, 9, and 10. This is what makes it an ideal chemo-prevention agent. Now, here’s your new meta-analysis on aspirin suggesting 39 studies, provides support that aspirin use is now inversely related to prostate cancer incidents and prostate cancer-specific mortality. There has been data out there for decades. I’ve talked to several people at this conference; for decades this data has been sitting out there, not just in colorectal cancer, and it’s intriguing. But, aspiring comes with serious toxicity just like statins. If you look at most of the randomized trials with women you see higher rates of hemorrhagic stroke, higher rates of major GI bleeds, so you want to be very careful about who you put on aspirin, or suggest aspirin with their primary care doctor. I’ll show you how to do that in just a moment. One of the scoring systems that we write about is called Reynolds Risk Score. It takes a patient 20 seconds to type in this number, they rip it out, they take it to their primary care doctor, and it helps them decide whether or not the benefits of aspirin outweigh the negatives. No one is asking anyone in this audience to be a cardiologist or to be a primary care doctor, but all you have to do is send them back to their primary care doctor when they start ADT, in any situation, and have them do this risk core and discuss it with their primary care doctor. We also have a new risk calculator from the American Heart Association that’s outstanding, and I’ll show you at the very end of my talk how simple it is. It’s called Cvriskcalculator.com, that tells you whether or not you qualify for an aspirin or a statin if you’re otherwise perfectly healthy, based on all the randomized data from the past 10 years. But, we also have a natural aspirin over-the-counter supplement. I am not a big fan of it. If you go to CVS right now or any Walgreens, you’ll see a number of doctors that endorse arthritis supplements, and most of those arthritis supplements end in the word ‘flex.’ So you name it, there’s all sorts of flex. The problem with some of these is that I always tell patients to look and see if it contains salicin, and many of them contain salicin, and they’ll cost $50 a month, and the patients will tell me that their pain’s gone. They feel pain-free. I show them that one of the primary ingredients in some of these products, not all, is salicin, which comes from willow bark. Salicin is metabolized to salicylic acid, which is the main metabolite of aspirin. So, patients are paying $50 a month for aspirin, so I just tell them to take the aspirin. My last drug, which really, all of these could be supplements. This came from the French Lilac, a natural source, it’s been generic for well over a decade. 21 studies right now suggesting that metformin use, the number one drug used in the world for Type 2 diabetics, the number one drug used in the world for pre-diabetes, suggests that metformin might reduce the risk of biochemical recurrence, but maybe not all-cause mortality. We do have an LHRH study published in The British Journal of Urology many years ago where they put patients on 850 mg BID and gave them their LHRH or not, and then follow them over six months. Tell me where in the LHRH world, or the ADT world, you see numbers like this. You actually lose weight, your BMI comes down, your body fat comes down, your blood pressure gets better, and there’s no change in lipids. That’s what metformin did in this trial, and that’s what we see it do in the breast cancer trials. So, it’s not just potentially going after the progression of the disease, in the worst-case scenario it reduces some of the side effects of hormone therapy, which I think makes it incredibly exciting at about a quarter of it a week. Remember, it’s about a quarter a week; it’s generic. Now, the Swiss just did a new small trial on CRPC patients on metformin suggesting that newly diagnosed CRPC patients put on metformin, it actually might slow the progression of the disease. They saw other benefits with markers. Again, does the benefit outweigh the risk for these patients? Absolutely. My final thoughts; a lot of patients will start metformin on ADT or another situation, they’ll immediately jump to 1,000 or 1,500 with their primary care. We like to recommend 500, the lowest possible dose. Then you take that for two or three weeks, always with a meal, regardless of what it says on the label. You want to take it with a meal, and then that keeps the GI side effects down to that of a placebo, and then you titrate up to the dose you want to get every two to three weeks, and that’s what they’re doing in all the major cancer trials. Keep in mind that this drug is in over 100 clinical trials right now on clinicaltrials.gov with a variety of cancers. It can cause soft stool, you can’t use it with contrast, so basically if you’re going to get contrast, you want to stop it for 48 hours, and the two biggest concerns I actually have on metformin is that we do recognize B12 and magnesium deficiencies, so those two levels have to be monitored with their primary care doctor. The primary cares know this; they know it well. My last point on metformin on this slide is quite remarkable. I wonder how many people in this audience know that in the United States right now there’s a Phase III trial, and adjuvant trial of metformin for breast cancer patients. They just reported on the mid-term analysis of that trial, and the average patient in that trial getting metformin, the average woman in that trial who has a BMI about 28, 29, has already lost about 6 or 7 lbs., blood sugar is down about 1 or 2 points, their numbers are all better across the board, cardiovascular-wise, versus the placebo group. So, we’re at least seeing them benefit in terms of the potential for side effect reduction. Whether or not it’s going to reduce the risk of breast cancer recurrence, we’ll know in the next few years. But either way, it goes after side effects. My final point about lifestyle, because I don’t want you to leave here thinking that I’m pushing these pills over lifestyle. This is a slide that no one ever gets to see in the primary care world. The trial that made metformin a billion-dollar drug was called the Diabetes Prevention Trial. It showed that within three years patients in one arm on metformin who weren’t even diabetics, they were prediabetics, reduce their risk of getting diabetes by 31% and it made every newspaper. There was a third arm in that trial; it was a lifestyle group that exercised 150 minutes per week. They cut back on about 450 calories a day. They lost about 7% of their body weight, and in that group there was a 58% reduction. It significantly beat metformin in the head-to-head trial, and both beat placebo, and people still walk out of that trial thinking metformin, when they should be thinking intensive lifestyle changes beat the drug. Thank you very much for your time. I appreciate it.
Instead of questions, can I just show them this? Because we don’t have ARS. Can you bring up cvrisk calculator to show–again, because I address this all the time in traveling. Patients say, I love what you’re saying, but I don’t want to be a cardiologist. No one is saying you have to be a cardiologist. This new heart risk calculator, you just type in the numbers. Let’s do Crawford’s age, 52, 55? All right, let’s type in 52. Let’s go total cholesterol 160. No, change the age to 66, for example. Let’s make it more realistic for patients that we see. Total cholesterol 160, do an HDL of 50, systolic blood pressure, let’s go with the standard 120/80, and they’re not treated for high blood pressure, not treated for diabetes, they’re not a smoker, that’s what we’re going to assume. Now click it. Boy, that was really difficult. That is how quickly ou can rapidly assess whether or not that patient needs an aspirin or a statin. It tells you that based on clinical trial data. This is a beautiful tool that I wish more primary care doctors would also use. So, this patient would potentially qualify for an aspirin and/or a statin because they have a double-digit risk. Once you hit double-digit risk, the benefit of these pills start to outweigh the negatives. DR. DAVID CRAWFORD: If you’re on a statin, do you– DR. MOYAD: Yes. The answer is– DR. CRAWFORD: You base the numbers on that, so if it has you at low risk then you – – . DR. MOYAD: Yes, exactly. DR. CRAWFORD: But, you’re the guy that’s been telling us not take an aspirin ever since I’ve known you. DR. MOYAD: No, that’s not true. I wrote a paper in 2002– DR. CRAWFORD: –risk, significant risk factors, right? DR. MOYAD: Absolutely; I’m saying that if I have to choose between statin, aspirin, and metformin, I will always choose a statin or metformin over aspirin, and there’s several reasons for that. We have kept a generation of gastroenterologists in business from all the ulcers we’ve created off of taking aspirin when we don’t need it. Remember, aspirin does not have a warning light. You don’t see liver enzymes go up. You don’t see CPKs go up. You just have an ulcer. Or, you just have an internal bleeding event. So, I get nervous that you really have to figure out if the benefit outweighs the risk and what I’m showing you is, I could type in your situation, Dr. Crawford, you would not probably qualify for aspirin, because if you’re able to keep your blood pressure low, you’re able to keep your cholesterol low, and you exercise, a lot of people actually don’t qualify for aspirin because– DR. CRAWFORD: You were just talking about, with prevention now, of colon and a few other cancers, so that–this doesn’t even mean anything, now. DR. MOYAD: No, it does mean something because you’re talking about America. So, America, this is the year where in 2015 we have more obese individuals and overweight individuals. DR. CRAWFORD: It’s 2016. DR. MOYAD: No, I’m saying in 2015, that’s where we have the data. So, now the average person we’re seeing in our office is a prediabetic or diabetic. They have so many potential risk factors. We have more people than ever based on these calculators that actually could qualify for aspirin, so as long as it’s done judiciously. DR. CRAWFORD: If I have no risk factors, so if I’m low, I should not take a baby aspirin now, based on the prevention stuff you were talking about? DR. KEANE: Well, let’s do a poll. How many people in this room take a baby aspirin? Wow. DR. MOYAD: The answer to your question is if you qualify based on cardiovascular risk, which many of our patients do, then after a radical prostatectomy or an ADT, why not? They should take it. DR. CRAWFORD: Okay, but I don’t qualify. DR. MOYAD: No, you don’t qualify. DR. CRAWFORD: So, I don’t qualify for a baby aspiring, I don’t have the risk factors, my cholesterol’s–I’m on Crestor and Zetia. DR. MOYAD: That’s right. I know, I gave you the recommendation. DR. CRAWFORD: You were against Zetia not too long ago. DR. MOYAD: No, I was waiting for the trial. We didn’t have a single randomized trial. DR. CRAWFORD: (Crosstalk) results were going to be positive, I just had a feeling. Should I take a baby aspirin for the prevention of colon, maybe prostate, other things– DR. MOYAD: No, because I’ll give you two pieces of advice that beat any baby aspirin when it comes to colon; it’s called colonoscopy is one, and not to smoke is two. Those far trump the data that you’re seeing on aspirin. And, to take care of yourself. You’re the kind of guy who’s run marathons, you’ve always stayed that slim. That’s not America, David. America are average, randomized trial. Just let me put this in perspective, so next time you’re doing a prostate trial you look at this. The average man or woman in a randomized trial in America today is perfectly healthy. Average, if you look at all your trials, Reduce, you look at all of them, PCPT, Select; the average BMI is running almost 30. So, the average participant in our clinical trials is pre-diabetic obese. They’re not you. Man, that was kind of profound. I feel like I should hang with that one for a moment. DR. KEANE: Should we consider at this point, seeing as how the prostate is such a major producer of cholesterol, this would be wonderful for business, let’s take a look at taking the prostate out of everybody who’s 60 years of age to decrease your cholesterol. That’ll be a good indication. DR. MOYAD: It would, but let’s look at a guy who has a radical prostatectomy, goes through radiation, and wants to take 100 supplements, and you can tell them that most of them already qualify for a statin aspirin metformin. At least you’re doing something for your patients, then the worse-case scenario they still win if they qualify. So, to see an ADT patient lose 5 lbs. while they’re on ADT, that’s a wonderful thing to give your patients. That’s why those three pills make more sense than any pill I’ve seen in the past 20 years. DR. KEANE: So, would you recommend metformin for people who are on ADT who have advanced prostate cancer, or somebody’s who’s going to go on intermittent therapy, would you recommend that 500 mg dose of metformin as a means to avoid some of the side effects? DR. MOYAD: We’ve been doing it for almost 4 or 5 years, and now I can tell you we’ve watched hundreds of men benefit from metformin on ADT, and you know what? They’re paying a quarter a week for it. DR. KEANE: So, why haven’t we done a randomized trial of it? DR. MOYAD: You haven’t done a randomized trial because there’s no sexiness in the generic drg that’s been sitting out there that you have to go find private money for that, or you have to get a bunch of people with a lot of power to walk in and get $100 million from taxpayer money for that. It’s not easy. I recognize it. But, in Europe they’re doing a trial right now with cancers where after treatment they give aspirin or another compound as an adjuvant. These are really good adjuvant studies, right? You take your high-risk patients, the ones that you know, or you think they’re going to recur, and you look to see if they qualify for one of these agents. UNKNOWN: Just to follow up to that, Mark, recently on one of these little websites it said that metformin increases overall survival, and the implication was that all people should be taking metformin every day. What is your recommendation for that? If you’re healthy and you’re doing the prevention, and you want to do some aspirin and maybe a statin, would you add metformin? DR. MOYAD: It depends. ADT, it becomes very simple, because you just see the weight gain coming. I’m not just talking about subcutaneously; what people forget is there’s two types of weight that we deal with in medicine. One’s a subcutaneous fat, the unsightly fat that’s right underneath the belly, but that doesn’t kill anyone. It’s the visceral fat that surround the organs. That changes your numbers and that increases the risk of cardiac disease. So, you see a reduction of both of those. If metformin was introduced today it would be a weight loss drug. It would be the only weight loss drug that’s ever been proven to be heart-healthy. The history of weight loss drugs in America have never been shown to be heart healthy, so the good news is, they help you lose weight; the bad news is, they kill you. That’s how they got taken off the market. So, our biggest seller, Sibutramine, was taken off the market because it caused strokes, but it helped you lose weight? Remember Fen-Phen and ephedra? So, these were all stimulants, and they help you lose weight, but they increase your risk of an early death. Here you have a weight loss pill, it doesn’t give you profound weight loss, but it gives you weight loss under these situations that cost pennies, that has been shown to be heart-healthy, or at least heart-neutral. We’ve never had that before. So, the answer to your question is, in ADT, yes. If I’m just treating them with radiation, or they’re going to get surgery by one of you guys or gals, I’m definitely discussing one of these three pills. If they’re overweight, I’m discussing metformin. If they have a high cardiac risk, or maybe colorectal cancer history, I might be discussing aspirin. If they already have high cholesterol like some of them do, they may pick a statin. And, I’ll add lifestyle, so the answer is yes; in almost every scenario that you treat, a patient qualifies for aggressive lifestyle changes and/or one of these pills.