Metabolic health & pharmacologic interventions: SGLT-2 inhibitors, metformin (AMA 53 sneak peek)

1. 0:00 – 0:10

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia.

2. 0:10 – 2:45

   Pharmacologic tools for improving metabolic health, and the relationship between statins and insulin resistance

   1. SPSpeaker0:10

      Peter, welcome to another AMA. How you doing?

   2. PAPeter Attia0:12

      Doing very well.

   3. SPSpeaker0:14

      How's that toothpick treating you?

   4. PAPeter Attia0:16

      Very well. Love me some toothpicks.

   5. SPSpeaker0:19

      Do you ever-- Did you ever tell the story about how you ended up with so many?

   6. PAPeter Attia0:22

      I think I have [chuckles] shared that story. In fact, I know I've shared that story because when I meet strangers sometimes, they've asked me if they can have some of those toothpicks.

   7. SPSpeaker0:33

      Are they still, to this date, the best toothpicks you've ever had?

   8. PAPeter Attia0:35

      No. I would actually say my toothpick game has evolved a little bit, and I have kind of started to like other types of toothpicks. Th-those toothpicks are still remarkable, but, um, I don't think I could call them the single best toothpick in the history of dentition.

   9. SPSpeaker0:53

      Well, maybe a future AMA, if there's enough demand, we can break out the different types of toothpicks and pros and cons of each. So, but not today. So today, we are gonna talk kind of in follow-up for the first part to AMA 51, which was on metabolic disease. And metabolic disease is one of your four horsemen that you talk about in the book and talk about on podcasts, the other three being cardiovascular disease, neurodegenerative disease, cancer. And in that AMA, we talked about how metabolic disease feeds those other types of diseases. We went into insane detail on how to measure and know where you're at and how your metabolic health is, and then we talked about some lifestyle factors that you can do to improve your metabolic health. The one thing that was missing from that AMA, which we get a lot of questions on, is what about the pharmacological options for people to improve their metabolic health? So the first part of this AMA will talk about that. That will include SGLT2 inhibitors, metformin, GLP-1, and a few others. And on some of those drugs, such as SGLT2 inhibitors, we'll also cover if there's potentially a geroprotective benefit to those, because we also see questions from people who may be in good metabolic health, but based on some study results, are curious on that. Part two, we're gonna cover something we get asked about an insane amount, and that is the relationship between statins and insulin resistance. And we see a lot of questions come through, and so we pulled all of them for that, and we'll get to those here. So all that said, before we get started, anything you want to add?

   10. PAPeter Attia2:37

       No, I think that's a great synopsis of our very ambitious goals today.

   11. SPSpeaker2:42

       We'll see what we can do. So the first

3. 2:45 – 9:10

   SGLT-2 inhibitors: how they work and help to manage type 2 diabetes

   1. SPSpeaker2:45

      one, SGLT2 inhibitors. This is something that you and Rich Miller talked about on the podcast where Rich kind of dove into the ITP. We're gonna have Rich Miller back on again. We receive a lot of questions on SGLT2 inhibitors, and it would be helpful, I just think, to just cover the basics of what are they and how were they initially developed.

   2. PAPeter Attia3:06

      Yeah. So, uh, I guess we could sort of demystify the acronym a little bit, right? So SGLT2 is kind of a crappy, um, way to abbreviate sodium glucose co-transporter protein two. I know what someone's thinking, which is, "But where's the L and where's the P?" Don't ask. That's just the way it works in biology. We come up with really, really bad acronyms. So, um, sodium glucose co-transporter protein two is SGLT2. And honestly, this is a great example of where a picture is gonna be more valuable than just me rambling. Uh, so for those of you that are just listening to us, uh, I'm gonna do my best to try to explain this, but anyone who can watch this on video, be it on, uh, YouTube or on our channel, please do that. Okay. So Nick, please pull up, uh, said figure of a nephron.

   3. SPSpeaker4:01

      Got it.

   4. PAPeter Attia4:02

      Okay. So the nephron is the functional cellular unit of the kidney. And, um, in the, uh, proximal tubule, so, so again, this... I, I don't, I don't wanna overwhelm us with renal physiology here, but the, the kidney's kind of a unique organ in that it's really a tiny organ, but it is overrun with blood. Uh, so there's lots of plasma that's passing through the renal arteries. Um, and the reason for that is, of course, the importance of filtration. So in a nutshell, this is the way the kidney works. And, and this was explained by one of my professors in medical school. I never forgot this, and I found it to be a very valuable way to think about it. You know if you were a kid and your mom said, "I want you to go into your room and clean your dresser out," you know, like y- where you have your socks, your underwear, your T-shirts, your shorts, and all that stuff? It's tempting to sort of go in there and, while everything is in the dresser, try to organize it and pull things out that you don't need and keep what you do need, right? The kidney doesn't work that way. The kidney has one way of filtering, which is it goes to the dresser and takes every single thing out, and then it simply pulls back in what it wants to keep. That's very different than the kidney saying, "I'm gonna go and identify things that we don't need or we don't want and pull them out." Why? Because in the case of the latter, it assumes evolutionarily that the kidney will forever be able to recognize bad things. But in the former, it assumes evolutionarily that the only thing the kidney needs to understand is what is good. And obviously, that's a much better strategy because that's a finite set of things as opposed to an infinite set of things. So the way this works at the cellular level is, as plasma rolls through the kidney, it pulls everything out. It just completely dumps everything out. Glucose, sodium, potassium, magnesium, chloride, you name it. And As the filtrate runs through the kidney, it selectively pulls back into the circulation the things that it knows we need. And that's why the kidney is the most important organ in the body for regulating our electrolytes. So there's an interesting opportunity here because one of those things that happens to get filtered is glucose. And even though the kidney's job is not really managing glucose concentration, there's an interesting opportunity to prevent the kidney from, uh, y- reabsorbing all of the glucose that it immediately shunted out when the plasma came through the kidney in the first place. So in other words, even though the kidney's goal is not interfering with glucose concentration the way it is doing deliberately with sodium, potassium, chloride, et cetera, there's an opportunity. So if you look at this figure now, you'll see on the left-hand side of it a, a little purple box, and that's called SGLT1 and 2. So that's, uh, there are two of them, but obviously we're talking about the sodium, uh, co-transporter, uh, two here. And you can see that it pulls sodium and glucose into the cell together. By the way, as an aside, people who may remember the podcast we did on hydration might recall that we talked about how mixtures of glucose and sodium are the best ways to hydrate cells if you're really optimizing for water movement. This kind of is a bit of a reminder why sodium and glucose move together very efficiently. But let's put that aside for a moment. So as you can see looking at this diagram, if you had a way to block that purple thing, you would be able to keep more glucose in the urine. On this graph, or this figure rather, the right-hand side is where things are returning to the plasma, going back to the body. The left-hand side is things that will be excreted in the urine. So when you block SGLT2, you prevent sodium and glucose from being reabsorbed by the cell to then be put back into the plasma, and therefore you will pee out more sodium and glucose. And therefore, this has become a very attractive solution for people whose blood glucose is too high. Again, taking a very big step back, how do we manage the problem of type 2 diabetes? That's really what we're talking about today. You can manage it by reducing glucose. You can manage it by increasing insulin sensitivity. You can manage it by increasing insulin itself. This is a strategy that says, "Here's how we're going to lower glucose." Metformin, which we'll talk about as well, is also a glucose-lowering strategy, whereas GLP-1, you know, tends to be probably more of an insulin sensitizing strategy coupled with, to some extent, a glucose lowering strategy by the fact that you simply eat less. So with that said, um, any other questions on SGLT2 inhibitors? That is to say, the class of drugs that block this protein.

   5. SPSpeaker9:04

      No, I think that's a good overview of what they do. I think some other people reached out, and a good follow-up to

4. 9:10 – 14:45

   The history of SGLT2 inhibitors – from discovery to the current state

   1. SPSpeaker9:10

      that is how were they developed initially in the first place to solve this problem?

   2. PAPeter Attia9:15

      Yeah. So it's not an uncommon story in pharmacotherapy where there is a, a naturally occurring substance that sort of does this, and then a drug company will come in or a scientist will come in and figure out a way to make a better version of the molecule that occurs in nature. By the way, metformin is a naturally occurring molecule. Statins are naturally occurring molecules. So, um, th- again, the naturally occurring molecules have pros and cons, but that's sort of an, a, you know, an impetus for, for further development. And the same is true here. So [clears throat] there's a, there's a, a, a chemical called phlorizine that, uh, was primarily found in, um, apples. Uh, I think it's found in the skin of a few other fruits in relatively small quantities. And, you know, it was originally isolated, if I'm not mistaken, in the 17th century, and it was, you know, part of the botanical solutions to people with various infectious diseases, malaria, things of that nature. To be completely honest with you, I don't actually know how efficacious it was. However, it started to become clear, and this is the important point, of course, is that when people were given phlorizine, they developed glucose urea. They developed, uh, glucose in their urine. And this became, uh, a very important early diagnostic step in the treatment of type 2 diabetes. In, in other words, uh, Sir William Osler, who's the father of, of, of modern medicine in this, in this country, um, and, and Canada for that matter, Osler was a Canadian, um, used to actually taste his patients' urine, uh, to determine if they had type 2 diabetes. So here you took patients who didn't have diabetes, and you could induce this idea that we saw in people with diabetes, which is they were peeing out urine. So people put two and two together and said-- Sorry, peeing out glucose. So people put two and two together and said, "Well, wait a minute. If we're giving this drug to people and they're peeing out glucose, then, and they're not diabetic to begin with, then this drug is doing something that is impacting that pathway." And that's effectively what led to the development of these drugs. In fact, if you pull up a photo, um, I think we have a picture of phlorizine next to a modern day, um, SGLT2 inhibitor, uh, you can see the similarity.

   3. SPSpeaker11:33

      Just pulled it up.

   4. PAPeter Attia11:36

      So there you go. Phlorizine naturally occurring on the left and an SGLT2 inhibitor on the right. And, um, again, you don't have to be a biochemist to recognize that there are some similarities here. Now, there are far fewer similarities between these two molecules than there are between the existing batch of SGLT2 inhibitors. Uh, and there are currently four of them out there, and they all have really, really unpleasant names, uh, that are not necessarily that important, but they all end in "-flozin," not surprisingly. So, um- Again, their names will come up as we go along, and we'll probably talk maybe a little bit more about canagliflozin in a minute because it ties into the ITP study. But the point here is all of these gliflozins, if you will, or gliflozins have kind of a similar structure, right, which is this sort of glucose ring with an aromatic group, and then they differ basically around that. And these differences produce, obviously allow you to have, you know, drug companies to make different versions of drugs from an IP perspective, but they also, you know, tend to be dosed differently and therefore that reflects a very different potency of the drugs as well.

   5. SPSpeaker12:57

      And although we're not talking about it today, you mentioned statins and metformin, which we'll cover, are naturally occurring. Rapamycin is also naturally occurring, correct?

   6. PAPeter Attia13:07

      That's right, yeah. And rapamycin, interestingly, is given basically in the format in which it was discovered, whereas, you know, obviously SGLT2 inhibitors are not. They're now basically derivatives of what exists in nature. Metformin is actually pretty close to the original molecule that was discovered in the lilac lilies. And the very, very weakest of all statins, which is Pravachol or pravastatin, is closer to the most naturally occurring statins that are found in red yeast rice. So yeah, it is really interesting that nature's kind of given pharmacologists a head start on drug development in many cases.

   7. SPSpeaker13:54

      The other follow-up is, push came to shove, would you be tasting your patient's urine to help diagnose anything?

   8. PAPeter Attia14:04

      Yeah, I mean, push comes to shove, the world has run out of glucose dipsticks and we have all of the exact same technology we have today, except we somehow have lost the ability to determine if there's glucose in urine. So we can still split atoms and do all those other things, but we just can't do that one thing. Is that what you're saying?

   9. SPSpeaker14:26

      Yes.

   10. PAPeter Attia14:26

       Yeah, interesting.

   11. SPSpeaker14:27

       Just really trying to understand if your patients are listening, how dedicated are you to their health?

   12. PAPeter Attia14:32

       Yeah, I'm going to go with a yes on that, I think. And I'm not going to do it alone. I'm going to enlist the help of my entire clinical team.

   13. SPSpeaker14:38

       The team will help.

   14. PAPeter Attia14:39

       That's right, yeah.

   15. SPSpeaker14:40

       I'm sure they're very happy to hear that as well. So the follow-up,

5. 14:45 – 20:37

   Comparing the various FDA-approved SGLT2 inhibitors

   1. SPSpeaker14:45

      which hints at what you talked about there is, the next question we get a ton of is, what are the different SGLT2 inhibitors and what do we know about the differences between them? I think anyone who's thinking about potentially taking these or is taking these will be interested in that. And so maybe we can just run through that quick as it sets the stage going forward.

   2. PAPeter Attia15:04

      Yeah, so I think I already alluded to one of them, canagliflozin, and I think it's probably the one for which we have the most data. It was approved exactly 10 years ago, so in 2013, and was looked at both in isolation and in combination with metformin, which was obviously the standard of care for initiation therapy, in many ways still is. So two things were observed, right? So the first was that in a dose-dependent manner, meaning more drug, more response, if I'm not mistaken, canagliflozin is dosed, I want to say between 100 and 300 milligrams daily. But as the dose went up, you saw a greater increase in hemoglobin A1c reduction and the results were reasonable, right? So somewhere between a 0.7 and 1% reduction in hemoglobin A1c. And by the way, what I mean when I say 0.7 to 1%, I mean absolute reduction in A1c, not relative. So if your hemoglobin A1c was 6.1, you would expect it to go down to as much as 5.1. So that's a very big reduction in hemoglobin A1c. And interestingly, when a second trial was done that looked at metformin plus canagliflozin, it found an average reduction in the hemoglobin A1c of 1.8%. That's really significant, right? So somebody shows up at 7.8% hemoglobin A1c, so they're clearly and well into the territory of type 2 diabetes where the threshold is 6.5%, and that person's going to come down to 6.0%. So they're going to go from being in a state of raging type 2 diabetes to being pre-diabetic. So again, metformin is typically first line. I suspect part of that has to do with cost, but I also believe it has to do with efficacy. I mean, metformin monotherapy is pretty robust. It depends on the study, but it's up to 1.3% reduction in hemoglobin A1c after about six months. So sizable benefits. Again, we've talked about metformin a lot on this podcast, but, and I didn't, you know, and I forgot to look for this earlier and I should have. I don't believe that we see the same amount of weight loss with canagliflozin that we see with metformin. So metformin is, if I had to guess, and someone will check me on this, I'm sure, if I had to guess, I would say monotherapy metformin would be associated with slightly more weight loss than monotherapy SGLT2 inhibitor. But again, that's something worth understanding. Now, we're going to talk about this in more detail, but the other important question here is, are there other benefits associated with, be it canagliflozin or other SGLT2 inhibitors that go beyond the glycemic control? And again, in addition to weight loss, we're also seeing a greater reduction in blood pressure. I've always wondered with the blood pressure improvement, if it's because of, if you go back to what we talked about earlier, remember when you block SGLT2, you're preventing the kidney from reabsorbing not just glucose, but sodium. So as a patient is excreting more glucose and sodium in their urine, you would think they have obviously less sodium within their plasma. That may explain the benefits we see on the blood pressure front as well. So I g- I guess maybe just to, to round this out, Nick, there are, as I said, sort of four of these drugs that are approved. Um, so the, the three others, and you'll have to bear with me, for, for whatever reason, I just have a complete brain thing that does not work when it comes to pronouncing the, the syllables in proximity of these things. But you have, um, uh, [chuckles] dapagliflozin, uh, empagliflozin, and, um, ertugliflozin, uh, as the other three. Um, and they were, you know, approved anywhere from 2013, 2014 actually, up until the most recent one in 2017, if I'm not mistaken.

   3. SPSpeaker19:13

      Why is it that drugs have such confusing names like that? Like, why do they purposely try and make it where any human can't pronounce it?

   4. PAPeter Attia19:23

      Yeah, it's actually a great point. So, um, it's, it's act- and it's a very deliberate point, right? So, um, uh, the reason that if, if you're a drug company and you're developing a drug, you really like it when it has an awful, awful name, is that the generic name, the molecule name, is free for anybody to use, right? So when the drug goes off patent, the, you know, anybody can sell that drug. But it's the trade name, so for example, for, um, empagliflozin, it's Jardiance. And honestly, like, that's way easier to remember, right? So if you're the company that's making that, you want everybody to forever remember Jardiance. Um, you want people to remember Crestor, not rosuvastatin. You want them to remember Lipitor, not atorvastatin. So, um, it's just, you know, classic pharma chicanery, which is let's make sure that doctors and patients alike are associating the brand name, uh, with it, and presumably there's some belief that that translates to a longer tail of sales. But anyway, I could be speculating on all of that, but, uh, that, that's sort of my two cents.

   5. SPSpeaker20:36

      And then

6. 20:37 – 23:32

   Other beneficial effects of SGLT2 inhibitors outside of glycemic control

   1. SPSpeaker20:37

      the next follow-up here is something you hinted at earlier, which is what do we know about other effects for SGLT2s outside of just the glycemic control?

   2. PAPeter Attia20:48

      Yeah, I think this is where things do get a little bit interesting and, and, and, you know, again, because we've talked about metformin, I think people are already familiar with the idea that, okay, metformin is kind of like bread and butter, early intervention type 2 diabetes, but that's not really the reason people are excited about it. People are excited about metformin and people talk about it and people ask me about it because it, the belief is that it's doing something beyond regulating blood sugar. And I think to a lesser extent in the public's eye, but probably to a greater extent in the scientific eye, uh, the excitement is the same for SGLT2 inhibitors. That's interesting, isn't it, right? The public is way more interested about metformin. I think the scientific community sees much more promise in SGLT2 inhibitors, at least on average, and that's based on my very unofficial survey of this. Why is that? So, um, one of the things is that the ITP, the Interventions Testing Program, has found a clear difference between them. We'll talk about that in a second, I'm sure. But the other one is just looking at the really clear differences in human clinical trials for the advantages associated with, um, SGLT2 inhibitors in terms of major adverse cardiac events, what are called MACE. So if you look at people with or without, this is the big point, without T2D, SGLT2 inhibitors have been shown to decrease the risk of hospitalization and death for heart failure patients, um, with reduced ejection fraction and in patients, uh, and improve basically all cardiovascular outcomes in patients with heart failure who have preserved EF. So you take people who have reduced ejection fraction, so what does that mean? So the heart pumps and we can measure with an ultrasound how much blood comes out of the heart with each pump. So if you're at rest, that number might be 40%, 50%, and if you're under great stress or when you're exercising, one of the tools that the body has to increase cardiac output is not just to beat faster, but also to beat, beat with greater contractility and get more ejection of blood volume. Well, when patients are in this-- Heart failure is basically a condition in which ejection fraction goes down. And when ejection fraction gets low enough, 20%, 15%, you're in a lot of difficulty. And what's been demonstrated, and this has been demonstrated repeatedly, is that when patients have, um, heart failure with or without, uh, reduction in EF, outcomes are better if they're taking SGLT2 inhibitor, even if they are not patients with type 2 diabetes. Again, I think there are lots of potential reasons why we might see that. Um, I think it probably has to do with the reduction in blood pressure, um, but it may have to do with other things as well, which we could explore.

7. 23:32 – 27:07

   Exploring SGLT2 inhibitors as potential geroprotective molecules

   1. SPSpeaker23:32

      And you also hinted at where we're going next there, which is a lot of people when they talk about SGLT2s and a lot of questions we get, it's much like metformin. It's not diabetics kind of wondering about metformin, it's people who are interested in the geroprotective side of it, and it's the same with SGLT2s. And so I think now would be a good time to just say, what do we know about SGLT2s as a potential geroprotective molecule?

   2. PAPeter Attia24:01

      Thank you for listening to today's sneak peek AMA episode of The Drive. If you're interested in hearing the complete version of this AMA, you'll want to become a premium member. It's extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free. So if you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription Premium membership includes several benefits. First, comprehensive podcast show notes that detail every topic, paper, person, and thing that we discuss in each episode. And the word on the street is nobody's show notes rival ours. Second, monthly Ask Me Anything or AMA episodes. These episodes are comprised of detailed responses to subscriber questions, typically focused on a single topic, and are designed to offer a great deal of clarity and detail on topics of special interest to our members. You'll also get access to the show notes for these episodes, of course. Third, delivery of our premium newsletter, which is put together by our dedicated team of research analysts. This newsletter covers a wide range of topics related to longevity and provides much more detail than our free weekly newsletter. Fourth, access to our private podcast feed that provides you with access to every episode, including AMAs, sans the spiel you're listening to now and in your regular podcast feed. Fifth, The Qualies, an additional member only podcast we put together that serves as a highlight reel featuring the best excerpts from previous episodes of The Drive. This is a great way to catch up on previous episodes without having to go back and listen to each one of them. And finally, other benefits that are added along the way. If you want to learn more and access these member only benefits, you can head over to peterattiamd.com/subscribe. You can also find me on YouTube, Instagram, and Twitter, all with the handle PeterAttiaMD. You can also leave us a review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peterattiamd.com/about, where I keep an up to date and active list of all disclosures.

   3. SPSpeaker27:03

      [outro jingle]

Episode duration: 27:07