#279 - AMA #53: Metabolic health & pharmacologic interventions: SGLT-2 inhibitors, metformin, GLP-1 agonists, and the impact of statins
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Welcome to Ask Me Anything, AMA number 53. I'm joined once again by my co-host, Nick Stenson. In today's episode, we'll discuss two different topics. First, we'll have a follow-up to AMA 51, where we focused on metabolic disease. One thing we didn't really cover in that AMA, which we cover in much more detail in this AMA, are the various pharmacologic tools that we have at our disposal to improve an individual's metabolic health. These include

a discussion around SGLT2 inhibitors, which are also of interest for their potential geroprotective benefits, along with metformin, GLP-1 agonists, and other drugs that can improve one's metabolic health. From there, we shift our discussion to look very specifically at the relationship between perhaps the most prescribed class of drugs out there, statins, and their relation to insulin resistance. This is a topic we get a lot of questions on,

In fact, so many that we decided that it was worth half an AMA. So we cover all of the issues here and all of the data around statins and not just the relationship to type 2 diabetes, which is generally recognized as a small issue with certain statins, but much more broadly around the relationship between statins.

and metabolic health. And of course, we put this in the broader context of net benefit versus net harm. So if you're a subscriber and you want to watch the full video of this podcast, you can find it on the show notes page. If you're not a subscriber, you can watch a sneak peek of the video on our YouTube page. So without further delay, I hope you enjoy AMA number 53. Peter, welcome to another AMA. How are you doing? Doing very well.

How's that toothpick treating you? Very well. Love me some toothpicks. Do you ever tell the story about how you ended up with so many? I think I have 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.

Are they still, to this day, the best toothpicks you've ever had? No, I would actually say my toothpick game has evolved a little bit and I have started to like other types of toothpicks. Those toothpicks are still remarkable, but I don't think I could call them the single best toothpick in the history of dentition. 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.

But not today. So today we are going to 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.

In that AMA, we talked about how metabolic disease feeds those other types of diseases. We went into insane detail and 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, we'll talk about that. That will include SGLT2 inhibitors, metformin, GLP-1, and a few others. And on

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 going to 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. We'll get to those here. All that said, before we get started, anything you want to add? No, I think that's a great synopsis of our very ambitious goals today. We'll see what we can do. The first one,

SGLT2 inhibitors. This is something that you and Rich Miller talked about on the podcast where Rich dove into the ITP. We're going to have Rich Miller back on again, but 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 are they initially developed. I guess we could sort of demystify the acronym a little bit. So SGLT2 is kind of a crappy word

way to abbreviate sodium glucose co-transporter protein 2. I know it's 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. Sodium glucose co-transporter protein 2 is SGLT2.

And honestly, this is a great example of where a picture is going to be more valuable than just me rambling. So for those of you that are just listening to us, I'm going to do my best to try to explain this. But anyone who can watch this on video, be it on YouTube or on our channel, please do that. Okay, so Nick, please pull up said figure of a nephron.

Got it. Okay. So the nephron is the functional cellular unit of the kidney and in the proximal tubule. So I don't want to overwhelm us with renal physiology here, but the kidney is kind of a unique organ in that it's really a tiny organ, but it is overrun with blood.

So there's lots of plasma that's passing through the renal arteries. And the reason for that is, of course, the importance of filtration. So in a nutshell, this is the way the kidney works. 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 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. 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 going to 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.

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 here.

to prevent the kidney from 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 little purple box, and that's called SGLT1 and 2.

There are two of them, but obviously we're talking about the sodium co-transporter 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.

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, 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. 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 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, any other questions on SGLT2 inhibitors? That is to say the class of drugs that block this protein?

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 that is how were they developed initially in the first place to solve this problem? Yeah. So it's not an uncommon story in pharmacotherapy where there is 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 the naturally occurring molecules have pros and cons, but that's an impetus for further development. And the same is true here. So there's a chemical called florazine primarily found in apples. I think it's found in the skin of a few other fruits in relatively small quantities. And it was

was originally isolated, if I'm not mistaken, in the 17th century. And it was 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 Florazine, they developed glucose urea. They developed glucose in their urine. And this became a

a very important early diagnostic step in the treatment of type 2 diabetes. In other words, Sir William Osler, who's the father of modern medicine in this country, and Canada for that matter, Osler was a Canadian, used to actually taste his patients' urine 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're 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 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, I think we have a picture of Florazine next to a modern day SGLT2 inhibitor, you can see the similarity.

Just pull it up. So there you go. Fluorazine naturally occurring on the left and an SGLT2 inhibitor on the right. And 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. And there are currently four of them out there, and they all have really, really unpleasant names.

that are not necessarily that important, but they all end in flozen, not surprisingly. Their names will come up as we go along, and we'll probably talk maybe a little bit more about Kanagaflozen in a minute because it ties into the ITP study. But the point here is all of these Giflozens, if you will, or Glyphlozens have kind of a similar structure, which

which is this glucose ring with an aromatic group, and then they differ basically around that. And these differences obviously allow you to have drug companies to make different versions of drugs from an IP perspective, but they also tend to be dosed differently, and that reflects a very different potency of the drugs as well.

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? That's right. Yeah. And rapamycin, interestingly, is given basically in the format in which it was discovered, whereas 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.

The very, very weakest of all statins, which is Pravacol or Pravastatin, is closer to the most naturally occurring statins that are found in red yeast rice. So it is really interesting that nature's given pharmacologists a head start on drug development in many cases. The other follow-up is Push Came to Shove.

Would you be tasting your patient's urine to help diagnose anything? 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?

Yes. Yeah. Just really trying to understand if your patients are listening, how dedicated are you to their health? I'm going to go with a yes on that. And I'm not going to do it alone. I'm going to enlist the help of my entire clinical team. That's right. I'm sure they're very happy to hear that as well.

So the follow-up, 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.

I think I already alluded to one of them, Canagaflozin, 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. So the first was that in a dose-dependent manner, meaning more drug, more response from

If I'm not mistaken, canagiflozin 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. 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. That's a very big reduction in hemoglobin A1C. And interestingly, when a second trial was done that looked at metformin plus canagaflozin, it found an average reduction in the hemoglobin A1C of 1.8%. That's really significant.

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. 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.

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. 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 kanagaflosin 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.

I guess maybe just to round this out, Nick, there are, as I said, four of these drugs that are approved. The three others, and you'll have to bear with me for whatever reason, I just have a complete brain thing that does not work when it comes to pronouncing the syllables in proximity of these things. But you have...

DAPA, DAPA, GLIP, DAPA, GLIP, FLOSEN, MPEGA, FLOSEN, and ERTUGA FLOSEN as the other three. And they were approved anywhere from 2013, 2014, actually up until the most recent one in 2017, if I'm not mistaken.

Why is it that drugs have such confusing names like that? Why do they purposely try and make it where any human can't pronounce it? Yeah, it's actually a great point. And it's a very deliberate point. The reason that 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

is free for anybody to use. So when the drug goes off patent, anybody can sell that drug. But it's the trade name. So for example, for Mpegaflozin, it's Jardians. That's way easier to remember. So if you're the company that's making that, you want everybody to forever remember Jardians. You want people to remember Crestor, not Razuvastatin. You want them to remember Lipitor, not Atorvastatin.

So it's just classic pharma chicanery, which is let's make sure that doctors and patients alike are associating the brand name with it. And presumably there's some belief that that translates to a longer tail of sales. Anyway, I could be speculating on all of that, but that's sort of my two cents. 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? Yeah, I think this is where things do get a little bit interesting. 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

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, 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?

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 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 with reduced ejection fraction 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 with greater contractility and get more ejection of blood volume. Well, 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 heart failure with or without 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. I think it probably has to do with the reduction in blood pressure, but it may have to do with other things as well, which we could explore. 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?

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