SGLT1 vs. SGLT2 inhibition: Downstream Effects and Physiologic Implications

I'm your host, Dr. Payal Kohli, an associate adjunct professor in the cardiology division at Duke University and founder and medical director of Cherry Creek Heart in Denver, Colorado. And I'm delighted today to be joined by my colleague and my close friend, Dr. Rodney Samaan, Rodney is the CEO of ProgressiveMD, a private cardiology practice in Los Angeles. He's also the co-founder of InVivoCure, which is a clinical research company. And you're really in for a delight today because Rodney's one of the most knowledgeable people about sotagliflozin. And today's episode is going to be about some of the off-target effects of sotagliflozin. Welcome, Rodney.

Thanks for having me, Payal.

So before I get started getting into some of the details, I was hoping you could tell me a little bit about sotagliflozin, how it's different than empagliflozin and dapagliflozin, and talk to me specifically about what cardiovascular outcomes this particular drug modulates that we haven't seen with some of the earlier SGLT2 inhibitors.

Yeah, thank you. Well, I knew you had another program with Dr. Bhatt who reviewed 2 well-known studies, very positive, SOLOIST and SCORED. So I'm not going to go into those studies, but basically this drug, sotagliflozin, has an SGLT1 and 2 effect.

Okay.

So in fact, people don't realize this, but actually most of the SGLT2s also have a slight SGLT1, but this one is much more selective for SGLT1 than 2. You know, for example, I had sent you some materials on this, that it's 20 times the SGLT2 versus 1 compared to empagliflozin, which is around 2,500 times the SGLT2 compared to 1.

Oh, fascinating. Okay.

So the closest one to sotagliflozin is actually canagliflozin.

Hmm.

And that one had issues with amputation and black box warning. But in general, that is as close to the sotagliflozin. But sotagliflozin has the most robust SGLT1 effect. And it's also— another way to look at it is this 50% inhibition of the drug. It's called the IC50, where you determine the potency of the inhibition. of the drug. And the effect from sotagliflozin is around 36 for SGLT1 and 1.2 for SGLT2. And if you compare that to empagliflozin, it's around 8,300 for SGLT1 and around 1.8 for SGLT2. So you could see that it takes a much higher concentration. of the drug to achieve that potency. And that's an interesting way to look at it. So—

Okay, so that's really interesting to me because it helps break down 1 versus 2. But talk to me a little bit about where do I find these receptors? We know that 2 is in the kidney. Many of us are familiar with that. Where do I find 1? And why would I want to inhibit 1 as well?

That's a great question. And it seems to be in many locations, the brain, And when we look at the brain, it's not just in one area. It actually is on the blood-brain barrier, the cerebrum, and the endothelial cells. And it's also in the heart, small intestine, and the kidneys, a little bit distal to where SGLT2 is, in the straight tubules of the kidneys versus the proximal tubules for SGLT2. So it's in many different areas of the body. And that's what makes it interesting for targets. All the effects are not well understood, but it certainly does have an effect on endothelial dysfunction and reactive oxygen species. And, you know, there tends to be an effect, especially in the small intestine, where it decreases the absorption of glucose.

Right.

And it may have a GLP-1 effect as well. It seems to— what it seems to do is delay the absorption from the proximal small intestine to the distal small intestine, which leads to bacterial fermentation and short-chain fatty acids, which cause vasodilation and a decrease in vascular resistance. And that seems to be an off-target effect of the drug as well.

That's fascinating, Rodney. So let's back up a little bit. You said it has receptors in the blood-brain barrier, and we know that this is one of the only types of agents of this class, an SGLT1 and 2 inhibitor that actually reduces ischemic stroke. In the trials, it reduced ischemic stroke by 32% and all-cause stroke by 34%. So talk to me a little bit about mechanism. Do you think this is part of the explanation for why it reduces ischemic stroke, or it could be some of the arterial resistance and some of the other mechanisms that you're alluding to?

So that's a great point. The SCORE study Showed this. It's the only study in SGLT2, any SGLT study that showed any benefit in stroke and MACE. There's a meta-analysis out there of like 78,000 patients that showed no benefit in stroke in any other SGLT study except this one study. And apparently, as Dr. Bach— But alluded to, there was an effect early on within the first 3 months, and that those curves kept separating even when the study was complete. And what, here's what's even more fascinating about it. It showed an effect in both ischemic and non-ischemic stroke. So hemorrhagic stroke showed a benefit, and that's not well understood why that would be the case. But for ischemic stroke, we think that it relates to platelet inhibition and platelet aggregation. There was a presentation last year at WCIR, World Congress on Insulin Resistance, by Dr. Robert Chilton that showed— that he showed in his lab that there was an effect on platelet reactivity. And then also, There was a study by Bertram Pitt at the University of Michigan. And that was the study that I sent you from ACC that showed a benefit in platelet reactivity. What they did in that study was the human platelet cells were stimulated with ADP and they assessed for aggregation of platelets and they showed a reduction in platelet aggregation. And so that's a potential mechanism. for the effect on reduction in stroke, which is very impressive.

That is really fascinating. So you're talking about inhibiting platelets, which certainly could explain the ischemic stroke signal, but to your point, may not necessarily explain all the benefits because we also saw a reduction in hemorrhagic stroke. We talked about, you know, how this particular medication could reduce vascular resistance. So I wanna spend a minute talking about blood pressure. And maybe you can take me a little bit through how this particular medicine, as opposed to the earlier SGLT2 inhibitors, might differ in its responses on blood pressure and even on other metabolic parameters like weight. Yes.

So, Abhijeet, there's a couple of— first of all, the other SGLT2s have shown some effect on blood pressure. I don't know all the studies on that. But there's— some of the data here is related to weight. Vascular resistance, vasodilation. But there's also arterial resistance. There's a couple— what I like to do when I want to dig deep into a drug like this is look at all the data. And there's some type 1 diabetes data called Tandem 1 and 2. And they showed a reduction in blood pressure. And they thought it was related to arterial resistance, or reduction in arterial resistance. But what's really interesting about the drug is that it probably has an effect on glucagon, and that seems to be not related. But what happens is you end up with a state of a more homeostatic state of glucose, where— what I mean is, you're— in those studies, they showed an improved time in range of glucose. So, in type 2 and in cardiology, we don't talk about time in range. of glucose. We talk about, like, A1C control.

Right.

The problem with even, like, the ACCORD study, the old famous ACCORD study trying to show aggressive control of glucose, what that was based off of— first of all, the drugs are very old drugs: metformin, sulfonylureas, theodoglitazone, the glitazones. And what they did in that was intensive versus routine care, but they had a lot of hypoglycemia in that study. And there's one theory that that's causing a lot of harm. And so when you dig deep in the data, you realize, like, hypoglycemia could be really catastrophic for patients. It actually is a very cortisol-driven, sympathomimetic response from that hypoglycemia that causes even endothelial dysfunction. And so the idea is when you're in time and range, when you're more steady with your glucose levels, then there's a theory there that it improves weight and blood pressure and inflammation.

It all kind of ties together, which is what's really fascinating about this. I mean, you've alluded to a total-body treatment, essentially, where we're talking about treating the central nervous system, we're talking about treating the gut. You mentioned the GLP-1 receptor-like activity. You talked about glucagon. What I find interesting is in disease states, like cardiomyopathies and diabetes and CKD, the disease states that we see these drugs hitting for, you actually get upregulation of many of these receptors in those particular disease states. So you're even getting more bang for your buck by inhibiting them in this particular fashion. But I really wanna dig a little bit deeper on the type 1 diabetics that you brought up, Rodney. So talk to me about this drug in type 1s. Would you feel comfortable using it in that patient population knowing that the SGLT2 inhibitors dapagliflozin, empagliflozin, we're not supposed to be using in type 1s, only in type 2s?

Well, certainly off-label, that could potentially be an effect. But going back to your point, Dr. Bodd alluded to this pleiotropic effect of SGLT1/2s. But your point is well taken. Right now, at this moment, there's no approved drug for type 1 besides insulin, except in Europe, EMA did approve this drug for type 1.

Yeah.

being used because of marketing, etc., but it was approved for type 1 in Europe. You know, I think that the future is bright for this drug. I do think it's going to eventually be used in type 1. I think we need more access. I think the effect on glucagon and control, just keeping your controlled state where you're not creating more glucose, like gluconeogenesis, glycogenolysis. Those kind of effects have a harmful effect. And the idea of hypoglycemia and time and range is really important. It's something that we don't really ever talk about in type 2. And going back to the ACCORD study, I think maybe it's time to do another ACCORD study because, if you really think about it, it never made sense to me why Controlling— aggressive control of glucose would have microvascular benefit but not macrovascular benefit. As you see, it was well noted. There was another trial, a veterans trial, that showed possibly a response with aggressive glucose control. At the end of the day, we know that glucose is toxic to the heart. And as you alluded, I do research. I've done a study with a company where we were looking at this specific topic with strain and trying to block aldose reductase inhibitors, basically trying to prevent that response. That was presented at ACC. That was a negative study. And also what's interesting, a negative study was IMPACT-MI, which was the famous—

Mm-hmm.

We were part I've mentioned this to you before. That was a study where basically they took empagliflozin and they gave it to patients in the hospital. And those patients were on basically standard of care, and they got it for patients with NSTEMI and STEMI patients who also had heart failure. And that failed its primary endpoint. And we enrolled about 5 patients into that study, and that failed. So there's something different. The SOLIVUS study was not exactly the same, but a very sick population that was in the hospital that was similar to IMPACT-MI, but a different population. And in that study, it did not show benefits. So something's going on. I think you're gonna see more research into these drugs. I think there could be more SGLT2 drugs coming down the pipeline. And I'm excited about these drugs. I would encourage people to consider them and look at them and see if there's a difference. We just need more time to figure out whether these drugs are, there's a difference there.

Well, one thing I really wanna emphasize is that, and I really wanna embrace, is that we as cardiologists have moved away from treating just the number, from treating that A1C, to treating the whole body, to treating the patient, to treating their organs. And the American Heart Association has really led this charge with the creation of the CKM syndrome, cardiovascular kidney metabolic syndrome, where C is that first kind of domino. But would it surprise you to know that 90% of Americans have stage 1 CKM? So CKM is a disease we stage like cancer, and 90% of us have at least risk factors for this. So to me, these types of drugs really offer us novel therapies in our armamentarium, and we have to be smart about how we use them. So not all SGLT2 inhibitors are created equal, just like you use different beta blockers for different you know, indications, different statins for different reasons. So I want us to get smarter about using them. And I know Rodney, after talking with you, I've certainly gotten smarter about sotagliflozin. But I wanna just leave you with one last thought, which is that when you are picking an SGLT inhibitor, you wanna be thoughtful of the things that we talked about, whether you wanna choose one that's more selective for 2 or one that's more selective for 1 and 2, and some of these other pleiotropic effects as well to really try to interpret the data at a deeper level. Any last thoughts, Rodney, before we sign off?

Yeah, I mean, I completely agree with you. I think there's a couple really interesting statistics out there that are just kind of going to blow your audience away, and that is the actual prescribing patterns of SGLT2s or SGLT in general is very low. And then you probably know this number, but it's around the prescribing cardiologists out there, It's around 10% are getting these drugs. I don't know if you knew that factor.

I would have— I thought I had heard 15%, but 10% is even more abysmal. And it's not because we're bad people or bad clinicians. It's because the science and the costs and the barriers that prevent us from using them, you know?

Yeah, I thought that was really interesting. And I think it's because these drugs started in the primary care field, in the endocrine field. not in the cardiology field. I think that's part of the reason. But I will leave you with a couple other studies at the end that I thought were interesting, that I found very intriguing. One was a sort of a natural history of patients who had like an SGLT1 inhibition just by nature. They had like maybe one gene that was off in the SGLT2 that allowed them to have like an SGLT SGLT1 effect, almost like your PCSK9 inhibitor, how they were discovered. They actually tend to have lower risk of heart failure and diabetes. And I thought that was interesting.

Fascinating. Yeah. So you're saying a loss-of-function mutation in SGLT1 protects you from heart failure and diabetes?

It's very interesting. The other one is a study with the C, CARDIA, And you probably are aware of it. It was one of the sites was Mass General where you trained. UAB, where I got my master's in public health, also was a site. And that's kind of like Framingham study for younger patients who are in their 30s and 40s that are at risk for heart disease down the road. And they've been doing echoes and blood draws and all sorts of genetics. And they found that in those patients with an SGLT loss-of-function genetic mutation that they had higher GLS, higher strain patterns, which is a protective benefit, almost 2 points higher, almost 2.8 in African Americans. And I thought that was very interesting. That was also done at Mass General, that paper.

So changes in the way that their cardiac muscle was functioning and looking on echo.

Yep.

Fascinating. Really fascinating. Yeah. So this really does push the envelope of the 1 and 2 combined dual inhibition, when we should use one, when we should use the other. If you have any questions, you can text Dr. Samaan late at night, no matter what time, he always has his phone on. But please do think about using these in your patients because these are really important medications that treat outcomes. They don't just treat the number, don't just treat the A1C. And really work on so many different levels. So Rodney, I want to thank you for being my guest today. It's been such an interesting conversation. I've learned so much. And thank you to our audience for listening as well. And we look forward to seeing you on the next episode of Conversations with Dr. Coley. Until then, take care.

Thank you, Payal.