Good morning, my name is Cecilia Lo Wong and I have the pleasure of moderating this next session. So this session is what's new in the management of diabetic kidney disease. So it's called a pro-con debate, not quite a debate. We'll actually hear from two really terrific speakers on this topic and they'll give two different perspectives. So our first speaker is Dr. Catherine Tuttle. She's executive director for research at Providence Healthcare and professor of medicine and co-principal investigator of the Clinical Translational Science Award at the University of Washington. Her major interests are in clinical and translational science for diabetes and chronic kidney disease and she's chaired numerous kidney and diabetes related working groups and committees for organizations including the NIH, NIDDK, National Kidney Foundation, the American Society of Nephrology, the International Society of Nephrology and the ADA. Her topic today will be the risks and benefits of finaranone and our second speaker will be Dr. Robert Stanton. He's the chief of kidney and hypertension section at the Joslin Diabetes Center and he's an associate professor of medicine at Harvard Medical School. His research is focused on an essential enzyme that plays a major role in regulating multiple cellular functions, glucose 6-phosphate dehydrogenase. He's involved in teaching at all levels and has received three honorary professorships and a major lifetime achievement award for sustained excellence in teaching from Harvard Medical School. His presentation will be on the risks and benefits of other therapies. So what we'll do is we'll have a talk by Dr. Catherine Tuttle and then one by Dr. Stanton and then we'll leave questions to the end. We'll have about 10 minutes hopefully for you to ask your questions. So without further ado, Dr. Tuttle. Well thank you very much. It's truly a pleasure to join you in 3D today. This is the first professional meeting I've traveled for in nearly two years. I imagine that's true for many of you and it truly is a pleasure and honor to join you today. And it's really such an exciting time if I can say in the triangle of cardiorenal metabolic medicine. We heard a wonderful lecture this morning from Dr. Garvey about the breakthroughs in obesity medicine. Diabetes technology is exploding and now we have truly breakthrough therapies for people with diabetes and chronic kidney disease. So I'm happy to be part of this, if you will, celebration of coming together again and really having made enormous progress for the large number of patients that we care for. These are my disclosures. So our objectives today will be to understand the prevalence and risks of diabetes and chronic kidney disease, to recognize what the current standards of care are for diabetes and CKD that reduce both kidney and cardiovascular risks in this population, and then discuss personalized approaches to use of finerenone for care of persons with diabetes and CKD. And as you heard in the introduction, Dr. Stanton will cover the other therapies. I will just give a brief introduction to set the stage. So setting the stage, I don't need to remind this audience that the other pandemic playing in the background is diabetes. So in December 2021, the International Diabetes Federation estimated that there were 538 million people worldwide. And by 2045, this number is expected to grow to 783 million. And in the region of the world shown in the ellipse, all will experience more than a 50% increase. And in some areas such as Sub-Saharan Africa, more than 100% increase. So while diabetes prevention is the holy grail, truthfully, it has not translated in a meaningful way to communities. What that means for all of us is that living with diabetes also means living with diabetic complications. And I'd like to make the case that kidney disease is a very serious matter. It's still common, even occurs in about a third of people with type 1 and about 40% of those with type 2. But remember that in people over the age of 50 and in non-white populations, this number exceeds 50%. From the nephrology perspective, this is now the most common cause of chronic kidney disease and kidney failure worldwide. It's responsible for more than half of all cases. And as somebody with a foot in both worlds, what I can tell you is we see more patients with diabetes in the nephrology clinic than in the endocrine clinic. And the prevalence of diabetes in patients with kidney failure is actually 66 to 86%. Why is that? Because diabetes is common and so are other forms of kidney disease. A person can have polycystic kidney disease and get type 2 diabetes. And in the transplant population, we give them diabetes because we give them glucocorticoids and calcineurin inhibitors. So it's a major problem for the care of patients with kidney disease. And for those of you who are interested in reducing cardiovascular risk and diabetes, I plead with you to screen for GFR and albuminuria. Some 13 years ago or so, we showed from at least in the NHANES population, which is thought to be representative of the United States, that almost all the excess cardiovascular risk, including cardiovascular death, was accounted for by the group with albuminuria, low GFR both. So persons with diabetes who did not have albuminuria or low GFR had almost no increase in risk compared to the background population. So this is half of people with diabetes, and this is the super high risk group you should be targeting for cardiovascular risk reduction. And we'll talk about the importance of albuminuria screening to identify hard cardiovascular risk as well as high kidney disease risk. So speaking of that, what are the risks of diabetic kidney disease? Well, the traditional focus has been progression to kidney failure, getting to the point a person has end stage disease requiring dialysis or transplant. But truthfully, this is a remnant ragtag survivor cohort of just 10%. And it's not because the other 90% are doing well, it's because the extraordinary mortality rate. We know from UK PDS before estimated GFR was used when the creatinine went above 1.5, the mortality rate approached 20% per year. Let's benchmark that. That's the same as a new diagnosis of non-small cell lung cancer. What happens if we make that cancer diagnosis? We have a fire drill, right? Biomarkers, imaging, hopefully a clinical trial. Why? Urgency about mortality. Yet we yawn when we see a person with low GFR. If our concern is mortality, we need to get very activated, especially now that we have highly effective therapies that save lives as well as hearts and kidneys. Half of the deaths are cardiovascular, but atherosclerotic disease does not dominate in people with more advanced CKD. Once the GFR drops below 30, it's heart failure. And this is again where we've had some major advances in terms of therapies that you'll hear about today. The other next most common cause is infection, particularly pneumonia and sepsis responsible for about a third of these deaths. These data were pre-COVID. One can only imagine what the data are going to look like since people with diabetes and CKD not only are highly susceptible to COVID-19, but to very severe complications. So I will project that the stage is going to look even worse when we get on the other side of having the data for what's happened the past two and a half years. This is the KDGO risk grid, and I'd like to use this to set the stage for really team care. This is not my problem or your problem. This is our problem. And what KDGO has done is really stratified risk, and the risk is for CKD progression and cardiovascular events both, because that's what GFR and albuminuria signify. In the boxes outlined in blue, green, and yellow, these are patients who can be ably managed by the person who's providing the primary care for diabetes. They should be screened when they, at least annually, when they still have preserved GFR and no albuminuria. Once they have albuminuria or low GFR, you'll see that we recommend that they're seen more often in orange boxes at least twice per year, and that you begin treatment at that point. We'll talk about what those treatments are. By the time you get into the red boxes, you're looking at three to four times per year, and that's when a nephrologist should become involved, because the therapies become more complicated, and it really, to get optimal patient care, we know that earlier referral actually produces better patient outcomes, and it's not taking patients away. It's a team sport. It's co-management along with the primary diabetes provider. You're going to hear a lot more about SGLT2 inhibitors from Dr. Stanton, but we have to mention them because they are the foundation of the new standard of care. They were the gift that kept on giving after cardiovascular outcome trials, which I'm sure you're all familiar with, but not only were they safe, they actually reduced risk of major cardiovascular events. Yes, ASCVD, which originally was the focus, but the real win was in heart failure, but the major secondary outcomes in all of these trials were kidney disease outcomes, and across the class, they decrease onset and progression to macroalbuminuria, GFR decline and kidney failure, and importantly, both the cardiovascular and kidney risks are present even in those who have established chronic kidney disease, the highest risk group of all for both outcomes. The GLP-1 receptor agonists have also been an enormous gift to this field, and you'll hear more about those in the next lecture, studied in the same way, but where they really delivered, and I think this is actually marvelous serendipity, is on atherosclerotic CBD, so we have complementary therapies depending on a patient's phenotype, and again, the major secondaries were kidney disease outcomes, and across the class, decreased albuminuria, slow GFR decline. We now have a major kidney disease outcome trial going on with somaglutide called FLOW. It's not completed yet, so we don't have the heart outcomes, but all the signals point in the right direction, and with regard to the kidney and cardiovascular outcomes, again, this high risk group with diabetes and CKD benefit even with established kidney disease. So we stumbled on the new drugs, glucose-lowering agents for diabetic kidney disease, really almost by accident. Really, if it hadn't been for the cardiovascular outcome trials, one can only wonder if we would have ever even figured this out. So it's kind of like this Jackson Pollock painting. It's a beautiful story, but rather non-directional. So how do we get to more specific therapies? Because there are residual risks, and there are patients who don't respond to these therapies, so what else do we have in the quiver now? Well, the next thing has been the mineralocorticoid receptor as a target. So we all learned about the mineralocorticoid receptor as a receptor in the collecting duct of the kidney that regulated electrolyte transport, sodium reabsorption, and potassium secretion, but it turns out that if you look at the nephron, the old-fashioned pictures showed nothing in between the tubules and the glomerulus. Well, we know that the tubulointerstitial compartment, which is what is actually there, the dark matter really is not dark matter. There are many cells there, and in diabetes, what we see is a very profound inflammatory infiltrate made up of macrophages, T lymphocytes, and actually other immune cells, but macrophages and T lymphocytes carry the GLP-1 receptor, and the concept is the GLP, excuse me, the MRA receptor, they have GLP-1 receptors too, but with regard to the MRA receptor, when it is activated, it goes to the nucleus and up-regulates both pro-inflammatory and pro-fibrotic factors, so the rationale for using mineralocorticoid antagonism really is not hemodynamic, and it doesn't have anything to do with electrolyte transport, and at another time, we can talk more about the GLP-1 receptor that also is present on these cells, so the idea is that the mineralocorticoid receptor, when inhibited, can block inflammation and fibrosis, and remember, for this endocrine audience, both aldosterone and cortisol are ligands that combine this nuclear receptor, and the new medication that now we are using for diabetic kidney disease is called finarinone, and it's different than iplarinone and spironolactone, it's much bulkier, it is a better competitor at the site, and it also has actions that, even if there's co-binding, are more, that it covers the site of where transcription regulators attach that promote gene transcription, so on the biological basis of this, this is thought to be a much more effective antagonist. So why does it matter? It matters because we now have the largest outcome trials ever done in the field of nephrology, more than 13,000 patients in the Fidelio Figaro program, which has been meta-analyzed together as Fidelity, so in the panels on the left, this was a group of people with diabetic kidney disease who had more advanced disease, so they had a baseline GFR on average of about 44, and a urine albumin to creatinine ratio of about 800 milligram per gram, so these were people who would be in that very high risk category in the Kedego heat map, and what you can see is the hazards ratio for the primary kidney disease outcome, which was 40 percent decline in GFR because it's highly predictive of kidney failure, and kidney failure events, kidney disease death and cardiovascular death, were reduced by some 17 percent, and then the Figaro trial was a group of people who had diabetic kidney disease, but not so far along, so their mean GFR at baseline was about 65, and they had microalbuminuria, the mean UACR was about 100, and these people were more likely to see CBD events early, so that's why it was the primary outcome, and you can see again another win with regard to the primary outcome, a hazard ratio of 0.87, so about a 13 percent reduction. These two trials were meta-analyzed together, over 13,000 patients, it used to be said we couldn't enroll people in diabetic kidney disease trials, hooray, we did it, more than 13,000 patients, I think that's respectable, and the CBD outcome in the meta-analysis held up, as did the kidney disease outcome, in fact, when the 50 percent decline in point was used rather than 40, the hazard ratio went down to 0.77, so a 23 percent risk reduction, and importantly, to set the stage for Dr. Stanton's talk, even in the SGLT2 inhibitor users, we saw this additional benefit of finarinone really moving to the new era of combination therapy, at least suggestive that these agents are acting in complementarity, and that together we may get even more benefit. There are some safety issues with finarinone, they mainly revolve around GFR and hyperkalemia risk, in people with a GFR under 60, the dose has to be reduced from the standard 20 to 10 milligram daily, and the drug should not be started in patients with a potassium over 4.8, and potassium and GFR should be monitored within the first four weeks of starting these agents, if the potassium grows goes above 5.5, we would recommend a temporary discontinuation, and then restarting when the potassium is less than 5, and if they were on 20 milligram, dropping to 10. This is why we talk about co-management, this drug probably is a drug that nephrologists will be most comfortable using, regulating doses based on GFR and potassium, although I'm sure many of you can do this, you've done much more complicated things, but this is an example where we can imagine co-management being part of the way we take care of our patients, not your patients or my patients, but our patients. So, CADIGO is the major international guideline organization that provides evidence-based guidelines for the kidney disease community, and of course, in earlier iterations, these guidelines were developed by regional professional organizations, and they still may be in some cases, but CADIGO has really come together around an international community, and is, I think, viewed as the leading guideline forming organization that we follow. CADIGO is updating this year, we have just completed the final draft, it's been to external review and should be published in the next couple of months, but I am allowed to give you a sneak preview of, if you will, the paradigm that we are recommending. I will also call out that we collaborated with the American Diabetes Association Standards of Care Committee and the American Heart Association, American College of Cardiology Guideline Committee, so that we have harmonized these guidelines. Of course, each group will have their own format and syntax, but the bottom line is, whoever's guidelines you want to read, the message is going to be the same, and that's really important in terms of implementation, so that clinicians are not confused. I will also mention that I had the privilege of serving on the new ACE diabetes guideline, and did participate in writing the kidney disease section, and took responsibility to make sure that the ACE guidelines are also aligned with these other groups. So, the bottom line is, we're now saying that first-line therapy for a person with type 2 diabetes and chronic kidney disease includes an SGLT2 inhibitor, whether or not they are on metformin, because we are giving these agents for organ protection. We've turned it around and said it's an organ protective agent, heart and kidney, with a glucose-lowering side effect. So, even if they don't need it for glycemic control, we give it for heart and kidney protection. The next line is a GLP-1 receptor agonist. Again, Dr. Stanton will go through that data with you, and again, these can be used if an additional agent is needed for glycemic control, or if someone has persistent albuminuria on an SGLT2 inhibitor, because even antedating flow, we know that GLP-1s are very effective at reducing albuminuria, and probably not by a hemodynamic effect that you'll hear about, and I'll just sort of harken back to my slip-up when I talked about immune cells in the kidney. GLP-1 receptor agonists are thought to be anti-inflammatory in the kidney by predominantly an effect on immune cells, not even intrinsic kidney cells, but invaders. So, from the science standpoint, this is an exciting time to understand that piece better. And then, where does finarinone fit in? Finarinone fits in in a person who is already on an ACE or an ARB, which is also first line therapy, who has persistent albuminuria, and who has a GFR and a potassium that will allow finarinone to be added. And you really can add either finarinone or a GLP-1 as the second step, depending on the patient phenotype. And we'll go through a case together that'll at least illustrate for you how I have implemented therapy and practice. But in order to treat disease, we have to identify disease. And we have a major problem with poor screening for chronic kidney disease and diabetes and elsewhere. This is from a table from one of our papers. I am the PI of the Cure CKD Registry, 3.6 million people with chronic kidney disease and also with diabetes and or hypertension. It's kind of complicated, but if you look at the boxes, it shows you how frequently albuminuria is measured in two very large healthcare systems, the Providence Healthcare System, where I'm Executive Director for Research and UCLA Health. And you can see that in the, I don't have a pointer, so the second column from the left are people with CKD, diabetes, hypertension, and or prediabetes, people who we would argue should at least have annual screening. And you can see that we only got it done in about 15% of patients. And this was as recently as 2017. If we aren't identifying albuminuria, we're not gonna identify people who need therapies. And if you look more broadly, this is actually national data from Medicare. So these are people 66 and older. Now remember that there are incentives in Medicare for screening. And people who receive Medicare and are older actually receive more services. The data I showed you is from the real world, from a healthcare system that has, like in my healthcare system, only 23% have commercial insurance. We take care of very sick communities. And so this data, even in Medicare patients, as recently as 2018, we were only at 40% screening. That's the best it gets. But older Medicare patients aren't really representative of the people in practice, the younger people who don't have insurance, who aren't touching the healthcare system so much. So this is a rosy estimate, and that's still a failing grade, to only be checking people with diabetes 40% of the time for albuminuria. And this has really led to this problem with implementation. So this is actually also data from Cure CKD through 2017, and it shows medication use in the CKD population. And just look at the box. The message is diabetes, CKD, and hypertension, probably the hardest indication to give an ACE or an ARB. We got to a whopping 25%. Use did go up over time, but we also used more non-steroidal anti-inflammatory drugs and proton pump inhibitors, potential nephrotoxins. So we did harmful things, and we didn't do helpful things. No wonder the outcomes are so abysmal. And if you look at more recent data on the newer glucose-lowering therapies, this is a paper in press for diabetes care, and it shows the bottom yellow line is SGLT2 inhibitors, and the orange line is GLP1s. And then at the bottom are juxtaposed at the time that these major trials came out that drive use of these agents beyond glycemia to heart and kidney protection. The bottom line is in 2020, we got to 13% on SGLT2 and 17% on GLP1. And also, always consider the source population. Again, I'm gonna emphasize this. This is from the Optum dataset, commercially insured patients, the privileged few who get more of everything. We've actually looked at medication use in Cure CKD. This is some work in progress, but what I can tell you is one of the predictors of not getting kidney protective therapies is not having commercial insurance. So these are the most privileged people, and we're at a whopping 15% of SGLT2 inhibitor use. So let's just talk about a person. So this is actually one of my patients. She's an older woman with hypertension, type 2 diabetes, and she's been hospitalized three times in the past four months for congestive heart failure. She's on a classic medication regimen, loop diuretic, beta blocker, ACE inhibitor, metformin. And she presented to her primary care physician's office with worsening dyspnea. Blood pressure was reasonable, but she had pulmonary congestion and edema, a potassium of 5.2, a creatinine of 1.5, and an EGFR of 34, an albuminuria of 800. A1c was reasonable for this person at 6.8, and her ejection fraction by recent echocardiogram was 36%. So this is a classic phenotype of type 2 diabetes with CKD and heart failure. Anybody ever see a lady like this? This is like welcome to your world, right? So the primary care doc called, and we had a conversation. We discussed what pillars of therapy could be initiated to optimize her care. And we don't have an audience response, so I'll just let you look at those. We could add an SGLT2 with proven benefit. We could also consider an ARNI. We haven't really talked about that, but saccubitril valsartan, proven to improve outcomes at heart failure in place of the ACE inhibitor. We could add a thiazide, or we might do two things at once. So what we did was A and B, and that's the other subtlety here too, is we need to get over therapeutic inertia. These people are sick. She's very high risk, not only of going back in the hospital, but dying. And these are life-saving therapies. Don't wait, get going, start them both. So that's what the primary care doc did. And in fact, this is data we recently published. I think it came out two weeks ago in Diabetes Care, looking at a pooled analysis of the empagliflozin studies, all to date, both for glucose lowering and cardiovascular outcome trials, and looked at side effects in people with low GFR, below 45. Well, guess what? There are actually some good side effects. On the left, the red line is empagliflozin, significantly less edema. She has edema. And on the right, significantly less hyperkalemia. That's what you're gonna see, is these agents not only work together for efficacy, but it makes it more safe to combine finarenone with an SGLT2 because SGLT2 is lower potassium. So what did we do? So the next time it was my turn. Again, team sport. So we didn't give her an MRA at the first visit, not because of therapeutic inertia, but because of hyperkalemia. So I see her four weeks later and her dyspnea is better. She still has a little bit of edema. Her potassium has come down into a reasonable range. Her creatinine's gone up a little bit. That's the GFR dip you're gonna hear about. That's not AKI and that's not exhilarating kidney failure. That's a therapeutic effect of reducing hyperfiltration. And albuminuria has come down. So what are we gonna do next? Do you wanna add some more diuretic, either in the form of thiazide or furosemide? Do you wanna add finarenone or do you wanna add thiazide and furosemide? We added finarenone. And in fact, this is data actually post-hoc from Fidelio, the trial I showed you. This is Peter Rossing. I just published this earlier this year, looking at rates of hyperkalemia events in the finarenone trial. And it turns out that, for example, if they were not on an SGLT2 inhibitor, they had hyperkalemia events 19% of the time and went down to 8% of the time or 8.7% of the time if they had drop-in use of an SGLT2 inhibitor. At the bottom, it just shows you, the box just shows you by whether you wanna call hyperkalemia 6 or 5.5. But either way, you see a reduced risk by some 50%. And this lines up very well with the data that we have for impagliflozin. So we'll wrap up by saying a non-steroidal MRA. So far, finarenone, but there may be others coming. SGLT2 inhibitors and GLP-1 receptor agonists on top of a conventional ACE inhibitor, A or B, you'll hear more about that from Dr. Stanton, are now recommended as the four pillars of therapy. We should not have therapeutic inertia and CKD risk assessment and monitoring is necessary for delivering goal-directed therapies. And the case I showed you is designed to think about how we might use, if you will, clinical phenotyping, CKD, heart failure type 2 diabetes, to select these agents, not only for efficacy, but for safety. Like, for example, the SGLT2s reducing the risk of hyperkalemia with finarenone. So with that, I'll stop and I thank you very much and look forward to our discussion. Am I on? Okay, it's a pleasure to be here. I wanna thank the organizers for inviting me and yeah, it's also the first time I've been allowed out of Boston, so this is wonderful. To escape, I don't have anything to talk about. I'm gonna go through this. We're gonna utilize new ideas on ACE inhibitors. I'm gonna go through risk and benefits of these drugs. I'm gonna give you some of my thoughts and some slightly different views on SGLT2s, although I entirely agree with Kathy about the treatment of the patient she was talking about, because of the, especially the severity of CHF and the efficacy of SGLT2s. So I wanna remind people that nothing happened to renin RAS inhibitors. Some years ago at the NIH, I was there and they said they thought they had cured diabetes with ACEs and ARBs and had to remind them we haven't. In fact, we haven't cured them with anything yet. We've slowed down the rate of decline and there still is a big deal of knowing who's gonna decline and who's not. So we still have to figure out who we should be targeting as such. So that's very important, but the new treatments are very exciting for different reasons and RAS has made a big difference. So some thoughts about the RAS system, remembering that they're important both for reducing cardiovascular disease and kidney disease, much like the other new drugs that are on the market now. So I wanna remind people, I usually ask this as a question, I say ACE inhibitors and ARBs should be given to, I mean, are good for lowering blood pressure, lowering albumin and increasing GFR and 70% of the people say yes. And then I remind people, no, they decrease GFR. And when they see that, a lot of people stop the drugs because they say, I'm hurting my kidney. And in point of fact, this is how the drugs work. I don't have time to go into efferent arterial mechanisms, but happy to tell anybody later, or you can look it up. But it's actually been studied too, that it's quite likely, and this is a study done some years ago, as you can see, looking at an original study from Losartan called the RENAL study. And it showed that the people that had the greatest initial decline in GFR had the best long-term outcomes, suggesting if you don't see a decline in GFR, you probably didn't get enough drug. So we as nephrologists, Kathy and I and others would go, how much is okay? Everybody'd say, well, how much is too much? And we say 30%, which was picked out of complete midair. There was actually zero data on that to know how much is a decent decline. There was a recent study that came out that looked retrospectively at this analysis, looking at people, what was the initial decline and what happened over time? And what was really interesting about this study was that when decline was greater than 30%, things didn't go so well. That's the initial decline. I can't say about later. So I'm a little more sanguine about seeing about, this was a large retrospective study, so I'm a little sanguine about pushing these drugs too much. So now, when should you stop the drug is another question we usually get. I can safely say, I don't know. And what I do is, generally, if everything is stable, I don't do anything. I don't care GFRs are 10, five, whatever. I don't change anything. Now, so there's a study looking at it right now, which every time before I give a talk, I look to see if the study is ever done. That's going on in Birmingham, you can look it up. It's still not done yet, I'm waiting to see, but they're looking to see if stopping the drug makes a difference or not. Now, a retrospective study came out and they looked back at time where the drugs were stopped and where they weren't stopped. And for my benefit, at least, they supported what I've been doing, which is when they stopped the drug, things got worse, actually, for most patients. The heart failure was worse, outcomes were worse. It was better to continue the drug to the bitter end. They said, well, didn't people get to dialysis faster? And the answer was no. They did not get to dialysis faster in a retrospective study. So my view is, unless they're tipping over the edge for some reason, keep the ACE and ARBs going as long as everything is stable. Now, so that's about RAS. Let's talk about the new kids on the block here, as Kathy talked about very well. So this is a general overview of all the things GLP-1 does. We tend to focus mechanistically for all these different drugs on a very specific mechanism, but almost all of them have specific effects, but a lot of off-target effects. As Kathy mentioned, from the Jackson Pollock painting, which I like very much, years ago, I gave my father a jigsaw puzzle of a Jackson Pollock painting. They thought I was trying to kill him or something like that. There's a thousand pieces, too. Anyway, that's what I thought of when I saw your slide. So GLP-1s do a lot of things, but we really don't know what's in the kidney unless it's inflammation, as Kathy pointed out. But these were fortuitous findings because in the midst of doing the cardiovascular outcome studies, which showed that there was true, significant cardiovascular benefits that were quite wonderful and remain quite wonderful to this day. Remember, the reason they find this out, this was back in 2007, because of Actos and everything else, people said, okay, because of the side effects from Actos, that every new drug for diabetes has to have a cardiovascular study. And that's why all these things were found. So this was the original LEADER trial, and there was a suggestion that there was albuminuria-lowering effects with liraglutide, not much different in GFR here. Now, dulaglutide has been reported to be protective. The differences, to me, are nice, not super dramatic. The main effects on albuminuria. And again, here, the GFR declined. As Kathy said, the sense is there's, in the right direction, the albuminuria effect is higher. And there's a clear association between albuminuria and cardiovascular disease. Now, in my view, it may or may not, it's not like albuminuria is causing cardiovascular disease, but the albuminuria is clearly a marker of cardiovascular disease. Likely inflammation is tying to, in other words. In other words, the same inflammatory things like, pick your inflammatory marker, interferon gamma, I1 beta, pick your whatever one, is causing, that might be causing albuminuria in the kidney, either at the glomerular level or the proximal tubular level, which is a longer discussion. And also affecting heart disease. So a lot of times when I see microalbuminuria, I'm thinking, and people send me patients with microalbuminuria, I'm really thinking I'm treating cardiovascular disease at that point until they get to a much higher level of being above 300 or so. But that's a strong association, and a real one. So it's not dismissing the effects of this, but the association is very important. And for the most part, when you lower albumin levels, you improve cardiovascular outcomes, and in general, improve kidney outcomes. So it's actually more impressive for the cardiovascular outcomes. Now, this is Kathy's study, the award seven she mentioned. This was impressive in the sense that it showed GFR improvements in the macroalbuminuria group, which is interesting about all these drugs, saying, are there subgroups that work better than others? It was a relatively small study, but promising in the right direction that GLP-1s appear to slow decline in GFR, and also, as we've already noted, improve albuminuria. Another more recent trial, as this drug's not available, F-paglenitide, again, I'm not a huge fan of composite outcomes, or MACEs, and all these things, because it tends to be one thing that drives it, so to me, it's sometimes hiding things, but here, the outcome was principally on albuminuria, and not GFR, whereas from 18%, from incident macroalbuminuria, versus 13% in the treated group. So again, this is very promising, and may be something to use. The problem with this is it's injected, so that's, whether people can inject themselves is a separate issue. DPP-4 inhibitors, I'll show you one slide that I would say they don't work. I was part of this group, finding out they didn't work. Everybody, I think, Martin Abramson, my colleague at BI in Jocelyn said, they're great for, all the primary care doctors love DPP-4 inhibitors, because they don't really work for anything, so they're safe. You're not gonna put anybody in trouble. But, so, I think there are clear cardiovascular benefits from GLP-1 agonists. They slow the rate, and appear to slow decline GFR, and I agree with Kathy that these are promising drugs, and remain to be seen. This is the study she mentioned. I mentioned it here, it's called FLOW. It's a big study. Semaglutide, estimated enrollment of 3508. It's gonna be completed in a few years, so we should have a reasonable answer of how effective these drugs are for being renal protective effects. And, DPP-4 inhibitors have no particular issue. We don't have any particular issues using these drugs, and we get questions as nephrologists all the time, should we use the drugs in kidney disease patients? And, the general answer is, drugs last longer in kidney disease patients. So, hypoglycemia's gonna be your biggest issue for most of these things. So, let's move to the last part of this. We're gonna talk about SGLT-2s. So, there are four, the ampiclifosin, caniclifosin, DAPA, and ERTU. ERTU was much less impressive, for some reason, than the other three in finding results. That remains sort of an open question as to why. But, the other three all showed very exciting findings. The initial finding was that Credence study, and this was a very well done study, it had albumin levels of greater than 300, and GFRs of 30 to 90. And, as the upper graph shows, albumin levels came down. And, there's an initial decline in GFR, which we'll discuss a little bit more in a minute. And then, there is a better outcome in the long run for GFR. The question always comes up, over and over again, does any nephrologist worry about the initial decline in GFR, the answer is no. The answer is no, no, no, no, no. So, don't worry about it. But, and I'll explain why. Now, DAPA CKD came out, and this was looking at a number of chronic kidney disease patients, both with and without diabetes. so this was anybody with kidney disease. And I won't go through all this, but even composite outcomes for the heart, for the kidneys, specific ones, they are better for almost any kidney disease that they, in the study at least. So what's going on? So this is from NIH group that Kathy led here. There's a lot of possible mechanisms involved with this. And I'm going to dive into the mechanisms some more about SGLT2s in just a minute. And they're shown up here. I won't go through every one, but they've been, and it's not a specific answer actually, but there's blood pressures and diuretic effect and decreased inflation and hypertension, all sorts of things. So I won't go through this in much detail. So to remind you, this is the nephron. The SGLT2 is found in, right after the glomerulus, which is the red thing in the middle there, then it comes down the proximal tubule. SGLT2 is found in the proximal tubule. Then important for my note later in the day is SGL, in the, when you get back up to the proximal tubule, so after you head down the tube and come back up where it says sodium chloride delivery at the macula densa, that macula densa is critical to understand this process and speaks back to the glomerulus. This process is called tubuloglomerular feedback. So the original paper on possible role for tubuloglomerular feedback was back in 2014, and I wrote the editorial about the paper and such. What they did was they took people with type 1 diabetes, type 1, gave ampaglifosin for 8 weeks, and then saw what happened to glomerular filtration. And what happened was glomerular filtration came down in the groups that were hyperfiltering. In the normally filtering groups, they didn't change actually. That's a step we can get into physiology later, but they didn't change. But in the hyperfiltrating group, they came down. The question was why. So getting back to our tubule again, the macula densa, that red thing in the middle there, in a simplistic sense basically goes, if I see a lot of particles, I'm going to tell the glomerulus to stop its filtering because plenty of cartels. If I don't see a lot of particles, then filtering better increase. That's TG feedback in a nutshell. So what the explanation proposed hypothesis is that when you block SGLT2, which is at the beginning of the tubule, and then it comes, all those particles start heading downstream. What was originally hyperfiltering said, hey, we have plenty of particles now. Let's decrease filtration. And that's certainly the reason for the initial drop in TG at the beginning of SGLT2s. That's physiologic. We don't care about physiology so much in that sense of causing damage in any way. Now the argument that's made is this continues after that, and that I'm not so sure of, but we can discuss my thoughts about that in a minute. But that is the argument for, at the beginning, and that's likely the reason. So TG feedback at the macula densa, a number of particles going by, tells the glomerulus to hyperfilter or not. So very nice review in Nature Reviews Nephrology from Ralph DeFranzo, who was the first really to use this. We all had fluorescent in the lab, and then as Kathy was telling me just a few minutes ago, she and Ralph were working together. And Ralph said, we should try using this for kidney disease. Fluorescent blocks SGLT2 and SGLT1, and it's too dangerous to use for people. And well, that's, but these are all mechanisms put together to suggest maybe why these drugs do what they do. Again, it's not definite. Why pouring glucose down the nephron should make things better is debatable. So the data is very exciting. It's cardiovascular data is amazing. The heart failure data is incredible. I agree with all that, so no problems with that. But I, there are some things to remember when you're seeing patients. These are all reasons to alert your patients about it. You may get people stopping the drugs because they had infections or other issues. You have to watch diuretics when you start these drugs, things like that. But, so I said this drug treats all kidney disease. And to me, when I say, have we found a drug that treats all kidney disease, I'm a little nervous when I hear that. So I'm wondering, is there other explanations or concerns about these drugs in the long term? And again, I'm not arguing about the cardiovascular data, but just thought process to think about it as you do. So let me go through some of my concerns. Is it good to pour glucose down your nephron for the rest of your life? So one of the major things that have been known for 30, 40 years in diabetic complications are advanced glycation end products. Advanced glycation end products are the formation of glucose that attaches to a protein and doesn't require any enzymes to get sugar-coated protein. If you take a glass of water and put albumin and glucose in there, you'll have a sugar-coated albumin the next day. There's nothing, this has been shown, these are advanced glycation end products here. It's been shown for many years, thought to be involved in diabetic complications. This is a big advanced glycation end product. So next time you have one, enjoy yourself, but this is cooked on. If you heat it up, it'll happen faster. There is debate actually about whether or not ingesting these are bad for you. So what do they cause? They cause oxidative stress, they cause damage, they reduce the nitric oxide. There's a lot of badness these things cause. So the question I have is if you're pouring glucose down your tubule and there's high levels of glucose sitting in the tubules, for the rest of your life are advanced glycation end products forming on the proteins of the cell membranes? And I don't think we know. It takes years to find out. So the experiment started now, or a few years ago. And so this is just another pathway of involving other papers. You can look them up, all the bad things that have been associated with advanced glycation end products for your. And so will there be transport over time? Now the argument against me has been, oh Bob, there are people born with defective sodium glucose co-transporters. And they're fine. They seem to be fine. So I go, how many people are born with this condition? Not too many I don't think. How many have diabetes? Probably very few. And how many have diabetic kidney disease? Maybe nobody. So this is not comforting to me, that it's going to be fine. And so I don't know. We're probably waiting another. It takes 5 to 20 years to see diabetic kidney disease under normal circumstances. Now it's on the basolateral side, not the luminal side. So we're really doing an experiment of nature when we start these drugs. That being said, when I get to Kathy's heart failure patient, I don't. Heart failure, they're going to be dead in 5 years. So that patient clearly is benefiting from this birth. So the other question is how to interpret the data. So the assumption is that GFR reflects nephron number. Does GFR always reflect nephron number, i.e. as you lose nephrons, GFR? Well, it doesn't. And we know that's the case. If you have 100 nephrons, you lose 50 over time. If the other 50 nephrons work twice as hard or harder, your GFR looks the same. And clinically, we see this all the time. We see patients going like this and they drop. And they go like this. And they're almost certainly losing nephrons over time. So GFR and nephron number are not aligned. They could be, but they're not always. So how do we reinterpret this data? So I have thought that maybe these, maybe why it works everywhere is because these are causing hyperfiltration, even though the dogma right now, they cause hypofiltration or lower filtration. So this was a paper done not by me, by Volker Wallen, who's a great, good guy. And he gave, this was an 80-minute study, actually, where they infused glucose into mice. And they found SGLT1 overexpression at our favourite site, macula densa, which led to hyperfiltration. So it was a short-term study. And the question was, his concern was, then you should block SGL2 and SGLT1 in the study. And Zhang was the first thought to hear it. So Zhang followed up with this study with Volker. And then they looked at 12 weeks, I forget if it was Akita or which mouse model. And I found basically the same thing at 12 weeks of hyperfiltration. Again, saying we got to block SGLT1 in addition, like a sonical flows in type thing. But I'm wondering, is really what's going on, you get the initial TG feedback drop. And then as glucose goes downstream over time, GFR goes up. And that the drugs ultimately cause hyperfiltration, which may or may not be bad. But we think it's bad. Every other setting, we think hyperfiltration is bad. So the viewpoint then, current viewpoint is that GFR goes down due to TG feedback. And then suggesting that both need to be drugged, which is why I'm saying both need to be treated. What I'm suggesting is that down regulation of hyperfiltration, but then persistent delivery to the SGLT1 site leads to hyperfiltration. What's the implication of that? Implication is that it'll work every time we use this drug with any kidney disease. So I'm wondering, is this, is what we're seeing for every kidney disease, this? Or does it treat every kidney disease? Now, I don't know the answer. I want to tell that with, I chair the ADA Guidelines Committee, and I'm not fighting with the, for CKD. And I don't fight with the guidelines right now because I go by data that exists right now. I'm just putting out there alternative hypothesis we should be thinking about as well, as scientists. So over time, this become a problem. I don't know. So there's sotaglifosin. It's out there. It's been studied in trials called SCORD and SOLUIS. They did not see a benefit in the kidney part of it. But they stopped the study early because they ran out of money apparently. So I can't, that's not a fair answer that this drug. But it'd be interesting, if sotaglifosin doesn't work for kidney benefit, that would be very interesting, obviously, if that's really what happens. But we don't know the answer, so I can't say. And it might be better, so I don't know. So all people with kidney disease, clear benefits for all the criteria, all the guidelines recommend it. But there may be long-term risks. Quickly, on combination treatments, I agree with Kathy entirely that it's exciting world of new combinations. This is showing with finarinone, a recent publication, that with or without SGLT2s, things were better. That's a good thing. That's a lowering albumin is always a good thing, either for the heart or the kidney. Certainly the heart, as I said. DAPO, it's been studied with a planarinone. Don't forget that, you know, everybody talks about finarinone, but, you know, spironolactone lowers albuminuria. That's been studied. Planarinone, so don't forget. And there are finarinone folks, they're a lot cheaper with spironolactone and planarinone. They cost as much as water, though, as compared to finarinone. Some rep is going to attack me in a minute. So prevention, I just want to point out that none of these have been proven for prevention. RASs even are not preventative. And there's mission creep that occurs with every drug. I don't have time to discuss why RASs have been shown not to be preventative, per se. But the only proven is the blood sugar. I'm talking about people without CKD, and blood pressure and blood sugar. So treatment, all these things that you all know. And again, SGLT2s have, especially with our cardiovascular risk, have worked their way into this field. My concerns are hypothetical at this point, but hopefully to be proven right or wrong. And so Kathy brilliantly went through the worldwide epidemic and made a point. To us, nephrologists, we're most upset about people not discovering this. Because I say to everybody, we do nothing for this epidemic because we don't diagnose it. It's endocrinologists, primary care, and everybody else who diagnoses it. We can only help with our together if somebody else diagnoses it. And, but as she said, we're in an extremely exciting era. And, of discovery, and this, there's a lot of interesting ideas, and there's a lot more to go. Even though all these have not cured diabetic kidney disease, but we're getting closer. So thank you very much. Perfect. Thank, I don't know, is this on? Thank you so much, Dr. Stanton. So I'd like to bring Dr. Tuttle back onto the stage. Please take a seat. And I think we have time for a few questions from the audience, so Dr. Suraj. Thank you. These were great talks. Dr. Stanton, we look forward to see you next week in Virginia. Oh, hi. You'll hear, you'll hear the same. I know. I only added finarinone back then. But I'm going to ask a different question today, next week. Yeah, so this is really a very exciting time. 20 years, it was, I was a fellow when we had S-inhibitors and ARBs 20 years ago, showed all this improvement in renal outcomes, and now it's another era, I guess, with SGLT2 inhibitors and finarinone. So the questions I have focused on, in particular, on SGLT2 inhibitors is, number one, is the improvement in renal outcomes dose-dependent? Do we know that? That's one. And the second thing is, in terms of monitoring microalbuminuria, you know, once the patients are on the right stuff, does it make sense to obsessively monitor microalbuminuria going forward? Thank you. You can, I'll say the microalbuminuria part. So first off, the good news is the effects of SGLT2 appear to be dose-independent. So whether you use 10 or 25 of EMPA, you get the same result. The DAPA dose used in DAPA CKD was 10 milligrams. So that actually turns out to be a good thing, especially in terms of trying to add therapies in people who are at risk of hypoglycemia, even at low dose, you get the kidney benefit. Yes, please obsess over albuminuria. Because people who have residual albuminuria are high risk. And then you need to add additional therapies, like I showed on the KDEGO pathways. So, you know, if you have an SGLT2 and you have persistent albuminuria and glycemia isn't controlled, we're recommending a GLP1. If glycemia is controlled and they have persistent albuminuria, we would use finarinone. And you use albuminuria as a readout of therapeutic responsiveness. If albuminuria goes down, that's a good thing. Stay the course. But if it goes up, it's a, bad things are happening. And you need to intensify therapy. So that's one of the pleas that we're making is, one, you should be screening. But it's very important in terms of monitoring therapeutic responsiveness. And albuminuria is your readout to titrate and add medications. I don't know if you want to add anything, Bob. I 100% and 200% agree. The American College of Physicians a few years back put a, well, a lot of guidelines have been insane in the last 10 years. But anyway, they put out a statement, just start 5 milligrams of lisinopril. Then forget, go away, never look at anybody again. It's so long, I don't know where to start. There's, I can send you tons of papers showing, especially in cardiovascular disease, any time you lower albuminuria, whatever level you're working at, you will improve outcomes. There's data from years ago showing in circulation from the Framingham Heart Study that high normal albumin people had worse outcomes than low normal. So you want to keep pushing the albumin levels down. One of the best signs of kidney disease getting worse is albumin levels chronically climbing. And the data on kidney disease is not as strong as cardiovascular actually. But it's good the same way that when you lower albumin, so you should be following and do the best you can. But then you, at some point, you know, depending on, you know, you may be held by hyperkalemia issues or tolerance or something else that stops it. So, yes, 100%. Well, and also if I can just add, I think this is important for this audience to know, the U.S. Preventive Health Services Task Force is now going to reevaluate the CKD recommendation because of the new therapies to, and we'll see what they say. But the reason they're looking at it, again, is exactly what Bob said, because it makes a difference. And now we have drugs that will titrate even to albuminuria. So, we're hopeful that they will come out with a recommendation because so many measures, if you will, clinical metrics are based on U.S. Preventive Health Services Task Force recommendations. And what we all know is what gets measured is what gets done. And also what gets paid for is what gets done. And this is sort of a health policy issue, but I think it's really important because, you know, to me, besides diabetes, chronic kidney disease is the other epidemic that has not been adequately addressed at a public health level. I totally agree. And I've always wondered for years why albuminuria wasn't screened in everybody. Like, it doesn't make any sense. Perfect. Thank you. So, let's move to the other microphone. And please limit yourself to one question. If I saw it correctly in the slide, you showed that in type 2 diabetes, you would add non-steroidal MRA as opposed to type 1 that should set steroidal MRA. Would you please elaborate? Did you say that? Well, the reason is that we have the outcome data for finaranone. And Bob, I mean, we've overlapped a lot. But, and Bob mentioned a planon and spironolactone do lower albuminuria, but there's no outcome data for that. And without going into a lot of details in the interest of time, there are theoretical reasons that these non-steroidal MRA should be more effective. But, you know, really what, like Bob said, what counts is the clinical trial data. And I don't think we'll ever see that for a planon or spironolactone. The problem, yeah, just because people, it's not going to do the study. So, you can decide on your own whether that's fair or not. But there is data showing albuminuria lowering for sure with spironolactone and planon. We have more hyperkalemia, though, with those older agents as well. And there are pharmacological reasons for that. And unfortunately, we're out of time. So, but I think the speakers will stay for a couple of minutes if you'd like to come up. So, again, thank you very, very much, Dr. Stanton and Dr. Tuttle. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you.

Management of Diabetic Kidney Disease

Dr. Catherine Tuttle

Dr. Robert Stanton

Finaranone

Therapies for Diabetic Kidney Disease

Albuminuria Screening

SGLT2 Inhibitors

GLP-1 Receptor Agonists

Cardiovascular and Kidney Disease Risks