So, quite excited to be here with all of you. Thank you to ACE for inviting me to present and to talk about my favorite topic, which is the kidneys. Okay. So, let's get started. These are my disclosures, some of which apply because I was an investigator for both FIGAR on Fidelio and the Xanax CKD trial, but other than that, nothing. So, I will talk briefly about the epidemiology of diabetes in the area, which I'm sure you're much more and more experts than I am. And then I'm going to discuss a little bit about the traditional treatments. And we've had a plethora of positive kidney trials in the last five years or so. So, there's a lot of good discussion to be had there. So, I will be mentioning all of those trials that you may or may not be familiar with. So, as I was researching, you know, my talk and coming to learn more about the region, I learned that other than Africa, this region, MENA, has the highest increase in diabetes in the world. So, while we always talk about diabetes is increasing worldwide, you are probably seeing and experiencing this firsthand. So, it's estimated in this from the IDF that your region will increase from, at the time, 2045, 87 percent increase compared to 2021. So, a huge increase. And then the diabetes report, also from the same organization, shows, and you can see there, from 2000 to 2045, there will be 135 million people in this area with diabetes. So, very, very impressive and just highlights the importance of treating diabetes in this area. And again, you can see there the prevalence of diabetes, age adjusted. You're going to go from 18 percent to 20 percent in that time period. So, these are some of the highlights. One in six adults will have diabetes, and one in three diabetes is undiagnosed. And one in seven people that are going to be born will going to have effects of hyperglycemia during pregnancy. So, in the kidney area, I couldn't find anything specific to the Emirates, but I found that in Qatar, which is close by, there is, again, the incidence of end-stage kidney disease due to diabetes is like the second or third in the world. So, again, just highlighting the importance of diabetes, nephropathy in the area. And why do we care about chronic kidney disease? So, chronic kidney disease is slow, progressive, and right now, it's the 16th disease by category for years of life lost. But again, as diabetes is increasing, so is chronic kidney disease, at least in the United States is the number one cause of kidney disease. In other areas, it is not. But by 2040, it will increase and surpass diabetes for years of life lost in the world. So, in order to decrease, which is sort of my passion and lifelong mission, is to decrease the incidence of DKD in the world. And I like this article by the ADA that basically shows what are the primary drivers, the secondary drivers, who are the stakeholders that can help us lower the incidence of diabetic kidney disease. Maybe I'll move over here. And you can see I'm going to be discussing mostly therapy, which is just one of the little lines that I'll show you. But all of these other things need to happen. So, we need to have a public policy that will improve lifestyle changes. We have to build capacity, meaning people that can do education, people that can treat the patients, et cetera. We need to get technology to the underserved, et cetera. Raise awareness of diabetes, awareness of kidney disease. I'm going to be focusing on, oh, I guess if I do it there, you don't see it. But anyway, I'm going to be focusing on evidence-based drug therapy. But that's just one of the lines of the many things that we need to work towards. So, one of the most important thing is to diagnose chronic kidney disease. And the current definition of chronic kidney disease is a GFR less than 60 or albumin to creatinine ratio greater than 30 and or. But we don't do a good job, as we should, measuring these two tests because both tests need to be measured. So, in this study, about half a million adults, each box, the bigger box are 50,000 patients. The smaller box are 5,000 patients. These are primary care practices. So, individual primary care practices in different health care organizations. And you can see that for eGFR, we're doing great because we measure in the chemistry. So, about 90% of individuals in the study had at least one GFR measured every year. But then when it comes to albumin to creatinine ratio, the distribution you can see varies. So, some did acceptable, but much lower, 60, on average about 53% of individuals that have diabetes that have an indication for urine albumin to creatinine ratio get it measured. And you can see that the distribution. And in this one practice where it's almost like 10%. But you can see that if you look at each practice in each of those health systems, you can see that even the best practice, the one that was doing almost 100%, they have a few practices that are only measuring at 40%. And that practice, the one that was in orange, that was not measuring the urine albumin to creatinine ratio. So, you can see that some practices in their group are measuring urine albumin to creatinine ratio at 77%, which basically means that we need to do more education all around. And why do we care about this? So, the reason that we have that cutoff of 60 and 30 is because that's where the events, the cardiovascular events, where all the mortality starts happening. And even in here in this graph, what we consider normal, which is 5 to 30, you can see there's a linear progression. So, 5 is better than 10, 10 is better than 20, and 20 is better than 30. And so, it's quite important to measure both things. And our patients are always, or at least mine, are always concerned about ending up on dialysis. But that's not the main concern because 9 out of 10 of them are going to die before they reach dialysis or have a cardiovascular event. So, yes, we want a slow progression of kidney disease. We don't want our patients to end up on dialysis. But more importantly, we want them to live. So, this is from the KDGO guideline. And you can see that now we have that heat map that we love. The chronic kidney disease is classified by the cost. So, for us, I'm in a diabetes center, everybody has diabetes. So, the cost is diabetes. The GFR is those Gs. So, from 1 to 5 are the different stages based on the individual GFR. And then the albuminuria goes from A1, A2, A3. So, that's how we classify kidney disease. And I like this particular graph because it reminds the primary care providers that if your patient is in green, they continue to screen. But if the patient is in yellow, orange, they have to treat. And then if they're, you know, severe albuminuria or very low GFR, they should also refer to the nephrologist. So, that's quite important. I know some of you are probably very familiar with this. This is the consensus statement of the KDGO guidelines and the ADA guidelines. And just highlighting that lifestyle is still the backbone of everything that we do in diabetes. And that circle that is yellow that shows around and around, that means that every time we see the patient in clinic, we have to ask about the healthy lifestyle. We have to ask about the physical activity. Did they quit smoking? How's their weight doing? All of that is always first. Then in blue, we have what we do for type 1 and type 2. That's the blood pressure control, the lipid management, the cardiovascular disease. And then in green are the medications that I'm now going to spend some time on, which are the SGLT2 inhibitors, the GLP-1s, and the non-steroidal MRA. So that, again, that right now is only for type 2 because they're not indicated for type 1 yet. But the studies are ongoing and hopefully in a year or two, we'll have those results. So I'm going to focus on progression of kidney disease, but you all know this, that now when we choose a hypoglycemic medication or management of diabetes, we're not only looking at A1c, we're looking at organ-saving medications. So again, I'm going to focus on kidney disease, but as you know, there's some that are good for heart failure, some that are good for atherosclerosis, et cetera. In the United States, I don't know how it works here, but the United States, there's still a large barrier because of cost of some of these medications. So these are the sort of pillar treatments. Still RAS blockade is the most important. So all of these studies were done on individuals that were on RAS blockade. So these medications do not substitute RAS blockade. That's ACE inhibitors or ARB. This is in addition to. And so the second pillar, I think mostly because it was the second to come, would be SGLT2 inhibitors. The third pillar would be finaranone, and we're calling it still a potential pillar, which is GLP-1s because they're not yet on the guidelines, but they should be coming soon. So by 2025, they will be there. We hope. I don't know. I haven't seen the guidelines yet. Okay, so here also showing you that they work in different areas, right? So RAS blockades are more about decreasing hyperfiltration and pressure within the kidney. SGLT2 inhibitors are more about improving the tubular glomerular feedback. They have a little bit of natriuresis. They decrease hyperfiltration. Finaranone is focusing more on inflammation and oxidative stress. And then the GLP-1s more on the metabolic, the A1Cs, the weight loss, the lipids, etc. So they're all attacking sort of the same problem in different pathways. So again, highlighting that lifestyle is very important and reduction of intense therapy of all the lifestyle changes is very important to slow progression of kidney disease. This is the Japan Diabetes Optimal Integrated Treatment where they use conventional therapy versus intensive therapy. You'll see there that intensive therapy was an A1C less than 6.9, blood pressure less than 130 over 80, and an LDL less than 120. And you can see that if you had that intensive therapy, your kidney events was decreased by 32%. And you can see from the graph that it was mostly individuals did not get severe albuminuria. That's where the change was. And then this is the STINO trial. This is a multifactorial intervention again. The patients were followed for seven years. And in this study, they went back and looked at what happened to those individuals that were on the trial 20 years later. So by then, the A1Cs were very similar. And they looked, and you can see here that those individuals that 20 years later they went back, those that were on the intensive trial lived almost eight years longer than those individuals that had not been on the intensive trial. So very important to have intensive therapy of control, multifactorial intervention. So for many, many years, I think this is like the most exciting time to be in nephrology because for many years, we had nothing. There was every negative trial that would happen to nephrology, and there were very little trials for many reasons. But one of them is that it takes so long to reach that outcome of kidney failure. So nobody was going to do a trial that was going to be 20 and 25 years. So that was part of the problem. And the National Kidney Foundation, it really worked with the FDA to do biomarkers. So that's why albuminuria now is a biomarker that can be used for trials. That's why GFR decreasing 40% or 50% are used in trials. So that really brought a lot of interest in kidney disease. And also, we owe it also to endocrine, right? Because you had those CAVA trials, and when that data happened, a lot of people were also able to see the outcomes in kidney disease. And so anyway, so that actually brought the era of great kidney trials now. So these were the last positive trials that was back in 2001, RENAL and IDTN, that showed that ARBs were successful for the treatment of type 2 diabetes. And then for 20 years, we had nothing. But then this also shows that even though we know for 20 years now that RAS blockade are very important, we are not at 100%. And this is data from different countries, Brazil, France, Germany, and the US. The US doing worse than everybody else. And as the individual, their kidney function declines, they're even less likely to be on RAS blockade, which just highlights the importance of having multiple medications that we can use to treat our patients. So here are the SGLT2 inhibitors. The first one was Credence. I'm going to give you a little bit about the entry criteria and the GFR. So the entry criteria for Credence was you had to be over 30. You had to have type 2 diabetes. And you had to have severe albuminuria. That was the entry criteria. And they started with higher GFR. So the average GFR for Credence was 56.2. Everybody, again, had severe albuminuria, so their average ACR was 927. And like I said, everybody was on RAS blockade. That was a positive trial. There was a decrease in the kidney outcomes of about 30%. Then the DAPA CKD came out. It taught us some more. They only had two-thirds of the individual had type 2 diabetes. And then they added individuals with non-diabetic kidney disease. They lowered the GFR, the entry criteria for GFR, to about 25. They still kept the severe albuminuria criteria. But then they were a little bit more lax. Like if you had a reason not to be on RAS blockade, you could still be in the study. So that's why individuals, only 98, still very good, but only 98% of the individuals were on RAS blockade. There was also a positive trial, similar results. Then they did the EMPA kidney trial. Now only 45, less than half of the individuals, had type 2. The rest didn't have diabetes. Then they lowered the GFR even further and included individuals that if your GFR was very low, you did not need to have albuminuria to enter the study. So now it gave us information about treatment of chronic kidney disease in individuals that did not have albuminuria. And that's why you see that decrease in the ACR now on average was 329. And they also did not require it for sure to be on RAS blockade. So 85% of individuals were not on RAS blockade when they were in EMPA kidney. Again, that was also a positive trial. So it's very important that you know the differences from the trial, because I get some questions sometimes like, is EMPA better than DAPA or DAPA better than canagliflozin? And we cannot say that because they're all three different trials, different inclusion-exclusion criteria, so you cannot compare each one with the other. So here I highlighted the differences, which one had just type 2, which one had type 2 and not type 2. And again, the EMPA, which had a non-diabetic and non-albuminuric. Then the times were different too. So Credence had probably zero people on GLP-1 and SGLT-2, maybe very little. By the time they did DAPA and EMPA, they were like 6%, and the EMPA was probably 10 or 12% that were on different medication. So all of that, you have to take that into account when you try to compare the studies. Okay, so now looking at kidney outcomes, it looks like this is data from canagliflozin that there is benefit across all GFRs, and there's benefit across, you know, if you have very severe, more than 1,000 versus less than 1,000. But it does look like the more severe and the lower your GFR, the more benefit you have. And here is just looking at GFR differences and the absolute risk reduction. And you can see that it's much higher if your GFR is less than 60. That's the very next to last column. Let me try it here. So here you can see that it's 52%, 72% the absolute risk reduction here, versus it's not statistically significant here, like 17%. So that's quite important to note. So this is very important because sometimes the patient comes to me and tells me, well, my doctor said that the SGLT2 is no longer good for me. And I always tell them, well, it's not good to lower your A1c because your GFR now is low, but you still need it for kidney protection. So it's a different concept. So we still want the patients to be on SGLT2, even though it no longer will help them lower their A1c because we're trying to keep them off dialysis and to live. OK. So now we're looking at this is impact CKD. And just to show you here, similarly, while there's a lot of enthusiasm for non-diabetic kidney disease, you can see that definitely the ones with diabetes benefited more. But anyway, all the point estimates favor empagliflozin. So different GFRs, different arbuminuria, it's all positive. Another thing that we should not be afraid of is this drop in GFR because here you can see the top is DAPA. Here's placebo. This is the DAPA CKD study. And you can see that individuals in this first box, let's say light gray, is dropping GFR more than 10%. The next one is 0 to 10, and this one is less than 0. So no change. And you can see that those individuals that their GFR dropped, they're the ones that benefited the most from less. They lost over the study less GFR than those where there was no change. And obviously the placebo, there's no difference because there's no difference. They were not a medication. Again, highlighting here that at least in the United States, despite what we know, there's still very little uptake of SGLT2 inhibitors for people that need it. This is data from three years ago, but it has not improved that much. You can see that CKD are less likely to be on it. Also individuals that were black or Asian, and we have the same problem. Women are less likely to have it, and people of lower socioeconomic status are less likely to be on it too. So a lot of teaching and trying to get our patients on it. So next I'm moving up to GLP-1, and GLP-1 also very exciting study for nephrologists that we are a little bit, same as endocrinologists, we're more physiologically oriented. We have a little bit of a philosophical issue there because there's no GLP-1 receptor in the kidney, so we not really understand how it works. But we're going with faith because the studies were positive, but there's only GLP-1 in the smooth muscle cells, some smooth muscle cells in the aferin arteriole. And some optimists have said that, oh, you know, those inflammatory cells that come to the kidney when you have diabetic kidney disease, they also have GLP-1 receptors, so perhaps that's the benefit. They're affecting those cells, et cetera. That could be true. We don't know. But I'll tell you what the study is. So when LIDER was done and they did that CAVOT study, that's the cardiovascular outcome studies, they looked at microvascular events, and you could see that it was positive. So liraglotide decreased microvascular disease. When they subdivided between retinopathy and nephropathy, you can see that it was the nephropathy that made it positive. And then when you looked at the different composite outcomes of that kidney outcome, you can see that it was really that it decreased albuminuria. So that's what drove the whole signal there. And then over time, here you can see different, all the CAVOTs that were done for all the different medications that were GLP-1s, they all decreased albuminuria. But then the GFR was sort of questionable. Did they do something there? It wasn't really clear. So they did a meta-analysis looking at kidney outcomes. And again, you can see all the trials here. But if you included microalbuminuria, perhaps there was a very significant signal there. But then if you took microalbuminuria out, it was not so clear that that was positive. It lost its significance, which is what led to the FLOW trial. So this was the FLOW trial. And here they gave one milligram of semaglutide versus placebo to individuals that met this criteria, which is similar to, was more similar to the later SGLT2 studies. And they picked the lower dose because they didn't want this to be an obesity trial. They wanted it to be a kidney trial. And so they followed individuals over time. It was supposed to last about five years. But as you know, it was stopped after like two and a half. The important thing is that most people, 93% of the individuals in FLOW, were at high risk or very high risk of kidney disease. So what we had seen in our previous one in red or orange. And the results came out. And yet again, you know, another positive trial. So it's specifically all the outcomes were positive here and all the kidney outcomes were also very positive. There was a 21% reduction in the kidney specific outcomes. So super exciting. But it was hard to, you know, when we tried to grapple on why this is, there were a little bit of differences. There was a weight loss. There was about nine pounds. There was a reduction in A1C of 0.81. And there was a little bit of improvement in the blood pressure. So perhaps that also contributed to the improvement. Doesn't matter. We're happy with a positive trial. And just letting you know. So there's been some studies that are doing mediation analysis to try to say, okay, what part is it that is really affecting the outcome? And again, these are all statistical studies, but basically it showed that perhaps the blood pressure reduction had some impact, 15%. But in patients that have GFR less than 60, there was, it says supposedly no benefit in the A1C and very, the body weight reduction had no impact in the study. We'll find out. And I'm going to move on to the Fidelio study, which is the kidney outcome study for finaranone. So finaranone is a non-steroidal selective mineralocorticoid receptor antagonist. The other older, let's say, steroidal mineralocorticoid receptor antagonists do not have an indication for kidney disease and have not really been studied because of the concern of hyperkalemia. As you understand, patients with chronic kidney disease on these medications are way more likely to develop hyperkalemia, which could be life-threatening. So these are the final results of Fidelio, and you can see, oops, no, there we go. You can see here that they had a baseline GFR of 44. They had severe albuminuria, but different from the SGLT2 trials, they had to be on a maximum tolerated dose, which meant that you could be on the SGLT2 trials if you were on 2.5 of lisinopril, but you had to be on 20 of lisinopril to be on Fidelio. So there's a difference in the doses of that. So there was a chart, and that's how it was done. But either way, all the kidney outcomes were positive, and they all favored fineranone. And we have to mention this. The hyperkalemia was more often seen in the individuals that were on fineranone compared to placebo. There was a 2.3 versus 0.9 hyperkalemia incidence in 2.3 in the ones that were on fineranone versus 0.9 in those that were not. So at least a 0.2 difference. Here, as I mentioned, when they did Fidelio, about 6% of the people were on GLP-1s and SGLT2 inhibitors, so they did separate studies to see if there was a higher impact. Because I think at this stage, we know that all three medications work well. What we don't know is which combination is the best for each patient. And I think that's what we're trying to learn now. At least in the kidney world. So here, they individually looked at GLP-1s, and there was a separate study on SGLT2s, but basically showing that neither for cardiovascular, kidney-composite, or all-cause mortality, there's no interaction. So meaning that whether you were on the medication or not, fineranone worked for you. And this is just looking at UACR and seeing if there was a difference in how much lower your albumin-to-creatinine ratio was. And you can see that they're all very similar. You could have been on both, or one, or the other, or neither, and the point estimates were very, very similar there. Again, very little numbers, because it was 6% of the cohort. Here are some other studies that have used other here. They had Xenotide and DAPA. Xenotide is hardly ever used, but you can see that the darker blue here had the higher reduction in albumin-to-creatinine ratio, which makes you think that if you use two or three of them, that your UACR would lower much more than if you didn't use them. This is a study that looked at, again, now discussing combination. When they did this study, fineranone had not been approved yet. But here they did DAPA and epleranone. And I just wanted to show you, this is interesting also, the individual, there was a higher decrease in urine albumin-to-creatinine ratio if you were on both. But what I wanted to highlight here is something that was also seen in the other trials, that if you are on an SGLT2 inhibitor and your potassium is lower. So here's DAPA alone, here's epleranone alone, here's the combination. So hyperkalemia does go up, but much lower than if you were not on the SGLT2 inhibitor. And there have been now at least three or four or five of these studies, and they all showed the same benefit. This is a study. We don't have results yet. This is the confidence trial, where the individuals are getting fineranone and EMPA, fineranone alone or EMPA alone, and where it's going to be comparing the dual therapy versus each one by themselves, just to make sure that there's decrease in UACR and also look at safety over the length of the study. So new kid on the block. This is the Senneth CKD trial. In this study, because now we consider SGLT2 inhibitors to be standard of care, individuals had to be on SGLT2 inhibitors plus the endothelial receptor antagonist. And in part, that's also because people with endothelial receptor antagonist are more likely to get heart failure because they get volume overloaded. That's one of the sort of side effects of the medication. So adding the SGLT2 inhibitor might, because it decreases heart failure events, maybe it was beneficial. And so here, just showing you the outcome, you can see that there were two different doses of the Cibotetan, which is the endothelial receptor antagonist. They used 0.25 and 1.5, and that's in the sort of green and teal colored here. But you can see that here, there's a decrease in the urine albumin to creatinine ratio and GFR. Okay, so the next problem that we have, people tend not to prescribe medications, so that's in the blue. You can see this is a study that was done using a big pharma company in the United States, and you can see that initiation of medications is quite low. But even greater is that it doesn't matter what medication it is for diabetes, et cetera, the discontinuation is quite high. So this is something that, again, we need to tackle with education of our patients and trying to remove barriers on why they're not getting their medications. In the United States, for example, you have to do these prior authorizations. So every three months, four months, five months, you have to do more paperwork to have our patients on the medication, so that becomes a barrier. There's now a new field called implementation science because it takes, on average, 17 years to take evidence into practice. So we did all these trials. We know all these things work, but we really don't have 17 years to get this into our patients. So this new science called implementation science hopefully will help us sort of move this faster into our patients. And I'm just highlighting here some of these guideline gaps, let's call it, for chronic kidney disease and diabetes. I mentioned already the UACR testing, which at best is about 40%, 45% in those individuals that have insurance. ACE and ARBs, again, probably 50%, 60%. SGLT2, I showed you data, 13%, 15% at least, at most. And then the non-steroidal MRA, there's not even data, so we don't know. But because we don't have the trials yet, some research groups have now used actuarial data, meaning they used the results of the trial and tried to see how it would look if individuals were on all these medications, if they had additive or multiplicative effects. So this is a study from Brendan Nguyen. And here he showed that the different sort of combinations and that you would have the highest impact if everybody was on all three medications. He used as the baseline case a 50-year-old man. And using that baseline case, if you were on combination therapy, you would gain an average of 5.5 years off dialysis. That's sort of the estimate that he did. Of course, the benefit would be less if the later, like a 60-year-old would be a little bit less, a 70-year-old would be less. I think it's very... I put this here because I think it's very important to note that our goal is to reduce albuminuria to not be severe. Severe albuminuria is more than 300. I sometimes hear people say that severe is more than 1,000, and that is not correct. More than 300 is already at increased risk. So if you have somebody at 1,000 and you started a medication and it came down to 600, that's great, but you're not done. You need to continue to try to reduce that UACR more and more. And then, so here we talk a lot. These are not the pillars of the AAC, but the pillars of the reduce the cardiorenal risk. I like this image because it shows the lifestyle reduction, because those are also important, and then the reduction in the cardiorenal events. And I modified it already. I moved the SGLT-2 pillar and I put the GLP-1 pillar there because I think that right now we do have evidence, and I know the guidelines don't show that, but I'm almost sure that the 2025 guidelines will show that next. So we're almost... You know, the guidelines come out in January, so I'm pretty sure that that will be there. So I also added this little kidney here to the consensus statement because now we have data that GLP-1s are not only cardioprotective, decrease weight, improve glycemic control, but they also are kidney protective. So in summary, diabetic kidney disease is the most common cause of kidney disease in the U.S. and worldwide. Blood pressure, glucose control, that's still, you know, paramount. Mass blockade is still very important, but now we have all these novel therapies for cardio kidney protection so that we need to avoid inertia and prescribe these medications and really work with our patients, our insurance, our government, et cetera, to make sure that our patients get that. We still need to work on multidisciplinary team, and again, these guidelines are evolving really quickly, so, you know, we have to keep up with that, too. So that concludes my presentation. I'm happy to take questions.

chronic kidney disease

diabetes

SGLT2 inhibitors

kidney therapy

MENA region

public policy

treatment integration