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Hi, my name is Bob Bush. I'm an endocrinologist in Albany, New York, and a director of clinical research, and we, we did some of the studies that I'll be reviewing with you. And, and we're gonna talk about the overlap between type 2 diabetes and chronic kidney disease to implement a multidisciplinary team approach that improves patient outcomes. You know, it's not just endos or nephrologists or primary care who manages diabetic nephropathy. Well, it's a team approach, including the patient in the center, but pharmacists. As well, so many of us are spoiled working with pharmDs who help out identify patients and tweak the medications appropriately. So that's what we'll be covering in the next half hour. The main objective is to get a deeper understanding of the pathophysiology of diabetes, the overlap of diabetes, chronic kidney disease, to have this multidisciplinary team approach. These are my disclosures, most of them are doing clinical trials with a variety of pharmaceutical companies, and some of these trials we'll be reviewing later on. So first polling question, which mechanism best explains why type 2 diabetes, cardiovascular disease, and chronic kidney disease overlap with each other? And you have these answers here, and I'll give you some time to answer. So here's the overlap where you have people who have diabetes, heart disease, heart failure, atherosclerotic heart disease, you know, so they all overlap with each other and, you know, that's why they call it cardio renal clinic. In fact, some hospitals are setting up uh cardiac renal metabolic, DCRM, diabetes, cardiac, renal, and metabolic as well, because of this tremendous overlap that they were all cross-trained in this. So you could see in the United States. 4 million Americans have diabetes, mainly type 2. Many of these patients have chronic kidney disease, and oftentimes it's not diagnosed until it's stage 4 or stage 5, because no one did a urine microalbumin or they may have done a GFR, but they didn't do a urine microalbumin. It certainly is important to know if there's kidney damage. Somewhere and then, uh, heart failure is very common. You've all heard in medical school that the, the kidneys wanna be wet, the heart wants to be dry. So if you have heart failure and less deficient blood volume, you get less, uh, you get worsening kidney disease and so on. If you volume deplete the patient, you get worse kidney disease when you're trying to treat the heart failure. And if you have diabetes and heart failure, it has tremendously high mortality. Now why this link of all these things? Well, we have chronic inflammation at the top, and then you have endothelial dysfunction, where you can get uh a vasoconstriction because of the impaired nitric oxide production. And then you get oxidative stress by reactive oxygen species being made and mitochondrial dysfunction, and then these all, it's a vicious cycle. Once you get more of uh inflammation and, and more oxidative stress, you get more inflammation and so on, so the cycle continues, and that's why um you, you wanna get this under control as early on as you can identify with the patient to benefit your patient. Now, what are these factors going on? Well, you have hemodynamic factors on the right. So, if you have a vasodilatation of the Afferent arterial inappropriately, you flood the glomerulus, and if you inappropriate vasoconstriction of the efferent arteriole, then you get worsening glomerular pressure and leakage of proteins and other factors from the glomerulus. So that's comes on by more ras activation, you can get fluid overload, etc. But then you have the metabolic, factors, the hyperglycemia and dyslipidemia that can lead to inflammation and fibrosis. So this combination of things, you end up with cardio renal syndromes and uh the, the diabetes is a systemic disorder can lead to these multiple problems with heart, with atherosclerosis, and with kidneys with inflammation. Now how do you reduce diabetes complications? Well, you need improved glycemic control with drugs that are heart smart or renally smart, good BP management, with drugs that are renally smart. Lipid management and aggressive lipid management, particularly if the patient has atherosclerosis, you know, the renal patient is an atherosclerotic equivalent, and you want to get the LDL as low as possible, oftentimes below 70 or below 55 with statins and other therapies as well. And then we wanna think of agents that specifically benefit the heart and the kidney. Some of these are diabetes agents, drugs that we treat diabetes with, and others are drugs that are specific for BP that may cause dilatation, for example, of the efferent arterial. Now, fortunately or unfortunately, in about 2007, 2008, The glitazones were beaten up by the FDA and they said every new diabetes drug had to have a cardiac outcome study showing safety. And it was because of this decision by the FDA that all of these trials were pursued to see was the drug, a diabetes drug safe for the heart. But then the spin-off of this is in some of these diabetes studies, for cardiac safety, they found there was renal benefit, and that led to dedicated renal trials. So, first, the cardiac studies occurred, and then we had dedicated. Renal studies that showed a diabetes drug would specifically benefit the kidney, aside from the heart safety. Most of the studies were done originally for heart safety until EPARG came out that showed cardiac benefit using Empagliflozin and SGLT-2. But in the SGLT-2 studies, it showed those had renal benefits as well. So then there were dedicated renal studies that I'll be reviewing with you. So how do you protect the kidneys? Besides good diabetes control and not giving nephrotoxic drugs like X-ray dye studies or uh Or, um, no X-ray dye, no NSAIDs, no COX-2s. What else can you do to protect the kidneys? Well, it turns out that the SGLT-2 studies that showed cardiac benefit, whether it was Emperreg showing that agliflozin lowered uh MI stroke death and lowered cardiac death by 38%, or the canvas program with canagliflozin showing it lowered MI stroke and death, or the declare trial with dapagliflozin, that showed that it also uh lowered heart failure. These were cardiac studies, but in those cardiac studies, if each of them showed renal benefit. And in fact, you could see on the right-hand side, how much renal benefit there was to lower end-stage renal disease or lower GFR by 40%. So because these cardiac studies show this, each of the companies making these drugs decided we'll do a dedicated renal study to look to see renal benefit to get the renal indication. Why did they do this? Because up until the SGLT2s were studied, the only drug that was approved to benefit the kidneys in type 2 was the ARBs. So the Renal trial showed losartan lowered end-stage renal disease by 16%, and the irbesartan diabetes nephropathy trial showed irbesartan with similar BP control to amlodipine lowered renal risk by 20%. So, all of a sudden, Grasses were in the drinking water to dilate the efferent arterial, to have hemodynamic benefit to allow glomerular pressure to lower by dilating the outflow from the kidney or the um efferent arterial. Well, then we had a flurry of all of these SGLT-2 studies. We had the CANVAS trial published in the New England Journal and type 2 diabetes with patients with type 2 who had proteinuria and a GFR above 30. And they had 4000 patients in the study giving canagliflozin, and after 2.5 years looking for a composite of end-stage renal disease, doubling of creatinine or renal or cardiac death, what was found 30% lowering of end-stage renal disease. So all of a sudden canoflozin got the indication for this, and the thinking was when you gave an SGLT-2 and urinating out sugar, salt, and water, more sodium was going past the macular denser and therefore there was a compensatory constriction of the afferent arterial. So constricting the inflow and dilating the outflow led to renal benefit. Similarly, Dapagliflozin did the study called DAPACKD. Similar study, 4000 patients looking for end-stage renal disease, again. After 2.5 years looking at decline of GFR 50% by 50% or uh or end-stage renal disease, which is dialysis or transplant or, or um you know, end-stage renal disease or they looked at cardiac or renal problems, but they found in the DAPA CKD 39% lowering of the primary renal composite. So once again, Dapala flows and another SGLT2 had benefit.