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Good evening, everyone. Um, so this is, uh, Shankar Navanetan, a professor of medicine at Baylor College of Medicine. Uh, I will now address the second learning objective of the evening. Uh, the focus is going to be how best to incorporate GLP-1 RAs into treatment plans for type 2 diabetes and CKD based on the current guideline recommendations. Uh, here are my disclosures. These were shown earlier. The objectives of this session is that we will review the mechanism of action of GLP-1RA with particular emphasis on the kidney effects. I will summarize the evidence supporting GLP-1 receptor agonists in those with kidney disease specifically, and how best to incorporate GLP-1 RAs in the therapeutic algorithm while we manage patients with type 2 diabetes and kidney disease. Before we start, uh, we have a polling question for you. Uh, in patients with type 2 diabetes and kidney disease, let's say estimated GFR of about 45 and persistent albuminuria, who has already been treated with metformin and SGLT2 inhibitor and maximally tolerated RASP blockers, which therapy is the most appropriate next step to improve kidney and cardiovascular outcomes? A. Increase the SGLT2 inhibitor to the maximum approved dose. Option B, switch metformin to a sulfonylurea. C, add a DPP-4 inhibitor. D, add a long-acting GLP-1 receptor agonist. E, stop RSP block A2 albuminuria. I'll give you a few seconds to think over and please complete the poll. All right. Thank you everyone for answering. We will move on and hopefully we'll answer this question at the end. Here is a case vinier which is similar to the poll that you just completed. A 56-year-old female with type 2 diabetes, hypertension, and hyperlipidemia was seen in your office for management of her chronic medical conditions. The current medications include losartan, metformin, Eagliflozin, and atorvastatin. Her exam showed a BP of 132/84 and a BMI of 29. Uh, her relevant laboratory parameters, um, include hemoglobin A1C of 7%. A creatinine of 1.5 that approximates an estimated GFR of 45 mL per minute with a UACR of 380 mg per gram. Her previous echo showed left ventricular hypertrophy. What is the next best therapeutic option to optimize her care? Uh, the talk of the topic today is the GLP-1 receptor agonist. The GLP-1 are secreted by the L cells in the small intestine, which have myriad of effects, as you could see in this slide. Uh, the GLP-1 receptors that are present at various tissues throughout the body, the primary action starts with the increase in the insulin secretion, which is glucose dependent. There's also decrease in glucagon secretion, which combined together with the increased insulin secretion uh leads to the hyperglycemia or the hypoglycemic effects. The notable effects on the gastric emptying, the decrease in the gastric emptying, and the decrease in acid secretion, and the effects on the brain, especially the decreased food intake and the increased satiety that comes with the GLP-1, leads to the weight loss effects. In addition to the hyperglycemia or hypoglycemia and the weight loss effects, there are other effects that are also noted. Uh, we have had now cardiovascular studies that have demonstrated that the GLP-1 improves cardiovascular outcomes in those with type 2 diabetes. Uh, there is data now have evolved for obstructive sleep apnea management and also for MASH. As such, The current role for GLP-1 RA, the there is FDA approval for management of obesity, glycemic control, cardiovascular risk reduction, sleep apnea, metabolic dysfunction associated steato hepatitis, and of course for kidney disease. How does GLP-1 agonist provide kidney protection? So there are 21, direct kidney effects and there are indirect kidney effects. We'll focus first on the indirect effects. Uh, there is obesity, hypertension, dyslipidemia, and diabetes that often accompanies patients with kidney disease, and these 4 are independent risk factors for kidney disease. And GLP-1 receptor agonist. Cause weight loss, reduces blood glucose, improves lipids, and reduces BP. So, therefore, you would anticipate that all these cumulatively would protect the kidneys. On the other side, you see that there are direct kidney effects. This is the topic of focus these days. We have an ongoing study that is looking at whether the GLP-1 agonist causes direct kidney effects. This is done by conducting MRIs. And kidney biopsies in patients with kidney disease to see what are the direct effects of GLP-1 RAs on the kidneys. But in short, what has been reported so far is there is an improvement in glomerular hyperfiltration. There is improvement in the kidney hypoxia. There is reduction in the inflammatory burden within the glomerulus. There is improvement in the lipotoxicity by the reduction in the weight reduction in the body weight. And also improvement in sodium retention cumulatively, these all lead to better kidney protection as we would see in the outcome trials. We will now review the evidence, the clinical trial evidence that supports the use of GLP-1 receptor agonist in CKD population. It started with the LEDA trial. LEDA trial focused on Llyr glutide and cardiovascular outcomes in the general population with type 2 diabetes. Um, the primary results showed there was an improvement in cardiovascular outcomes and a secondary analysis that showed that, uh, there was improvement in the composite renal outcomes. In the composite renal outcome, the most important measure was there was an improvement in the new onset persistent macroalbuminuria. However, the renal replacement therapy, i.e., needing dialysis or death due to renal disease, there was no significant benefits. But of course, the study was not power to detect, but this study put on the limelight that potentially the GLP1RA can have significant kidney benefits. This was more so uh confirmed uh in a large dedicated uh kidney disease trial called flow CKD trial. The trial enrolled about 3500 patients with type 2 diabetes and CKD. Kidney disease was defined by an EGFR of 50 to 75 and a UACR of over 300 and less than 5 g per gram or an estimated GFR 25 to 50 and a UACR over 100 mg per gram. To less than 5 g per gram. The intervention in this case was semaglutide, 1 mg weekly. The dose was not increased, and it was compared to placebo, but the primary outcome measure was the major kidney disease events. It's a composite of the onset of kidney failure. Um, either they needed dialysis, transplantation, or if their kidney function hit EGFR less than 15. Um, or if they had a death from kidney disease or cardiovascular disease. The primary results showed there was a 24% reduction in the first major kidney disease event. And if you look at the kidney disease specific component events, there was also about a 21% reduction in several of the kidney disease-specific component events. What is more interesting is in these patients with type 2 diabetes and CKD, both the first major cardiovascular events and the death from any cause, not just from cardiovascular disease, but death from any cause, there was almost a 20% reduction in these risks. There were also improvement in metabolic outcomes and adverse events. For instance, the most notable thing was there was about a 4 kg reduction in the body weight. And again, it's important to note the dose was about only 1 mg subcutaneous, and the dose was not titrated, so this was not intended for weight reduction. The study was intended to see if these drugs provide kidney benefits. Uh, the glycated hemoglobin level dropped by about 0.8%. There was a modest improvement in systolic BP while there was no improvement in diastolic BP. Um, the notable thing is that with the serious adverse event rate was actually lower in semaglutide overall, even though the there was a higher permanent discontinuation slightly as you could see, 13% versus almost 12%, which was actually due to the higher side uh GI side effects which are well known with this class of agents. Um, the flow CKD was the largest study, but prior to this, there were also general population studies that have enrolled patients with kidney disease. Uh, this is a meta-analysis in which the investigators, uh, pooled data from 12 randomized controlled trials.