I'm Dr. Joe Alloy, and I'd like to welcome you to the American Association of Clinical Endocrinology Learning Module, Connecting the Dots, Diabetes, Chronic Kidney Disease, and Cardiovascular Disease Pathways. We have commercial support by an educational grant from Abbott Diabetes Care. Our faculty include myself, I practice at Wake Forest University in Winston-Salem, Drs. Contesaro in Edinburg, Texas, Dr. Sharma at the Scripps Clinic in California, and Dr. Afreen in Charlottesville, Virginia at the University of Virginia. These are our faculty and planner disclosures and our learning objectives. We will explain the complex relationships that exist between insulin resistance, chronic kidney disease, and discuss the underlying mechanisms driving cardiovascular disease development and progression, identify and apply evidence-based risk assessment strategies for cardiovascular disease in patients with metabolic risk factors, such as hypertension, diabetes, chronic kidney disease, or a combination of these using tools such as risk calculators, biomarkers to help facilitate early detection and timely intervention. Identify guideline-based treatment options for managing cardiovascular disease in patients with metabolic disease, diabetes, and kidney disease, including lifestyle modifications, emerging and existing pharmacologic interventions, such as sodium glucose transporter 2 inhibitors, and glucagon-like peptide 1 receptor agonists, antihypertensive therapies, lipid-lowering agents, and importantly, digital health technologies also. Apply clear referral criteria to identify patients requiring specialized care to ensure timely and appropriate referrals to endocrinologists, cardiologists, nephrologists, and other members of the patient's care team. I will set the stage and start the module by discussing the interplay between type 2 diabetes, chronic kidney disease, and cardiovascular disease. So why is this important? If we focus first on type 2 diabetes, at a minimum, it's impacting 1 in 10 Americans. It's expanding very rapidly in our teens and young adults, creating a pool of persons possibly with complications in early adulthood. Importantly, it can be prevented with lifestyle and pharmacotherapy, and unfortunately, we expect these rates to increase by 50% in the next 20 years. For chronic kidney disease, diabetes is the leading cause, affecting 1 in 7 Americans. Unfortunately, 90% are unaware of their condition. Cardiovascular disease prevalence increases two to fourfold with the diagnosis of diabetes. And to put that in perspective, in the United States, diabetes contributes to one stroke every two minutes, ischemic heart disease cases, one every 80 seconds, and a case of kidney failure every 10 minutes. Importantly, early detection and intervention can slow progression of chronic kidney disease and reduce complications of diabetes. These are complex relationships, but if we think about approximate cause, we can think of insulin resistance. It contributes to endothelial dysfunction and inflammation. Chronic kidney disease progression increases cardiovascular stress and mortality risk. Cardiovascular disease complications are the most common cause of death in both chronic kidney disease and type 2 diabetes patients. We have early evidence that suggests GLP receptor agonists improve both insulin resistance and endothelial dysfunction. Chronic kidney disease is highly prevalent in the United States, impacting approximately 36 million persons. This looks like a large problem, but it's also a huge opportunity to prevent or slow future renal function decline. Who's on our team? Who do we have to rely on? Well, if we look at the large pool of primary care providers, it's 210,000. But in the United States, we only have approximately 8,000 nephrologists, 7,000 endocrinologists, and a higher representation by cardiologists to help treat these patients and prevent early death or dialysis. This graphic is my view and a way to think about end-stage renal disease and kidney disease progression. If we look at stage 1, 2, and 3, which represents moderate to severe loss of kidney function, I see this when I describe it to patients that this part of kidney disease is reversible in the sense that you can prevent or improve kidney function during this period. So it's an important opportunity to intervene. By stage 4, you have severe loss of kidney function. And really, we are preparing patients for end-stage renal disease, which requires dialysis or transplant at stage 5. If you think about it, the dots are these organs, the brain, the heart, the kidney. We have one vascular system connecting each of these organs. The vascular system is damaged by insulin resistance. This is what we call endothelial dysfunction. We have alternate multiple pathways that lead to inflammation, vasoconstriction, accelerated atherogenesis, and renal hyperfiltration, all leading to cardiovascular complications, stroke, and end-stage renal disease. This metabolic effect also increases the risk of other comorbid conditions, such as metabolic-associated liver disease and Parkinson's and colon cancer. One way of looking at this is the cartoon in the center demonstrates the insulin receptor. When it's functioning normally, it largely acts to vasodilate the vascular system. But if genetic or acquired changes in the insulin receptor or insulin action are blocked, we promote cell growth, vasoconstriction, and a prothrombotic state, which is approximate cause for vascular disease. And the blood sugar rises, and the ability to metabolize triglycerides is impaired and rise, leading to glucotoxicity and lipotoxicity, which further impair insulin action, increasing insulin resistance, and perpetuate the cycle. So how do we put these together for a patient? And I view this almost as putting together a jigsaw puzzle. First, identify the risk. Screen for type 2 diabetes, hypertension, lipids. Identify complications. Urinary albumin creatinine ratio is associated with vascular disease, retinopathy, neuropathy, heart failure. Easy to do. Base your therapies on preventing morbidity and mortality, and not solely on controlling blood pressure or blood glucose. Base the treatment plan on connecting all the pieces, and not simply focusing on one factor. The American Association of Clinical Endocrinology has created guidelines to help you manage this system. But I would highlight the key algorithm recommendation as early risk stratification for patients with known type 2 diabetes, or patients with metabolic risk factors at risk for developing type 2 diabetes. First line treatment selection includes GLP receptor agonists and SGLT2 inhibitors. We always include lifestyle interventions. But again, disease evolves, conditions change, and importantly, continually monitor the patient. The specialists listed can participate in a multi-specialty collaboration, and we can frequently involve our education team. This graphic is mainly for your reference, but I point you to the red band after lifestyle intervention. Independent of glycemic target and other type 2 therapies, if a patient has these existing metabolic risk factors and risk for arteriosclerotic cardiovascular disease is high, start your therapy with a GLP receptor agonist or an SGLT2 inhibitor. Individualize that glycemic target, assess, and continue to adjust therapy, as this graphic can walk you through your choice of pharmacotherapy options. Let's talk about ways to individualize patients. This is looking at coronary calcium score, which predicts cardiovascular disease, mortality, and type 2 diabetes. This is looking across a range with a relative risk of 1 with a very low or undetectable coronary calcium score, which some of our diabetes patients do have, and they rarely have early cardiovascular disease. But as the coronary calcium score increases up to over 1,000, you have an 11-fold increased risk of cardiovascular mortality. Results like these can help motivate you, as well as the patient, to be aggressive in your therapies. Risk stratification and prevention framework includes identifying those high-risk patients, and who are those? They're ones with proteinuria, poor glycemic or blood pressure control, and elevated lipids. If we start early, lifestyle, medications, blood pressure control, we have ongoing studies that keep lowering our systolic blood pressure target, because that demonstrates improved outcomes in certain patient groups. Think about utilizing our newer therapies. We still have a large room to initiate GLP receptor agonists, and the primary care community is first-line therapy. And monitor and adjust the treatment plans based on evolving risk factors. If we look at the impact of STLT2 inhibitor monotherapy, the left-hand panel is showing something interesting. Here we have a group of drugs that result in lowering of blood glucose, but also drop in body weight, up to three kilograms. This was one of our first hints that these drugs were different. Most of our drugs that we used before this, with the exception of metformin, increased weight while we improved blood glucose. We know about the cardiovascular impact of STLT2 inhibitors. We now use them in patients without diabetes to mitigate further cardiovascular disease risk. And one of the reasons this may be is an improvement in diastolic blood pressure. And it's across the board between canagliflozin, DAPA, or empoflozin. They all seem to do this. If we look at the DAPA CKD trial, which was a trial that looked at a composite risk of greater or equal to a 50% decrease in glomerular filtration rate, development of end-stage renal disease, or cardiovascular death over a three-year period, it reduced the impact of all of these variables by 40%. And you can see that in panel A, primary composite outcome. And you'll see that the placebo group starts to develop their problems at about the 8-12 month period. So the display of the impact of the drug starts very early in its use. If you look at the specific renal outcome, you could show about a 30% decrease in that urinary albumin creatinine ratio excretion. There is a decrease in progression of the GFR. And importantly in this trial, there is not a huge safety signal. These were high-risk patients that we demonstrated marked improvement in all of these characteristics. And we've seen this also in patients in the EMPA-REG and EMPA kidney study. It's important to note that as the GFR decreases, these drugs have less impact on hyperglycemia. So we're now seeing impacts on chronic kidney disease improvement and mortality independent of the blood glucose lowering effect. GLP receptor agonists have positive impact on renal outcome. And there's ongoing studies looking at the combination of these. This is a practical guide for initiation of SGLT2 inhibitor therapy. It's a complex graphic, but I would call out two sections. Let's start with potential contraindications. Recurrent or current genital infection risk for vaginal yeast infections. Or in men that have had recurrent perineal infections with yeast, there have been cases of Fournier's gangrene described. Diabetic ketoacidosis, we can precipitate euglycemic decay. And under sick day rules in the middle panel, we should be telling our patients to hold their SGLT2 inhibitor at least two days before elective surgery. If we go to the bottom panel, we can see volume depletion risk. And who's at risk? Diuretic users, people with tenuous volume status, or persons with a history of acute kidney injury. Educate the patient. What are volume depletion symptoms looking like? And consider dropping the dose of the diuretic in use and very closely monitor the volume. Our nephrologists typically measure a basic chemistry one to two weeks after initiating SGLT2 inhibitors in their patients. Now, let's take a look of the impact of GLP receptor agonists, in this case, semaglutide in the FLOW trial. Agonists with type 2 diabetes and high-risk chronic kidney disease, GFR here again, 25 to 75, urinary albumin creatinine ratio greater than 300, on maximum tolerated doses of our traditional therapy, renin-angiotensin 2 inhibitors. Primary outcome, major kidney disease event, onset of kidney failure, sustained 50% reduction in GFR, and death from kidney or cardiovascular disease, similar to the DAPA CKD study we showed you in the prior slides. The results are shown in the graphics. In the top panel A, first major kidney disease event, significantly delayed by semaglutide. If we look at death from cardiovascular causes and the slope of GFR decline, all improved with semaglutide to result in a 24% lower relative risk of the primary outcome, 21% lower risk of kidney disease events, and importantly, a lower risk of death from cardiovascular disease. These studies do not compare the results of SGLT2 versus GLP receptor agonist, but I think it's important to take away that they both work to improve renal and cardiovascular outcomes. Veneronone, a non-steroidal mineralocorticoid antagonist, was studied in the FIGARO trials. And while not lowering blood sugar, it does have a big impact on a 14% reduction in composite cardiovascular death, non-fatal stroke, hospitalization for heart failure, and a 23% reduction in the composite kidney outcome. In starting veneronone, monitoring for hyperkalemia is an important point. And this graphic shows you for potassium ranges less than 4.8, 4.9 to 5.5, and not to consider or holding veneronone if started when the potassium is greater than 5.5 millimole. But the doses are indicated in the boxes for your reference. So what's the treatment strategies? What do current guidelines and innovations tell us about evidence-based treatment approaches? Well, we've discussed and I've shown you data that GLP receptor agonist and SGLT2 inhibitors reduce cardiovascular risk, slow chronic kidney disease progression, and in the diabetic patient, improve blood glucose control, and result in weight loss. So these are, in my view, cardiorenal drugs that also offer blood glucose lowering. And as I mentioned earlier, studies are ongoing to look at the impact of combining these drugs and how to profile their best use. Lifestyle interventions, such as an appropriate diet, physical activity, and weight management are all important to maintain the efficacy of our pharmacotherapy and frequent patient interaction to help motivate them to stay engaged and to minimize therapeutic inertia. Importantly, we can now touch patients and connect with them in many different ways and think about employing digital health tools, such as telemedicine, glucose monitoring apps, and remote patient tracking into your practice to remain engaged with the patient. I'm going to turn this over to Dr. Sharma, who will now discuss evidence-based screening and early intervention. I thank you for your time.

type 2 diabetes

chronic kidney disease

cardiovascular disease

GLP-1 receptor agonists

SGLT2 inhibitors

multidisciplinary care