To understand the rationale for evidence-based screening and early intervention, we will first review the clinical data that reflects the interplay between diabetes, chronic kidney disease, and cardiovascular disease that was discussed by Dr. Aloi in Module 1. Cardiovascular disease and diabetes presents in various forms, such as acute coronary syndrome, myocardial infarction, stable or unstable angina, coronary or other arterial revascularization syndromes, stroke or TIA, and peripheral artery disease, including aortic aneurysm. As we all know, diabetes is a coronary equivalent. The Framingham study showed a 2 to 3-fold increase in the risk of cardiovascular disease in patients with diabetes as compared to those without diabetes. In a different study by the Emerging Risk Factors Collaboration, patients with diabetes were more than twice as likely to die from cardiovascular disease as compared to those without diabetes. Patients with diabetes also have a shorter life expectancy because of cardiovascular disease. The same Emerging Risk Factors Collaboration study showed that cardiovascular disease accounted for about 60% of life years lost from diabetes. Patients with diabetes also had worse cardiovascular disease outcomes in the survival and ventricular enlargement randomized double-blind placebo-controlled multicenter trial. Heart failure is also more prevalent in diabetes. Patients with diabetes are at risk of developing structural heart disease and heart failure with reduced ejection fraction, even in the absence of obstructive coronary artery disease. A population-based study conducted in Scotland, which is shown here, showed that there was a higher risk of incident heart failure hospitalizations in individuals with diabetes as compared to those without. While obesity and hypertension are risk factors for heart failure with preserved ejection fraction, CAD and prior MI are risk factors for heart failure with reduced ejection fraction. So while diabetes is a coronary equivalent, chronic kidney disease in diabetes is also a risk multiplier for cardiovascular disease, irrespective of the severity. The ACCORD study showed that mild CKD in diabetes increased the risk of cardiovascular disease by 41% and increased mortality by 30%. The ADVANCE trial showed that worsening GFR was associated with an increasing risk of cardiovascular events and mortality. There is also a higher risk of heart failure in patients who have diabetes and chronic kidney disease. Obesity, inflammation, and vascular disease are the common risk factors for heart failure, CKD, and diabetes. About 42-53% of heart failure patients have comorbid CKD, while about 25-40% of heart failure patients have comorbid diabetes. About 16% of patients with heart failure will have comorbid chronic kidney disease and diabetes. In fact, cardiorenal disease, which is characterized by the presence of heart failure and chronic kidney disease, tends to be the most frequent first manifestation of cardiovascular disease in patients with diabetes. In this large, multinational cohort study of patients with type 2 diabetes, cardiorenal disease was more common than stroke, MI, and peripheral artery disease. Any degree of albuminuria is also a risk factor for cardiovascular events, even in those without diabetes. The risk increases with increase in albumin to creatinine ratio. The Heart Outcomes Prevention Evaluation, or the HOPE study, evaluated individuals with microalbuminuria, with and without diabetes, and determined that cardiovascular events in general, death, as well as heart failure hospitalizations, were all higher in those with more significant albuminuria, and were highest in those who had diabetes with albuminuria. The estimated GFR is also associated with cardiovascular risk. The Chronic Kidney Disease Prognosis Consortium meta-analysis, which is shown here, showed that lower eGFR was an independent predictor of all-cause mortality, as well as cardiovascular mortality, as you can see from the table. So since chronic kidney disease and diabetes independently increase the risk of cardiovascular disease, and together multiply this risk significantly, early screening for chronic kidney disease in diabetes is very important. This is done through an annual urine albumin to creatinine ratio as an initial preferred screening method, because it is relatively inexpensive. However, hydration affects urine concentration, which could then produce false positives or negatives, which is something we should keep in mind. The estimated GFR measured by the CKD-EPI creatinine equation is another preferred method to screen for chronic kidney disease. Cystatin C, another marker for estimated GFR, may be used along with serum creatinine to improve the accuracy of eGFR estimation. The diagnosis of CKD in diabetes is clinical. It is made based on the presence of albumin urea, more than 30 mg per gram creatinine, and or reduced estimated GFR, which is less than 60, in the absence of signs or symptoms of other primary causes of kidney damage. The typical presentation of chronic kidney disease in diabetes would be a patient who has longstanding diabetes, a patient with type 1 diabetes who also has retinopathy, a patient who has albumin urea without gross hematuria with gradual loss in eGFR. Alternate causes of chronic kidney disease must be considered in patients who have type 1 diabetes less than 5 years, no retinopathy in type 1 diabetes, chronically well-managed glycemic control, presence of active urinary sediment that might contain red or white cells or cellular costs, rapidly worsening albumin urea, nephrotic syndrome, rapidly worsening eGFR. Retinopathy has an interesting relationship with chronic kidney disease in patients who have diabetes. In those with type 1 diabetes, it is rare to have chronic kidney disease without retinopathy. In type 2 diabetes, retinopathy is moderately sensitive and specific for CKD. A kidney biopsy is the gold standard to determine the cause of CKD and is recommended if there is a concern for a non-diabetic cause of CKD. Let's turn our attention to cardiovascular risk calculation. There are several risk prediction models that have been recommended to calculate primary ASCVD risk. While several such as the ACC AHA risk calculator are recommended to be used in the general population, risk calculators such as the UKPDS risk engine and the advanced risk score are specifically used in the diabetes population. It is to be remembered that these risk calculators should not be used in patients who already have a history of cardiovascular disease. The US Preventative Services Task Force, the American College of Cardiology, the American Heart Association, the American Association of Clinical Endocrinology, and the American Diabetes Association all recommend the use of the ACC AHA pooled cohort equations risk calculator to calculate the 10-year risk of developing cardiovascular disease in adults between 40 and 75 years. The original calculator takes the presence of diabetes into consideration but not chronic kidney disease. So additional risk modifiers should be considered especially in patients with diabetes. These include longer duration of diabetes, microalbumin urea, chronic kidney disease, presence of other microvascular complications such as retinopathy or neuropathy, and presence of peripheral artery disease. This table shows the classification of individuals based on their cardiovascular risk and recommendations of lifestyle and pharmacological prevention therapies. Adults with diabetes or metabolic syndrome between 40 and 75 years of age are considered to be moderate to high risk for cardiovascular disease and should be managed accordingly. Recommendations for low-dose aspirin remain controversial due to data showing benefit, neutral effects, as well as a higher complication rate, primarily bleeding, especially in those people who are older, with anemia, and even in chronic kidney disease to begin with. To stratify the risk of cardiovascular disease and tailor aggressive preventive therapies, a coronary artery calcium score can be used in addition to the ASCBD risk calculators. In patients with diabetes, a CAC score of 0 would merit moderate intensity statin and standard treatment targets for glucose and blood pressure management. A higher CAC score, on the other hand, would show higher risk of ASCBD and suggests the need for intensification of therapy, such as by the addition of non-statin cholesterol lowering medications or utilization of aspirin if the risk of bleeding is low. Chronic kidney disease presents a dilemma for cardiovascular risk and aspirin use. On one hand, a higher CAC score suggests increased vascular calcification, thereby increasing cardiovascular risk. But chronic kidney disease itself also increases bleeding risk, which then makes aspirin therapy complicated. Therefore, it is essential to discuss the benefits and risks of aspirin therapy not only with the patient, but also their care team to make sure everyone is on board and that the benefits of aspirin use in CKD overcome the risks of using aspirin in CKD. While different national and international endocrinology and cardiology societies have different approaches to stratifying the risk of ASCBD in diabetes, the general rule of thumb, as you can see from this table, is that patients who have diabetes with an additional history of a previous cardiovascular event, chronic kidney disease, or a higher CAC score are considered to be at the highest risk of having future cardiovascular events. As compared to this, those with diabetes without additional risk factors tend to have a lower risk. So when it comes to screening for cardiovascular diseases, patients with type 2 diabetes, chronic kidney disease, hypertension, hyperlipidemia, being overweight, or obesity are considered to be those at highest risk. The tools that can be used for early detection of cardiovascular disease include a blood pressure check at every visit or at least every six months, evaluating for signs of volume overload at every visit, getting an annual urine albumin to creatinine ratio as well as an estimated GFR measurement, and obtaining a non-fasting lipid panel at diagnosis and then annually. Based on the evidence available so far, the American Association of Clinical Endocrinology does not recommend utilization of additional biochemical measurements such as ApoB, CRP, or lipoprotein little a. Screening for cardiovascular disease involves screening for coronary artery disease, heart failure, and peripheral artery disease. The ACCAHA, the American Diabetes Association, as well as the European Associations do not recommend screening of asymptomatic individuals with diabetes for coronary artery disease. Symptomatic patients, that is those with symptoms of a carotid brui, a history of a DIA or a stroke, claudication symptoms, or an abnormal EKG should be evaluated or screened for coronary artery disease. Additionally, functional status of an individual is very important in making a decision regarding screening for coronary artery disease, and this is something that we should keep in mind when evaluating patients. Since heart failure is so common in patients with diabetes, all patients with diabetes should be screened for heart failure. Peripheral artery disease screening should only be done in patients who have diabetes and who are above 65 years of age, who have had diabetes for more than 10 years, who have associated microvascular or foot complications, who have associated hypertension, hyperlipidemia, a history of tobacco use, or a prior history of cardiovascular disease. Screening for coronary artery disease involves obtaining a resting EKG, which if abnormal, is followed by an exercise EKG with or without an echocardiogram. Screening for heart failure involves getting a one-time BNP level and then an echocardiogram if the BNP is greater than or equal to 50 picograms per ml. Peripheral artery disease screening involves an ankle brachial index testing. So considering the high risk and the incidence of cardiovascular disease in patients with diabetes and chronic kidney disease, the pillars of decreasing cardiovascular risk in patients with diabetes and chronic kidney disease include glycemic control, management of chronic kidney disease, as well as risk factors such as dyslipidemia and hypertension. We have already discussed the glycemic control management in the previous module. In this module, we will look at managing the other three pillars. Dyslipidemia is managed by lifestyle changes and pharmacological therapy. The most recent ACE guidelines recommend initiation of a statin medication based on the ASCVD risk as calculated by validated calculators. And then the recommendation for additional medications is based on a shared decision-making discussion with the patient. So individuals who do not have ASCVD do not require additional medications. But individuals who have cardiovascular events or are at a higher risk of having cardiovascular events should have additional medications such as PCSK9 inhibitors or bempedoic acid. Individuals with hypertriglyceridemia who also have ASCVD or a higher risk of ASCVD should be advised to start taking EPA. The current ACE guidelines recommend an LDL target of less than 70 as compared to the previous guidelines which suggested an LDL target of less than 55. Managing hypertension involves keeping blood pressures below a goal of 130 systolic by 80 diastolic. This is achieved by lifestyle interventions such as decreasing salt intake, DASH or Mediterranean diets, regular physical activity, and achieving optimal weight loss as well as pharmacological therapy. The renin-angiotensin system inhibitors such as ARBs or ACE medications are considered first-line medications for management of hypertension in patients with diabetes and chronic kidney disease. Additional medications such as calcium channel blockers, thiazides, beta blockers, mineralocorticoid receptor antagonists, etc. can be added on top of these medications if the goal blood pressure has not been achieved. This flowchart lists the importance of a multidisciplinary approach to managing chronic kidney disease in diabetes through lifestyle interventions as well as pharmacological treatments. Regular risk assessment is required every three to six months. As you can see, several different classes of medications may be used to ensure that these patients are at the lowest risk of cardiovascular events. With this, we will now move on to the next module on digital health technology by Dr. Samina Afreen. Thank you very much for your time and over to you, Dr. Afreen.

diabetes

chronic kidney disease

cardiovascular disease

evidence-based screening

early intervention