THE CARDIOVASCULAR, RENAL, AND METABOLIC SYSTEMS ARE INTRICATELY LINKED¹

Dr. Wright: Hello! Thank you for taking the time to join us. I'm Dr. Eugene Wright, Medical Director for Performance Improvement at the Charlotte Area Health Education Center and Consulting Associate in the Department of Medicine at Duke University Medical Center. Our discussion today is going to focus on the interconnectivity of the cardiovascular, renal, and metabolic systems, an important topic for health care providers across multiple specialties and one that has substantial implications for patients.

In my experience as a primary care physician, conditions like diabetes, cardiovascular disease, and kidney disease rarely exist in isolation. More often than not, my patients with diabetes also have cardiovascular diseases or multiple cardiovascular risk factors, and patients with cardiovascular disease often present with some degree of renal impairment. So, when it comes to cardiovascular, renal, and metabolic diseases, it's becoming increasingly difficult to classify patients into discrete categories. As we'll be discussing today, this emphasizes the importance of taking a holistic approach to patient care, one that addresses the interconnectivity of these conditions.

On that note, I'm glad to be joined today by several colleagues to discuss the implications of cardiovascular, renal, and metabolic dynamics for patient care. They are here representing the different specialties most impacted by this issue. We have with us cardiologist Dr. Pam Taub, endocrinologist Dr. Rosemarie Lajara, and nephrologist Dr. Matthew Weir. Pam, would you care to introduce yourself first?

Dr. Taub: It's great to be here today. I'm Pam Taub. I'm a cardiologist and Associate Professor of Medicine at University of California, San Diego.

Dr. Lajara: Hi. I'm Dr. Rosemarie Lajara, an endocrinologist in Dallas, Texas.

Dr. Weir: My name is Dr. Matthew Weir. I'm a Professor of Medicine and Chief of Nephrology at the University of Maryland School of Medicine in Baltimore, Maryland.

Dr. Wright: Now, as specialists, you can share with us your experiences in managing patients with overlapping conditions. Why don't we start with you, Pam?

Dr. Taub: Thanks, Gene. I'm happy to be joining you today to discuss this really important topic. Your observations in primary care definitely resemble what I see in my own practice as a cardiologist. Cardiovascular disease, kidney disease, and type 2 diabetes share many of the same risk factors, and I think that's one reason why so many of my patients are affected by more than one of these diseases. This means that, even as a cardiologist, I'm concerned with managing risks associated with multiple organs, not just the heart.

Dr. Weir: I agree, Pam, and this is also consistent with what I see as a nephrologist. Patients with renal impairment have an increased risk for both cardiovascular disease and diabetes. Close to two-thirds of patients with heart failure have renal disease, and we see a direct linear increase in the prevalence of cardiovascular events as renal function decreases. So, similar to the way you view your role as a cardiologist, as a nephrologist I also need to be taking a comprehensive approach to patient care, one that accounts for the effects of renal impairment on the other organ systems.

Dr. Wright: What about you, Rosemarie? What has been your experience as an endocrinologist?

Dr. Lajara: Unfortunately, so many of my patients with diabetes are affected by cardiovascular and renal disease, but I'm equally concerned about patients who don't necessarily have a formal diagnosis of cardiovascular or kidney disease because diabetes increases their risk for both conditions. As Pam noted, much of the overlap we're seeing can be attributed to shared risk factors like hypertension and obesity, and most of my patients have at least one of these risk factors.

Dr. Wright: Thanks, Rosemarie. It's interesting that, despite our different areas of concentration, our patients have a great deal in common, which is just another example of why a comprehensive approach to patient care is so important.

Dr. Lajara: I agree, Gene. As an endocrinologist, cardiovascular risk and renal risk are major factors in my approach to caring for patients. I need to consider that the mechanisms underlying each of these diseases have a compounding effect. So, not only does diabetes increase the risk of developing cardiovascular disease, it's also associated with worse outcomes. The risk of heart failure hospitalization is twofold higher in patients with diabetes compared to those without, something I'm sure Pam is well aware of.

Dr. Taub: That's right, Rosemarie, diabetes is a predictor of poorer outcomes in patients with cardiovascular disease. That statistic you mention is really alarming when you consider that heart failure is the leading cause of hospitalization in the United States, and the risk of death in patients with heart failure increases with each hospitalization.

Dr. Weir: As you are all aware, diabetes is also associated with poor renal outcomes. It's the leading cause of end-stage renal disease in this country. We know that in patients with longstanding diabetes, the microvascular damage caused by persistent hyperglycemia over long periods of time ultimately impairs the ability of the kidneys to function normally.

Dr. Taub: And, of course, kidney function can have a substantial impact on cardiovascular outcomes. In heart failure patients, we see a direct increase in the risk of hospitalization or cardiovascular death as eGFR decreases.

Dr. Weir: That certainly makes sense given that the underlying mechanisms of heart failure and renal disease are so intertwined that it's difficult to tease them apart. For example, we have reduced cardiac output in heart failure leading to decreased renal perfusion, and decreased renal perfusion, in turn, disrupting cardiac function. So, the onset of dysfunction in one system can set off a vicious cycle.

Dr. Wright: We should also mention that the interconnectivity of the cardiovascular, renal, and metabolic systems works both ways. You've all mentioned how dysfunction in one system has a compounding effect on the other systems, but there's also evidence demonstrating that improving the function of one system can improve the function of the others.

Dr. Weir: That's a great point, Gene. In fact, I recently read about a study in which cardiac function improved in late-stage CKD patients that had undergone kidney transplant. And when it comes to patients with diabetes, we know that intensive glycemic control has a positive impact on kidney disease progression. Rosemarie, can you discuss that further? Can you speak to that from an endocrinologist's perspective?

Dr. Lajara: That's right, Matthew. Multiple studies have shown an association between glycemic control and a reduced risk for microvascular outcomes, including nephropathy, although the association between glycemic control and cardiovascular risk in patients with diabetes isn't quite as clear.

Dr. Wright: I think all this evidence that the cardiovascular, renal, and metabolic systems can work together synergistically to improve outcomes really emphasizes the importance of us—as primary care specialists, endocrinologists, cardiologists, and nephrologists—working together to help improve the lives of our patients.

Dr. Lajara: I couldn't agree more, Gene, and this means addressing multisystem risk early in the course of disease progression, instead of managing individual diseases in isolation as they arise. My patients may come to me thinking that I'm solely focused on managing their diabetes, but if I want to do what's best for them, I need to be thinking about their cardiovascular and renal health as well.

Dr. Taub: Well said. I think it's great that, as providers of different specialties, we're coming together and recognizing how the link between these systems affects all of us in similar ways. As the body of knowledge around this topic continues to grow, I expect that we'll see more and more conversations among healthcare providers on how to integrate it into patient care.

Dr. Wright: Great point, Pam, I certainly hope that recognition will come as this idea becomes more prevalent. In the meantime, it's going to be up to us to spark reform at an individual patient level by recognizing how these systems are interconnected and, most importantly, by integrating that knowledge into our daily practice.

Unfortunately, we're running out of time, but I'll try to summarize our discussion with a few takeaways.

• First, the cardiovascular, renal, and metabolic systems are tightly linked, something exemplified by the frequent overlap of diseases affecting these systems
• Second, cardiovascular disease, kidney disease, and diabetes have a deleterious effect on one another, and, conversely, improvements in one condition can have a positive impact on the others
• Finally, all of this reminds us that we need to be adopting a comprehensive approach to patient care—early—and to help address the risk associated with these interconnected conditions. Not only will this help our patients, it will also allow us, as physicians across specialties, to work together toward our shared goal of optimizing care

With that, I want to thank Dr. Pam Taub, Dr. Rosemarie Lajara, and Dr. Matthew Weir for joining me today.

Dr. Lajara: And thank you, Gene, for leading us through this discussion.

Dr. Weir: Yes, thank you, Gene. I think it's really important for us, as clinicians with our different areas of expertise, to share our perspectives.

Dr. Taub: I agree, Matthew. And thank you, Gene. I enjoyed this discussion.

Dr. Wright: I did as well. Thank you again everyone and thank you to our viewers who took the time today to join us.

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Dr. Wright: Hello and thank you for joining us. I'm Dr. Eugene Wright, Consulting Associate in the Department of Medicine at Duke University Medical Center. I also serve as the Medical Director for Performance Improvement at the Charlotte Area Health Education Center.

Our discussion today is going to focus on shared risk factors among the cardiovascular, renal, and metabolic systems. As many healthcare providers know, there is an ever-growing body of clinical data showing that diseases affecting one of these systems often exert a negative effect on the others. As a result, we as clinicians are being increasingly called to adopt integrated care strategies—ones that account for comorbidities and risk factors across all 3 systems—rather than manage single conditions in isolation. Understanding how to recognize and address early markers of disease can help us do just that.

I'm joined today by a panel of experts who have agreed to lend us their perspectives on this topic. We have with us cardiologist Dr. Robert Mentz, endocrinologist Dr. Leigh Perreault, and nephrologist Dr. Christian Mende. Rob, would you care to introduce yourself first?

Dr. Mentz: Sure thing, Gene. I'm Dr. Robert Mentz. I'm a cardiologist and Associate Professor at Duke University and I also serve as Chief of our Heart Failure Section here.

Dr. Perreault: Hello, I'm Dr. Leigh Perreault. I am an endocrinologist and Associate Professor of Medicine at the University of Colorado.

Dr. Mende: And I'm Dr. Christian Mende. I'm a nephrologist and a Clinical Professor of Medicine at the University of California in San Diego.

Dr. Wright: Thank you all, and thanks for being here to help us delve deeper into this important topic. Now, can each of you start by speaking just a bit about how cardiovascular, renal, and metabolic interconnectivity manifests in your practice? Namely, what sort of multisystem risk factors do you observe most often, and how do they influence your clinical approach?

Dr. Perreault: Well Gene, as an endocrinologist, I see metabolic disease in the form of obesity, prediabetes, and diabetes, all of which are extremely common. When a patient comes to me, I view my role as one mostly of prevention, so educating patients about their risk of end-organ complications and making suggestions on how to avoid them is my main priority. Some of the things I make sure to talk about are the increased risks for cardiovascular and renal disease, as well as the importance of healthy lifestyle choices in helping to reduce those risks. Unfortunately, it isn't always that easy and most people require medical management. In those cases, it's often necessary to enlist the help of a cardiologist or a nephrologist!

Dr. Mentz: Well, Leigh, while I bring the cardiologist perspective to this discussion, the data support that the cardiovascular system greatly affects, and is affected by, the rest of the body. Case in point: a large proportion of my patients with cardiovascular disease also have diabetes, and many of them are already starting to experience complications by the time they see me. This is a common clinical picture that can't be resolved by looking at the heart in isolation, so it's critical for me to factor in the health of the metabolic and renal systems to make sure my patients are getting the best outcomes they can. And when you consider the complex, progressive, and heterogenous nature of entities like heart failure and atherosclerotic disease, you can appreciate why early and accurate risk stratification is so important. This is a major unmet need for patients with heart failure, and there's actually some parallels with renal disease in that way too. Christian, would you agree?

Dr. Mende: Absolutely, Rob. The progressive renal damage associated with conditions like chronic kidney disease is a lot like what we see in patients with heart disease, atherosclerosis, and other kinds of cardiovascular disease, in that we can usually preserve organ function to a greater degree when we address the problem early. However, issues like chronic kidney disease tend to be silent until the kidneys are badly damaged, so early detection is both a challenge and a major unmet need. And when we consider that declining kidney function has serious implications for volume status, hormone production, and glucose homeostasis, it's easy to recognize that the relationship between cardiovascular and renal disease is very much a two-way street.

Dr. Wright: That's consistent with what I see in my patients with diabetes as well. It seems we have ample evidence to suggest that progressive damage to any one of these systems eventually impacts the others. I'm sure this isn't groundbreaking news for any of you, nor for most of our listeners, but it's important to keep this at the front of our minds so that when we see patients with multiple risk factors, we can adopt a comprehensive approach as early as possible.

Dr. Mentz: I couldn't agree more, Gene. But even though this is a pretty foundational concept, that's not to say that the connections between these systems aren't complex. And really on the contrary, there's a lot we don't know about how they influence one another, particularly in an individual patient. However, examining the interplay of these shared risk factors across these systems can give us some clues as to what's going on. Obesity is a great example that really illustrates this point, since it has so many different ramifications throughout the body. Leigh, I'm sure that's something that comes up in your work quite a bit.

Dr. Perreault: All the time! As people become overweight and obese, they fill up their fat cells until the triglycerides spill over into other tissues like the skeletal muscle, liver, and heart. Those organs were never meant to store fat and they don't like it! A major inflammatory response ensues, causing insulin resistance, and the resultant diabetes then further exacerbates the whole-body inflammation.

Dr. Mende: To that point, many of those same inflammatory processes also have implications for the kidneys, with the potential to cause direct renal damage via oxidative stress and RAAS activation. And once established, renal disease itself can contribute further to a chronic inflammatory state. So even though obesity is a common precipitating factor, you could go one layer deeper and say that chronic inflammation is one of the primary threads tying these issues together. And that touches on another important point, too, because a lot of those same processes can contribute to the development and progression of hypertension, something that's well-known to be hazardous to the microvasculature of the kidneys. Plus, it has been repeatedly associated with insulin resistance.

Dr. Perreault: Many experts believe that insulin resistance is the fertile ground that leads to all the diseases we are discussing today. It has been linked to hypertension, diabetes, atherosclerotic cardiovascular disease, congestive heart failure and chronic kidney disease. Of course, each of those diseases compels its own inflammatory responses that then feeds back and makes the insulin resistance worse. There is no way to truly unlink the cardiovascular, renal, and metabolic axis because it is so interrelated.

Dr. Mentz: Exactly. Take the relationships you just described, Leigh. In the absence of proper care, those kinds of vicious circles are bound to worsen over time, greatly increasing the risk for cardiovascular diseases like heart failure and coronary artery disease. The cycle doesn't end there either, because overt cardiovascular disease itself is a major risk factor for CKD and diabetes. In fact, that really captures a critical point that can't be overstated: disease in any one of these systems can act as a prognostic risk factor for the others. That's why we as clinicians need to look at these issues from a holistic standpoint rather than trying to manage single conditions in isolation.

Dr. Wright: That's so true, Rob. If you all wouldn't mind joining me in a quick exercise, perhaps we can illustrate this point further by examining a hypothetical patient case.

Let's say that a 65-year-old woman has come into your office as a new patient. She was diagnosed with diabetes 3 years ago and also has Stage 2 chronic kidney disease with albuminuria. She's hypertensive, overweight, and has dyslipidemia. On top of all that, she recently received a diagnosis of coronary artery disease, roughly 3 months ago. Given that information, how would you go about caring for this patient, and what would be at the forefront of your minds throughout the process?

Dr. Perreault: Gosh, she already has complications of diabetes, so my guess is that she must have been living with it for a while before she was finally diagnosed. Undiagnosed diabetes remains a major issue in the U.S. That said, if this patient came to me, I would indeed address her diabetes—meaning her hyperglycemia—but you need to do that in a way that's safe to use in someone with compromised renal function and hopefully will prevent further decline of her eGFR. This would be a busy clinic visit!

Dr. Mentz: You won't be surprised to hear this from me, but I would spend much of my time primarily on reducing her cardiovascular risk. Even though she hasn't yet experienced a cardiac event, her coronary artery disease still raises some red flags with regards to CKD progression and worsening insulin resistance. So I view this as a critical point around communication, implementing strategies across the multisystems of care. So it's the cardiologist working with the endocrinologist and primary care physician, as well as with the patient and their family to bring all of these multisystem components together.

Dr. Mende: Well, looking at this patient from a nephrologist's perspective, halting the decline in her kidney function would have to be a top priority for me. Getting her blood pressure down to at least 140/90 or, if possible, to 130/80 would be one of my first concerns. With that, I'd also prioritize getting her LDL below 70 mg/dL and her A1C below 7%, although 6.5% would be a more ideal target. I would also speak to her about her current lifestyle practices and look for areas where we could improve those. Reducing her salt intake to less than 5 grams per day, limiting her protein intake to 0.8g/kg per day, and encouraging weight loss would be the main priorities.

Dr. Wright: All good points, Christian. As you just touched upon, one thing that really can't be overemphasized for a patient like this is the importance of lifestyle interventions. Encouraging healthy habits such as eating well, increased physical activity, and smoking cessation are foundational to a successful care plan.

I think it's fair to say that, even though we're approaching care from a different perspective, we're seeing more commonalities than differences in the way we would prioritize multisystem risk in this patient. I think that reflects our shared goal of optimizing outcomes for our patients. And perhaps most importantly, it shows just how inextricable the link between the cardiovascular, renal, and metabolic systems really is.

Unfortunately, we're running out of time, but I'll try to summarize our discussion with a few key takeaways:

• First, the interconnected nature of the cardiovascular, renal, and metabolic systems is evidenced by the presence of shared risk factors, many of which stem from common pathophysiologic mechanisms
• Second, these shared risk factors can serve as important prognostic tools to help us recognize and address progressive diseases as early as possible
• Third, as physicians, we need to prioritize cardiovascular, renal, and metabolic health by adopting comprehensive care strategies that simultaneously address risk across multiple systems

I want to thank Dr. Leigh Perreault, Dr. Robert Mentz, and Dr. Christian Mende for joining me today and lending their expertise on this topic.

Dr. Mentz: Thanks very much, Gene, and thank you for leading the discussion.

Dr. Perreault: Thanks, everybody!

Dr. Mende: Thanks for having me, I've enjoyed speaking with all of you.

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