From Assessment to Intervention: Managing Cardiorenal Risk in Type 2 Diabetes and Stage 1-2 Chronic Kidney Disease

The text transcription has been edited for clarity and length.

Lucia Novak, CRNP (LN): My name is Lucia Novak. I am a nurse practitioner, and I am board certified in both adult health and advanced diabetes management. I am president of Diabesity, LLC, which is located in North Bethesda, Maryland. I am just outside of DC. And I am also the co-executive director of the Capital Health and Metabolic Center with Capital Diabetes and Endocrine Associates located in Camp Springs and Silver Spring, Maryland. And I’m so happy to be here today with Dr Gene Wright. Gene?

Eugene E. Wright, MD (EW): My name is Eugene Wright. I’m an internist by training. I currently serve as the medical director for performance improvement at the South Piedmont Area Health Education Center here in Charlotte, North Carolina. And I am also a consulting associate in the Department of Medicine at Duke University Medical Center in Durham, North Carolina. And I’m extremely happy to be here with my good friend and colleague Lucia Novak.

Updated Guidelines for Cardiorenal Risk Reduction in Patients With Chronic Kidney Disease (CKD) Associated With Type 2 Diabetes (T2D) With Persistent Albuminuria

LN: The Kidney Disease: Improving Global Outcomes (KDIGO) American Diabetes Association (ADA) consensus statement is really based on the understanding that the pathogenesis of CKD is initiated and maintained by 4 known factors. The first factor is metabolic, so the hyperglycemia and the byproducts of glucose metabolism, such as the pathophysiology of the polyol pathway, anti- and proinflammatory cytokines, and those kinds of things that contribute to that metabolic soup. And then there’s hemodynamic factors, which increase the glomerular capillary pressure in the kidneys, and growth factors, which also increase vascular proliferation, but they tend to be much more fragile when they are proliferated in that manner and, therefore, have increased permeability as well. So they’re not as good as being the regulators and barriers to certain things entering in and exiting out of the vascular structure of the kidney.

And, of course, as I alluded to with the metabolic factors, there’s proinflammatory as well as profibrotic mechanisms in place, which includes the infiltration of macrophages, and that leads to the subsequent tubular and interstitial fibrosis. So, therefore, the KDIGO ADA consensus statement recommends some things that Gene will cover that play a critical role in overcoming barriers to care and, when combined, can actually prevent or even slow the progression of CKD in people with coexisting diabetes. Gene, would you like to explain those mechanisms of how we can overcome the barriers?

EW: Absolutely, Lucia. And that’s a great overview of the pathophysiology and what’s driving CKD in T2D. Well, the guidelines or the recommendations from the consensus statement go on to recommend a team-based care model using a chronic care model. Also, structured indication to engage patients with diabetes and CKD with self-management in their diabetes and to participate in shared decision making. It goes on to recommend comprehensive diabetes care to include regular, timely, and appropriate screening for complications; management of the cardiovascular risk factors, such as hyperglycemia, hypertension, dyslipidemia, and obesity; and lifestyle factors, such as diet, smoking, and physical activity. And finally, the multifactorial interventions, which must include pharmacotherapy in addition to lifestyle modifications. These would include renin-angiotensin system (RAS) inhibition with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), sodium-glucose cotransporter-2 (SGLT2) inhibitors, or in some cases glucagon-like peptide 1 (GLP-1) receptor agonists when an additional glucose lowering is needed, or if atherosclerotic cardiovascular disease (ASCVD) is a risk reduction requirement, statins and nonsteroidal mineralocorticoid receptor antagonists (MRAs), such as finerenone.

Improving Urinary Albumin-to-Creatinine Ratio (uACR) Testing Rates in Diabetes Care: Enhancing CKD Detection and Management in T2D Patients

EW: You know, I think that increasing the recognition of what I call the “perilous paradox” — and what I mean by that, this perilous paradox is when some of the greatest human and economic burden is caused by one of the most underdiagnosed and undertreated conditions — CKD. The cause of this paradox and the unnecessary burden associated with it in our current practices is to diagnose too late, begin treatment too late, too conservatively, and for too few people. We need to study implementation strategies that can be practice-specific, guideline-directed medical therapy, and guidelines inform what to do while clinical care pathways inform how to do this. These are the kinds of strategies that we need to help improve our testing.

LN: Gene, I couldn’t agree more. And perhaps the understanding by healthcare providers is that the diabetes isn’t just about the “sugar-sugar.” It’s a cardiorenal disease, and it must be addressed as such. So what are some of these potential barriers interfering with the screening that you just laid out that are so important? Well, most of us — in the United States anyway — are using some form of an electronic record. And so perhaps when we’re building our templates and order sets, we can include the uACR in those order sets to kind of prevent us from forgetting or overlooking the necessity for that test.

The estimated glomerular filtration rate (eGFR) has actually been included almost automatically in most basic metabolic panels or comprehensive metabolic panels, which is why I believe the screening rate for the eGFR is so high. It’s happening automatically without us having to think about it. And I think that’s pretty much how we have to think about using the uACR, somehow integrating it into our order sets. And I also think that some of this is also on the grounds of what the patient understands. And I believe there needs to be some form of direct education to patients as to what they should be expecting as part of their care. And unfortunately, many patients are still not referred to diabetes education, management support classes, and they’re also not being referred to a diabetes care and education specialist for education.

But perhaps a poster in the waiting room or in the exam room that lists important tests that perhaps they should be inquiring about. And, more importantly, programs like the one Gene and I are presenting today, which provide easy, accessible information for the healthcare provider and bite-sized chunks of information that are easily applied. Tell me what to do, and please keep it simple.

EW: You know, Lucia, you hit on a very interesting point about patient activation and awareness. We should learn from the lessons that we’ve learned in the past. Remember the “Know Your Number” campaign? Everyone wanted to know their number. So we should have a similar campaign, I think, for patients who want to know their numbers.

LN: Yes. And so they come into the office and they ask what their “AC1” is. I’m curious as to how they’ll jumble up the uACR letters when they’re inquiring about that. But it is so empowering when patients are involved, and that’s really the heart of that shared decision making that we are trying to achieve when we are conducting care and setting goals with our patients. And if they have not been included in that conversation, they don’t know the questions to ask, or how that information is important, then I think that we’re never going to achieve that shared decision making that we’re aiming to really include in the appointment.

EW: And a great resource and tool for that is the KDIGO heat map that you talked about. It’s a great color-coded map. It’s very easy and somewhat intuitive. People know they don’t want to be in the red. They’d like to be closer to the green, and that’s a great conversation starter for patients and clinicians to be able to engage in shared decision making.

LN: And the KDIGO guideline, if you just have that sitting out, it shows you that in order to properly stage CKD you need to include that uACR because it’s not enough, especially in people with diabetes — it is not enough to just have that eGFR. We really do need that added layer of the story of what is actually happening. I tell my patients the eGFR tells me how your kidneys are functioning, but the albumin-to-creatinine ratio that I’m obtaining from them helps me to understand the structure of their kidney and how well it’s standing. I have my patients, when I try to explain complications, I tell them, “Think of a house and think of termites and what do termites do to the foundation of a house?”

So now we’re going to look at glucose molecules floating around in the blood. Those are termites and your kidneys — the structure of your kidneys — is the house and that termite is starting to erode. So if we start to see things like protein showing up in the urine, that’s telling me that the termites are starting to invade the structure of your kidney. And that really helps to illustrate, and they have that “Aha!” moment because nobody wants protein in their urine. And one of the things that my patients always tell me is, “I really don’t want to end up on dialysis.”

EW: It’s great. Since we’re telling stories, I have to use my little analogy. I tell them that where there’s smoke, there’s fire. I tell them that the albuminuria is the smoke that may precede the fire. You may not see the loss in function that comes from the fire yet, but if there’s smoke, you know to start looking.

LN: I love it. These are things that help patients understand and, you know, I am one of those providers. I love analogies like that and it helps me to understand. And so I learned a really good nugget as I always do from you, Gene, and I’m going to use that one, too.

EW: Steal it shamelessly.

Early Signs of eGFR Decline and Albuminuria in T2D: Providing Appropriate Cardiovascular Disease (CVD) Risk Factor Modification

EW: I think it’s pretty simple. The implications are that we can diagnose earlier and treat sooner and better all of those patients who are at risk for CKD and the associated CVD. It’s so important that we start — if we diagnose it, we can treat it and treat it appropriately.

LN: I completely agree. CKD unfortunately is clinically silent in almost every stage, even late-stage kidney disease. And it is especially silent in the early stages where treatment is most cost efficient and beneficial. I tell my patients the heart and the kidney are twins separated at birth, or — as Dr George Bakris once corrected me — more like a spousal relationship where the health or sickness of one partner directly impacts that of the other. Unfortunately, screening and disease prevention are not things that the US healthcare system does very well. We are more inclined and better paid, unfortunately, to treat complications and advanced disease. And it is one of the reasons why cost care is high and the distribution of our services is low. What do you think, Gene?

EW: You know, I’m encouraged that we’re starting to move a little bit now. ADA’s criteria has now started to incorporate both eGFR and uACR testing annually for those patients at high risk and those with hypertension and T2D. Also, I understand that the Medicare Incentive Payment System (MIPS) is considering incorporating this measure again as one of their quality metrics, which will translate to incremental reimbursement for practitioners who are doing the screening. So we’re starting to get the message that perhaps moving more toward prevention of illness and treatment of these early, early diseases can prevent some of these complications or significantly delay the time to complications, such as dialysis or death.

LN: Absolutely. If there’s anything that we learned from the Epidemiology of Diabetes Interventions and Complications trial (EDIC; ClinicalTrials.gov identifier: NCT00360893) that followed the Diabetes Control and Complications Trial (DCCT; ClinicalTrials.gov identifier: NCT00360815) as well as the United Kingdom Prospective Diabetes Study follow-up (UKPDS; ClinicalTrials.gov identifier: NCT01099865), it’s never too late to intervene when it comes to microvascular complication of nephropathy. We can make things better at any point, at any stage, of this disease.

Unraveling the Link: Mechanisms of Heightened CVD Risk in Early-Stage T2D-Associated CKD

LN: Traditional risk factors would include hyperglycemia; hypertension and the activation of the RAS system; obesity, which actually is an independent risk factor for the development of CKD even without T2D, prediabetes, or hypertension; and dyslipidemia, especially elevated triglycerides. And then there are things that we really don’t have much control over: ethnicity, genetics, and let’s not forget about the social determinants of health, which actually will determine access to care as well as the type of lifestyle one may actually be able to lead just because of where they live and how much money they make and whether or not they went to school, so on and so forth.

So while the mechanisms of what causes CKD are still poorly understood, we do know, like I mentioned before, that there is a symbiotic relationship and it’s not just between the heart and the kidney. It’s also that metabolic system that’s involved as well. And so those previous risk factors that I just mentioned are so common in people with CKD and T2D. If we look at the cardiac system, the heart is the most metabolically demanding organ. And it requires and relies on adequate energy supply coming from the metabolic system and volume maintenance coming from the kidney system to actually function optimally.

The kidney requires adequate profusion from the heart and normal hormonal signals for appropriate function that come from the metabolic system. And then finally, the metabolic system requires a healthy functioning heart as well as kidneys to prevent the neurohormonal activation of hyperglycemia, insulin resistance, hypertension, dyslipidemia, etc — that whole metabolic-dysmetabolic milieu that patients with CKD and diabetes have. So even mildly elevated glucose, blood pressure, and lipids can lead to complications and morbidity, which we often see happening in people with even prediabetes. So, Gene, can you talk a little bit more about what the effects of these complications really mean?

EW: Absolutely. What we know for sure is that the association between CKD and those with T2D and their cardiovascular mortality is quite strong. In fact, the risk of cardiovascular death is increased 3 to 6 times for those having both T2D and CKD compared with those having either T2D or CKD alone or not at all. Additionally, having CKD stage 3 or below doubles your risk from having CKD above stage 3 — stage 1 to stage 2 — for cardiovascular death. So this is a big deal when we talk about the cardiovascular death that’s associated with T2D and CKD.

Combination Therapies That May Be Good Treatment Options in Lowering uACR

LN: Optimizing glucose management, optimizing hypertension management, optimizing dyslipidemia — for those 3 things, it oftentimes is not about addressing a specific number. I can’t tell you how many times I have patients that have a low-density lipoprotein (LDL) of 80, but their high-density lipoprotein (HDL) is way below where they should be, whether they’re a man or a woman, and their triglycerides are high and they’re not on a statin. And the guidelines clearly state that we need to be addressing risk and not a number. And so again, making sure that our patients, if they have hypertension, are on an ACE or an ARB. And that if they have T2D and they’re over the age of 40, they need to be on a statin. And when things progress, using the SGLT2 inhibitor to not only improve glucose management, but we also know that the SGLT2 inhibitors actually start losing benefit on glucose reduction with an eGFR as high as 60. I’ve learned that one. I always thought —

EW: If it’s 45 — yeah, but they start losing effectiveness at 60.

LN: Yeah. But the beautiful thing about those drugs is that even when they’re not impactful at all on the glucose, with glycosuria they still have this magic. And I’m going to call it magic for lack of really understanding how these drugs do their job on preventing heart failure, on reducing the risk of progression of CKD, on normalizing proteinuria in patients who have those things. So those have to be included and they’re in other guidelines. They’re not just in the ADA and KDIGO guidelines, but they’re in cardiovascular guidelines.

EW: Absolutely. So, you know, the interesting thing — I think the combination therapy is greatly underutilized. And I call that the old treat-to-failure paradigm where we start with one therapy. When that one fails to give us the result, we add another one. We’ve learned from hypertension, we’ve learned from oncology, that that strategy doesn’t work. And the example that I’ve used is that it’s hard to find someone today on just one drug for hypertension.

Most recommendations are for at least 2 therapies to start. Similarly, no one would ever think of treating cancer, any cancer, with one therapy and wait for that one to fail and then add another one. We have to look at a holistic approach and recognize that with this cardiorenal metabolic system, we’re not just treating the kidney. We’re not just treating the blood sugar. We’re treating the heart, the kidney, the blood sugar, the liver. We’re treating all of those things. Therefore, our therapies need to be all inclusive and we need to look at them not in a sequential manner, but really simultaneously. We’ve already seen when these things are going on even when they’re underrecognized and underdiagnosed. We need to be aware that when we see one of these conditions to look for the others and, more importantly, treat the others.

LN: It’s almost like a cockroach: you see one and you know there’s a thousand more hiding.

EW: That’s it. Like whack-a-mole.

LN: So while I know we’re talking about people with T2D, people with type 1 diabetes can also develop CKD, and unfortunately because of the issue with SGLT2 inhibitors in that population, we increase the risk of diabetic ketoacidosis, so a lot of people are hesitant to use them. But that is probably prime where finerenone would be my next favorite choice over an SGLT2 inhibitor in that specific population because it’s not going to contribute to an increased risk of diabetic ketoacidosis, but it’s going to really home in on helping that kidney survive. And, you know, it’s definitely a drug that is underutilized in people with T2D as well.

EW: That study is ongoing to find one. I think the study is going on now and that will answer that question. But you’re absolutely right. There’s no reason to believe that the CKD associated with type 1 diabetes is different than the CKD associated with T2D. And when you cannot use one therapy, you’ve got other therapies. That’s the beauty of our current milieu of therapies we have. We have multiple therapies that operate at different levels, different mechanisms of action, to give a better result.

Disclosures

Lucia Novak, CRNP, reported affiliations with Abbott Diabetes Care, Inc; Ascencia; Boehringer Ingelheim Pharmaceuticals, Inc; Eli Lilly and Company; Medtronic plc; and Novo Nordisk, Inc. Eugene E. Wright, MD,reported affiliations with Abbott Diabetes Care, Inc; Bayer HealthCare Pharmaceuticals, Inc; Boehringer Ingelheim Pharmaceuticals, Inc; Eli Lilly and Company; Embecta Corp; Medtronic plc; and Sanofi-Aventis US LLC.

Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR had no role in this content’s preparation.

Reviewed August 2023