← Diabetes Core Update
Diabetes Core Update
Special Edition: What's Next—Cardiovascular Risk in CKD—The Overlooked Burden
00:30:56
Loading summary
Transcript30 lines
- [00:04]
A
Welcome to this special series of Diabetes Core Update where we will discuss chronic kidney disease and cardiovascular risk. The overlooked burden. This is an important area for all of us in primary care and endocrinology because when we treat people with ckd, we need to keep in mind two parallel and important issues. Slowing progression of CKD and also increasing the likelihood of that person developing heart disease or having progression of their heart disease. This tight and coupled relationship between the heart and the kidneys is something that we've only become aware of in the last decade or so and was brought to the forefront of our attention two and a half years ago with the publication of an important paper in the journal Circulation titled Cardiovascular Kidney Metabolic A Presidential Advisory from the American Heart Association. I'm your host, Dr. Neal Skolnick, professor of Family and Community Medicine at the Sidney Kimmel Medical College of Thomas Jefferson University. This special series of Diabetes Core Update is sponsored by Bayer. Joining us to discuss this topic is Dr. Josephine Harrington. Dr. Harrington is an advanced heart failure and transplant cardiologist who is also boarded in obesity medicine. She is an Assistant professor of Medicine in the Division of Cardiology at the University of Colorado School of Medicine where she specializes in heart failure and and cardiometabolic disease. She has been an author on approximately 100 publications, which is no small feat, including the recently published 2025American College of Cardiology Scientific Statement on the Management of Obesity in Adults with Heart Failure, A Report of the ACC and the paper Changing the Paradigm in Heart Failure Shifting from Treatment to Prevention, published in Heart Failure Reviews. Josephine, I'm so glad that you you agreed to come and join us on this podcast. Welcome to our podcast.
- [02:26]
B
Thank you so much. I'm really excited to be here talking about truly one of my favorite topics. So thank you for having me. Sure.
- [02:33]
A
Now when I think about advanced heart failure specialists, I think about people who are just fascinated by the biomechanics of the heart, these implantable devices and really sick, complicated patients. And it seems like you are also interested in prevention of heart failure. Can you share with us how you became interested in prevention?
- [02:59]
B
Sure, absolutely. You're completely right. I started in heart failure and especially in HFPEF where I think sometimes the mechanisms are a little bit more complicated or perhaps less clear. And then I, I very quickly became especially interested in obesity related HFPEF and really because of overwhelming data that patients with obesity related HFPEF had greater disease severity, but also that there were sort of emerging opportunities to treat them effectively with some of the new new sure and creatine based therapies. And once I started seeing that population of patients, I very quickly started being asked to see patients with other forms of cardiometabolic disease as I became a little bit more comfortable practicing in that space. And I think, you know, increasingly we're really realizing that the treatments for primary prevention across the CKM spectrum are very similar to the ones that are used for secondary prevention. So kind of expanding that focus felt very natural to me because the toolbox is so similar.
- [03:56]
A
Interesting. And I'm so happy to hear that, because as a primary care physician, it's become clear to me, as we've begun to understand HFPEF better, that there is a lot, an enormous reservoir of HFPEF out there, that as we have begun to look for it more frequently, we're beginning to find it and really need to become comfortable both with its treatment and prevention at early stages, as we are really finding it more at early stages now than just when people are admitted into the hospital with fluoride failure. Is that correct?
- [04:34]
B
Yes, absolutely. I think we're doing a better job diagnosing HFPEF now and doing a better job diagnosing it in the outpatient setting. There are populations, you know, if you show me somebody who has overweight or obesity, who's older, who's female, who has atrial fibrillation, you almost have to convince me that she doesn't have HFpEF, not that she does have HFpEF, but you're right. You know, I think there are always opportunities to improve diagnosis, and I think your index of suspicions should always be high. But once you've made that diagnosis, it's. That's so important for the patient, because you can't treat a condition that you haven't diagnosed yet. And so once you acknowledge that somebody has or recognize that somebody has HFpEF, that's when you can start to go through your treatment algorithm. And now there is a treatment algorithm. Right? That's the other really special thing. Ten years ago, the treatment for HFpEF was Lasix. You used, you know, or furosemide. You used a diuretic. And that was really it. And it didn't improve. It didn't improve lifespan. It didn't reduce your risk for hospitalization necessarily. It was really just to. To manage symptom burden. And now we have classes of medication that have proven efficacy.
- [05:41]
A
Yeah, it's pretty amazing. Yeah.
- [05:43]
B
Oh, no, it's, you know, it's just. It's really amazing to see how much this field has changed. I agree.
- [05:47]
A
It really is. And we'll have to have you come back on to do a deep dive at some point on those treatment algorithms for HFpEF. Today's discussion, we're going to focus more on this underappreciated relationship ckm, the underappreciated relationship between chronic kidney disease and cardiovascular risk. And when I think about it, one of the clearest and most nicely illustrated illustrations that I have ever seen about this increased risk of cardiac outcomes in patients with different levels of CKD is in the Kidigo guidelines. And it's actually for our listeners. Figure 1 of the 2024 Kidigo guidelines. Now, obviously we can't hold up that figure here and show that to our listeners. So can you, can you go over with our listeners what's conveyed in that figure so that they understand how just incredibly linked CKD and cardiovascular disease outcomes are?
- [06:49]
B
Yeah, absolutely. So this is a really powerful figure that uses both kidney function. So EGFR and uacr. So a ratio of protein to creatinine in a patient's urine to approximate a patient's cardiovascular risk. And the major takeaway one is that you can use EGFR and UACR to approximate cardiovascular risk, but also that both of these things together drive cardiovascular risk really synergistically. So even at a completely normal egfr, if your UACR if that, if that protein ratio is over 30, you're at a 50 to 100% higher risk of having a cardiovascular event. If your UACR is over 300, that number drops, that number jumps to somewhere between 250 to 350% depending on your age. And, you know, I think most of us track kidney function fairly closely. Most patients get a BMP from somebody at least once a year. But UHCR may be a little bit more variable. As a cardiometabolic doctor, I get a UACR at my first visit every time. People are usually a little surprised that their cardiologist wants a urine sample and, and then I get it at least yearly afterwards, more often if it's abnormal. One of the really rewarding things I think about UACR that we maybe don't see as much with, with EGFR or honestly with many of the biomarkers that we use in medicine, is that you actually see it decrease as you optimize treatment so you get feedback. So as you improve blood pressure control, as you inhibit the rest system, both you and the patient get feedback. So patients start to actually really like knowing what their UACR number is and seeing how it's respond, responding to effective treatment.
- [08:34]
A
That's Interesting. It's such a great idea because I don't think most of us use UACR in that way. First of all, it's way underutilized to begin with. We know that from the evidence out there. But then when we use it, it's to make a diagnosis, to make a decision about are we starting treatment often in people with diabetes and an elevated uacr. But using that as a biomarker that you can follow is fascinating because I'm just thinking I had evening hours last night and how interested patients are when they come in to know their numbers. Their cholesterol is commonly what they're always waiting to hear. And to have another marker that motivates patients to stay on their medicines and to give them that feedback loop that, you know, we're accomplishing something is, is a really interesting and I think helpful way to use that.
- [09:38]
B
Yeah, I, I often tell my patients that I consider UACR to be a little bit of a crystal ball for future cardiovascular risk, so.
- [09:46]
A
Oh, that's interesting. You know, and, and the degree of risk I, that you just went over, you know, is not appreciate. I think most of us know if you have chronic kidney disease, have an elevated cardiovascular risk, you were talking about numbers that are 2 to 300% increased risk. That is mind boggling. Let's shift a little bit and talk about ckm. That was discussed in the presidential advisory two years ago. Can you explain that concept to our listeners?
- [10:15]
B
Yeah, absolutely. So this is a really powerful framework that I think resonates with a lot of people because I think we've all kind of intrinsically realized that the patient that that nephrologist is seeing is actually the same patient that the endocrinologist and the primary care doctor is seeing and the cardiologist. And you may be seeing them at different points in their natural history, but fundamentally a lot of these patients have a very specific constellation of conditions and they manifest them sort of in concert with each other. And so the CKM framework is based on the idea that many of these diseases are really fundamentally driven by excess or dysfunctional adiposity. So fat tissue, which we know is a huge issue that we face in the United States and globally. And that as you progress across the CKM spectrum, you start, you move from having sort of just excess or dysfunctional adiposity to accumulating other cardio metabolic risk factors. And these are the things that we all kind of look for, screen for, treat high blood pressure, high cholesterol, diabetes, metabolic syndrome, and then you move into having subclinical cardiovascular disease. So you start to develop kidney disease, and all these things work together. So you can kind of imagine you stack your risk, just excess or dysfunctional adiposity. You've got risk, you add hypertension, you add some diabetes, Suddenly that risk has gone up a lot. That UACR goes up, you start to develop some kidney dysfunction, that risk goes up even higher, and then you start to develop subclinical cardiovascular disease. So you start to develop some abnormalities in terms of how your heart squeezes or how it relaxes, some subclinical cardiac dysfunction that may or may not have symptoms. You start to develop subclinical atherosclerotic disease. And then the last stage, stage four, is when you have overt heart failure or overt cardiovascular disease, which feels like it's very far on the spectrum. But I often say to people, the only difference between being stage two or stage three and being stage four is one bad day. All that it takes as one event for you to kind of declare yourself and move over. So people really do move across this spectrum a little bit more quickly than we think. And I think that the other thing that's really important here is that it brings more focus to kidney disease. Kidney disease is important in of itself, but it's also a huge marker for increased cardiovascular risk. So these are. Patients with CKD are more likely to die of cardiovascular disease than they are to end up on dialysis, and they're more than twice as likely to end up to die of cardiovascular disease in a patient who doesn't have kidney disease. You know, sort of the day that you walk out the door of your doctor's office with a diagnosis of ckd, the likelihood that it'll be a cardiac event that ultimately causes you to die has just gone up astronomically.
- [13:05]
A
Well, and that's so important. There really are two parallel things that we need to pay attention to, often at different times. One you alluded to is a root cause, dysfunctional adiposity. And clearly we've talked about that often on our podcast, treatment of obesity. And then the other one that we're focused on today more, is the relationship between CKD and cardiovascular outcomes. Now, we have someone say with early mid to early CKD, stage 3a, 3b, maybe even stage 4, does treatment of CKD help improve those cardiac outcomes? We know there's a relationship there. It's a whole nother thing to say that treatment is effective at interfering with that relationship.
- [13:59]
B
Yes. So the answer is yes, Absolutely. And in fact, in studies of kidney disease in general, the things that improve kidney disease also improve cardiovascular outcomes. So treating kidney disease is also a very powerful way to control cardiovascular risk. And you know, again, I think I said this earlier, but if you have a patient who's got that stage of ckd, their likelihood of progressing to dialysis is very small compared to their risk of experiencing cardiovascular death before they ever make it to dialysis. This is really important. And again, many of, and this is one of the most powerful things I think about CKM is that many of the treatments that you would use anyways for kidney disease, so we're thinking about now RAS inhibitions, like an ACE inhibitor or an ARB, an SGLT2 inhibitor, potentially depending on whether they have things like diabetes or not, considering a GLP1 or a non steroidal MRA, those are also core treatments for cardiovascular disease. And so you're really starting. When you treat kidney disease, you're also really trying to target some of that subclinical cardiovascular disease. And you can think about some of the reasons that these are so tightly linked to each other. So kidney disease and cardiovascular disease share a lot of common risk factors, many of which are on that stage one or stage stage two of ckm, right? Adiposity, high blood pressure, hyperlipidemia, diabetes, other things like smoking. But then when you add kidney disease, we know that patients get more calcification of their blood vessels, they get more calcification of their valves. Even children who have kidney disease have advanced calcification of their blood vessels. They're more likely to have electrolyte imbalances. And those can actually be very powerful. When you think about things like cardiovascular death risk, kidney disease drives inflammation. It tends to drive left ventricular hypertrophy. So you already have this. Perfect. The milieu that sets you up for kidney disease also sets you up for cardiac disease. And then the kidney disease is really just sort of pouring, pouring oil or pouring gasoline on those flames.
- [16:03]
A
Well, that's interesting. And it really, as you describe it, one feels that sense of urgency in terms of addressing it that isn't there as much as you say dialysis is years away and right in, even in paintings, there's perspective. Things that are far away, look small. And I think it's that way in life too. When we think about how important is it to treat this person's kidney disease and we only focus on kidney outcomes, my sense is most people don't have as much of a sense of we really need to jump on this and do it. When we look at those cardiovascular outcomes and you said it so nicely. That's scary. And can you go over some of the evidence that shows that when we address chronic kidney disease, it actually improves cardiac outcomes?
- [16:57]
B
Yeah, I'm, I'm happy to, you know, I think some of this. So. And first of all, you're completely right. And I think many of us see an EGFR of 50 or 60 and sort of feel like that's good enough and that it's. And we, we know intuitively that if that's in a 70 year old, that their kidney disease is unlikely to kind of progress to a point where it needs, you know, some dialysis or some tremendous intervention. So we sort of tend to say, like, oh, yeah, it's really kind of a marker of other disease conditions. But what we should probably be doing is saying that's a huge red flag that we need to be optimizing their cardiovascular risk. And I can give you maybe one of the more contemporary examples of trying to treat both. A lot of this is in clinical trials, and a lot of this is also best looked at in patients with earlier stages of kidney disease, which again, I think really emphasizes that you do want to try to treat earlier. As patients get to more and more advanced stages of kidney disease, as they start to go on dialysis, it's a little, it seems that there's probably still benefit to using some of these medications to modify their cardiovascular risk, but the data become a little bit trickier. And in general, you know, your, your life expectancy once you're on dialysis is so short that the opportunities there to really affect major change, maybe, maybe smaller. It's really the patients who have sort of those earlier stages of CKD that we tend to view as kind of like reassuring or like, good enough, good enough for them to walk around and do anything that they need to do. Those are the real patients who probably derive the best benefit from these conditions. So in general, the same drugs that have been shown to control kidney disease have also been shown to, to improve atherosclerotic disease and heart failure, and in many cases in the same population. So phenarinone is a great example of this. A non steroidal sort of novel MRA that is now approved to slow the rate of progression of kidney disease, cardio, kidney death and need for dialysis. But in a very similar population of patients with type 2 diabetes and CKD was also shown to significantly reduce cardiovascular death. Non fatal mi, non fatal stroke, heart failure, hospitalizations. And I think with this, again, it's really kind of emphasis and There are more events. Right. So you're more likely to have one of those cardiac events as a kidney patient than you are to even necessarily have an overt, you know, greater than 30% worsening of your kidney failure, ending up on dialysis, dying of a kidney related disease. And so there's, you know, although there is a lot of focus on trying to maintain kidney function in patients with this kidney, with these, with ckd. The bigger thing is that these patients are at such a high risk for cardiovascular disease that you want something that will do both, that will get in there. And that's why the CKM toolbox is so effective.
- [19:49]
A
Yeah. And just to be clear, so in the fidelity analysis, which is, I believe the pooled analysis of, of phenurenon, there was close to a percent reduction in the composite cardiovascular outcomes. And sometimes when we think about cardiovascular outcomes, we think only about coronary disease. But here a big effect was in heart failure, is that right?
- [20:14]
B
Yes, yes, that's absolutely true. And the drugs in general that have sort of proven efficacy at protecting patients from a kidney disease perspective, I would say from a cardiovascular perspective kind of separate out into two different flavors broadly. And so, you know, SGLT2 inhibitors, very robust data from EMPA, kidney and other populations of patients with and without diabetes. Probably a little stronger for patients with diabetes that it slows the rate of disease progression from a kidney disease perspective. And then from a cardiac perspective, really the best strength is in for every as just cute virus is in heart failure. So reduction of heart failure events. Yeah, the you know, RAS inhibition in general seems to be good for you. And again, very protective from a kidney perspective. Very effective at reducing rates of progression to things like heart failure. GLP1s. I think we're still trying to understand the impact of these on manifesting heart failure, but very good evidence that they're great for kidney disease and then also that they actually reduce your throw sclerotic risk profile. So when you use these drugs in combination, the hope at least is that you can really kind of affect the entire profile of stage three to stage four ckm. So you can affect, you know, PAD risk, ASCVD risk, heart failure risk.
- [21:41]
A
Yeah, I remember, I think it was about two years ago at the ADA scientific sessions when the flow trial of semaglutide was presented. And you know, it was a big deal because we hadn't seen this really solid endpoint with kidney slowing kidney disease progression that was there, but even a bigger deal was its cardiac outcome. And that was very impressive. Putting the GLP1s clearly on the map in that regard. And, you know, it's funny, Josephine Dapa CKD is a trial I'll often mention to the residents because of the short time frame in which we saw benefit. And the trial had, you know, follow up about two and a half years. And even in that short period of time, there was a decrease in its composite cardiac endpoints. And in my world, in the primary care world, when we think about treatment of cholesterol or treatment of hypertension, those trials all ran a whole lot longer, you know, five, six, seven years to get those impressive endpoints. The trials in the cardio, kidney, metabolic disease world, and particularly the CKD trials, we're seeing effects in a relatively short period of time that are real and are large.
- [23:11]
B
Yeah, you're, you are absolutely correct. And I think it really does sort of underscore the imperative to start patients on these medications quickly because we know that we'll see them benefit quickly as well. I think the other, you know, the other thing that I think about when you mention the quick timeline to effect is I do think it's worth acknowledging for our listeners that many of these medications, especially ras inhibitors or SGLT2 inhibitors that we're talking about as core therapies, actually do cause a small initial drop in egfr. And I think you need to prepare yourself emotionally for that. But also the patient, if you have a patient who watches their numbers really closely, let them know that it's normal to see that small drop, that it's, it's sort of artificial, it does not correlate with actual worsening of kidney function, and that, in fact, in many analyses, it's been a marker for efficacy of the drug. So that's a, that can even be a good thing to see. But make sure that you don't start it, see a small drop in EGFR and then think, oh, gosh, this is actually hurting my patient, because it's not.
- [24:17]
A
Oh, gosh, I'm so glad you've mentioned that because, like, even knowing this just recently, I didn't mention it ahead of time. I had a very knowledgeable patient who is right, really on top of their numbers, saw that drop in EGFR, stopped the SGLT2. I put them on and, you know, first action always serves as an anchor for anything that comes afterwards. And it was so hard to convince that patient to go back on the SGLT2 because once you've figured it out to your own understanding, changing that understanding is very hard. And so many other times when I've done It right, as you suggested, and things go smoothly, we see that, we say, okay, good, we're going to check it in another way. Three months, six months, and sure enough that it comes back up and, and that EGFR dip is, has nothing to worry about as long as you address it ahead of time. We're getting toward the end of our podcast, last podcast on this topic, we talked to Holly Kramer, and, you know, we went over identification of ckd, and it's clear you can't, you can't address any of this unless you diagnose it to begin with. You mentioned that earlier. Can you remind us who should be screened for chronic kidney disease? That screening, of course, is both a creatinine that gives us an EGFR and a urine for albumin, a creatinine ratio, a uacr. But I think the recommendations and the thoughts about who should be screened have changed a bit over the last few years. It used to be just people with type 2 diabetes or type 1 after they've had it for a while. But who's recommended for screening now?
- [26:17]
B
So at this point, I think the data really support, and you're completely right, this is an evolving field. I think the direction that we're moving into is really anybody with stage 1 CKM that includes patients with high blood pressure, patients with diabetes, I think about patients with metabolic syndrome, even in the absence of overt diabetes, patients with hyperlipidemia, certainly anybody with. With a known cardiac disease or known kidney dysfunction. Those are all patients where you, at a minimum, want to probably be checking UACR once a year to look at Trends. And usually 30 is sort of the line in the sand for normal versus abnormal. We know that as it goes up higher than that, there's increasing risk. But I will also point out that even below 30, if you get an, if your lab reports out an actual number, there is some prognostic value in that as well. So if you see someone who's slowly climbing closer and closer to 30, it's sometimes a good chance to start to lay the groundwork for why that, for why that risk exists. And then once someone has an abnormal uacr, I'm usually rechecking every three to six months in the setting of escalating therapy to try to understand how we might be changing their risk profile. And I, you know, I, for patients, I call it a crystal ball. I think for clinicians, one of the other things that's helpful to think about here is that when you think about, you know, why does protein in your urine go up it goes up because there are disrupted, inflamed endothelial cells in your kidney and they're allowing the leakage of protein. Where else do you have those same endothelial cells? They line your blood vessels. And so I think of this as sort of like the smoke. You're seeing this smoke coming off of endothelial cells. You, you know that you have inflammation. And so if you see that, if you see that smoke, you know there's fire. But I say, I often say to both patients and sometimes other doctors who are asking about uacr, this is a really good marker of endothelial sort of inflammation and disruption. And if it's happening in your kidneys, it's probably also happening in your heart. And that's one of the reasons that treating it is so important.
- [28:20]
A
That's so helpful to understand that conceptualization. We've covered a lot of ground today. In a subsequent episode, we'll be discussing our approach to the treatment of CKD with both renal and cardiovascular endpoints in mind. We'll do a deeper dive, but for now, we're about out of time. Josephine, any final thoughts you want to share with our listeners?
- [28:45]
B
Sure. You know, I would say don't let the perfect be the enemy of the good in general. If you have a patient who seems like they're a high risk patient, just check a uacr, add it to the bmp. Once you start checking it, it becomes much more habitual. And once you start checking it, you can also use that as sort of your prompt to decide whether or not you need to treat. And, you know, we just, we have such great opportunities. So keep, keep looking at your crystal ball and keep trying to modify your patient's risk.
- [29:13]
A
That is so helpful. And, you know, it really is now on the map that checking that UACR from large guidelines. We have the American Heart association hypertension guidelines. I think we were all waiting for them to say check a UACR in our people with hypertension, which is a lot of people. And they now say that. So those are important points. Dr. Josephine Harrington, thank you so much for joining us.
- [29:38]
B
Thank you.
- [29:40]
A
And most of all, of course, as always, thank you to our listeners. Thank you for joining us on this special edition of Diabetes Core Update discussing CKD and cardiovascular risk. The overlooked burden. We covered a lot of ground. I love, Josephine, that idea of endothelial damage being the smoke, but, you know, there's a lot more going on throughout the body. And thank you for going over in detail that relationship between even small amounts of CKD and adverse cardiovascular outcomes, as well as the promise of treating that and improving outcomes. This special edition of Diabetes Core Update is sponsored by Bayer. We thank you for listening. For the American diabetes association, I'm Dr. Neal Skolnick. Till next time, stay safe and keep learning.
- [30:36]
B
Sam.