Dr. Ben Hippen: Welcome to Global Medical Office Dialogues. I'm Dr. Ben Hippen.
Classes of drugs such as GLP-1 receptor agonists and SGLT-2 inhibitors have been shown to improve the control of blood glucose, blood pressure, body weight, and reduce the risk of different types of adverse cardiovascular events in diabetic patients, a comorbidity common in patients with chronic kidney disease. Early results from clinical trials studying these drugs showed signs of success in delaying disease progression.
Dr. Frank Maddux, Global Chief Medical Officer at Fresenius Medical Care and host of Global Medical Office dialogues, is in the guest seat today discussing these drugs and their potential impact on kidney disease care.
Frank, welcome to Global Medical Office Dialogues.
Dr. Maddux: Thanks, Ben.
Dr. Hippen: Let's begin by talking about what these drugs are. We're talking specifically about the SGLT2 inhibitors as well as the GLP1 agonists. Talk a little bit about what these drugs are, what they do, and what their indications for use are.
Dr. Maddux: The SGLT2 inhibitors were drugs that have actually been on the market for about 10 years or so at this point. And they were designed for patients with type 2 diabetes mellitus. And were designed to actually change the way that glucose reabsorption occurs in the tubules of the kidney and in that way try to help control glycemia. They’ve been found to have other effects and they've been seen to have effects that include cardiovascular effects as well as effects on chronic kidney disease progression as a class. The GLP-1 receptor agonists are a little bit different drugs but also designed for patients that have type 2 diabetes mellitus and they were also originally designed to try to assist in glycemic control. But they too have a variety of additional secondary effects that have proved to maybe even be more important than their primary effect. Those have included everything from appetite suppression and weight loss to the ability to impact cardiovascular health and they're being studied at this time for their role in what they do for progression of chronic kidney disease in patients with CKD and diabetes.
Dr. Hippen: It might be worth telling our listeners a little bit about what chronic kidney disease actually is, how it progresses, and the relationship between the population of patients with chronic kidney disease and the populations of patients with CKD, chronic kidney disease, who actually evolved into developing end-stage kidney disease.
Dr. Maddux: Some years ago, a system was designed to recognize different stages of chronic kidney disease. Most kidney disease is associated with other disorders. In many cases, those diseases impact the kidney in a way where the kidney actually over time develops some injury that cannot be remediated. And ultimately, the filtering units in the kidneys become scarred and that scarring actually begins to impair their ability to do their job.
We're all born with about three and a half million filtering units in each kidney and those filtering units in each kidney live with us for our life. Part of the normal aging process is that there is some senescence of those filtering units over time. And after the age of 35, we probably lose anywhere from one half to one percent of our quote, normal kidney function per year simply with age. Beyond that, diabetes, hypertension, cardiovascular disease, and a wide variety of inflammatory diseases can affect the kidneys and cause the kidneys not to be able to do their job of both modifying the blood, helping control the fluid balance in a person, as well as the secondary things that have to do with hormone production, both to make good bone health and to help a person produce red blood cells.
So as the kidneys fail, we begin to look at that through a series of blood tests and urine tests. And the blood tests primarily allow us to calculate what's called an estimated glomerular filtration rate, or GFR. And the GFR gives us a signal of what amount of kidney function compared to what normal might be is current for that patient. Over time, patients with advancing kidney failure develop a reduction in their GFR. And at the point there, GFR is very low in the 5, 10 to 15 milliliter per minute range.
Severe symptoms can begin to develop, and those symptoms are the things that lead physicians and patients to make that decision to consider either a kidney transplant or kidney replacement therapies like dialysis. So the CKD stages show that there are a lot of people in the very early stages. They have some evidence that their kidneys are not working completely normally. But as this progresses and you get down to a GFR that is less than 60, you begin to identify people that are at higher risk for progression to kidney disease.
In the United States, for example, we recognize many patients that are in stage three, this mid-range of kidney disease. But by the time you get to those that are close to end-stage kidney disease but not quite there, that number's fallen off really dramatically to the tune where in the most recent United States renal data system.
I would say in stage three kidney disease, there was something in the range of about 12 million people in the United States. But by the time you get to stage five, excluding those that are already on dialysis, you're probably under 400,000 at that point. So it's a big drop off. And those deaths are predominantly due to cardiovascular disease, age, and other things. But cardiovascular disease is a huge component of that.
Dr. Hippen: These new drugs, these SGLT2 inhibitors, the GLP-1 agonists, are not a cure for these kidney diseases. They really just change the natural history. And really the way to think about chronic kidney disease is more as a continuum rather than a one or a zero, I have it or I don't, is that right?
Dr. Maddux: Yeah, I think it's not binary. You're neither fully have it because it progresses over the course of your life or you fully don't have it because you can have very early stages two-thirds of diabetics that have type 2 diabetes never actually get chronic kidney disease. And those that do develop it, it takes many, many years. I think on average you begin to see sort of kidney and eye disease changes after a decade plus of having the disease. So when we think about both chronic kidney disease progressing to end-stage kidney disease we really do think about the continuum of care that patients go through and the fact that their course is frequently not linear.
And although we have really elegant artificial intelligence models to try to predict the rate of progression and the time that somebody might get close to the point where they might consider kidney replacement therapy, those methods are reasonably good, but any individual patient can have a very stuttering sort of course during progressive kidney disease. And in most cases that disease takes years to develop. There are some disorders where it's quite quick, but the majority are slow.
Dr. Hippen: And by virtue of this very slow natural history there's lots of other opportunities for other clinical events to intervene like a cardiovascular morbid event or even cardiovascular mortality. As we understand it now these classes of drugs both have a salutary effect on slowing the progression of chronic kidney disease, but also reducing major cardiovascular events and in particular cardiovascular mortality. Which leads us to think that there's a phenomenon here of competing endpoints. How do we think about the competing endpoints of reducing cardiovascular mortality on the one hand and slowing the progression of chronic kidney disease? What's the implication of those competing endpoints for the purposes of projecting what the future CKD and ESKD population might look like?
Dr. Maddux: Both of those effects are good for patients, okay. Fewer deaths mean people live longer and they're living longer means that if and when they do progress, they're likely to be healthier at the time they progress than they might have been otherwise. The second thing that I think is really, really important here is to recognize that these two endpoints in trying to project the future size of the population is a very complex calculus because the amount of time that it takes to develop kidney disease progression, the fact that none of the drugs, whether the SGLT2 inhibitors or the GLP1 agonists are not cures, they may slow down the progression of CKD, means it's sort of a complicated calculus to determine what that population begins to look like. So the way we've begun to look at it and the way, as you know, our computational medicine teams have begun looking at it, is to look very carefully at both the effects of reducing cardiovascular death that might shift that distribution of CKD patients in general to the right where you wouldn't have this drop off where you may, you know, you have 12 million stage three patients and, you know, a half a million or less stage five patients. But in fact, shift to more patients into those that over time will either continue to age or progress with their kidney disease, and that opportunity expands the number of people that we have to treat and try to help control that latter stage kidney disease. And for those that do progress to end stage kidney disease, it provides the opportunity with a slower rate to give them time to be well prepared for either a transplant or well prepared for dialysis therapies if they choose to do that.
So, in either case, the competing effects may make it a little difficult for us to predict exactly how the population will change in each of those buckets, stage three, stage four, stage five, and on dialysis or transplant. I think that in our general view, and we're super interested in watching how these clinical trials evolve, is that the effect of extending the life of patients in a healthier state with less cardiovascular disease is to the benefit of our population in general. And that benefit will provide a wider substrate of patients that we can intervene on as they do age and have progressive kidney disease.
Dr. Hippen: It's interesting to see the extent to which the possibility that these drugs may allow some subpopulation of patients to live long enough to see their kidney disease progress to end stage and require dialysis or transplant. There's been a lot of attention to what this might mean for the dialysis population. I've become quite interested in what this might mean for the transplant population. We already live and function in a milieu in which the number of organs available for transplantation are insufficient to the supply. And of course we have a number of patients with chronic kidney disease who, as you mentioned, pass away presumably prematurely in the absence of the availability of these drugs from cardiovascular causes. And this of course is something that transplant centers are acutely aware of and they really want to identify and avoid cardiovascular morbidity and mortality, particularly immediately post-transplant. What do you think the effect of the broad availability of these drugs would be on the demand for kidney transplantation?
Dr. Maddux: My hope is that it's going to actually increase both the demand but also the health and the, you know, adjusting the criteria for what is an acceptable patient for a transplant. My view is that kidney transplantation is a form of kidney replacement therapy, a really good form of kidney replacement therapy because it's a human organ that has both the endocrine function and the other functional components of a normal human kidney.
When we look at that, my anticipation would be, and what my hope is for these drugs, is that they'll bring to the point of consideration for transplant patients who are healthier, patients who've had the opportunity to live longer and had an adequate amount of time to prepare for what modality is really best for them.
And in that regard, I think the drugs offer significant opportunity to create a different problem for us, in the field that you spend a lot of your time in. And that is we aren't necessarily as good as we could be on developing really robust organ availability. We have this very high rate of organs that are rejected from being accepted for transplant.
And the opportunity to really advance the field so organ availability is expanded while we're trying to create a more robust environment of people that would qualify for a kidney transplant as an option. Those are things that I think will be really good effects from these drugs over time.
Dr. Hippen: You're a historian of medicine, a historian of our field of nephrology. I am.
Dr. Maddux: Old.
Dr. Hippen: Well, and not as, but equally a student of the history of our field. The interest in the recent explosion of evidence around these drugs reminds me of the interest and excitement generated by a previous class of drugs, namely the rennanangiotensin inhibitors. We now have three decades worth of data showing the benefits of Ras inhibition for diabetic nephropathy and its complications. These drugs are now widely available, largely generic, inexpensive, and yet we have not seen the revolution that those drugs promised come to fore in the clinical realities that we see and deal with every day. Why do you think that is?
Dr. Maddux: A couple of things sort of feed into that in my view. One is we have to go back to say, how do we understand the effects of a class of drugs? We understand them through a variety of randomized controlled trials that recognize both their primary effects and their side effects.
And when we do that, we tend to take a progressively narrower and narrower population of patients that we test them on so that we can get very distinct results. So the distinction between the impact of a randomized control trial and the real world evidence that occurs when you look at how does this get deployed in practice patterns that physicians have to manage in practice, you suddenly begin to have a winnowing of the aggregate effect in many of these drugs because patients develop side effects and the side effect profiles invariably grow a little bit as there's more use of the drugs as one side.
So physicians are then observant of what are those side effects and who's going to be a good candidate to have the drug. Physician practice patterns in and of themselves are hard to change and the difficulty in changing those practice patterns means there may be people that could expand their use of Ras inhibition but are persuaded to slow down on that because of hyperkalemia and they aren't yet ready to use some of the newer hyperkalemia drugs on that. So there are a lot of reasons. The patients are some of the reasons. Patients themselves we know have difficulty with compliance with things we ask them to do permanently. And it's very difficult to get into that disciplined routine day in and day out, especially if there may be some effect from that drug that is, you know, complicating to the quality of life that an individual has. So I think all of those reasons generally mean that you can move the field in a direction, but to completely replicate the results of an RCT is quite difficult, I think, in the real world. As you know, the patients that we actually take care of in our dialysis clinics...
Just under half of those patients come to us without having had significant medical care for their kidney disease in the prior year to year and a half from having had to start. That's an enormous number and you say that's a broken system if that's happening. But the reality is that's been consistent for almost two decades now. And it's not changing a lot. Now with electronic health records we can recognize that those people have touched the health care system at times and probably there could have been either recognition of kidney disease or a patient couldn't quite follow up once it was recognized at that point.
All of those become part of the story of these drugs so if we're only really attaching ourselves to the 50 plus percent of patients that we have regular medical care access to, there's a huge opportunity still out there of how you actually get these drugs out. And the RAS inhibitors are a good historical example, I think, of how we've shown the drugs to be quite beneficial to patients, but it's really quite difficult to get them fully penetrated into the right patients at the right time.
Dr. Hippen: And over the right period of time.
Dr. Maddux: Yes, period of time.
Dr. Hippen: In particular some of the studies with the GLP-1 agonists that both have a renal secondary endpoint as well as a study we'll talk about in a minute that is actually focused on a renal primary endpoint postulates that these patients are not only on full RAS inhibition in addition to the drug under study, but that they're on full RAS inhibition as well as the GLP-1 agonist for a period of years to realize the benefits that we're looking forward to hearing the reports of in the forthcoming months.
If we've got less than 50% of patients who are seen by a nephrologist before they end up in one of our dialysis clinics for greater than 12 months before the onset of their kidney disease, and we have hesitation for any number of reasons for maximally prescribing RAS inhibition in the patients that we actually see, the other 50% or so that actually we do see in our clinic.
How much can we really hope for the overall penetrance of these new drugs? And to what extent can we really generalize on a population level as to what the population effects will be?
Dr. Maddux: Directionally you have hit on some of the key points of what happens in the real world. And that real world is that there's a progressive winnowing effect of something that's good for patients, but practically is not something that can be ubiquitously used like our cell phones are, as an example in a whole different area. When we think about this and we look at what we think the population impact will be, the best way that we've chosen to look at this is to develop a very detailed series of mathematical models that take into effect the assumptions and ranges around which some of these kinds of effects might play into the population dynamics, and we've called that the patient flow model.
And the patient flow model, recognizes that you don't have full prescription adherence across the entire population of prescribers. You don't have full compliance across the population of patients. You don't necessarily have the persistency of continuous use, which is required by the GLP-1 agonist to keep the effect going over a period of time.
You don't have use in some cases because there's a financial hurdle to overcome and there may be an insurance hurdle in some cases to overcome. So all of these things getting factored into the model of who flows into and out of the various stages of CKD, End-stage kidney disease, and you recognize there's this other effect of changing the population dynamics because of the impact of death, you can begin to then create sensitivities around what the population impact might be to the overall population. We've done that in quite some detail for the SGLT2 inhibitors. We're still awaiting more data on the GLP1 agonists and ways that we can validate how we're looking at this model.
My sense is, and we've come up with this recognition, that we think the competing effects of improved cardiovascular health and reduced cardiovascular death and slowing progression of CKD is going to build the population of patients that have CKD, advanced CKD as a substrate over time and that its overall impact on our population today with what we know looks to be either neutral or slightly positive over the long term.
Whether that's how it will bear out, we're all going to see. But that's the premise that we have right now that we'd rather have more healthier patients to address. And be less concerned over the speed of which their progression occurs because it's very slow anyway in most cases. To recognize that over the next 10 to 15 years there are huge opportunities for us to see a population of patients that are healthier on the input side, will be healthier through the early phases of dialysis therapy which as you know is extremely risky to them.
And then secondarily, gives us the opportunity to innovate around what can we do to improve the treatments that will reduce mortality and therefore increase the population of prevalent patients that we care for.
Dr. Hippen: I want to pivot a little bit to talk about the FLOW trial which was we learned was recently stopped early. The FLOW trial was conducted by Novo Nordisk using some aglutide in a cohort of patients that are thought to be at very high risk for progression of kidney disease.
These are roughly speaking, patients with chronic kidney disease stage three that have at least 300 micrograms per mil of albuminuria up to five grams and patients with chronic kidney disease stage four with a little more liberal albuminuria enrollment criteria but overall patients thought to be at fairly high risk because of their macroalbuminuria, purportedly related to diabetic kidney disease.
There certainly could be some other things going on. They indicated that at a minimum, they would be stopping the trial if they realized a risk reduction of 20% in the treatment arm. And about 15% of these patients were concomitantly on SGLT2 inhibitors in addition to semaglutide, which is a GLP-1 agonist. The composite endpoint was cardiovascular mortality and a split renal endpoint, which is a 50% reduction in estimated GFR or initiation of dialysis or receiving a kidney transplant. How do you think about, knowing that we don't have the results of it yet, a trial structured in this manner with this kind of a composite endpoint?
Dr. Maddux: I think the composite endpoint is somewhat essential for most of these studies because these impacts that are being looked at are both to the benefit of patients. And as you and I have discussed before, if you had a drug that you were giving to a patient that slowed kidney disease progression but increased the risk of death, there'd be little value to that. So when you look at the value of the drug, it needs to actually make sure that at worst it's neutral to death. And at best it actually improves cardiovascular event and death rate and slows down kidney progression. So the endpoint makes sense to me, honestly. If you're trying to predict the future of what the trial's gonna show, the composite endpoints are difficult because what we don't know is whether the major impactor of getting the trial to end early was reduced kidney function or cardiovascular death or death of any kind.
Given that the trial basically sounds like it will have had about three out of five years that it's ending about two years early, my guess is gonna be that it's some combination of both of those things that we'll see an impact on. Because you've neither had all that much time to get to end-stage kidney disease for many of these patients who had, I think, a mean GFR of 47 as they entered the trial, nor would you likely have seen with mid-stage three kidney disease that many deaths right at that point in time over a period of three years. Now the kicker in that is going to be a lot of this trial was through the pandemic.
So what is the impact of COVID? What is the impact of changing death rates that we saw in the population in general? And how did this population get impacted by that? So I don't know today whether the weight of ending the trial early because it was efficacious is gonna be on kidney function decline regression or on fewer death events. But my guess is it's gonna be some combination of both.
Dr. Hippen: If hypothetically it were primarily on reduction of cardiovascular death events, these are patients who still have macralbuminuria. They are all on maximum RAS inhibition that they can tolerate, but they still have a natural progression to their chronic kidney disease.
Dr. Maddux: Yeah, they do and the slowing of chronic kidney disease doesn't mean the absence of progression. And I think that's gotta be remembered in the discussion. And we've seen reactions to the early ending of the trial that to me feel a little bit exaggerated in that the sense that there'll be no more patients to ever progress. I think that seems remarkably unlikely to me, even though from a patient's perspective that would be a wonderful result because that would look like a cure. I don't see a cure in these drugs. I do see improvement in the health of the patient and that's a good thing.
Dr. Hippen: There's been a lot of interest in looking even further upstream in the continuum of diabetic related disease. So another trial that we've gotten early reports on but no formal data has been reported upon is the Select trial. Which looks at semaglutide, comparatively speaking, healthier patients compared to the patients who were in the Flow trial. They typically have a BMI of greater than 27 and are 45, 55 years of age. So overall, we would think, but don't know yet because we don't have the results, that this is a group of patients that would have a fairly low event rate for major adverse cardiovascular events, which is what's being looked at in Select and as a secondary endpoint, these kidney outcomes.
So I think the premise here is that by lowering BMI with these drugs before the onset of disease, you can attenuate the onset of disease. But when you have a fairly low event rate in an otherwise relatively low risk population. How do you think about that from a population health standpoint and how can one, how does one really think intelligently and in an evidence-based way about what this will actually mean years or decades down the road?
Dr. Maddux: It's first of all very early to make any definitive conclusions on that. I think that the opportunity given the rather aggressive increase in the number of people in our population that have severe obesity, substantive obesity, and just being overweight, there could clearly be some attenuation of that steep rise that those populations of patients have been on. And that may clearly create some adjustment in the degree and the timing of people that develop insulin resistance to some degree.
I do think there are more than a few long-term side effects that I'm interested in watching with regard to these drugs because in effect you're losing weight because your appetite's being suppressed. That appetite suppression and clearly we have all in practice seen patients that we've taken care of that had obesity and malnutrition at the same time and that doesn't necessarily reduce their complication rate for a variety of things simply because they're overweight, they can still be significantly malnourished.
Combined with more advanced kidney disease, that can be a very difficult, malnutrition is a difficult problem to deal with in the population of patients that you and I have treated over the years. So I think as I look at this early stage study, I'm especially interested in a couple of things. One is the top line result that Select had around MACE events and cardiovascular event rates, I think is important because this is a population that has significant opportunities for progressive cardiovascular disease. So that could change the inflow population as people do slowly progress. Secondarily, I think it will be interesting to see, and over time we'll understand, can people in fact lose weight and maintain that weight loss?
And even with maintenance of that weight loss, still preserve reduction in insulin resistance because we've seen some reports that insulin resistance can recur. I guess that may be the right word, may not be the right word, but basically you see insulin resistance over some time that's independent of the weight loss. And so those features to me become things that are gonna be really important for the long-term use of these drugs.
I think there will be some opportunity to look at early stage CKD progression. I don't know whether that will be significant or not in what comes out in the Select trial when it's reported at the American Heart Association. But I'm especially interested in the cardiovascular outcomes that will come from that trial because I think again, people with type 2 diabetes, people with advancing chronic kidney disease both have a remarkably increased risk of cardiovascular disease and as you know the vintage a patient is in the various stages of that disease can change the general nature of what kind of cardiovascular disease they have. So I think there's a lot to learn there.
Dr. Hippen: Given all of the challenges our patient population faces, we've already talked about in terms of access to physicians on a regular basis, access to these, in many cases, expensive medications, the need to have them on concomitant medications like RAS inhibition, how do we think through developing a different system of care delivery so that these medications get to the patients or the subclasses of patients who clearly benefit from them?
Dr. Maddux: Our current system is very much event driven and many of these drugs are drugs that are going to have their greatest impact probably as you're looking to try to mitigate or prevent some disease. And so the ability to create the right environment where the side effect profile, the cost of the drug, the access to the drug, the comfort of the medical staff in being able to monitor and aggressively manage the patient to certain endpoints all become critical components that the system has to support. Whether that's supported through more directed payment models for these kind of drugs or earlier access to a higher level of attention to the issues of kidney disease.
All of those things become part and parcel of whether these drugs will achieve the full impact they could achieve in the future. The corollary to that is just having the drugs on the market actually increases awareness in the general population of chronic kidney disease as a public health condition. And we've seen very successful campaigns over the years for heart disease, hypertension, smoking, breast cancer, and a variety of diseases, but we've never seen what I would call Ad Council level attention to chronic kidney disease, despite Anton Schoolworth in 2005 or six, but a long time ago, recognizing that chronic kidney disease meets the criteria for a public health condition and yet, if you go out on the street, very few people would be able to tell you much about. what they understand about chronic kidney disease or their own kidneys for that matter.
I think that's changing a little bit with some of the marketing and advertising for these drugs when you see every night on the television or the streaming service you have an advertisement for one of these classes of drugs. I'm sure it does some good for the drug and the drug maker, but what it really does good for is raising the awareness of chronic kidney disease, I think even beyond the work that we've done, the work that the NKF and other groups have done, I think this is one of the things that actually has raised awareness more than anything.
Dr. Hippen: This recent attention to these class of medications and the diseases for which they're being treated can be redirected toward expanding access to RAS inhibition, which is an inexpensive and widely available and well vetted therapy for a wide variety of kidney diseases that would really be an excellent result and a necessary first step to then taking the second step in adding an SGLT2 inhibitor or a GLP1 agonist. We may come to find in the course of future studies that taking these medications by themselves may have a salutary benefit in the absence of RAS inhibition but the preponderance of evidence to date suggest that you really do have to take these drugs together and for several years.
Dr. Maddux: Yeah, I think the combination of the tools that are available today is changing. And the impact of the combination of those tools will get hints at from these current clinical trials, but it will require real world evidence and future clinical trials to really understand the depth to which the combination actually is beneficial to patients.
Dr. Hippen: Well Frank, do you have any other parting thoughts on this very interesting and wide-ranging topic?
Dr. Maddux: We went many, many years where patients with kidney disease had very little new medications to look at, excepting for a handful of very distinct illnesses, glomerular diseases and other such things. This is a very, very important time in the field to look at this in a way that all of this attention and investment that's being placed into what do we do for people with kidney disease and the ability to recognize that the continuum of a person's life flows through chronic kidney disease, end-stage kidney disease, transplant being part of the treatment for that, end-of-life care, all of those become part of this lifetime journey that a patient goes through. And I think these drug classes will be important in trying to create healthier patients, that live longer, and have a better quality of life, hopefully. And we'll see whether that actually comes to fruition over time because none of these drugs come without significant investment of either time of the patient and consistently using the drugs, cost to the health care system and individuals and potential side effects that we don't yet fully know the scope of today because the drugs are, for these purposes, being used, you know, have been used at relatively low levels.
Dr. Hippen: Well thank you Frank. I've been joined today by Dr. Frank Maddux, global chief medical officer for Fresenius Medical Care, and we've been discussing the potential impact of GLP-1 receptor agonists and SGLT-2 inhibitors on chronic kidney disease care. Frank, thank you again for this interesting conversation.
Dr. Maddux: Thanks, Ben.