Podcast – How SGLT2 Inhibitors and GLP-1 Agonists are Transforming CKD Care

In this episode of Kidney Health Connections, Dr. Katherine Tuttle, a leading nephrologist and researcher, explores transformative advancements in chronic kidney disease (CKD) treatment. She discusses the revolutionary impact of SGLT2 inhibitors and GLP-1 agonists, which have shifted the landscape from modestly effective therapies to groundbreaking treatments that significantly slow disease progression, reduce cardiovascular risks, and even prevent kidney failure. These innovations align seamlessly with value-based care models, offering both clinical and economic benefits.

Dr. Tuttle also highlights the potential of combination therapies and the critical role of implementation in maximizing patient outcomes. As Dr. Tuttle puts it, this is a monumental time in medicine, with the potential to conquer CKD and transform lives. 

 

Transcript

Introduction: Innovations in CKD treatment usher in a new era in nephrology

Dr. George Hart: Well, hello everyone and welcome to today's episode of Kidney Health Connections. In my view, now is a really exciting time to be a nephrologist. There are new payment models and innovative transplant and dialysis offerings which are offering hope for today's late-stage CKD and ESKD patients.

But what excites me the most is the opportunity to impact future generations of CKD patients by slowing their disease progression and delaying the onset of kidney failure. This supports our mission in value-based care, which is to improve the lives of our patients. In particular, there are two classes of drugs, SGLT2 inhibitors and GLP-1 agonists, which show tremendous promise.

Today we're fortunate to have as our guest Dr. Katherine Tuttle. She's the executive director for research at Providence Inland Northwest Health. She's also the regional principal investigator at the Institute of Translational Health Science and professor of medicine at the University of Washington.

Dr. Tuttle, it's nice to have you with us today. Thanks for joining us.

Dr. Katherine Tuttle: Thank you. It's wonderful to join you and to be at this exciting point where there's so much to talk about.

 

From endocrinology to nephrology: Dr. Katherine Tuttle’s journey to transforming kidney care

Dr. George Hart: You've been at this now studying diabetic kidney disease for most of your career and it's led to the development of a lot of the modern treatments that we are going to talk about today. You oversee this large network now of 17 clinical research centers. Can you give us a little bit of an idea of your background and how you got into studying kidney disease and specifically developing these medications?

Dr. Katherine Tuttle: I started out in endocrinology studying diabetes and was really doing very basic physiology—counter regulation of glucose in the early days of insulin and glucose clamping. We were some of the first people who did those techniques in humans, but it was all about glucose regulation and physiology.

The experiments were long. The artificial pancreas we used filled an entire room; people wear that on their belt now with the closed loop system. But these individuals would altruistically spend eight hours a day, sometimes six or eight experiments in a row, to help us understand physiology, with the hope that someday it was going to make a difference for them.

And I'd spend the entire day with these people who were all about my age—we were all in our 20s at the time. And it just seemed like they deserved something better than what they were getting—and especially when one of our young people with type 1 diabetes who was in these physiology studies crashed into dialysis at Barnes Hospital.

I had this epiphany. One, that we hadn't even thought about whether or not these patients had kidney disease. Nobody was really testing for it in that era, we're talking about 1985. And I even began to wonder if the physiology was going to be right because these were people who, unbeknownst to us, already had kidney failure and we were assuming this was normal physiology.

And I really decided at that point to pivot my career to something more directly focused on identifying how people develop kidney disease and to start thinking about therapeutic approaches. And while the physiology is critical, I really became interested in science with a purpose. So then I decided to move on to nephrology.

 

The pre-SLGT2 inhibitors and GLP1 era: modest improvements in CKD treatment

Dr. George Hart: While you were doing all of that, I was learning how to be a nephrologist and going through internal medicine. And honestly, once we diagnosed someone with diabetes, you know, we were kind of thinking there's a 20-year runway here, but there is an inevitable decline. And there weren't a lot of ways to change that trajectory.

For our listeners, many of whom are now in the payer space. What was the landscape for how to treat CKD before SGLT2 inhibitors and GLP-1s came to the market?

Dr. Katherine Tuttle: We were diagnosing people very late when they would have what we call now high-level albuminuria—severely increased albuminuria, then it was called macroalbuminuria. And many times—this was even before we were doing estimated GFR—they would have an elevated creatinine, which meant a creatinine above 1.7. We know now we were really picking people with very advanced CKD.

And these treatments were just modestly effective. Like I said, we weren't even screening people routinely; they came to our attention when something happened. So it was very haphazard. And no wonder the outcomes were so poor. We were seeing people very late and we had really very minimally effective therapies.

Of course, the world changed with the onset of the ACE inhibitors and the ARBs. The first trial was done in type 1, which was the captopril renal trial, in ‘93 they published that. But again, the effect sizes were really modest in comparison to the newer agents that we have now.

But it was the first time that beyond risk factor control, in this case blood pressure control, there was an additional benefit. But we're talking about relative risk reductions, adding somewhere in the range of 15 to 20 percent. But it was really very modestly effective therapy, which is why, when you were doing nephrology fellowship, most people with diabetes who got kidney disease, if they didn't die, they did end up on dialysis.

 

From past to present: Modern breakthroughs in CKD care

Dr. George Hart: It feels like the dark ages now when I look back and think about what we were doing and kind of flying and treating blindly.

Well, let's fast forward now. It's 2025. It's a new era. You and I are excited, and we're excited because of SGLT2 inhibitors and some of the other drugs out there. So maybe it's important now to explain, you know, what is the landscape now that we have these choices and maybe explain to our audience what is so groundbreaking with these drugs?

Dr. Katherine Tuttle: It's been really a collusion of occurrences. It's the science, preclinical science, that was translated to clinical trials. It's also the fact that we have a lot of real-world evidence now, so in a much broader sense we can track what's happening in the population. So not only what are we developing, but how are we doing with implementing, and how are people faring.

So with regard to SGLT2 inhibitors, the first clinical translation was in 1987. But in those days, it took a long time to go from giving phlorizin to diabetic rats to clinical development. So we really didn't see the SGLT2 inhibitors come on the scene until the early 2000s in clinical trials. And originally, they were trialed for glucose lowering, even though there were reasons based on the biology to expect the effects would be broader. But that was where the commercial development went first.

At that time, another class of agents was coming forward called the TZDs, or PPAR agonists. Those were drugs like rosiglitazone and pioglitazone. And there was an unfortunate occurrence with rosiglitazone that opened the door, though, to SGLT2 inhibition becoming the go-to organ protective therapy.

It was a convoluted twist of events, many post-market approval reports of major adverse cardiovascular events. The primary focus originally was myocardial infarction, stroke, and cardiovascular death. So the U.S. FDA said, “Well, if any other new glucose lowering agents are approved, there will have to be a cardiovascular safety study done.” That was 2006.

By 2008, after the SGLT2 inhibitors had come on the market for glucose lowering, or were moving toward market approval for glucose lowering, the sponsors were required to do this cardiovascular safety study. And that really was the gift that kept on giving because it forced the sponsors to test these agents for something more than glucose lowering.

And in the beginning it was focused on, of course, cardiovascular safety. But the people who set up the trials were prescient in the sense that they knew the biology. And we said, “You know, we ought to be able to test these things for heart and kidney protection as well if they make the safety bar.” Well, it's been the gift that keeps on giving, right?

 

SLGT2 inhibitors: “The world changed at that moment”

Dr. Katherine Tuttle: By the time this plays out, the first cardiovascular safety trial reports out in 2017, and that was EMPA-REG. And that was empagliflozin in people with type 2 diabetes who had established cardiovascular disease, in this case atherosclerosis. And not only were the agents safe, they were highly effective. And the big win was not on atherosclerosis, it was on heart failure, and on CKD. And the world changed at that moment.

Then we had an explosion of heart failure and CKD trials where those were the primary outcomes. And for the kidney trials it was CREDENCE, which was canagliflozin, all type 2 diabetes. They had to have 300 milligram per gram or more of an elevated urine album to creatinine ratio, or albuminuria. Then we went to DAPA-CKD—and CREDENCE they had to have a GFR of at least 30—then we dropped the GFR criteria to 25, uACR to 200.

And by the time we got to EMPA-KIDNEY, 51 percent did not have diabetes and they didn't have to have any albuminuria if their GFR is below 45. And that's important because, irrespective of diabetes and irrespective of albuminuria, the benefits were the same. And on top of conventional risk factor control and an ACE or an ARB, we saw relative risk reductions of 40 percent [for major kidney outcomes]. We had never seen that.

And it was diabetes that opened the door, diabetic kidney disease, to therapies we now apply broadly because the mechanism has really, for kidney protection, nothing to do with glucose. It has all to do with glomerular hemodynamics and perhaps some off-target effects. The opener was the SGLT2 inhibitors.

 

Beyond the buzz: GLP1 trials reveal cardiovascular and kidney benefits

Dr. George Hart: I love this concept of the gift that keeps on giving. But it's not just limited to the SGL2 inhibitor drugs. I think GLP-1s are creating just as much, if not more, of a buzz because of the systemic effects they have. You can hardly watch a sporting event anymore without seeing advertisements for these medications. How are they fitting in into the armamentarium now?

Dr. Katherine Tuttle: The story just keeps getting better. We start with the SGLT2s—and again for this audience, I'll just kind of keep it at a fairly high-level view—but these drugs, it's really important to know mechanisms. Because whether you're a clinician or you're a payer trying to decide whether people should get more than one therapy, the bottom line is they work differently, and that gives us multiple opportunities to continue to improve the treatment and ratchet down the risk.

So SGLT2 inhibitors are primarily what we call hemodynamic drugs. George, they're complementary to ACE inhibitors and ARBs in reducing glomerular hyperfiltration. And actually, to my test of reason, they're even more effective, but they work in a different way. So even with ACEs or ARBs, they're complementary; it sort of finishes the job on hyperfiltration.

But [hemodynamic disturbances are] not the only thing that's causing either heart or kidney demise.. So enter the GLP-1s. These agents were studied for cardiovascular safety, again, because they were new glucose lowering agents. Frankly, the sponsors would not have done these studies if they weren't forced to do them in the beginning.

The GLP1 trials came out in the like 2017 to 2019 phase, and we saw the same thing. Not only were they safe from a cardiovascular perspective, but they had cardiovascular benefits, and they had marked kidney benefits. So it also gives us a chance to not only prevent kidney failure, but reduce the complications that kill our patients.

With regard to the kidney outcomes, same song second verse as with the SGLT2, but with a really important caveat that you brought up: they maintain very highly effective metabolic effects even in people with very low GFR—including people treated by dialysis or transplant—meaning lowering blood glucose and managing body weight. And they also markedly reduce cardiovascular risk in those advanced CKD patients, which is the major competing risk for kidney failure.

There's only been one dedicated kidney outcome trial with a GLP1, and that was FLOW with semaglutide. And clearly a huge benefit, even on top of SGLT2 inhibition in a subset, of reducing risk of major kidney outcomes, including kidney failure, by over 25 percent, and then concurrently reducing risk of cardiovascular events, and also all-cause mortality by 20 percent.

 

The first ever drug approved to prevent death in CKD

Dr. Katherine Tuttle: And in fact, this year in January, semaglutide was approved in the United States by the FDA and in Europe by the European Medicines Agency, their regulatory body, not only to prevent loss of kidney function and kidney failure, but to also reduce atherosclerotic cardiovascular disease and mortality in patients with kidney disease.

And the reason I bring that up is this is the first drug ever in the history of nephrology that has a labeled indication to prevent death. And if you stop for a minute, that is just enormous. The bar to get approval to prevent death is very high. And if you think outside of our rarefied atmosphere of nephrology—in medicine, how many drugs do we have that are approved to prevent death from anything? Very, very few.

Dr. George Hart: Very few.

Dr. Katherine Tuttle: This is a moment that we should be proud of. Our field has delivered a first-in-class for a drug that can prevent the death of people with diabetes and CKD. And among the living, many fewer cases of kidney failure. The number needed to treat to prevent a [major] kidney outcome at three years is just 20, and at the same time reducing the competing cardiovascular risk. It's a monumental time.

 

The future of combination therapies to reduce the risk of major kidney events

Dr. Katherine Tuttle: And back to SGLT2s, the combination therapies studies are starting to roll. But in the meantime, we can use data sources like subgroups of people who got both in the trials, or real-world data sets out of our electronic health records, to see what happens with either one or both. Everything points in the direction of additive benefit. Then you start to see the risk really ratchet down. And in modeling studies, if we combine these drugs, the expectation with very conservative assumptions is the risk of major kidney events will be reduced by more than 50 percent.

Dr. George Hart: Which is a staggering…

Dr. Katherine Tuttle: It's a staggering—and again, outside of nephrology—a staggering risk reduction from anything bad that can happen to people.

Healthier patients, healthier economy: The economic impact of CKD therapies

Dr. George Hart: I live in this world of value-based care. So our goal is: we want to slow disease progression, we want to manage comorbidities, reduce hospitalizations, improve patient outcomes, all of that while trying to lower the cost of care. It sounds like these medications were almost designed to fit in a value-based care world. Am I thinking about it correctly?

Dr. Katherine Tuttle: Most importantly, it allows people to stay alive and stay healthier. But this can actually be a win for the economy in general and health economics.

First off, people can stay in the workforce and contribute because they're alive, and they're healthy.

Second—and you're the expert on this, but you know my simple way of thinking about this when we talk about value-based care and total cost care. If people stay healthier, and we don't have these terribly expensive complications like heart failure, like acute kidney injury requiring dialysis—which by the way is reduced by 25 percent as well—we don't have the myocardial infarctions, or whatever expensive hospitalization leads to death, then I can imagine a scenario where the savings would be large and hopefully more than enough to pay for the medications and give back to our health economy.

So that's my hope. I'm an idealist and we'll look to folks like you who really design these systems to figure out the processes and what the math is exactly. But it should work.

 

The role of PCPs and nephrologists in moving treatment upstream and managing complex therapies

Dr. George Hart: Well, I think there's a lot of hope that it will work. You know, as I listen to you, where my head goes is: this isn't just a nephrology challenge. This bleeds down into primary care and involving them and starting these medications further upstream than when nephrologists are getting involved. Do you agree with that concept?

Dr. Katherine Tuttle: Yes, I do. And I would nuance it a little bit. These are not fire and forget medicines like statins; they do require monitoring. And not just lab studies, clinical assessments. Because they affect volume, they affect blood pressure, they affect potassium, they affect GFR. After doing this for a long time, and among other reasons—this is one of the reasons I stay very involved clinically—is to understand how it's going, what's working, what's not working.

I do think there's a role for nephrologists there. And to be honest with you, we want to have a role in this, otherwise we'll become irrelevant. We have a lot to offer, especially with complexity.

 

Addressing nephrology workforce challenges

Dr. George Hart: I agree with you. And as I've talked to nephrologists around the country, I think they would agree and are excited because, as we've talked about, this is really the first time in our career where we can really feel like we're making a difference in a big way early on in the management of CKD.

I think the balance is going to be, you know, how do we address the opening floodgate of patients to come our way when there's a dwindling workforce. But maybe our excitement will become palpable for others and we'll recruit more nephrologists into the workforce.

Dr. Katherine Tuttle: Well, I think we will. Maybe I just live in a little microcosm, but where I am at Providence Healthcare—it's the academic medical center for both University of Washington and Washington State University here in eastern Washington—and we have a waitlist for nephrology rotations, both students and residents. And that didn't even happen here a few years ago.

And the clinic has gone from being—they used to, frankly, not like nephrology that much. Right? I mean, let's just be honest about it. But now, it's like a happy place. They call these things the “magic meds.” And the students and residents love learning about it. They love seeing the patients, and the patients are excited too.

 

A new lexicon for CKD: From progression to maintaining kidney health

Dr. Katherine Tuttle: I would even challenge us to get rid of the term “CKD progression,” because it's not very hopeful. It just sounds like a slow speed crash instead of a fast crash.

And truthfully, if you look at the data, I think that people can get better. And I think that there's a real possibility in sight that kidney function. Not only—even if it doesn't improve, it might not get worse, it might not be progressing. And then on top of that, when the terrible complications that accompany CKD, particularly the cardiovascular complications that lead to most mortality, are concurrently reduced, we can go into those patient rooms with a smile on our face, a spring in our step, and a twinkle in our eye and say, “We have a treatment for you and it works. And you can maintain health.”

That's the message. That's what we're really trying to do in our teaching programs is talk about maintaining kidney health and no longer CKD progression and that dialysis is a fait accompli. And that's what gets people excited. And we fill our nephrology training program every year and get some of the best applicants.

And I think that we aren't unique, but I think in nephrology we need to change our lexicon, we need to change our own attitudes, and we need to say it's our job to do this and embrace it and that'll bring people into the workforce.

 

Closing thoughts: Ensuring access to live-saving CKD therapies

Dr. George Hart: I think you're right. You know, I spent a lot of time in conversations across my career reassuring people that they could still be a father, they could still be a provider, they could still be there to take care of their kids, and work, and have a meaningful career. I think now I could say that with even more confidence than I did back then because of the work that you've been a part of here over the past years.

There's a lot of new medications that are still being developed in the pipeline. We still need to improve the adoption of the medications that we have today. What advice or suggestions do you have for all of us to help spread the word to the rest of the medical community about the benefit of these medicines and encourage the interest in actually prescribing these drugs?

Dr. Katherine Tuttle: Well, you know, that's a multi layered question, but the first thing I'm going to say to my beloved nephrology colleagues is, “Come out of your silo. Come out of the kidney silo. Reconvene with the department of medicine. Show up and give medical grand rounds. Be willing to attend on the general medical service. If you're in private practice, do the same thing with your internal medicine colleagues."

You know, I oversee a research program in a very large health system, which isn't just nephrology. All [of the research] rolls up to me. I know what's going on in oncology and cardiology and infectious disease. We have nothing to be ashamed of. We are not behind anymore. And I would say we're on the leading edge.

Do you know right now there's 70 trials open in IgA nephropathy alone? Because what this did was it was the opener to say kidney disease is treatable. And now from rare to common diseases, there are many sponsors jumping into this space to develop highly effective therapies.

I'll take a little bit of pride and say it took diabetes to be the opener, but then the field is just exploding now. And so I think that, you know, these are the kind of things that reinvigorate a field. Look what happened to rheumatology with the biologics—the field came back. But this is much bigger, with all due respect. I mean this is life-saving therapy in a very common condition that's highly fatal. We should be shouting this from the rooftops and waving the flags.

And then, payers and health systems, right? We need good economic analysis. To date, that's been done for SGLT2 inhibitors. And even at today's prices, based on information you're probably very familiar with, particularly on hospitalizations, they clearly meet the bar for willingness to pay. I think you'll see the same thing, especially as prices drop, for GLP-1s.

And then health systems need to prioritize this care. Right? Because, other than dialysis and transplant, there's not much reward in the system. And that needs to change at a policy level.

I think we can reduce kidney failure 25 percent by 2030. Now in 2019, I wasn't sure. I thought that was a pie in the sky. If we get it right on implementation, we could do it with the drugs we have now.

Dr. George Hart: That's something to go for. Look, this has been great. You and I could probably go on and talk about this for hours, but we're not going to be able to do that. Thank you for joining us today. This has been a tremendous opportunity to learn how kidney care is transforming and the advances that are being made. And you're a large part of that. And I thank you for it.

Listeners, I hope you'll join us for more conversations on the future of kidney care. For more episodes, please subscribe to Kidney Health Connections or visit our website at interwellhealth.com.