Hi, welcome back to Medicine Matters Diabetes Ask the Expert series. Today we're going to talk about the nexus between diabetes, the kidney, and cardiovascular disease. My name's Jay Shubrook. I'm a family physician. I'm happy to have back for our third part of the series, Dr. Katherine Tuttle, who's both an endocrinologist and a nephrologist. What an exciting time to talk about this interaction.
It is. And I think this is really taking it to the finish line with regard to what we've talked about before in terms of improving awareness, detection, and team care for chronic kidney disease. So since we last talked, two major clinical trials have reported out on kidney disease outcomes in patients with type 2 diabetes. And these trials were really heralded by the cardiovascular outcome trials that have received a lot of attention, appropriately so.
Just to recap and center us on the main theme, the SGLT2 inhibitor class was tested for cardiovascular safety, because of an FDA mandate that newer glycemic agents needed to have post-market approval testing to assure safety. But they have really been the gift that's kept on giving.
The people who designed the trials were prescient in the sense that they designed them so that if the agents were safe, they could also proceed on to a higher level of statistical rigor to test them for benefit. And the first one to report was EMPA-REG empaglioflozin, which showed remarkable cardiovascular protection. So reduction in major adverse cardiovascular events, particularly heart failure events and death.
On top of its benefit in diabetes.
That's right.
Yeah.
And really beyond what could reasonably be ascribed to glycemic control. And the truth is, glycemic control doesn't do a lot for cardiovascular events anyway in type 2 diabetes, arguably, nothing. So on the heels of EMPA-REG came CANVAS, which was a similar study in canagliflozin. Then DECLARE, one of the TIMI trials with dapagliflozin.
Each of those studies though, had progressively lower CVD risks, so while they were all high CVD risk, EMPA had the highest. But irrespective of going to lower risk populations, there was the consistent finding on heart failure. And they were also prescient in identifying kidney disease as main secondary outcomes.
So in those three big trials, the new onset of kidney disease or progression of kidney disease and diabetes was averted. But because the patients were selected for cardiovascular risk, they either had very early or no kidney disease. So that we couldn't get to really understanding if they'd prevent the kind of things that matter to patients, which is not being dead. And among the living, staying healthy without end-stage kidney failure.
You've given us a really good background about, we have good cardiovascular data, but this is the year of the kidney.
That's right.
So tell us about some of the new trials, like SONAR or CREDENCE this year.
OK, so let's first start with CREDENCE. So CREDENCE was the first trial to report on kidney disease outcomes in patients selected for kidney disease. So by analogy to the heart trials, selecting for patients with heart disease enriches in a population where you can test for heart events.
In the kidney disease trials, we selected for kidney disease so that we enhance our chance of seeing an effect on things that matter to patients, which is staying alive and staying alive without kidney failure. That said, the main secondary outcomes of the cardiovascular outcome. So we've just reversed, if you will, the prioritization.
CREDENCE was stopped a year and a half early by the data safety monitoring board, for overwhelming efficacy. And I would like to take a centering moment here as well. In the field of nephrology, we have never had a clinical trial stop for efficacy. We've had trials stopped for safety, but there's never been a trial stopped because patients were doing so well. It is really a landmark.
A new day.
In terms of clinical trials. So in April of this year at the World Congress of Nephrology, they reported out the results, which published online immediately in the New England Journal of Medicine and what CREDENCE showed, is in patients with type 2 diabetes who had clear kidney disease, they had an elevated. albuminuria, a urinary albumin creatinine ratio of more than 300 mg per gram, what we would call macro albuminuria or severely elevated. albuminuria.
And a GFR, estimated GFR based on serum creatinine between 30 and 90. And what they showed clearly, was that there was a 30% reduction in the things that matter to patients, which was end-stage kidney disease, a 40% decline in GFR, which is a proxy for kidney disease and death due to cardiovascular events and kidney events.
And these are in people that clearly have kidney disease that we've been trying to get help for anyway. So now we have a tool in our toolbox that could help.
And it really shows that the harbinger from the cardiovascular outcome trials and early kidney disease was predicting that this would be beneficial across the spectrum in terms of preventing kidney function loss and end-stage kidney disease. The other thing that's quite remarkable, is that the sponsor of the trial has gone to the FDA for an approval, not only to prevent end-stage kidney disease, but also to prevent death.
We don't know if that approval will be granted. But I'd also like to say that in my field of nephrology, we've never had a therapy approved to prevent death. And actually, if you look across fields of medicine, those are very rare approvals. Like maybe beta blockers after myocardial infarction. They're very rare. So this really is a transformative time in terms of patient care. The other piece is, everybody was getting the standard of care. There was 99.9% coverage with ACE inhibitors or ARBs.
So this is on top of standard of care.
And they had good control. At least it's as reasonable of glycemia and blood pressure. And to put this in perspective, if we look at the angiotensin receptor blockers, which were the last approved drugs for diabetic kidney disease in 2001, the relative risk reductions were only the 15% to 20% range. And that was on no background therapy. So the effect sizes are double and they're on top of what we've considered standard of care.
So it really is quite remarkable. It's a complete game-changer in the field. There are all already the major professional organizations are quickly moving to update guidelines. There are other studies being done with SGLT2 inhibitors. DAPA CKD, which is dapagliflozin. That study also includes non-diabetic patients. EMPA kidney includes non-diabetic patients, patients without proteinuria, and even type 1 diabetic patients. And that's important, because we have a huge unmet need for type 1 diabetes.
Sure.
And almost no therapies are studied for type 1. So stay tuned, the story isn't entirely written yet. And we have a need for more therapies. I think that's where SONAR comes in.
OK.
And SONAR was presented in the same late breaking trial session at World Congress of Nephrology, published online immediately at the major European journal, The Lancet. And SONAR took a similar population of patients. Same background therapy, but used an endothelin A receptor antagonist.
And this is, if you will, a kidney-specific therapy. The biology was based on experimental models showing a clear role for endothelin in the mechanisms of kidney disease progression. That field has been sort of percolating for a while. Earlier trials were stopped, because of a higher rate of fluid retention and heart failure with agents in the class.
So one of the things that was really unique about SONAR was something called an enrichment design. So there was a run in period where everybody was exposed to atrasentan, the study drug. And if they had evidence of heart failure, either by clinical findings or an elevated BNP level, they didn't go on into the trial.
They also did a responder assessment, so that if patients had a reduction in albuminuria, they were selected to go into one randomization group. But the other really smart thing they did too, is even patients without albuminuria were randomized, but they were in a separate group, but quote, non-responder group.
SONAR was stopped early by the sponsor for a low event rate, predicting a negative trial. But they really made the wrong bet on that one, because despite stopping the trial early, there was a 35% reduction in the comparable primary endpoint. End-stage kidney disease, a 40% GFR decline and death.
The truth is, that in that trial, all of the events that benefited were end-stage kidney disease and GFR decline, but that's still another huge win. And that trial also taught us really to learn about precision approaches in clinical trials. So basically, predicting who might have an adverse effect and taking them out.
The really smart thing to do, though, is to include the non-responders, because if you look at the data by responder status, the non-responders had almost the same benefit as the responders. So it sort of showed us that you can't necessarily predict what's going to happen based on albuminuria, which was another important piece.
Unfortunately, that drug isn't going to be developed. The sponsor walked away from it. But there are other drugs in the class that are being developed and being tested, actually in some other kidney diseases. So I'm very hopeful that one of those other sponsors is going to take the ball and run with it.
So we know that, we have so many new diabetes treatments, and we know that both microvascular and macrovascular complications are important to patients. And while we've seen a massive reduction in other microvascular complications, it's been harder to change kidney disease.
Yes. In fact, data from the CDC showed over the past 20 years, a 50% to 60% reduction in myocardial infarction, stroke, and no benefit on end-stage kidney disease. And I think a lot of the innovation had stalled. And I think the challenge though, really hearkens back to our previous discussions.
Is now that we have these breakthrough therapies, we have something to offer, we do need to make sure that we're implementing those therapies. And that really starts with dissemination of knowledge, awareness, detection, and then intervention. Because even if you look today across different data sets, the uptake of ACE and ARB use in clinical practice is abysmally low.
Depending on the health care system and setting, it's as low as 20%, but no higher than 60%. And usually the benchmarks for an indicated therapy are like 80%. So I'm very excited about it. I think we have to consider that piece as well. And work harder at dissemination and implementation at the point of care.
So I want to really tie this together with a patient. So as I look at my spectrum of patients with type 2 diabetes, we have so many things to choose from. When am I going to use one of these renal protective agents? Who's the best patient?
OK, and I'd like to bring the GLP-1 receptor agonists into this discussion too, because I think that at the present moment for the treatment of diabetes, SGLT2 inhibitors and GLP-1 receptor agonists are very complementary. And I'm not talking about combination therapy yet, although that probably is a fertile area for future research. But I think those two therapies really fill a lot of gaps across the spectrum.
So with regard to SGLT2 inhibitors, I think that they're especially beneficial in people who have kidney disease, but earlier kidney disease. Because they haven't been tested below a GFR of 30. Now maybe for a lot of people that seems like advanced kidney disease, but in my world, it's not.
Yes.
And the current label, at least in the United States and I think much of the world, is for most agents, GFR above 60. Although I believe that several of them might go down to a GFR of 45. You'll have to check your agent and wherever it is you're practicing. So there's a limitation in that they are not available for use in more advanced stages the CKD.
They also, the ability, the anti-hypoglycemic effect attenuates with lower GFR. So honestly, for kidney protection, we're not using them so much for glycemic control, as we are for kidney protection. You might get a little bit, but you're not going to get a lot. So people who have relatively good glycemic control, relatively well preserved kidney function, and particularly if they have a heart failure phenotype. They've been admitted for heart failure, risk of heart failure. After metformin, which is still our first line therapy, an SGLT2 inhibitor would be a good choice for that sort of patient.
A different sort of patient would be the person with lower GFR. In fact, GLP-1 receptor agonists are mostly labeled as low as a GFR of 30, and dulaglutide is standard with GFR of 15.
Wow.
They're much more potent for glycemic control. It's really, the benefits on the GLP-1 receptor agonist studies have been on athrosclerotic events, mainly MI and stroke. Liraglutide had a benefit on cardiovascular death, but not the other agents to date. So to my test of reason, a patient with lower GFR, like a GFR below 30 or 45. A patient who has poor glycemic control and you really need to add something for glycemic control.
Or the person who has an athrosclerotic heart disease phenotype who's been admitted for angina, maybe who's had an MI, or where they have a multiple risk factors for athrosclerotic disease. Then I think about GLP-1s. And this is why we need a menu of therapy. So we're starting to individualize and tailor therapy to individual profiles.
With regard to the other agents, like atrasentan, there are other novel agents that are kidney-specific, especially in the anti-inflammatory field. And the way I see that developing, is that those agents would be, could be additional agents for, particularly for people who are at high risk of kidney disease progression.
We really do need a menu of therapies, because patients come in all shapes and sizes, literally and figuratively, with different complications. Even though we lump cardiovascular and we lump kidney together, there's really a spectrum of types of complications and severity and different drugs will be a better fit. And then, of course, with regard to their diabetes and whether we're using these agents for glycemic control, organ protection or both.
So as we think about this, I think that one of the things I've taken from today, is that we now have ways to really impact renal disease and diabetes. And commonly, we will shy away from medications when there's renal disease. But now really is the time to engage, and engage early, so that we can make a difference for the progression.
And in primary care, in specialty care, this is a time for us to be working together to optimize both the glycemic and the non-glycemic benefits. And I loved what you said about, we use metformin for its non-glycemic benefits. There's probably a time now to be considered SGLT2s or GLP-1s for their non-glycemic benefits. And stay tuned, some day we'll know how they work together. But certainly individually, this is an exciting time for diabetes.