This transcript has been edited for clarity.
Silvio Inzucchi, MD: Welcome to Medscape InDiscussion. I'm Dr Silvio Inzucchi, and today we're talking about type 2 diabetes and our move away from glucose-centricity, trying to harness the revolutionary renal effects of newer antidiabetic agents. I can't think of anyone more qualified to talk about this than my colleague, Dr David Cherney. David is professor of medicine at the University of Toronto in Canada, and he also serves as a nephrologist and clinician scientist at the University Health Network and Toronto General Hospital Research Institute. Dr Cherney's research program focuses on the physiologic factors that initiate kidney disease in patients with diabetes. Welcome, David.
David Cherney, PhD, MD: Thanks so much, Silvio. It's great to be here with you today.
Inzucchi: Before we get to our main discussion, can you tell us a little bit about how you became interested in studying the crossroads between diabetes and kidney disease?
Cherney: Absolutely. I did my PhD in this area and studied the effect of glucose and the effect of medications that affect the renin-angiotensin system (RAS) and other factors that are important for controlling kidney function. I got interested eventually in sodium-glucose co-transporter 2 (SGLT2) inhibitors and other therapies that impact how the kidney regulates itself, and subsequently in trials that have emerged in this field that have fortunately shown very significant benefits for our patients in the setting of diabetes and, now, in people without diabetes. I went from the factors that initiate disease to the trials where these therapies were used and have fortunately shown benefits.
Inzucchi: That's one of the interesting aspects of this field, particularly the SGLT2 inhibitors: how we've grown from thinking of these medications as diabetes drugs. Now they're certainly used in patients first with heart failure and now in patients with chronic kidney disease (CKD).
Cherney: I agree. That's also been one of the challenges because we've had to change our way of thinking from a glucose-centric way of approaching them to thinking about their salt handling and other mechanisms, which I'm sure we'll discuss afterward, that are probably much more important for how they protect our patients.
Inzucchi: Let's start off by discussing the latest Kidney Disease Improving Global Outcomes (KDIGO) guidelines. These are refreshed every couple of years. I think the last version came out in 2020. Will you review for us the major changes in the latest KDIGO guidelines, specifically regarding the prevention of kidney disease in patients with diabetes?
Cherney: The latest KDIGO guidelines have been important in many different respects, and they've outlined how to use newer therapies in this area too. Some of the key messages and the key factors are, first, thinking about how to layer therapies on top of one another. When thinking about broad approaches, there's the nice print pyramid figure in the guidelines for blood pressure control, glycemic control, and lifestyle modification — all the things that we recommend for all our patients.
And then layered on top of that in a smaller group of patients beyond those lifestyle changes, we are trying to use RAS inhibitors and SGLT2 inhibitor therapies more effectively, and some other medications as well that are used in subgroups of patients for reducing cardiovascular risk. So that approach is very helpful because it shows that there are layers of therapies that we should add on top of one another.
Another important aspect of the guideline is thinking about glomerular filtration rate (GFR) cutoffs and where we should be using newer therapies — for example, how to layer an SGLT2 inhibitor and metformin as a first-line agent on top of standard of care in patients who are eligible for these therapies. Thinking about how to initiate them, at what GFR thresholds, and the important message around continuing SGLT2 inhibitors down to the level of dialysis or GFR of 15. Then also touching on some of the future directions around, for example, glucagon-like peptide 1 receptor agonists (GLP-1 RAs) as next-line therapy to reduce kidney risk. The guideline authors really did a nice job of thinking about broad therapies and then honing down into those newer emerging therapies that are now part of standard of care. These guidelines are now almost 2 years old but are honed down into new standards of care that can be used to further reduce risk.
Inzucchi: I really like the so-called heatmap that I believe first appeared in those guidelines. You know, we as endocrinologists, as primary care physicians, used to think about CKD in the classic stages 1 through 5. But now we're asked to think about how important the albuminuria cutoffs are as well.
Cherney: The albuminuria cutoffs are absolutely critical, and the albuminuria is sort of a gate that we should be using based on available data to know where we should target newer therapies. We, of course, measure albuminuria in people with type 2 diabetes on a yearly basis. And that used to be just in some ways part of good clinical care, but it didn't necessarily change practice or what we prescribe for our patients. But now we know that in patients with higher levels of albuminuria, there is a clearly a rationale for giving, for example, SGLT2 inhibitors, or for giving finerenone in people with diabetic kidney disease. So not only is it part of good clinical care to measure GFR and albuminuria on a yearly basis, it also really translates into changes in practice, which we didn't necessarily used to act on over the past couple of decades, where we had nothing beyond an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Now we have those new therapies that can be added on to an ACE inhibitor or ARB in people who are eligible for these therapies.
Inzucchi: So we started our discussion about the SGLT2 inhibitors, and they've clearly garnered lots of attention over the past few years. I know you've studied these drugs for many years, and they clearly reduce the progression of CKD and are now widely endorsed for this specific role by diabetes professional societies, as well as by nephrology professional societies. Clearly, if our patients have CKD as denoted by a reduced GFR, if there is substantial GFR left and the drugs still work, these are considered almost first-line therapies. But what about the majority of patients we see who still have normal renal function and just some albuminuria. Should these drugs be used in that setting?
Cherney: That's certainly a little bit more of a controversial area right now. And it's controversial because the studies that have been completed to date, including CREDENCE and DAPA-CKD, which were the dedicated kidney trials, included patients with a degree of kidney function impairment and also with albuminuria more than 200 mg/g (DAPA-CKD) and more than 300 mg/g (CREDENCE). So strictly speaking, in terms of the renal dedicated trials, it's those patients who demonstrated the protection with SGLT2 inhibitors.
But it's important to also realize that in the cardiovascular safety trials that have been published to date — and there are many of them — there were also benefits from a kidney perspective shown across those different trials. And those benefits extended to people with a range of GFR, including patients with relatively good kidney function and also extended to patients with normal micro- or macroalbuminuria. So although the renal trials have not yet studied and included those patients in terms of the trials that are complete, there are secondary analyses from these cardiovascular trials that have also shown benefits in people with just microalbuminuria.
I think in terms of practice, we have to recognize that there may be benefits in patients without macroalbuminuria, with lower levels of albuminuria. And then ultimately committing a patient to one of these therapies in the absence of macroalbuminuria needs to be a conversation on an individual patient level to weigh the risks and benefits and to decide what to do. And also to take into account the cardiovascular risk because of the substantial benefits with the SGLT2 inhibitors around reducing cardiovascular risk in patients with and without established cardiovascular disease, and also the benefits around heart failure, which are seen in patients with and without heart failure at baseline. All of those risks and benefits need to be taken into account.
Inzucchi: I find this a fascinating area. Do you think that microalbuminuria reduction is the way these medications are working? In other words, is that a marker of the effectiveness of the medication?
Cherney: That's an age-old and very important question, because albuminuria is a very good surrogate marker of risk at baseline, so patients with high levels of albuminuria are at high risk for future renal and cardiovascular disease down the road. And in addition to that, we know from the SGLT2 trials and with other medications that a significant reduction in urine albumin-creatinine ratio (UACR) and albuminuria of around 25%-30% correlates beautifully with a reduction in "hard" renal endpoints in terms of composite endpoints: loss of kidney function, dialysis, transplant, or renal death. Although it is a surrogate endpoint, it's a very good surrogate endpoint, and there probably is very little else that surpasses it in terms of its predictive value, both for future risk and as a predictor of responses to therapy.
Inzucchi: Now on that point, clinically, I'll pose two questions. One is for a person who has relatively preserved renal function and just some albuminuria: Would you advise rechecking the UACR after initiation of medication? Is that of interest to you? Not from a research standpoint, but clinically, is that of any benefit in rechecking that after initiation of SGLT2 inhibitors?
Cherney: It's a really important point, too. The changes after initiation of therapy are interesting, and it's important to check on a regular basis, because patients who have albuminuria tend to still have it down the road. But importantly, it doesn't really change the management in terms of the therapy that started. For example, the patient is started on an SGLT2 inhibitor or on mineralocorticoid receptor antagonist like finerenone that's been shown to have benefits in the kidney. If the patient doesn't have an albuminuria response, I would continue that therapy. And that's a critical point, because some patients have a huge albuminuria reduction. I've seen 90% and greater reductions, and some patients have relatively modest benefits in terms of UACR reduction. That wouldn't make me abandon a therapy. So that's point one.
Point two is that if someone still has persistent albuminuria when they're on a RAS inhibitor, then on an SGLT2 inhibitor, it's important to remeasure the UACR because that will tell you what to do next. If a patient still has persistent albuminuria, that might be an indication to add a GLP-1 RA or to add finerenone, or perhaps some of the emerging therapies that we'll hopefully have in the future. It's still important to think about what to layer on next. When patients are on an SGLT2 inhibitor, finerenone, or a GLP-1 RA, they still have residual risk. The purpose, just like our heart failure colleagues do for heart failure, is that we have these pillars of therapy. The idea in the future is that we're not going to be choosing between different kidney protective therapies. We're going to think about how to use those therapies together. So we now have kidney pillars, not just heart failure pillars, to maximally reduce residual risk as much as we can. And albuminuria helps to guide that.
Inzucchi: So the second patient type is somebody who has reduced renal function. Let's say their GFR is 45. Same question. Rechecking albumin certainly makes sense, but what about rechecking the creatinine? Has that been your practice? Because, as we all know, you do get a little bit of reduction in GFR initially with these medications.
Cherney: In terms of checking serum creatinine and GFR, certainly the first important point is to check it on a yearly basis or more frequently, depending on the level of impairment in kidney function. And then check it after initiation, as we do with an ACE inhibitor or any ARB. With an ACE inhibitor or ARB, I definitely check the creatinine after initiation — generally about 2-4 weeks after starting — because (1) ACE inhibitors and ARBs can cause kidney injury (rarely), especially in people with serious renal vascular disease, and (2) they can cause hyperkalemia. So we want to know about those two issues if they arise, because that will change our management. We might back off on a diuretic or back off on another antihypertensive or reduce the potassium levels with a novel binder, for example. So it would change management.
In contrast with an SGLT2 inhibitor, we know that these therapies actually reduce the risk for acute kidney injury. They reduce it consistently by about 20%-25% in real-world evidence studies (so in electronic medical record database studies). And we know that is the case from clinical trials as well, including in people with impaired kidney function, such as in patients with diabetic kidney disease, who are enrolled in the existing studies. We know there's a reduction in acute kidney injury (AKI) risk.
We also know, interestingly, that with some SGLT2 inhibitors, there is a bit of a reduction in the risk for hyperkalemia, probably because of the natriuresis and increased urine flow that gets rid of potassium, so I actually do not recheck. That's a long-winded answer, but it's important to understand why I don't check the creatinine or the electrolytes in most patients after starting an SGLT2 inhibitor, because of those factors that are different and contrast with what we see with an ACE inhibitor or an ARB. I tend to just check it at the next visit unless there's some particular concern that I have about an individual patient based on lowish blood pressure, or age, or frailty, or other issues that are important in that specific person. But generally, I don't.
Inzucchi: Even in a patient with a GFR hovering around 30, you wouldn't recheck after a month?
Cherney: Thirty is around my cutoff (25-30), which is where we're typically at the lower end of where we're using SGLT2 inhibitors in patients with kidney disease. At a GFR of 25-30, I typically do. Those patients also tend to have a lot of other comorbidities. They tend to be frail and elderly. So those are the usual reasons. But if I have a robust 35-year-old or 40-year-old with albuminuria and a GFR of 30, then I would not check it. I would check it at the next visit.
Inzucchi: That's what I've been doing. Another related question: Is there any drop in the initial GFR that would compel you to discontinue the medication? That always comes up.
Cherney: Absolutely. I would discontinue the medication at a GFR reduction of around 25-30%. When it's that degree or more, then that's concerning, and I would certainly repeat GFR measurement within 3-5 days to see that it's coming back up again. What we typically see is that after the GFR dip, the GFR tends to return to where it was. And if it's back to where it was, I would just sit on my hands, do nothing, and then watch and wait. If the blood pressure is low in that setting, lower than I want (typically less than about 120/70 mm Hg), then I would think about backing off on other antihypertensives or diuretics and reversing anything that I can. But most of the time, I just watch and wait. That's very rare by the way — that reduction of 25 or 30% is extremely rare.
Inzucchi: Most reductions are in the range of 5%-10%.
Let's talk about the American Diabetes Association guidelines. These are published annually in the journal Diabetes Care. They're called the Standards of Medical Care in Diabetes. There's an algorithm that's well-publicized that tells us how to use glucose-lowering therapies sequentially, typically starting with metformin, although some of us are getting away from that as foundation therapy. And then over the past 4 or 5 years, there's been a focus on the comorbidities of our patients, whether it's atherosclerotic cardiovascular disease (ASCVD) or heart failure or CKD. Let's focus on the CKD group.
It used to be that if CKD was present but sufficient GFR was preserved to allow for use of the SGLT2 inhibitors, those would be the natural choice. Because our goal — at least one of our goals — here is to prevent the progression of CKD. In the last couple of iterations of these guidelines, there was this change — a little bit of a nuance — but there this notion that if the patient had CKD and albuminuria (micro or macro), then the SGLT2 inhibitors would be the obvious choice. But if there was no albuminuria (and the inference, I think, was that this was not really diabetic kidney disease [DKD] — which, you know, one can argue with), that then the choice would be either a GLP-1 RA or an SGLT2 inhibitor. I'm not sure I practiced that way. I think anyone with CKD, irrespective of the presence of albuminuria or not, should be on an SGLT2 inhibitor. What do you think?
Cherney: I think it's a very important point, and I agree that is a little bit difficult to follow in the guideline. It seems to be that the recommendation is that the CKD in that flow diagram might in fact reflect future cardiovascular risk and therefore equate an SGLT2 inhibitor and a GLP-1 RA, which I disagree with. From a renal perspective, we are thinking about CKD risk, not thinking so much about the cardiovascular risk. But if we're thinking about the CKD risk and the benefits of these therapies, there's no question that there is a huge body of evidence in support of the SGLT2 inhibitors as medications that reduce renal risk, both in patients with albuminuria and as mentioned before, even in analyses from the cardiovascular outcome trials (CVOTs) in patients with and without impairment in GFR, with and without elevations in UACR. So there's a huge body of evidence that supports a preference for an SGLT2 inhibitor over a GLP-1 RA from a renal perspective right now, with the caveat that there are ongoing trials with the GLP-1 RAs that will elucidate some of the mechanisms and also whether there are benefits in patients with established CKD, like the FLOW trial. But I think the preference should clearly be for an SGLT2 inhibitor.
The other important point to mention is that the most compelling data for the GLP-1 RAs — based on secondary analyses from LEADER and SUSTAIN and REWIND and others — the best evidence supporting GLP-1 RA protection for the kidneys is in patients with low GFR (between 30 and 60) who have micro- or macroalbuminuria. It's those higher-risk patients who appear to benefit the most with the GLP-1 RAs. There are also nice data by Kathy Tuttle from AWARD-7 showing the same thing. I think the best data is on people who have kidney disease for the GLP-1 RAs. So again, SGLT2 inhibitors are clearly the preferential therapy and then a GLP-1 RA would be a next-line treatment, just like the KDIGO states in the flow diagram.
Inzucchi: The suspicion is that these drugs, although it's obviously an expensive undertaking, could have complementary benefits as far as the kidney is concerned. We don't know that for sure.
Cherney: From the perspective of complementary mechanisms of benefit with the SGLT2 inhibitors, they are potentially much more or predominantly hemodynamically protective; they probably have benefits on suppressing inflammation, fibrosis, hypoxia, and so on in the kidney as well. Whereas in contrast, the GLP-1 RAs are probably predominantly beneficial in the kidney by nonhemodynamic mechanisms by reducing inflammation and fibrosis, as well as the powerful metabolic effects they have on reducing weight and A1c, which may reduce microvascular risk, too. There are definitely rationales for different mechanisms of benefit.
Inzucchi: Let's talk briefly about mechanisms. How the heck does a drug that increases glucose in the urine have such a dramatic benefit on the progression of CKD?
Cherney: That's a very good way of phrasing it, because absolutely these therapies increase glucose in the urine. They increase glucose in the urine in people without diabetes too — just to a much lesser extent compared with someone who has ambient hyperglycemia and diabetes. But we also know that these therapies, in terms of their benefit in the kidney, have a mechanism of action that is completely independent of glucose. And in fact, they are effective for reducing kidney risk even in people who have normoglycemia and no diabetes.
There's a beautiful figure that was published in Diabetes Care some time last year, which shows the hazard ratio or the benefit across the DAPA-CKD cohort, where the hazard ratio was below 1 and was significant from an A1c of 4-12. It didn't matter what the A1c was, there was clearly a significant, statistically significant, benefit across the entire spectrum of A1c. But it doesn't matter what the A1c is. So the benefit is likely on the basis of changes in glomerular pressure.
These medications are natriuretic, and they kind of trick the kidney into reducing pressure at the level of the glomerulus, sort of like an ACE inhibitor or ARB does. Doing so reduces albuminuria and reduces all the intraglomerular pressure and wall tension that causes fibrosis. That's probably the main mechanism, but there are other mechanisms that are probably important too, like the anti-inflammation, antifibrosis, and antihypoxia mechanisms as well.
Inzucchi: But also complementary to RAS blockade, correct?
Cherney: Absolutely. RAS blockers probably have a similar effect on reducing glomerular pressure, but they probably act differently. They act at the outflow arterial at the glomerulus, whereas the SGLT2 inhibitors work predominantly at the inflow arterial of the glomerulus (although that's also become a little bit more controversial recently). But that's probably the main mechanism of how they reduce pressure in the kidney, and that's why they work so well in a complementary way.
Inzucchi: David, we're running out of time. I wanted to pick your brain once more about RAS blockade in patients who are not hypertensive. In a person with type 2 or even type 1 diabetes who has microalbuminuria but normal blood pressure, are we still supposed to be using RAS blockade in those individuals?
Cherney: Yes. To some degree, it depends. In very low-risk patients — patients without albuminuria, with normal kidney function, no hypertension — it depends a little bit on type 1 vs type 2 diabetes. And clearly there, from my readings of the previous trials, there's no supportive data for use of an ACE inhibitor or ARB in someone with type 1 diabetes who has no hypertension, no kidney disease. We have trials like the RASS trial, for example, that didn't even show any benefits on kidney biopsies in terms of primary prevention with an ACE inhibitor or ARB.
The story is probably pretty different in type 2 diabetes, though, because there are nice primary prevention data, albeit with a surrogate, with albuminuria showing that ACE inhibitors and ARBs in the BENEDICT trial, the ROADMAP trial, and others had reductions in new onset of albuminuria with an ACE inhibitor or ARB as primary prevention. And then most of my patients would have gotten into the HOPE trial, which is now more than 20 years old. The HOPE trial included people who were aged 55 years or older who had either established cardiovascular disease or type 2 diabetes with another risk factor. With hypertension or with albuminuria, microalbuminuria, or hyperlipidemia, for example, most of my patients would have gotten into those trials. So even though they don't necessarily have kidney disease, there was a very significant benefit in the HOPE trial. That's another potential indication for treating a patient like the one you described to reduce cardiovascular risk. Then there are those other trials suggesting renal benefits, even in patients who don't have very much clinical disease.
Bottom line, there is usually a reason to treat someone with type 2 diabetes with an ACE inhibitor or ARB. The obvious exception, of course, is someone who's very young who wouldn't have gotten into any of those trials, whom you're committing to a medication for many, many years; that is certainly a more personalized discussion.
Inzucchi: Very good. Well, Dr David Cherney from the University of Toronto, thanks so much for sharing your thoughts today. It's been a fun discussion.
Cherney: I really enjoyed it. Thanks for including me.
Inzucchi: Thanks for listening. I'm Dr Silvio Inzucchi for Medscape InDiscussion.
Change in Albuminuria and GFR as End Points for Clinical Trials in Early Stages of CKD: A Scientific Workshop Sponsored by the National Kidney Foundation in Collaboration With the US Food and Drug Administration and European Medicines Agency
The Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) Observational Follow‐Up Study: Benefits of RAS Blockade With Olmesartan Treatment Are Sustained After Study Discontinuation
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Cite this: How to Reduce Renal Risk in Type 2 Diabetes - Medscape - Apr 13, 2022.