Activity Transcript

Lawrence Leiter, MD, FRCPC, FACP, FACE FAHA, FACC: I am Dr Lawrence Leiter and I would like to welcome you to this session on what is the expert accord on identifying and protecting the patient at early stage of CKD. We hear a lot in the last few years about very exciting trials on treatment of patients with advanced kidney disease, but of course what is more important is identifying our patients with early stages of CKD and preventing them from moving on to more advanced stages.

I am an endocrinologist. My interest is prevention of the complications of diabetes, and I have been very fortunate to be involved in a number of large outcome trials. And I am very pleased to be joined by two experts, Professor Per-Henrik Groop from the University of Helsinki, and Dr Radica Alicic from the University of Washington, School of Medicine. So, let us start with Radica. Welcome and thank you for joining us. Perhaps you can just tell us a little bit about your interests?

Radica Alicic, MD, MS, FACP, FHM: Lawrence, thank you very much for inviting us. It is my distinct pleasure to be part of this group. As you pointed out, nephrology, primary care, and endocrinology colleagues must work together. So, my clinical practice is with Providence Health System in Spokane, Washington, and my clinical appointment is with University of Washington. I am interested in diabetes and diabetic kidney disease and had very good fortune to be part of big outcome trials, including CREDENCE and EMPA-CKD. Thank you for having me.

Dr Leiter: Welcome. Thank you for joining us. And Per?

Per-Henrik Groop, MD, DMSc, FRCPE: I'm a nephrologist from Finland. In fact, I studied as a diabetologist a long time ago. And at the moment, I'm a professor of internal medicine at the University of Helsinki, and also a chief physician at the Department of Nephrology at the Helsinki University Hospital. But sometimes, I say that my main work is being the principal investigator of the Finish Diabetic Nephropathy Study, which is the largest collection of patients with type one diabetes (T1D), with and without diabetic kidney disease in the world. So there, I am joined by 58 scientists, and exciting work where we are trying to find out why some people with diabetes develop kidney disease.

Dr Leiter: Okay, great. So, we have people with both research and clinical interests in diabetic kidney disease, and together we will discuss the importance of early CKD detection, not only in patients with diabetes, as well as the benefits and practical use of renal protective therapies, including sodium-glucose cotransporter 2 (SGLT2) inhibitors in the holistic approach to the management of CKD. So, let's start, Per, we just watched what's a very common day-to-day interaction between a primary care physician and a patient with type 2 diabetes (T2D), in this case, at risk of progressing to CKD. So why is it important to detect CKD as early as possible

Dr Groop: Larry, that is a very important question and issue in the day-to-day treatment of patients with T2D. Because when you screen the kidney function by testing for the eGFR, and then albuminuria to see and find the early signs of CKD in patients with T2D, you will find that more than every second one will have signs of CKD.

Done by Hans-Henrik Parving many, many years ago on a global scale, patients screened for the presence of albuminuria and eGFR below 60 mL/min/1.73 m², and 56% had signs of CKD. So diabetic kidney disease is common, and what is more important is that what comes with the presence of CKD is that these patients have an increased risk of dying early. And already, with albuminuria, many-fold increased risk of dying early, the same goes for an eGFR below 60 mL/min/1.73 m², and if you have both, again, much, much more increased risk of mortality.

But it's not only mortality, it is also increased risk of cardiovascular events like myocardial infarction or stroke. So, the less the kidney function, the more albumin that leaks into the urine, the more likely these patients are to face a cardiovascular event. And very important is that, when you lose kidney function, if you have T2D, the risk of ending up in hospital because of heart failure increases dramatically, and the same goes for an increase in the albumin excretion rate.

And if you want to put this into context, think about your patient with diabetes in your clinic. Just by having diabetes, that patient will have 6-year shorter life expectancy. But if the patient has suffered a myocardial infarction or stroke, you can expect 12-year shorter life expectancy. When you find the early signs of CKD in a patient with T2D, you can expect 16-year shorter life expectancy. So, Larry, diabetic kidney disease, or today we should more talk about CKD, in patient with type 2 diabetes, is common, and the consequences are grim.

Dr Leiter: Great. Now, so thank you very much for highlighting the many ways in which these are at-risk individuals. So Radica, we saw this Oliver patient with a history of T2D. What can we be doing better to manage and decrease Oliver's cardiorenal risk?

Dr Alicic: That is an excellent question, Lawrence. So, I think since early 2000s, when we had main studies showing effects of the angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) agents, we had a huge two decades of therapeutic vacuum. So, I think a lot of my colleagues in primary care did not see much use in testing and discovering this disease, because there is so little we can do for these patients. So, if you look at the data from different countries, including the United States, somewhere about 50%, or between 50% and 60% of the patients, were actually tested for this disease.

But what can we do? Now, we are living, we have good fortune to practice in a very fortunate moment. So, once we detect patients -- who Per-Henrik outlined very well the risk of cardiovascular disease and progression to kidney disease, and, of course, mortality -- now we do have some arsenal, therapeutic arsenal that we can use. So, what do we need to do? When we see patients with T2D, we need to start testing them at least yearly, checking both blood, for eGFR, and urine, for albuminuria, to detect kidney disease.

So, what does chronic kidney disease in diabetes, mean? That means abnormal eGFR, albuminuria or structure abnormalities persistently, and they must have 2 abnormal readings within 90 days. That means that one-time abnormal reading is not consistent with chronic kidney disease. When we are checking for albuminuria, we will check for first morning urine, because albuminuria is one of the biomarkers that tends to have a great variability, up to 30%. And the bone morphogenetic protein (BMP) or kidney function for glomerular filtration rate can be checked any time of the day. In people with T1D, we can start screening for chronic kidney disease at 5 years after diagnosis.

So why is it important to check both albuminuria and eGFR? I think it's important, as Per Henrik pointed out, as these people are at increased risk of cardiovascular mortality. Now, we always think about dialysis, but only about 10% of people who develop chronic kidney disease will progress to renal replacement or kidney replacement dialysis. So, once we diagnose patients with chronic kidney disease, so that means that they will have 2 abnormal measurements, we need to follow them. Probably if the albuminuria is less than 300 mg/g, we can follow them yearly. If albuminuria is higher than 300 mg/g and their eGFR is between 30 and 60 mL/min/1.73 m², we should follow them at least twice a year. If you pay attention to heatmaps from Kidney Disease: Improving Global Outcomes (KDIGO), which is a very good tool to describe risk of patients with chronic kidney disease, you'll see that someone who has the same eGFR between 30 and 45 mL/min/1.73 m², can have very different risk depending on the level of albuminuria.

Dr Leiter: Okay, so thank you. So, you have raised a number of important points, and I think both of you have highlighted the fact that patients with early kidney disease are at increased risk, both of more advanced kidney disease, as well as cardiac disease, cardiovascular disease. Unfortunately, some of the interventions we have been shown to both reduce the risk of kidney, as well as cardiovascular disease. And before we move on, I just want to clarify. So, I think you very, Radica, you very nicely highlighted the fact that it is important to screen, because we now have interventions that have clearly been shown to be of benefits. So, Per, why aren't we doing better? So, 10, 15 years later, why are, depending on where you live, about half of our patients still not being screened for albuminuria?

Dr Groop: Larry, this is very important issue that we need to address from now onwards, because this is not what it should be in clinical practice, that only half of patients are screened, even in many countries, even less than half are screened, given that how common CKD is and the grim consequences that come with this. So, we need all of us, of course, especially the primary care physicians to make sure that you screen all the patients for the presence of CKD, and you should screen not only for albuminuria but also for the kidney function. It is important to have them both because they give slightly different information. So, when you have a reduced eGFR, it means that you already have scars in the fibrotic changes in the kidneys. Albuminuria means that basically every single basement membrane in the body is leaking albumin, we just measure it from the urine, but it's also telling us that something is wrong with the kidneys.

And let me just briefly comment on what Radica was saying, that not many of these patients end up on dialysis, and the reason for that is that most of them die of cardiovascular disease before they end up on dialysis. This is also important to keep in mind.

Dr Alicic: The reason why we do not test. When you have someone with a back pain, they come with a horrible pain, and they want to be tested immediately. If you have a kidney disease, it is silent for a long time. So, we know that both practitioners and both providers and patients have very low awareness of kidney disease. And honestly, I think that awareness of cardiovascular risk and increased risk of dying and shortened life expectancy is not that well understood in general practice. We always think about dialysis, and what Per just pointed out, people who survived to dialysis are survivors of cardiovascular disease, so they made it. But 90% of people with similar problems did not make it, so we need to raise awareness of this disease.

And one more point is that for 2 decades, we had therapeutic inertia. And I know in United States and especially in other parts of country, some of the measurements of insurance companies was, “It was when you put patient on the ACEi/ARBs, you are fine. You don't even need to depict measurement of proteinuria”.

Dr Leiter: Yeah. No, so thank you both for raising very important points. So, Per, let's come back to Oliver. He has an eGFR of 75 mL/min/1.73 m², an albumin-to-creatinine ratio of 210 mg/g. You are the nephrologist. So first of all, what stage of disease is he at? How much risk does he have, and should we be referring all these patients to a nephrologist?

Dr Groop: Very good question, Larry. First of all, if you put these patients on the KDIGO heatmap, so based on his eGFR and based on his albumin secretion rate that means he has moderate risk of progression of CKD to end-stage kidney disease (ESKD). That needs to be taken into account when we tailor treatment because he is already at risk.

And this KDIGO heatmap is based very much on risk calculation equations that were originally derived from two Canadian populations, patients with CKD stage 3 to 5, referred to nephrologists. And these equations were then validated in more than 700,000 individuals across more than 30 countries worldwide and turned out to predict rather accurately the 2- and 5-year probability of treated kidney failure, so dialysis or transplantation, for patient with CKD stages 3 to 5. So, they work very well.

The second question was, "Should he be referred to a nephrologist?" I would say no, he is still early stage, and he can be treated by primary care physicians. And the reason why I am saying this, in many countries all over the world, access to nephrologists is not that good. In my country, these patients are referred to me when their eGFR is around 30 mL/min/1.73 m², in many other countries, when the EGFR below 30. So, I think it is important to keep in mind that these patients, majority of them, are treated by primary care physicians, and they have the means now also to take care of these patients.

Dr Leiter: Okay, perfect. So, let's go through that. What exactly should be done to try to reduce this patient's risk of progressing?

Dr Groop: What I usually say to my colleagues and patients, we need to be pragmatic. So, I call it, "A 5-finger rule." We all know that we have five fingers, so it is easy to remember: HbA1c below 7, so optimal glycemia control; optimal blood pressure control, blood pressure below 130 over 80 mm Hg; and use a RAAS blocker; also, strive after optimal lipid control, at least an LDL cholesterol below 1.8, but preferably, if there are any signs of CKD, go down to below 1.4; and, lifestyle, smoking is extremely important. And unfortunately, I can tell you that not even standard of care is provided to all patients. So, if we are talking about suboptimal screening, it is also suboptimally provided to patients, this 5-finger rule.

Dr Leiter: Right. Now I like that, people should be able to remember how many fingers they have. So, let's, again, so based on this, what do our guidelines tell us? What should we be doing, and if you could just briefly tell us, what is the evidence for these current guidelines?

Dr Groop: Of course. Five-finger rules are standard of care. All the trials have been done are on top of standard of care, so standard of care we need to provide in the first place. But now, we have during recent years, so many wonderful trials with SGLT2 inhibitors, also with a non-steroidal mineralocorticoid receptor antagonist, and glucagon-like peptide-1 (GLP-1) receptor agonists. And now, the guidelines of different societies around the world, specialist societies like the European Society of Cardiology (ESC), the European Association for the Study of Diabetes (EASD), the KDIGO, the European Renal Association (ERA), and then also, of course, American Diabetes Association (ADA). They all recommend that, on top of the standard care, so the five-finger rule, we should consider the use of an SGLT2 inhibitor because, SLGT2 inhibitors have been shown to be, not only cardioprotective, but also renal protective. And the good news is that we can now initiate these treatments, according to ADA guidelines, if the eGFR is below 20 mL/min/1.73 m².

So, if you look at the major outcome trials for SLGT2 inhibitors, there is a meta-analysis that I urge you all to read, in Lancet, showing that you can reduce the risk of kidney disease progression by roughly 40%, irrespective of whether a patient has diabetes or no diabetes. And then, newer trials in patients with kidney disease, so dedicated kidney trials, very similar data showing that you can reduce the kidney disease progression by about 40%. This is very nicely highlighted then in the ADA guidelines using a so-called, "pillar approach," but that consists, basically, of 5 pillars. So, lifetime modification, optimal glycemic, blood pressure, lipid management, and then on top of that, agents that have shown cardiovascular and kidney benefit.

“What about the evidence?" It is very interesting that, in the past, the RAAS blocker trials, they didn't show any effects on mortality, but SGLT2 inhibitor trials also shown that they quite effectively reduce the risk of mortality. And as I already pointed out, the nonsteroidal mineralocorticoid receptor antagonist, also showing a wonderful effect on reducing the risk of a composite kidney endpoint, something between 18% to 23%. And if you then finally look at the trials with GLP-1 receptor agonists, what is conspicuous with these trials is that GLP-1 receptor agonists, they reduce albuminuria, but they do not seem to have the effects on the heart/kidney endpoints as the SGLT2 inhibitors have. So, Larry, we have a lot of evidence at the moment, and that has now crept also into the guidelines. So, all of you listening, five-finger rule, and on top of that, provide also organ-protective medications.

Dr Leiter: Yeah, great. So, thank you very much for summarizing so beautifully. Just before we move on, just want to clarify one point. So, you said you can use the SGLT2 inhibitors down to an eGFR, we now have evidence down to 20 mL/min/1.73 m², but one question I often get from clinicians is, "When do we start it?" So, do we need both a decrease in eGFR and albuminuria, or is either one sufficient to initiate an SGLT2 inhibitor?

Dr Groop: I would say the earlier you can initiate the better, and keep in mind that SGLT2 inhibitors, in the beginning, they were, by definition, glucose-lowering medications. So, there is an indication for the treatment of diabetes in patients with T2D. So, they can be started very, very early. Now, of course, the trials that I've alluding to are done at much, much later stages. But I would say that, at the latest, when you find albuminuria or a reduced eGFR, and if you find both, it is definitely a call for action. But very, very early, and when you find the first sign of CKD, I think that is the time to start.

Dr Leiter: Okay perfect. So, Radica, let us to try to put this all together. So again, can you just go over with us how exactly we should be using these agents in our practice? And there continue to be some safety concerns, I think some of them may be real, some of them not so real, and perhaps you can just highlight these issues for us please.

Dr Alicic: Thank you, Lawrence. So, after several years of conflicting or not harmonized recommendations from different Endocrinology, Nephrology and Cardiology Societies, and KDIGO, we finally got the joint ADA-KDIGO consensus report in 2022, on how to treat patients with chronic kidney disease in diabetes. So, lifestyle modifications on all patients. Patients who have either albuminuria or low eGFR should be started on SGLT2 inhibitors, which, I will point out, that this is different from the 2020 ADA and previous KDIGO recommendations, that recommended starting SGLT2 inhibitors only in patients with significant albuminuria. Now, we all agree that anyone with chronic kidney disease in diabetes should be started on an SGLT2 inhibitor. Metformin can be used if needed.

If patients are obese, if they have coronary artery disease, or not at the therapeutic target for hemoglobin A1c, we can add a GLP-1 receptor agonist. One of the advantages of GLP-1 RAs is that they have preserved anti-hyperglycemic action, even in advanced stages of chronic kidney disease. For blood pressure or presence of albuminuria, all patients should be on RAAS inhibitors, either ACEi or ARB. We just need to remember that all trials discussed were conducted on the background of patients being on ACEis or ARBs. If we deal with the residual albuminuria in a patient after starting SGLT2i and RAAS, you can add finerenone, which has shown in FIGARO-DKD and FIDELIO-DKD trials, to reduce residual albuminuria and increase cardiovascular and renal outputs.

Please do not forget that patients with chronic kidney disease are the highest risk for cardiovascular events, and we should check their lipid profile and start them on statin therapy. Because these are new therapies, we do have to remember the adverse events and effects. So, let us start with the expected adverse events. These patients have increased risk of genital infections, which is happening purely because of the increased glucose secretion in the urine. What I recommend to my patients is to be vigilant about their hygiene and to keep their genital areas are clean and dry.

Another adverse event in patients started on SGLT2is is volume depletion, so we must keep in mind to follow them closely for signs of hypertension, adjust the diuretic, and to ask them to maybe hold SGLT2is on the days that they are sick with decreased oral intake, nausea, or vomiting. A very serious adverse event that we noticed, even with the preclinical and early clinical status of SGLT2is, was diabetic ketoacidosis. This was noticed in all trials. The absolute number is very small, we are talking about several cases per thousands of participants in different trials. Recommendation is that, in the case of feeling ill, having nausea, vomiting, decreased oral intake, patients should hold medication. They should also keep in mind not to decrease the baseline anti-hyperglycemic therapy, use maintenance and supplemental insulin, and to be vigilant in the face of lethargy, loss of appetite, nausea, or abdominal pain, to alert their providers or local emergency room.

Amputations were primarily reported with canagliflozin, and one of the ways to deal with that is to ask patients, especially those who had previous amputations, to check their extremities daily. Hypoglycemia is very infrequently observed with this medicine. SGLT2is, let us not forget, were initially approved for their anti-hyperglycemic effect, and renal protection and cardiovascular outcomes were noticed later, in specific cardiovascular trials.

One effect that I have a lot of questions about, or I receive a lot of questions about, is the dip in the estimated GFR. This is not an adverse effect; this is the way the SGLT2is are working. They decrease glomerular hyperfiltration and glomerular hypertension. The dip in eGFR occurs about 2 weeks after initiation of therapy, would be anywhere between 3 and 5 mL/min, and majority of people have recovered to baseline kidney function within 4 weeks. So, one important point to keep in mind is that despite this initial dip, within 2 weeks, all patients in the trials with all 3 SGLT2 inhibitor agents, that means canagliflozin, dapagliflozin, and empagliflozin, in both heart failure and kidney outcomes trial, preserve kidney function compared to placebo. So, the initial dip in the eGFR is not a reason to discontinue these medications. The one word of wisdom that I follow is not to start several agents that are expected to cause a dip in eGFR at the same time. For instance, if starting an SGLT2 inhibitor and need to add finerenone, you should probably stagger initiation of these therapies for 4 to 6 weeks.

Dr Leiter: Okay, perfect. No, thank you very much. A lot of important practical messages there. So, we could continue this much longer, but unfortunately, our time is up. So, if I could try to summarize. We started off with a not at all uncommon scenario of a patient presenting to a primary care physician's office with early evidence of kidney disease. And importantly, what we have heard highlighted so well by my co-panelists is that patients such as Oliver, even at early stages of kidney disease, is at increased risk for more advanced kidney disease, and also an increased risk for cardiovascular disease.

So, in order to help patients like Oliver, first of all we must be screening them appropriately with not just an eGFR, but also looking for proteinuria. And if it is found, either of these abnormalities is found, we have interventions now which can dramatically reduce the patient's risk, and importantly, drugs such as an SGLT2 inhibitor, will not only reduce the kidney risk, but will also reduce the cardiovascular risk. And we now have new guidelines which have incorporated these newer agents and which we should use to help guide our practice.

So, I would like to thank my fellow faculty, I would like to thank you for participating in this educational activity. I hope you enjoyed this discussion and have gained a greater understanding on the importance of early CKD detection, not only in patients with diabetes, as well as the benefits and practical use of renal protective therapies, in CKD management. Thank you.

This transcript has not been copyedited.