Activity Transcript

Pantelis Sarafidis, MD, MSc, PhD: Hello, I am Pantelis Sarafidis, an associate professor of nephrology at the Aristotle University of Thessaloniki, Greece. Welcome to this program on Novel Nonsteroidal MRAs for Chronic Kidney Disease in Type 2 Diabetes – A Step Change in Treatment. With me today to discuss these important topics, I am very happy to have Professor Janet McGill, professor of medicine at the Washington University School of Medicine in St. Louis, Missouri. Dr Katharina Schütt, a cardiologist from the University Hospital of Aachen in Germany. And Dr Beatriz Fernandez-Fernandez, a nephrologist and professor of medicine at the Universidad Autónoma de Madrid, Spain. Together we will discuss the serious health risks associated with CKD in patients with type 2 diabetes and the novel treatment options available to reduce the risk of complications of these two diseases. So, let me begin with a brief overview of the interplay between major comorbidities in patients with type 2 diabetes at risk of CKD progression and the scale of the challenge we face in day-to-day clinical practice.

So, as you know, type 2 diabetes is a very prevalent condition. And 12 or even 13% of the adult population in the Western societies have type 2 diabetes and of those patients, one third have cardiovascular disease and about 40% or even 50% of those people with type 2 diabetes have or will develop at some point chronic kidney disease.

So, if we assume the diabetes currently affects about half a billion people worldwide, CKD is also a very prevalent disease. It affects even more people, about 10% of the adult population and is a silent killer because it is asymptomatic, at least in stages 1, 2 and 3A. On the other hand, from causes of CKD, diabetes is the leading cause, the most important cause, followed by hypertension. So, with this, let me pass on to Professor McGill who will talk us through the next presentation. So, the question Janet is, if CKD is a disease that is treatable and how can we identify it early to be able also to treat it early?

Janet B. McGill, MD, MA, FACP: Thank you Dr Sarafidis, and thank you for that introduction. In answer to your question, I am going to outline the renal function assessments that should be carried out on a regular basis in patients with chronic kidney disease and type 2 diabetes so that we are able to identify any progression in kidney function deterioration early and adapt our management accordingly.

The detection of chronic kidney disease in patients with type 2 diabetes is something that we do in primary care and endocrinology. We are responsible for identifying those patients who are at risk for progression of their chronic kidney disease. Early detection is crucial to preserve kidney function and reduce the risk of end-stage kidney disease (ESKD), cardiovascular events and mortality. At a minimum it is necessary to perform an annual urine albumin-to-creatinine ratio and estimated GFR assessment in all patients with type 2 diabetes, irrespective of treatment. It is necessary to monitor more frequently in patients with diabetes and existing chronic kidney disease who are at higher risk for progression. It is also important to check for factors that further compromise kidney function such as nephrotoxic drugs and dehydration.

Let us talk about the decline of estimated GFR. Normal eGFR decline is 0.8 to 1.5 mL/min/year and this is associated with normal aging. This occurs in people without diabetes. The estimated GFR decline in diabetes is more rapid. It is 2 to 5 mL/min/year and can increase up to 10 mL/min/year in patients with nephrotic-range proteinuria or uncontrolled blood pressure or uncontrolled diabetes. Urinary albumin-to-creatinine ratio (uACR) shows albumin in urine and is a marker of kidney damage. Additional factors to consider are hypertension, obesity, smoking, all contribute to estimated GFR decline. normal loss of estimated GFR is 0.5 to 1.0 or 1.5 [mL/min] in those without diabetes due to aging. In diabetes, the loss of estimated GFR of minus 2.0 to 3.5 [mL/min], which varies by albuminuria status. Rapid loss is defined variably and is either minus 4 or 5 mL/min/year, but kidney function can decline at greater than 10 mL/min/year. The risk factors for rapid progression include proteinuria, elevated systolic blood pressure, heart failure, anemia, smoking, and, interestingly, these factors are present in many of our patients with diabetes.

The five stages of chronic kidney disease are well known to this audience and includes stages 1 to 5. I would draw your attention to stage 3a and stage 3b where we begin to see more rapid drop in kidney function, and we begin to see the presence of albuminuria if it is not present already. The prognosis of chronic kidney disease varies by GFR in albuminuria categories as demonstrated on this heatmap. As albuminuria increases and estimated GFR decreases, the risk for ESKD increases as we see going from green to yellow to orange, red and dark red on this heatmap.

There is a kidney failure risk calculation. This risk calculator was developed by nephrologists in Canada, and it was developed for persons in stages G3 to G5. The risk calculator has been validated and accurately predicts the 2- to 5-year probability of kidney failure, meaning dialysis or transplantation for a patient with stage 3 to 5 chronic kidney disease.

One of the subtleties of management of patients is how often we should test their kidney function. This augmented heatmap shows how frequently these measurements should be done. In patients with severely increased albuminuria greater than 300 mg/g, it is appropriate to monitor that patient at least twice per year. If that patient has reduced estimated GFR below 60 [mL/min/1.73 m²], then move that up to 3 times per year. Patients with stage 3b chronic kidney disease should be monitored 2 to 3 times per year based on their level of albuminuria. And those with severe loss of kidney function, with or without albuminuria, should be monitored 4 times per year.

The recently published joint ADA/KDIGO consensus report on CKD screening and diagnosis for people with diabetes is a valuable resource. When and where to screen? The recommendation is to start within 5 years after diagnosis of type 1 diabetes but yearly beginning at diagnosis in patients with type 2 diabetes. How to screen, it's exactly what we discussed, spot urine, ACR, and estimated GFR. Then what do we do with a positive result? If it is the first time that albuminuria has been identified, then repeat the test after a month or two to make sure that there wasn't an illness or a patient exercise that caused the elevated albuminuria. What defines a chronic kidney disease diagnosis? Persistent urine ACR greater than 30 mg/g and/or persistent estimated GFR less than 60 mL/min/1.73 m², or other evidence of kidney damage.

I would now like to pass the floor to my colleague Katharina Schütt. Katharina, what do we need to know about cardiovascular risk in patients with chronic kidney disease and type 2 diabetes?

Katharina Schütt, MD, FESC: Thank you, Janet. Let me begin by highlighting why we need greater cardiovascular protection in patients with CKD and type 2 diabetes. First of all, we know that CKD, diabetes and heart failure are highly interrelated. And this is of importance because we know that patients with both CKD and type 2 diabetes are of increased risk of cardiovascular mortality.

So, if you compare these patients with patients with no diabetes and no CKD, the risk to die from cardiovascular disease is 6-fold elevated. And even if you compare them to patients with diabetes alone, their risk is 3-fold elevated, and it is still 2-fold elevated if you compare them with patients with CKD alone. So, patients with both CKD and type 2 diabetes are cardiovascular high-risk patients.

So, when we look at these patients, we know that the risk of cardiovascular mortality and heart failure hospitalization increases when eGFR drops below 75 mL/min/1.73 m². And as Janet just highlighted, we need to measure uACR and it is pretty much the same as with the eGFR. So, if the uACR increases or exceeds from 5 to 10 mg/g, we know that cardiovascular or the risk of cardiovascular mortality and heart failure hospitalization increases in our patients. And this is of importance because if you look into a patient's histories and what you can see here is time since type 2 diabetes diagnosis, we know that in many patients the uACR increases before the eGFR drops. So, the uACR is a very good measure for cardiovascular risk as I just showed you. It shows or it is associated with an increased cardiovascular mortality and hospitalization for heart failure.

So, what do we do about this? And this is another glance at the ADA/KDIGO consensus report and what you can see is a holistic approach for our patients and it starts with lifestyle recommendations: healthy diet, physical activity, smoking cessation, and weight management. But if you look to the second line, there are first-line drug therapies, and you find here the renin-angiotensin-system (RAS) inhibition at a maximum tolerated dose as well as sodium-glucose cotransporter-2 (SGLT2) inhibition.

So, if you look into patients with CKD and at mortality in different studies, you can see here with maximum RAS inhibition in the light blue compared to placebo in dark blue and different SGLT2 inhibitor studies in orange compared to placebo in the dark blue again. And what you can see is that in the RAS inhibitor studies, there was no effect on mortality, but we saw a substantial reduction with SGLT2 inhibition. And in the next presentation, Pantelis will outline the treatment options for patients with CKD and type 2 diabetes and tell us what the available treatments are and what is the evidence for the clinical benefits of novel treatment options for CKD from major outcome trends.

Dr Sarafidis: Thank you, Katharina. So, what is the current standard of care according to guideline recommendations and how may we further reduce cardiorenal risk factors with novel therapies? As you all know, for several years the standard of care for treatment of diabetic chronic kidney disease was angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and there were several trials in proteinuric diabetic kidney disease. Two of the most important were RENAAL with losartan and IDNT with irbesartan, both showing significant reductions, 15 to 20% in risk of the primary composite endpoint as you can see here. However, there was a lot of residual risk remaining and a lot of our patients progressed to ESKD. So, that is why there was a lot of recent efforts coming in for new nephroprotective therapies.

So, for us nephrologists and for the diabetologists, endocrinologists, cardiologists, it was very good news to see a novel class, SGLT2 inhibitors, coming into the equation. These are the CREDENCE study in diabetic CKD with canagliflozin and the DAPA-CKD study in diabetic and non-diabetic CKD. Here you can see only the patients with diabetes with dapagliflozin showing very good nephroprotective properties, significant reductions in the risk of the composite outcomes, where the primary ones were renal prognosis. Yet again, there is still some residual risk.

So, we now have selective nonsteroidal mineralocorticoid receptor antagonists (MRAs) to help us with diabetic CKD. Diabetic chronic kidney disease has metabolic, hemodynamic, and inflammatory pathways participating into kidney injury. So, these new agents, nonsteroidal MRAs, can bind the MRA receptor and inhibit inflammation and fibrosis in a way that is different as you will hear in a bit, from classical steroidal MRAs.

And the one that is of course much more studied is finerenone. We have two major studies with finerenone: FIDELIO-DKD, with a primary renal outcome, and FIGARO-DKD in a slightly different population with a primary cardiovascular outcome. So, both these studies were combined also in a pre-specified pooled analysis called FIDELITY.

So, this is the FIDELITY pooled analysis with regards to the kidney composite outcome. And as you can see here, there is a significant reduction with finerenone versus placebo in time to kidney failure, sustained more than 57% decrease in eGFR, or renal death. Clear renal protective action. And if you want to see some more details, you can see here the components of the primary outcome that were reduced or less to the same extent. So, finerenone works well for both, if I may, soft endpoints as well as the hard endpoints, for example, ESKD.

The composite cardiovascular outcome was also reduced in both FIDELIO -DKD and FIGARO-DKD trials and of course in the pooled analysis. And here the interesting thing is that this is mainly driven by reductions in heart failure hospitalization (HFH) and cardiovascular death. Another important point with finerenone is that if you combine data from these major trials, FIDELIO-DKD and FIGARO-DKD, you can see that on top of what I just told you, there is a reduction in on-treatment analysis of both all-cause mortality and cardiovascular mortality. And this is extremely important for a population of patients with chronic kidney disease because this happened in some of the trials with SGLT2 inhibitors, but it has not happened in any of the seminal trials of the past with ACEs or ARBs. So now, we have two drug classes SGLT2 [inhibitors] and novel MRAs that can also reduce mortality in patients with CKD.

What about if you use both an SGLT2 inhibitor and finerenone? The major studies that I was telling you about were run in parallel. So, both the SGLT2 inhibitor studies and the finerenone studies were performed on top of an ACE or an ARB. So, this is a very interesting analysis showing us what happened in patients who were treated with SGLT2 [inhibitors] in baseline from the finerenone trials. And as you can see, finerenone was able to reduce the kidney outcomes independently of whether the patient was or was not using an SGLT2 [inhibitor]. And if anything, most probably there seems to be a synergistic effect here. So, when you use these two drug classes in combination, it will probably be the best thing you can do to preserve kidney function.

And with this, I hand over to Beatriz. So, Beatriz, what do we need to look out for when using nonsteroidal MRAs in terms of safety and how can we mitigate potential adverse effects?

Beatriz Fernandez-Fernandez, MD, PhD: Thank you, Pantelis. So, now we are going to talk about what potential adverse effects of novel treatments should we be aware of and what can we do to mitigate some of these effects. So, here we can see what the difference between steroidal MRAs and nonsteroidal MRAs is. So, currently, there are 2 steroidal MRAs in clinical use. The first one is spironolactone that was discovered in 1957 and derived from the chemical structure of progesterone. And that has been followed by eplerenone as the second steroidal MRA discovered in 1987. Both substances have a similar binding mode to the mineralocorticoid receptor ligand-binding domain preventing the binding of agonist ligands. They are both called passive MRAs, which means that these compounds are not able to stabilize the receptor conformation in such a way as to effectively bind transcriptional co-regulators, especially co-repressors. This type of binding is essentially different from the binding of so-called bulky antagonism that we can see here that are nonsteroidal MRAs. One of those, is finerenone.

So, in terms of their specific pharmacodynamic or pharmacokinetic profiles, major differences are observed between both steroidal and nonsteroidal MRAs. Spironolactone has got a flat structure as well as eplerenone. But spironolactone has high potency whereas eplerenone has low potency. Finerenone has a different structure, that is a bulky structure, with high potency to the mineralocorticoid receptor and high selectivity. But whereas spironolactone has sexual side effects such as gynecomastia, eplerenone and finerenone do not have that. So, the risk of hyperkalemia exists in spironolactone and eplerenone, it is lower in finerenone but still exists. And there is a high risk of blood pressure reduction with spironolactone and a little bit less with eplerenone, with a moderate risk of BP reduction in finerenone.

So, we can see here the FIDELITY pool analysis with the safety outcomes. Finerenone showed a modest change in systolic blood pressure of 3.7 mm Hg at 4 months, and it has no sexual side effects, whereas hyperkalemia was a little bit increased because we had a 14% of patients developing any kind of hyperkalemia; hyperkalemia leading to permanent discontinuation, that means with clinical impact, was only 1.7% compared with placebo. The FIDELITY pool analysis had some limitations as FIDELIO-DKD excluded patients with non-albuminuria and patients without diabetes. There were only few African American patients, 4.7% of total of number participants. And in FIGARO-DKD, 85 patients were prospectively excluded.

So, what can we do to mitigate hyperkalemia? Okay, the first thing we must know is when to start finerenone. We should start it when serum potassium is below 5 mmol/L (5 mL/L) and eGFR is below 60 mL/min/1.73 m². We can start with 10 milligrams. When we have an eGFR over 60 mL/min/1.73 m², we can start with 20 milligrams. And how do I monitor potassium during treatment? We must request a potassium level at the first month after treatment and every 4 months thereafter. What do we do if serum potassium is over 5 mmol/L (5 mL/L)? We should temporarily stop treatment and we should consider starting diuretics, giving dietary advice to the patient. And of course, we must review all the drugs because some painkillers, nonsteroidal, can be deleterious for the potassium. Also, we could consider gastrointestinal cation exchangers. What do we do when potassium is below 5 mmol/L (5 mL/L)? We can start again finerenone, but we should start it at the dose of 10 milligram once daily.

So, how do I reduce the potassium in my patient's diet? There is some advice we must give to the patient. First of all is food labeling. The patient must read food label and heed the serving size. Some other considerations are canned foods, drain and rinse canned foods. Learn how leach-soak raw or frozen vegetables for at least 2 hours in water before cooking. And ensure vegetables are cooked in unsalted water. There are some other considerations about carbohydrates. When we add potassium-rich foods in combination with carbohydrates, there is more insulin released and that can lead to decreased potassium in the diet. But what happens when the patient's eating a lot of meat or dairy products? Animal products can be rich in potassium but not in carbohydrates. That leads to decreasing the insulin release and that could increase potassium in the blood of the patient.

So, we must educate the patient on healthy, low, or moderate potassium diet. What means healthy diet? It is vegetables, leguminous, nuts, and wholegrain cereals. And what is unhealthy but very high in potassium? Ultra-processed foods. We must decrease potassium additives that are not healthy for the patients and also have a lot of potassium. The European Renal Nutrition (ERN) has a cookbook and a leaflet in different languages, to help us how to decrease potassium in the diet.

Dr Sarafidis: So, thank you Beatriz for this excellent overview. That was really exciting. And with this we can now come to the final part of this educational activity. What do the guidelines recommend about the management of chronic kidney disease in patients with type 2 diabetes? And for the sake of time, I would like all of you to give a comment on these other guidelines in 2022. And the good thing about these guidelines is that they appeared first as every year in January 2022 and then in June of the same year we had an update. And this was among other things done to include the latest evidence from the FIGARO-DKD trial and the FIDELITY analysis. So, there is a level A recommendation to add finerenone in patients with type 2 diabetes and chronic kidney disease treated with maximum tolerated doses of ACEs and ARBs. Not only to reduce the risk of chronic kidney disease progression, but also to reduce the risk of the cardiovascular outcomes. So now, finerenone, at least for other guidelines appears as an equal choice in terms of level of evidence to SGLT2s. And as I told you before, perhaps the combination of both added to the therapy of ACEs and ARBs could be also very helpful. So, I would like a short comment from each of you. And I would start with Janet, please.

Dr McGill: Thanks, Pantelis. These guidelines are very important in directing the care of people with diabetes. The ADA and EASD guidelines have taught us how to preserve kidney function in people with diabetes and chronic kidney disease. It is important to note the evidence level A, that confirms the effectiveness, the position, and the evidence that finerenone is a valuable asset for reducing progression of chronic kidney disease and reducing cardiovascular disease events in people with type 2 diabetes and CKD.

Dr Sarafidis: Thank you, Janet. And Katharina, what do you think in terms of cardiovascular disease, which as we discussed, is not something easy to reduce in people with chronic kidney disease? What do you think? Are these guidelines in line with the evidence?

Dr Schütt: Thank you, Pantelis. Yes, I think they are in line, and I think they are very important for our patients because I highlighted earlier that these are really cardiovascular high-risk patients. And as you just said, you can give finerenone or SGLT2 inhibitor not only to reduce renal progression, but also to reduce cardiovascular events. And that's cardiovascular mortality and it is heart failure hospitalization. So, two very important endpoints from a cardiologist's perspective. So, I think these guidelines are very important for our patients and hopefully we will use them and implement them.

Dr Sarafidis: Great. And Beatriz, now to you, I would like to have your comment on the everyday nephrologist life. So, what do you think that these new drugs will bring to the table?

Dr Fernandez-Fernandez: From the everyday point of care, I really believe that we must use every day everything at the same time because our patients are dying from cardiovascular death prematurely. That means we must use everything available to stop it and a little bit more. We must lift everything that is not really significant for decreasing cardiovascular mortality and everything that lacks evidence. I really believe that we should use everything we can because our patients are really, really in a very, very high risk.

Dr Sarafidis: Thanks again to all you my fellow faculty and thanks to all of you for participating in this educational activity. I hope you enjoyed the presentations and discussions and have gained a greater understanding of the challenges involved in managing patients with CKD and diabetes, and of course how we should best use the novel nonsteroidal MRAs to improve our patient outcomes. Thanks for watching. 

This transcript has not been copyedited.