Activity Transcript

Jolanta Malyszko, MD, PhD: Hello. I'm Jolanta Malyszko from the Department of Nephrology, Dialysis, and Internal Diseases at the Medical University of Warsaw, Poland. It's my pleasure to welcome you all to this program entitled Novel Treatment Options for Chronic Kidney Disease in Type 2 Diabetes: Evaluating Latest Landmark Trial Results. Joining me today is Eugene Wright from the Charlotte Area Health Education Center, Charlotte, North Carolina, United States. A very warm welcome to you, Eugene. This is going to be a quick-fire program. It's just like in our busy clinics. We have only 60 to 120 seconds, 1 to 2 minutes, to answer your questions. Strap yourself in and let us get started. To start off, Eugene, could you give us a 1-minute introduction to the epidemiological situation and human economic burden of chronic kidney disease (CKD) in type 2 diabetes (T2D)?

Eugene Wright Jr., MD: Absolutely. Of the 34 million Americans with T2D, approximately 40% have CKD. Diabetes is the number 1 cause of kidney failure and CKD associated with T2D increases the risk for cardiovascular events 2 to 3- fold. More than 1 in 7 American adults are estimated to have CKD. That is about 37 million people. In 2017, treating Medicare beneficiaries with chronic kidney disease cost more than 84 billion dollars and treating people with end stage kidney disease (ESKD) cost an additional 36 billion dollars. In a study of adults with T2D in 466 primary care practices, proteinuria, urine albumin creatinine ratio and estimated glomerular filtration (eGFR) had not been tested in 51%, 53%, and 15% of patients, respectively, in the prior 15 months. More than half, approximately 54%, had stage 1 to stage 5 CKD, but clinicians had only identified 12% of these patients as having CKD.

Dr Malyszko: Great start, Eugene and important figures there. However, you must remain in the hot seat because I have another question for you. What are you at in terms of addressing the primary targets of disease progression within the current standard of care? You have 2 minutes.

Dr Wright: Well, there are 3 main factors that may contribute to chronic kidney disease progression. There are the hemodynamic factors, typically related to elevated blood pressure, metabolic factors, related to elevated hemoglobin A1c (HbA1c), and inflammatory and fibrotic factors, that are related to mineralocorticoid receptor overactivation. This is thought to contribute to fibrosis and inflammation. Knowing this and remembering the earlier data that CKD is regularly not recognized in patients with T2D, we need to improve communication among different specialties attending to these patients. The standards of care for CKD and T2D primarily target metabolic and hemodynamic factors. However, these inflammatory and fibrotic factors in the kidney that are related to the mineralocorticoid receptor overactivation and contribute to inflammation and fibrosis are largely unaddressed. Inflammation and fibrosis are a potential treatment target to address the risk of CKD in T2D. This inflammation and fibrosis are thought to be related to the mineralocorticoid receptor overactivation.

Jolanta, let's switch over to you and you can sit on the hot seat. Continuing with this topic, could you tell us briefly about the evidence we have that support inflammation and fibrosis as independent drivers of chronic kidney disease in type 2 diabetes progression?

Dr Malyszko: Thanks, Eugene. As we do know, both T2D and CKD cause subclinical inflammation. The Chronic Renal Insufficiency Cohort (CRIC) study showed us that the inflammatory biomarkers are associated with faster progression of CKD. What's more important, CKD progression was most frequent in the patients with the highest plasma levels of fibrinogen and TNF-alpha. Moreover, if we have the elevated plasma levels on inflammatory biomarkers, they are associated with greater decline in eGFR over time. On the other hand, we do know that fibrosis biomarkers are upregulated in patients with this double trouble, CKD and T2D, and are correlated with albuminuria severity like TGF-beta.

Dr Wright: Thank you, Jolanta. Very nicely done. Building upon what you told us, what do we know about the mineralocorticoid receptor (MR) overactivation that may underline this inflammation and fibrosis? Is MR blockade a potential treatment target to slow CKD progression?

Dr Malyszko: As you told us, in cardio-renal diseases, the mineralocorticoid receptor pathway becomes overactivated through multiple mechanisms, such as increased gene expression or NADPH oxidase, proinflammatory cytokines and profibrotic mediators. It leads to inflammation and fibrosis. Finally, it leads to kidney damage, which could be reflected as glomerular damage, proteinuria, tubular injury, reduced renal blood flow, vascular damage like vascular remodeling, endothelial dysfunction and increased vascular stiffness. I would like to add that the endothelium is the largest organ in the human body because it weighs up to 2 kilograms and covers the area of a soccer playground. So, any damage is really important to our body. Heart damage is reflected by myocardial hypertrophy, ventricular remodeling, fibrosis, reduced coronary blood flow, ischemia, infarction and myocardial injury. As you told us, if we can target mineralocorticoid receptor over-activation that can contribute to inflammation and fibrosis, this could be the potential treatment target to slow progression of chronic kidney disease. So, at this particular point, we can touch the third pillar called inflammation and fibrosis.

Eugene, back to you. We have drugs that can target this mineralocorticoid receptor overactivation. What can you tell us about this new class of drugs, the nonsteroidal MRAs? How do they compare to the conventional steroidal MRAs which we have known for ages?

Dr Wright: The preclinical data shows us that finerenone is a novel, selective, nonsteroidal MRA that is different from the currently available steroidal MRAs based on preclinical data. The ones that we are familiar with under the steroidal MRAs are spironolactone and eplerenone. You can see here their geometric biochemical structure: very high potency for spironolactone, relatively low potency for eplerenone and the selectivity is low to moderate from spironolactone to eplerenone. We look at the nonsteroidal MRA, finerenone. It has a bulky nonsteroidal structure, very high potency and very high selectivity for the mineralocorticoid receptor. Finerenone also has a different safety profile compared with the available steroidal mineralocorticoid receptors. If we chose spironolactone as representative of the steroidal and finerenone in the nonsteroidal, you could see that the sexual side effects are high for the steroidal MRAs and rare and balanced with placebo in the nonsteroidals. The risk for hyperkalemia is high with the steroidal MRAs and moderately increased with the nonsteroidal MRAs. The effect on systolic blood pressure reduction for mineralocorticoid receptors is high and only moderate with the nonsteroidal mineralocorticoid receptors. We must talk about the structure of the finerenone molecule. It is a bulky nonsteroidal molecule. It's unique structure results in selective and potent interaction with this mineralocorticoid receptor and regulation of gene expression. It exhibits antifibrotic and anti-inflammatory effects. There are other nonsteroidal MRAs under development. Esaxerenone, which is currently available in Japan, is indicated for hypertension.

Clinical data on the first in class nonsteroidal MRA, finerenone, is out now: the FIDELIO-CKD and FIGARO-CKD clinical trials. Jolanta, can you quickly walk us through how these trials complement one another?

Dr Malyszko: FIGARO-DKD and FIDELIO-DKD, coming both from big operas. FIGARO, Mozart, FIDELIO, Beethoven. Both included more than 13,000 patients with CKD and T2D. The cardiovascular outcomes were as follows: time to cardiovascular death, non-fatal MI, non-fatal stroke, or hospitalization due to the heart failure that were primary endpoint in FIGARO-DKD and secondary in FIDELIO-DKD. In FIDELIO-DKD, the primary endpoints were cardiac endpoints: time to kidney failure, sustained decline in eGFR by more than 40%, or renal death. As we can see the heatmap, we look at patients including across the spectrum on CKD severity. And in FIGARO-DKD, there were patients with urinary albumin creatinine ratio between 300 and 5000 [mg albumin/g creatinine] and eGFR between 25 and 90 [mL/min/1.73 m²], all much higher urinary albumin creatinine ratios. While in the FIDELIO-DKD, there was similar inclusion criteria, however, with the urinary albumin creatinine ratio between 30 and 300 [mg/g] and eGFR between 25 and 60 [mL/min/1.73 m²], and a history of diabetic retinopathy. FIDELIO-DKD showed us that the finerenone significantly reduced the risk of primary composite kidney outcome by 18% and cardiovascular outcomes by 14%. While in FIGARO, finerenone significantly reduced the primary composite cardiovascular outcomes by 13%. However, it reduced the risk of the first secondary kidney composite outcome. However, the pre-specified kidney endpoint was not statistically significant.

Dr Wright: Well, that's interesting, but you went over 60 seconds. What can you tell us about the FIDELITY pooled analysis of the 2 trials? Now you'll have fewer seconds.

Dr Malyszko: Okay. So, after both operas came FIDELITY, which is in 21^st century and in the FIDELITY pre-specified analysis, I would like to point out that the kidney composite endpoint was time to kidney failure, but the sustained decline of eGFR was more than 57%, which is much stronger than in the FIDELIO-DKD. And what I would like to stress is that patients in the FIDELITY pooled analysis were very well treated. They have well controlled blood pressure and glycated hemoglobin. And as you can see, the renin-angiotensin-system (RAS) inhibition was used by all of the patients and statins by 72%. So, it means that there are patients who are not so often treated with us, and they have really the best possible standard of care. Concerning the lab results, 40% of patients had albuminuric CKD with preserved kidney function. And in the pooled analysis, it was shown that finerenone significantly reduced the risk of kidney composite outcomes by 23%, using this much stronger composite point, like 57% of sustained decline. And what is really important that the number needed to treat (NNT) after 3 years was 60. Finerenone significantly reduced the incidence of all components of kidney composite outcomes, except renal death, but they were negligible numbers. And also, that the cardiovascular benefits of finerenone were primarily driven by reduction in hospitalization, due to the heart failure and cardiovascular death. It should be also stressed that cardiovascular benefits of finerenone were consistent regardless of baseline eGFR, urinary albumin creatinine ratio and use of inhibitors of SGLT2s or GLP-1s. So, summarizing this part in FIDELITY, finerenone significantly reduced the risk of the cardiovascular composite outcome by 14%, but finerenone significantly reduced risk of kidney composite outcome by 23%, using this much stronger point as a 57% decline in eGFR.

Dr Wright: Thank you for that excellent overview. But what about safety?

Dr Malyszko: As every doctor, we are looking very careful at the safety profile and finerenone showed modest effects on systolic blood pressure and no sexual side effects, which is an excellent message. Hyperkalemia was increased but the clinical impact was low, which is also extremely important for practicing physicians. In every study, FIDELIO-DKD, FIGARO-DKD and in the FIDELITY analysis, we found some limitations. Mainly patients with Caucasian origin were included. Patients with non-albuminuric CKD were not included. Since the design of the FIGARO-DKD and FIDELIO-DKD studies, SGLT2 inhibitors have emerged as therapeutic options for patients with T2D and CKD. Some patients in the finerenone phase 3 trials also received these novel agents at the study commencement and consistent cardiovascular benefits were observed in these groups. So, Eugene, could you tell us how we can select patients who will best benefit from this new treatment?

Dr Wright: We have learned that there are at least 3 targets for treatment of CKD associated with T2D. As with other disease states, we should seek to identify and treat all targets early and aggressively with a goal of seeking remission or significant slowing of the progression of the disease. Therefore, we should approach our patients with CKD associated with T2D with early detection through appropriate screening with eGFR and urine-albumin-creatinine ratio and aggressive treatment targeting hemodynamic, metabolic and inflammatory and fibrotic factors with the goal for our patients of preventing complications and optimizing their quality of life. Therefore, we should think of all patients with T2D being at high risk and screening according to the guidelines. Once CKD is detected, it should be appropriately staged using the KDIGO heatmap that you've shared with us and managed according to the guidelines, treating all contributing factors to include inflammation and fibrotic factors.

Dr Malyszko: Eugene, thank you so much. This has been an enlightening discussion. I would like to finish by sharing some thoughts on the impact that adding this third pillar of therapy, targeting inflammation and fibrosis, will have on patients with T2D who are at risk of progressing to or who already have established CKD. You go first, Eugene.

Dr Wright: Thank you. I think that if we'd had some practical guidance, we'd want to think about finerenone as being safe and it's simple to start and it's effective. The focus, I think, should be on safety. We think about hyperkalemia and sexual side effects. We see from the studies that you've shared with us that this had really been not a significant problem with starting or treating patients with finerenone.

Dr Malyszko: Honestly, there is a practical guidance to the management of hyperkalemia, which is extremely useful in everyday clinical practice. We can start finerenone with potassium levels below 4.5 [mmol/L] and we should discontinue when potassium levels are more than 5.5 [mmol/L]. We can restart with the lower dose, like 10 mg, when serum potassium is below 5 [mmol/L]. However, in comparison with the traditional MRAs, the spironolactone or eplerenone, we do not see such a problem with hyperkalemia. Close monitoring is a crucial for us to avoid any potential complications. What is really most important is dietary advice for our patients and also not to use supplements because they might contain potassium as well. Eugene, maybe some other thoughts?

Dr Wright: If I could add one thing, I would say how important it is to screen patients who are at high risk, in particular patients with T2D, for CKD using the guideline-directed UACR and the eGFR. By finding these patients early, we now have treatment options that can significantly reduce their risk of progression of chronic kidney disease.

Dr Malyszko: I would say that this is the most important message. First to screen, then to diagnose, then offer the best possible treatment to lower the residual risk for the best outcomes. Again, Eugene, thank you for this terrific discussion and thank you for participating in this activity. Please continue to answer the questions and follow and complete the evaluation. Thank you so much.

This is a verbatim transcript and has not been copyedited.