Nonsteroidal MRAS to improve outcomes in patients with CKD and T2D – Organised by BAYER AG

Symposium Summary

Written by Jasna Trbojevic-Stankovic
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Welcome & Introduction

María José Soler, Spain

As symposium chairwoman Maria José Soler pointed out in her introduction, the prevalence of type 2 diabetes (T2D) is high and keeps growing. This threatens kidney health, because T2D is the leading cause of kidney diseases. Renin–angiotensin–aldosterone system inhibition can slow the process of diabetic nephropathy but cannot effectively stop it. A high percentage of patients will still progress and require renal replacement therapy. Maria Soler emphasized that nonsteroidal mineralocorticoid receptor (MR) antagonists (MRAs) might be a new and promising treatment option in these patients.

Inflammation and fibrosis: An overlooked driver of CKD progression in T2D?

Katherine Tuttle, United States of America

Katherine Tuttle provided some details regarding the pathogenesis of diabetic nephropathy. As she pointed out, chronic kidney disease (CKD) progression in T2D is driven by the combined effects of metabolic, hemodynamic, inflammatory and fibrotic factors. One of the hemodynamic factors is elevated blood pressure, often seen in patients with T2D, and among the metabolic factors is poor glycaemic control; both factors are well known, but the key significance of inflammation and fibrosis was not recognized until a few years ago. It is known that diabetes is associated with chronic inflammation leading to an influx of macrophage lineage cells in patients with CKD and diabetes, which then promotes fibrosis. It is also known that the degree of interstitial fibrosis on biopsy can predict progression to kidney failure. The degree of fibrosis correlates with estimated glomerular filtration rate (eGFR) category and time to dialysis. The higher the degree of fibrosis, the shorter the time until replacement therapy is needed.

Fibrosis biomarkers in blood and urine are upregulated in patients with CKD and T2D and can be used as progression markers. It has been shown that transforming growth factor beta (TGF β) levels correlate directly with albuminuria severity in patients with T2D. Inflammation is a common attendant symptom of fibrosis, so a robust “Kidney Risk Inflammatory Signature” (KRIS) is also associated with an increased risk of kidney failure and is elevated in patients with diabetes.

We know that aldosterone has many important effects on the kidneys and that local aldosterone is a driver of inflammation in diabetes. It has been shown that local renal aldosterone production induces inflammation and fibrosis in a streptozotocin-induced diabetic rat model – a process that could be inhibited by inhibiting aldosterone production, thus resulting in a reduction of albuminuria.

So how can hemodynamic and metabolic factors be addressed in patients with CKD and T2D? To control hemodynamic factors, we have angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs), endothelin receptor antagonists – and, more recently, sodium-glucose co-transporter-2 (SGLT-2) inhibitors. To control metabolic risk factors, there are glucagon-like peptide-1 receptor agonists (GLP-1RAs), metformin, and other antihyperglycemic agents. There are no therapeutic options available at present for targeting fibrosis. However, when we come to think about treatment targets for addressing fibrosis, the first that comes to mind is the MR, because among many other functions, the MR regulates inflammation and fibrosis, as well as fluid and electrolyte homeostasis, via differential gene expression.

The FIDELIO-DKD trial: New insights on the benefits of MR antagonism

Rajiv Agarwal, United States of America

That the observed effects in preclinical trials translate into better outcomes for patients has now been demonstrated in a large phase 3 study that Rajiv Agarwal presented at the symposium. It investigated the efficacy and safety of finerenone in comparison with placebo in addition to standard of care for the reduction of kidney failure and kidney disease progression in patients with CKD and T2D. The “FInerenone in reducinG cArdiovascular moRtality and mOrbidity in Diabetic Kidney Disease” (FIGARO-DKD) trial was a double-blind, randomized, placebo-controlled trial in which 13,911 patients from more than 1000 sites across 47 countries worldwide were enrolled. During a run-in phase of 4–16 weeks, the ACEi/ARB therapy of the patients was optimized, as the maximum tolerated dose of ACEi or ARB for ≥4 weeks was one of the inclusion criteria. This was not tolerated by all, as Rajiv Agarwal pointed out: in the end, 5734 patients were randomized to receive either finerenone 10 mg or 20 mg orally once daily or placebo when added to standard of care, including blood glucose-lowering therapies and maximum tolerated dose of renin–angiotensin system (RAS)-blocking therapy such as ACEis or ARBs. At baseline, patients had advanced CKD, with a mean eGFR of 44 ml/min/1.73 m2 and a median urine albumin-to-creatinine ratio (UACR) of 852 mg/g. The primary endpoint was a composite renal endpoint comprising kidney failure, sustained ≥40% decrease in eGFR from baseline, or death from renal causes, whereas the secondary endpoint was the composite risk of cardiovascular (CV) death or nonfatal CV events (myocardial infarction, stroke, or heart failure hospitalization), assessed in a time to event analysis.

The study showed that, when added to maximum tolerated RAS therapy, finerenone significantly reduced the primary kidney outcome by 18% (p=0.001). The key CV outcomes assessed in the secondary endpoints were reduced by 14%. It was shown that these effects were not due to stricter blood pressure or blood glucose control but were effects of the agent: finerenone had modest effects on blood pressure and did not affect blood glucose compared with placebo; the difference in mean systemic blood pressure (SBP) between groups was –2.9 mmHg at month 1 and –3.0 mmHg at month 12. No safety signals were observed, and there were 75 serious adverse events leading to permanent treatment discontinuation in the treatment group and 78 in the placebo group. Although the rate of hyperkalaemia was higher in the group of patients treated with finerenone, its clinical impact was minimal. The incidences of permanent treatment discontinuation or hospitalization due to hyperkalaemia were low in both the treatment and placebo groups (2.3% vs 0.9% and 1.4% vs 0.3%, respectively).

CI, confidence interval

A subgroup analysis showed that younger age and female sex were associated with higher risk of hyperkalaemia, as well as higher baseline [K+], lower eGFR, and higher UACR. It is important to note that kidney benefits of finerenone were also maintained in the patient subgroups at highest risk of hyperkalaemia, and that elevations in [K+] are predictable and manageable through routine monitoring.

Rajiv Agarwal concluded that finerenone showed long-term kidney and CV benefits in patients with CKD and T2D. Further studies must now investigate whether this effect can already be seen in patients in very early stages of CKD. These trials will address the question of whether the use of finerenone can prevent renal and CV disease in these patients.

From the trial to the clinic: Applying the evidence to everyday practice

Pantelis Sarafidis, Greece

An important question answered by Pantelis Sarafidis in his talk was “what types of patient with CKD and T2D could be considered candidates for treatment with finerenone?” In the FIGARO-DKD study,3 patients with eGFR 25–75 ml/min/1.73 m2 and UACR >30 mg/g were enrolled, all of them patients with “common” comorbidities. As Sarafidis pointed out, it is well known that patients with CKD and T2D are at high risk of CKD progression as well as at increased risk of death from CV-related causes – and the risk of CV mortality increases with albuminuria and decreasing eGFR. “We are seeing patients at very high risk, and we have to ask ourselves: are we doing our best in the management of patients with CKD and T2D?”

Pantelis Sarafidis pointed out that ACEi/ARBs, considered standard care, reduce renal risk but do not reduce mortality in patients with CKD and T2D. Despite best standard of care with ACEIs or ARBs, patients with CKD and T2D are at high risk of CKD progression. Sarafidis pointed out that finerenone had consistent beneficial effects on kidney outcomes, regardless of eGFR or UACR at screening and baseline blood pressure or glycated haemoglobin in the FIGARO-DKD study. “The main result was: finerenone gives you an additional 18% reduction in the risk of CKD progression. Furthermore, it offers important cardio protection in this population.”

Pantelis Sarafidis pointed out that the diagnosis of CKD in patients with T2D is often too late and the treatment is often inappropriate. New treatment options such as SGLT-2 inhibitors and MRAs have opened up new avenues to CV protection in this heavily burdened population.

Further reading

Chen YL, Qiao YC, Xu Y, et al. Serum TNF-α concentrations in type 2 diabetes mellitus patients and diabetic nephropathy patients: a systematic review and meta-analysis. Medicine (Baltimore) 2017;96:e6563

Siragy HM & Xue C. Local renal aldosterone production induces inflammation and matrix formation in kidneys of diabetic rats. Exp Physiol 2008; 93:817–824

Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 2020; 383:2219–2229

Agarwal R. Presented at: ISN Virtual World Congress of Nephrology 2021 (WCN’21); April 15–19, 2021; abstract WCN21-0607