New therapy standard on the rise

Several innovative therapeutic options are expanding the options for treating patients with chronic kidney disease ( CKD). SGLT-2 inhibitors (SGLT-2-i) can now be considered an established treatment option – even for non-diabetics with CKD. Second, the mineralocorticoid receptor antagonist finerenone has been shown to halt the progression of diabetic nephropathy. The combined use of both therapeutic strands is currently being investigated in studies.

While staging of chronic kidney disease is based on glomerular filtration rate (GFR), the so-called Mitch curve is often used as a predictor of further progression. Here, the reciprocal value of creatinine over time is presented [1]. Intervention that can flatten the Mitch curve can prolong the time to dialysis. “We have several ways to slow down this progression – that’s what we mean by nephroprotection,” explained Prof. Thomas Fehr, MD, Chief of Internal Medicine, Cantonal Hospital Graubünden [2].

How SGLT-2-i revolutionized the therapeutic landscape

“SGLT-2 inhibitors are the new standard of nephroprotection ‘on-top’ of ACE inhibitors and also in non-diabetics,” said Prof. Fehr [2]. Taking a brief look at milestones in the treatment of nephropathy, the introduction of RAS blockade (ACE inhibitors, AT1 receptor blockers) stands out in the 1990s, and in the 2000s it was recognized that slowing of CKD progression could also be achieved via acidosis correction. Another major breakthrough has occurred more recently with the demonstration of the nephroprotective potential of SGLT-2 inhibitors. In 2012, dapagliflozin was approved in the EU as the first active ingredient of the substance class originally used exclusively as antidiabetic agents [3]. With regard to nephroprotective effects, initial studies were initially limited to diabetic nephropathy. Meanwhile, results were published from the DAPA-CKD and EMPA-KIDNEY studies, in which the two SGLT-2-i dapagliflozin and empagliflozin were specifically studied in patients who had CKD but not diabetes.

The EMPA-KIDNEY study impressively demonstrates the treatment effects of empagliflozin on-top of those induced by ACE-i: “Diabetics and non-diabetics both benefited significantly,” summarized Prof. Fehr. together [2]. Benefit was seen in all stages of renal failure, including GFR below 45 mL/min, with those with higher proteinuria having greater benefit compared with the others.

Non-diabetics with CKD can also benefit

Participants-a total of 6600 CKD patients (46% diabetic and 54% nondiabetic)-received either 10 mg empagliflozin or placebo as an add-on to renin-angiotensin system (RAS) exertional blockade [4]. Patients with stage 3b/4 CKD or other stage but with macroalbuminuria were included. Exclusion criteria included polycistic kidneys and kidney transplantation [5–7]. The composite primary end point included sustained deterioration in GFR (by at least 40% or to a value <10 ml/min), renal failure, or death from renal or cardiovascular causes. As a result, the primary endpoint showed a relative risk reduction of 28% (hazard ratio [HR], 0.72) (Table 1) and a number needed to treat (NNT) of 26. All secondary renal endpoints were also positive. For cardiovascular end points (e.g., hospitalization for heart failure), in contrast to other SGLT-2-i trials, the significance level was not reached, but a trend emerged.

The GFR curve shows a typical course for SGLT-2-i treatment, explained Prof. Fehr. At the beginning of therapy, there is a decrease in GFR, after which the curve flattens out and only after about 12-18 months does an improvement manifest itself in the placebo comparison. This course was known from previous therapy studies with SGLT-2-i. The explanation: SGLT-2-i cause vasoconstriction in afferent vessels of the glomeruli, leading to an initial decrease in GFR.

The gradually discovered spectrum of activity of SGLT-2 inhibitors is impressive. In the euphoria over this, the findings on the mineralocorticoid receptor antagonist finerenone were almost somewhat lost, the speaker said.

Finerenone – “New kid on the block” for the treatment of diabetic CKD

Finerenone is an active substance from the group of aldosterone antagonists. This is an active substance from the group of aldosterone antagonists. That finerenone can slow the progression of diabetic kidney disease in a placebo comparison is demonstrated by two large parallel studies: FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) had a renal endpoint and FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) had a cardiovascular endpoint [8,9]. FIDELITY represents a pooled analysis based on these two studies with data from a total of approximately 13,000 patients with CKD and T2D [10]. In conclusion, patients treated with finerenone were less likely to develop end-stage renal failure (dialysis or renal transplantation) and to experience a decrease in GFR of more than 57%, and CKD-related deaths were less frequent. The mean age of patients was 65 years; an exclusion criterion was heart failure with reduced ejection fraction (HFrEF), as this was considered an indication for spironolactone. The study population included patients who were unable to tolerate SGLT-2-i due to side effects and those who had rapid progressive renal failure despite SGLT-2-i and ACE-i. As shown in a subgroup analysis of the FIDELIO study, the combined use of finerenone with an SGLT-2-i has the beneficial side effect of reducing hyperkalemia, the most important side effect of finerenone. To find out more, the currently ongoing CONFIDENCE study is investigating the combination of finerenone plus SGLT-2-i in a larger study population.

Take-Home Messages [2]

SGLT-2-i are the first choice after ACE-i/ARB for nephroprotection in CKD patients with and without diabetes.
For patients with diabetic nephropathy who are progressive despite RAS inhibition and SGLT-2-i or who are intolerant of SGLT-2-i, a new therapeutic option is available with finerenone.
The evidence and findings to date indicate that the combination of SGLT-2-i and finerenone may be useful and has synergistic effects.

Congress: SGAIM Spring Congress

Literature:

Mitch WE, et al.: A simple method of estimating progression of chronic renal fail ure. Lancet 1976; 2: 13.
«Therapy of chronic renal failure», Prof. Dr. med. Thomas Fehr, SGAIM Frühjahrstagung, 10.–12.05.2023.
«Neues Antidiabetikum Dapagliflozin», 04.12.2012, www.deutsche-apotheker-zeitung.de/news/artikel, (last accessed June 20, 2023)
Herrington WG, et al: The EMPA-KIDNEY Collaborative Group: Empagliflozin in Patients with Chronic Kidney Disease. NEJM 2023; 388(2): 117-127.
Bakris G, et al: Effects of Canagliflozin in Patients with Baseline eGFR <30 ml/min per 1.73^m2: Subgroup Analysis of the Randomized CREDENCE Trial. Clin J Am Soc Nephrol 2020; 15(12): 1705-1714.
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Rossing P, et al.: FIDELIO-DKD and FIGARO-DKD Investigators. Finerenone in Patients With Chronic Kidney Disease and Type 2 Diabetes by Sodium-Glucose Cotransporter 2 Inhibitor Treatment: The FIDELITY Analysis. Diabetes Care 2022; 45(12): 2991–2998.
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