Imagine Halting Progression of Kidney Disease in Patients with Type 2 Diabetes

From the Chair

Nearly one-half of all patients with kidney failure requiring dialysis have diabetes as the cause of the kidney disease. Patients with end-stage renal disease have a higher mortality, rate of hospitalization, and increased cost to the health system. Ninety percent of these patients with diabetes have type 2 diabetes mellitus (T2DM).

Over the past two decades, control of blood sugar, managing blood pressure, and renin-angiotensin system blockade (RAAS blockade), using ACE inhibitor or angiotensin receptor blocker (ARB) therapy, have been the mainstay of slowing kidney progression. However, it is estimated that renin-angiotensin blockade contributes only approximately 20% relative risk reduction in patients with T2DM and chronic kidney disease. Therefore, finding newer agents for reducing the progression of kidney disease, especially in patients with CKD from T2DM has been a holy grail of sorts.

On May and July of 2021, the FDA approved dapagliflozin (Farxiga®) based on results from the DAPA-CKD trial,¹ and finerenone (Kerendia®)  based on the FIDELIO-DKD² trial, as agents for slowing progression of CKD. Another agent,  atrasentan, an endothelin-A receptor antagonist, while not approved has generated excitement based on findings from the SONAR (Study of Diabetic Nephropathy with Atrasentan) trial.³

In a Perspective article in CJASN,⁴ Moura-Neto and Ronco contend that “until more robust evidence is available, we must still be careful when deciding to prescribe finerenone to patients with advanced CKD.” Their caution centers around three concerns: first that the finerenone in the FIDELIO-DKD trial used a composite outcome; second that the relative risk reduction with finererone was less than that for dapagliflozin or atrasentan and third that finererone was associated with significant hyperkalemia. They suggest that “recent data suggest that dapagliflozin, atrasentan, and canagliflozin may be better alternatives than finerenone for patients with CKD and diabetes mellitus.”

The criticisms by Moura-Neto and Ronco can be rebutted: both the DAPA-CKD study and the FIDELIO-DKD used composite outcomes; while it is true that dapagliflozin in the DAPA-CKD study was associated with a greater risk reduction than finererone in FIDELIO-DKD, these studies were designed differently -only a head-to-head study will be able to ascertain their differential benefits to preventing CKD progression. The hyperkalemia associated with finererone is a legitimate concern: as noted in their paper,² patients treated with finererone had twice as many hyperkalemia-related adverse effects as compared with placebo (18.3% and 9.0%, respectively). In a more recent post hoc analysis Agarwal and colleagues⁵ report that 4.5% and 1.4% of patients randomized to finererone and placebo experienced moderate hyperkalemia (defined as a K of >6.0 mmol/L). They suggest that because hyperkalemia is an uncommon phenomenon it can be medically managed.

Still, I suggest that Moura-Neto and Ronco are missing the point. The opportunity with these newer agents is to use them concurrently so that we can obtain more than the 20% contribution to slowing kidney progression with renin-angiotensin blockade. The goal is to largely halt the progression of kidney disease in patients with T2DM.

The currently approved agents target different pathways in preventing kidney progression. The primary effect of renin-angiotensin blockade is in improving glomerular hemodynamics, with perhaps a secondary effect on kidney fibrosis. Dapagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, reduces hyperglycemia in T2DM and improves glomerular hypertension through a reduction in blood pressure and extracellular volume. Finererone, a selective third generation nonsteroidal mineralocorticoid receptor antagonist, confers kidney protection through its anti-inflammatory and anti-fibrotic effects. Could using a combination of agents have additive effects on kidney protection?

In Fidelio-DKD, the majority of patients received some form of RAAS blockade (~34% ACE inhibitor, and ~66% ARB), but only 4.6% were being treated with an SGLT-2 inhibitor. Thus, the FIDELIO-DKD trial demonstrates that patients can be concurrently treated with RAAS blockade and an MRA.  While hyperkalemia was an issue in a small proportion of patients, in a real-world clinical setting, hyperkalemia could be managed using newer agents.⁶ It is certainly possible that using all three agents concurrently (and possibly a fourth in the form of atrasenta) is where the future lies with slowing the progression of kidney disease. The next series of trials need to combine all of these therapies and evaluate their aggregate benefit for kidney protection.

References

1. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al.; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24. PMID: 32970396.
2. Bakris GL, Agarwal R, Anker SD, et al.; FIDELIO-DKD Investigators. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020 Dec 3;383(23):2219-2229. doi: 10.1056/NEJMoa2025845. Epub 2020 Oct 23. PMID: 33264825.
3. Heerspink HJL, Parving HH, Andress DL, et al.; SONAR Committees and Investigators. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): A double-blind, randomized, placebo-controlled trial. Lancet. 2019 May 11;393(10184):1937-1947. doi: 10.1016/S0140-6736(19)30772-X. Epub 2019 Apr 14. Erratum in: Lancet. 2019 May 11;393(10184):1936. PMID: 30995972.
4. Moura-Neto JA, Ronco C. The RALES legacy and finerenone use on CKD patients. Clin J Am Soc Nephrol. 2021 Sep;16(9):1432-1434. doi: 10.2215/CJN.02150221. Epub 2021 Aug 6. PMID: 34362811; PMCID: PMC8729570.
5. Agarwal R, Joseph A, Anker SD, et al.; FIDELIO-DKD Investigators. Hyperkalemia risk with finerenone: Results from the FIDELIO-DKD trial. J Am Soc Nephrol. 2022 Jan;33(1):225-237. doi: 10.1681/ASN.2021070942. Epub 2021 Nov 3. PMID: 34732509; PMCID: PMC8763180.
6. Rastogi A, Arman F, Alipourfetrati S. New agents in treatment of hyperkalemia: An opportunity to optimize use of RAAS inhibitors for blood pressure control and organ protection in patients with chronic kidney disease. Curr Hypertens Rep. 2016 Jul;18(7):55. doi: 10.1007/s11906-016-0663-4. PMID: 27230070.