By Julie Anne Gabat-Tan, MD, FPCP, FPCEDM and Gretchen Ang-Manuel, MD, FPCP
De La Salle University Medical Center
Diabetes is the leading cause of End-Stage Renal Disease (ESRD) and dialysis worldwide. All efforts to manage this dreaded growing epidemic likewise include prevention of the development and progression of kidney disease. The American Diabetes Association 2024 (ADA 2024) Guidelines on the Management of Diabetes recommends the use of renin-angiotensin-aldosterone-system (RAAS) inhibitors at maximum tolerated doses in the management of hypertension. It has been established from several studies that treatment with ACEi or ARB, whether in patients with diabetes or no diabetes, reduces albuminuria and the risk of progression to ESRD. However, recent ADA guidelines now recommend addition of non-steroidal mineralocorticoid receptor agonist (MRA) on top of ACEi or ARBs if the albumin to creatinine ratio (ACR) is at least 30mg/g provided that the serum potassium levels are normal.¹
The mineralocorticoid receptor (MR) is a nuclear receptor found in many tissues including the kidneys and the heart. Aberrant and chronic activation of MR by aldosterone in patients with Type 2 Diabetes mellitus trigger inflammation and fibrosis in these tissues, hence, the suppression of aldosterone has been a strategy for the management of Diabetic Kidney disease. However, its use has been limited due to the risk of hyperkalemia and worsening of kidney function when given on top of RAS inhibitors to patients with advanced CKD (eGFR 15 to 44 mL/ (min·1.73 m²). Hyperkalemia-associated hospitalization is 3-fold greater in patients with CKD stage 3 to 4 given spironolactone than those who are not.²
Strategies to address this dilemma include the use of potassium-binding agents to allow for the addition of an MRA or the use of novel non-steroidal MRAs which are associated with a lower incidence of hyperkalemia compared to steroidal MRAs (eg. Spironolactone and eplerenone.)3-4 Finerenone, a first-in-class, orally administered, selective, non-steroidal MRA recently approved in the country to reduce the risk of sustained eGFR decline, ESRD, CV death, non-fatal MI and hospitalization due to heart failure in patients with Diabetic Kidney Disease.5
Two well-conducted randomized controlled trials showed the efficacy and cardiovascular safety of Finerenone among patients with Type 2 Diabetes and Chronic Kidney Disease. The Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) study is a randomized, multi-center, double-blind, placebo controlled trial investigating the efficacy of Finerenone in reducing chronic kidney disease progression and kidney failure among patient with Type 2 Diabetes and Chronic Kidney Disease. This study enrolled adults patients (> 18 years old) with Type 2 Diabetes and urine albumin creatinine ratio of 30 to less than 300 mg/g and eGFR of 25-60 ml/min or urine albumin creatinine ratio of more than 300 to 5000mg/g and eGFR of 25-75 ml/min. The study showed that use of finerenone resulted in a significant reduction in the primary composite outcome of kidney failure, eGFR decline by 40% or more and death from renal causes by 18% (HR 0.82, CI 0.73 to 0.93). Quite interesting are that fact that this benefit of finerenone is seen on top of maximal tolerated dose of ACEi or ARBs and that you only need to treat 29 patients to prevent 1 kidney disease progression and renal death (NNT 29).6
The Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) study showed that treatment with Finerenone among patients with Type 2 Diabetes and Chronic Kidney Disease from diabetic nephropathy resulted in a significant reduction in the primary composite outcome cardiovascular death, non-fatal MI, non-fatal stroke and hospitalization due to heart failure by 13% (HR 0.87 CI 0.76 to 0.98). This result is driven mainly by the significant reduction in hospitalization due to heart failure which is 29% (HR 0.71 CI 0.56 to 0.90). This trial excluded patients with symptomatic heart failure with reduced ejection fraction since these patients definitely require mineralocorticoid receptor antagonist as part of standard of care. Quite notable in this study as well, is that only 45% of patients have eASCVD. Main side effect noted in both trials is hyperkalemia, however, no deaths were related with hyperkalemia. Part of the inclusion criteria in these studies is a serum potassium level of less than 4.8 mmol/L. Finerenone is likewise withheld if the serum potassium increased to 5.5 mmol/L and resumed only once the serum potassium level went down to 5.0 mmol/L.7
The results of these studies equip us with another armamentarium to delay the progression of kidney disease among our patients with Type 2 Diabetes particularly those patients in whom SGLT2i is contraindicated or are quite difficult to maintain on such medication due to intolerable side effects.
References:
1. American Diabetes Association Professional Practice Committee. 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes-2024. Diabetes Care. 2024 Jan 1;47(Suppl 1):S179-S218. doi: 10.2337/dc24-S010. PMID: 38078592; PMCID: PMC10725811.
2. Yang CT, Kor CT, Hsieh YP. Long-term effects of spironolactone on kidney function and hyperkalemia-associated hospitalization in patients with chronic kidney disease. J Clin Med. 2018;7:E459. doi: 10.3390/jcm7110459
3. Bakris GL, Agarwal R, Chan JC, Cooper ME, Gansevoort RT, Haller H, Remuzzi G, Rossing P, Schmieder RE, Nowack C, et al; Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy (ARTS-DN) Study Group. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a Randomized Clinical Trial. JAMA. 2015;314:884–894. doi: 10.1001/jama.2015.10081
4. Pitt B, Kober L, Ponikowski P, Gheorghiade M, Filippatos G, Krum H, Nowack C, Kolkhof P, Kim SY, Zannad F. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J. 2013;34:2453– 2463. doi: 10.1093/eurheartj/eht187
5. Finerenone. MIMS Philippines. https://www.mims.com/philippines/drug/info/finerenone?mtype=generic
6. Bakris, George L., et al. FIDELIO-DKD Investigators. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med 2020;383:2219-2229. Published October 23, 2020. Retrieved from https://www.nejm.org/doi/full/10.1056/NEJMoa2025845 on September 4, 2024.
7. Pitt, Bertram, et.al. FIGARO-DKD Investigators. Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes. N Engl J Med 2021;385:2252-2263. Published August 28, 2021. Retrieved from https://www.nejm.org/doi/full/10.1056/NEJMoa2110956 on September 4, 2024.
