A Fine Renal Breakthrough?

Big announcement from Bayer on Thursday 9 June. Are we on the verge of a major step forward in the pharmacological fight against diabetic nephropathy?

We all know diabetic nephropathy (DN) is by far the most common cause of end-stage renal disease in Mauritius and worldwide. The inhibition of the renin-angiotensin-aldosterone system (RAAS) has been the mainstay of treatment of diabetic nephropathy for a long time. First, the angiotensin converting enzyme inhibitors (ACE I) were first shown to slow the progression of DN in 19931 followed by the angiotensin receptor blockers (ARB)at the dawn of the millenium2. Direct renin inhibitors have been disappointing with serious adverse side effects like hyperkalaemia and worsening of kidney function.

For the last 7 years, the talk of the town has been the Sodium-glucose co-transporter 2 inhibitors (SGLT2 1). This is without doubt well deserved as positive clinical trials succeed each other. Those yearning for a little distraction may welcome the announcement made about FIDELIO-DKD trial3 investigating finerenone.

Another class of RAAS Inhibitors, the mineralocorticoid receptor antagonists (MRA) have had a long and chequered history. The first one, spironolactone, was discovered in 1957. It was initially used as a diuretic to treat odema and ascites without any thought given to clinical outcomes. It was soon considered as weak and largely superseded by loop diuretics. It had adverse effects on potassium levels. Even a niche role as potassium sparing diuretic was compromised by the fact that it became known as a ‘dirty’ drug.

This is due not only to its potent mineralocorticoid activity (hyperkalaemia) but also its moderate anti-androgen activity and weak steroidogenesis action. It caused breast tenderness and menstrual abnormalities in women and gynaecomastia (10–15%) and sexual dysfunction in men. These adverse side-effects led to the use of the drug in acne, hirsutism and transgender hormone therapy.

In the 1990’s, the ACE I revolutionised hypertension and heart failure treatment. Spironolactone was surely on the way out as it was too much of a hyperkalaemic risk as an add-on to ACE I. However, some researchers were collecting evidence of aldosterone’s role in myocardial and vascular fibrosis.

The Randomized Aldactone Evaluation Study (RALES)4 in September 1999 triggered a seismic change in thinking about spironolactone and, ultimately, in the treatment of many of today’s heart failure patients. It was a placebo-controlled study of over 1,600 patients with severe heart failure that achieved a 30% mortality reduction mortality in patients treated with spironolactone 25mg daily added to previous therapy (ie, ACE I, loop diuretic, with or without digoxin).

Use of spironolactone went through the roof but so did the admissions for hyperkalaemia5. The search for a ‘cleaner’ version of spironolactone had been on for a couple of decades. Eplerenone, a second generation derivative of spironolactone, with a lower risk of gynaecomastia (<1%) but similar cardiovascular benefits6,7 was approved soon after. Both MRAs have a grade 1A recommendation for patients with heart failure with reduced ejection fraction (HFrEF) with persisting symptoms despite ACE I (or ARB) and beta-blocker treatment. Their use remains suboptimal in clinical practice because of real concerns for hyperkalaemia in a population at high risk of CKD and AKI.

What about the kidney disease? Many trials have shown better blood pressure control and a marked reduction in proteinuria without any benefits in renal hard end points like slowing CKD progression. Hyperkalaemia, again, caused the withdrawal of many patients from these trials8.

Enter finerenone, a third generation non-steroidal MRA. The dihydropyridine-based (similar to nifedipine etc) compound has high affinity for the MR like spironolactone but very low affinity for androgen, glucocorticoid, and progesterone receptors like eplerenone. Finerenone concentrates equally in cardiac and renal tissues unlike spironolactone and eplerenone which have a higher tendency to concentrate in the kidney suggesting a more favourable balance between cardioprotection and renal side effects. Phase II trials suggest finerenone have a lower incidence of hyperkalaemia with better cardiovascular outcomes compared to eplerenone9.

Now let us talk about the FIDELIO-DKD3 trial. With over 5600 patients, it is the largest renal study recruited to specifically investigate the progression of kidney disease in T2D patients with CKD. It has recruited patients with eGFR down to 25ml/min/1.73 m2 and UACR from 30 to 5000mg/g. See the following slides for details.

So, on 9 July 2020, Bayer announced the Phase III study FIDELIO-DKD has met its primary endpoint early. The results finerenone delayed the progression of CKD by reducing the combined risk of time to first occurrence of kidney failure, a sustained decrease of eGFR > 40 percent from baseline over at least a 4 week period, or renal death. Finerenone also reduced the risk of the key secondary endpoint, a composite of time to first occurrence of cardiovascular (CV) death, non-fatal MI, non-fatal stroke, or heart failure hospitalization.

Obviously, there are no details to scrutinise yet until the clinical data from FIDELIO-DKD is presented at an upcoming scientific meeting. Until then, we can only speculate. Will we be able to halt the progression of diabetic nephropathy? Has hyperkalaemia been banished? Will the nephrologists lose their distrust of MRAs? What will be the dream combo pill of the future?ACE I or ARB + SGLT2 I + finerenone???

Top picture from Bramlage, P., Swift, S.L., Thoenes, M., Minguet, J., Ferrero, C. and Schmieder, R.E. (2016), Non‐steroidal mineralocorticoid receptor antagonism for the treatment of cardiovascular and renal disease. Eur J Heart Fail, 18: 28-37. doi:10.1002/ejhf.444

1. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329: 1456-62

2. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345: 861-9

3. Bakris G, L, Agarwal R, Anker S, D, Pitt B, Ruilope L, M, Nowack C, Kolkhof P, Ferreira A, C, Schloemer P, Filippatos G: Design and Baseline Characteristics of the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease Trial. Am J Nephrol 2019;50:333-344. doi: 10.1159/000503713

4. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. New England Journal of Medicine 1999;341:709–17

5. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. New England Journal of Medicine 2004;351:543–51.

6. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309–1321.

7. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21.

8. Currie, G., Taylor, A.H.M., Fujita, T. et al. Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analysis. BMC Nephrol 17, 127 (2016). https://doi.org/10.1186/s12882-016-0337-0

9. Filippatos G, Anker SD, Böhm M, Gheorghiade M, Kober L, Krum H, Maggioni AP, Ponikowski P, Voors AA, Zannad F, Kim S, Nowack C, Palombo G, Kolkhof P, Kimmeskamp-Kirschbaum N, Pieper A, Pitt B. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes and/or chronic kidney disease. E Eur Heart J 2016;37:2105–2114.

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