Mineralocorticoid Receptor Antagonists for Diabetic Kidney Disease

Ten years ago, I presented an outline for a study aiming to prevent diabetic kidney disease (DKD), with early intervention in subjects with type 2 diabetes and high risk for DKD assessed by a urinary proteomic–based biomarker, at Kidney Week hoping for positive feedback. Diabetes is one of the most important health problems of our time: 460 million people globally have diabetes, it is the leading cause of kidney failure, and 30%–40% of people with diabetes have CKD. US population–based data demonstrated a 28% reduction in kidney failure in diabetes from 1990 to 2010, but due to the increase in diabetes prevalence and better survival, subjects referred for kidney replacement therapy due to diabetes increased from 20,000 to 50,000 during this period. DKD is associated with cardiovascular morbidity and excess mortality. Thus, prevention studies are urgently needed, and I was therefore surprised by the very negative response I received from colleagues.

The problem was we had planned to use the steroidal mineralocorticoid receptor antagonist (MRA) spironolactone as the intervention in high-risk individuals for prevention of DKD. Although we would include only normoalbuminuric subjects with eGFR >45 ml/min per 1.73 m², normal serum potassium, and a small dose of spironolactone, I was told the use of MRAs in CKD, including DKD, was not appropriate due to the well-known side effects.

The pivotal trials with angiotensin-converting enzyme inhibitors and angiotensin receptor blocker in DKD reduced hard kidney endpoints, but the residual risk was obvious, and, subsequently, there was focus on increasing the incomplete blockade of the renin angiotensin aldosterone system. Long-term treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blocker is often followed by “aldosterone breakthrough” or escape because of insufficient blockade of the renin-angiotensin system (RAS) or concomitant increases in potassium. We found this to be associated with a faster decline in GFR. Overactivation of MRs by aldosterone in kidney and heart disease results in fibrosis and inflammation, and in addition to the effect on MRs in the classic location of the distal nephron, aldosterone effects are mediated through MRs on smooth muscle cells, endothelium, fibroblasts, podocytes, and inflammatory cells (1). It was suggested that adding spironolactone to patients on RAS blockade with aldosterone breakthrough had additional albuminuria-lowering effects in DKD, and thus potentially would be beneficial for kidney and cardiac outcomes. Spironolactone demonstrated a significant 39% reduction in albuminuria, with the major concern being a >6-fold higher risk for hyperkalemia, particularly in subjects with impaired kidney function, and there was a three-fold higher withdrawal because of hyperkalemia (2). The problems with hyperkalemia led to a contraindication for the use of the steroidal MRA eplerenone in type 2 diabetes with DKD, and thus hyperkalemia and the concern of reduction in kidney function precluded long-term studies targeting aldosterone in CKD. This was the background for the well-meant criticism of our study aiming to prevent DKD.

In recent years, new opportunities for mitigating the damaging effect of aldosterone have appeared with the development of new nonsteroidal MRAs, such as esaxerenone and finerenone. These nonsteroidal MRAs have been developed with the expectation that they provide renoprotection by blocking aldosterone with fewer side effects, that is no hormonal side effects, and less hyperkalemia than the classic steroidal MRAs. The difference in the mode of action of the nonsteroidal MRA finerenone compared with steroidal MRAs has been explained by the different physiochemical properties affecting (1) tissue distribution and cellular penetration, (2) mode of binding to the MR, and (3) blockade or recruitment of tissue-selective or ligand-specific cofactors leading to differential gene expression (3).

A short-term phase 2b study in Japanese subjects with type 2 diabetes and elevated urinary albumin excretion of 12 weeks demonstrated that esaxerenone as an add-on therapy to RAS inhibitors dose dependently reduced the urinary albumin-to-creatinine ratio (UACR) by 38%–56% versus RAS inhibitors alone, with 3% of subjects on esaxerenone stopping treatment due to hyperkalemia (4). Esaxerenone was recently registered in Japan for the treatment of hypertension.

In this issue of CJASN, the findings from the phase 2b study (4) are extended significantly, as a group of Japanese investigators present the data from the Esaxerenone in diabetic nephropathy (ESAX-DN) study, demonstrating that the nonsteroidal MRA esaxerenone induces significant remission of microalbuminuria in type 2 diabetes when added to RAS inhibitors for 52 weeks, compared with RAS inhibitors alone (5). Overall, 49 (22%) and nine (4%) patients in the esaxerenone and placebo groups, respectively, achieved UACR remission (normoalbuminuria) and a 30% decline in UACR from baseline (treatment difference P<0.001). The change in UACR from baseline to the end of treatment was −58% with esaxerenone versus 8% with placebo. There was a significant reduction in BP of 10/5 mm Hg, but this was not associated with the reduction in UACR. In addition to the induction of remission of albuminuria, there was a significant improvement in the time to first transition to overt albuminuria (hazard ratio [HR], 0.23; 95% confidence interval [95% CI], 0.11 to 0.48).

A reduction in UACR of 58% is clinically very meaningful. As discussed by the authors, a National Kidney Foundation–organized conference on endpoints in kidney trials in 2018 demonstrated how a 30% decrease in albuminuria compared with placebo will provide an average HR for the hard clinical kidney endpoint of 0.68 (6).

Regarding adverse events, more patients had a serum K+ level of ≥6.0 mEq/L or ≥5.5 mEq/L on two consecutive measurements in the esaxerenone group (20 [9%]) versus placebo (5 [2%]), but these events were asymptomatic and resolved after dosage reduction, or in 4% resulted in treatment discontinuation. After a 4-week wash out from the end of treatment, a significant difference in UACR remained between groups, suggesting a lasting effect, in line with potential modification of inflammation and fibrosis, in contrast to a shorter-lasting hemodynamic response, although this may require a longer wash out to fully clarify.

Recently, sodium glucose cotransporter 2 inhibitors were recommended for renoprotection in type 2 diabetes with DKD, based on a significant reduction in progression of DKD (7). The mode of action probably involves hemodynamic action reducing intraglomerular pressure and an improved oxygen tension in the kidney, which are different pathways than suggested for the MRAs and, in line with this, the effect of esaxerenone on UACR was independent of the use of sodium glucose cotransporter 2 inhibitors, although additional data are needed to clarify if there is an additive effect.

Finerenone (BAY 94 8862), another nonsteroidal MRA, was evaluated in the Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy for 90 days in patients with type 2 diabetes and albuminuria (UACR ≥30 mg/g) on RAS inhibitors. Finerenone led to a dose-dependent reduction in albuminuria of <38% from baseline. Hyperkalemia and subsequent discontinuation of the study drug occurred in 2% of patients receiving finerenone compared with no patients on placebo. There were no differences in the incidence of an eGFR decrease of ≥30% between the groups (8).

Only 7% of the participants in ESAX-DN were treated with diuretics, known to enhance the effect of RAS inhibition, compared with 72% in the Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy, and it is not known if this can contribute to a difference in effect on UACR or potassium increase of the nonsteroidal MRAs.

The first long-term study of a nonsteroidal MRA demonstrated that the effects on UACR translate into prevention of cardiovascular and kidney events. In the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial (NCT02545049) and Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease Trial (FIDELIO-DKD) (NCT02540993) studies, finerenone is being compared with placebo in addition to optimized RAS blockade in individuals with type 2 diabetes and CKD. In the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial, the primary endpoint is cardiovascular death or nonfatal myocardial infarction, stroke, or hospitalization for heart failure in type 2 diabetes with DKD and microalbuminuria. Secondary endpoints include a kidney endpoint. The study has randomized 7437 subjects and is expected to end in July 2021. FIDELIO included 5734 subjects with CKD and type 2 diabetes (a UACR of ≥30 to ≤5000 mg/g, eGFR of ≥25 to <75 ml/min per 1.73 m²⁾, and the primary endpoint (kidney failure, sustained decrease of eGFR ≥40% or kidney death) was reduced significantly (HR, 0.82; 95% CI, 0.73 to 0.93; P=0.001). The key secondary outcome (cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure) was also reduced (HR, 0.86; 95% CI, 0.75 to 0.99; P=0.03). UACR was reduced 31% at 4 months. The incidence of hyperkalemia-related treatment discontinuation was higher with finerenone than placebo (2% and 1%, respectively) (9).

Our study was completed without major safety issues, but also without significant benefit on the prevention of DKD with spironolactone in type 2 diabetes, maybe because of the use of a steroidal MRA, lack of power, or because it was too early in the disease process for this mode of action (10). In established CKD, spironolactone and eplerenone reduced albuminuria but were stopped for hyperkalemia. ESAX-DN has demonstrated an impressive UACR reduction with the nonsteroidal MRA esaxerenone, prevention of progression of early DKD with remission of microalbuminuria, and only minor potassium-related drug discontinuation. Hard outcome studies with esaxerenone in DKD are needed. FIDELIO demonstrated kidney and cardiac benefit of finerenone in the first hard outcome study, also with minor drug discontinuation due to potassium, showing finerenone may be an effective treatment for kidney and cardiovascular protection. Together, the studies suggest a role for nonsteroidal MRAs in DKD.

Disclosures

P. Rossing reports receiving fees (to his institution) for consultancy and/or speaking from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, MERCK, Merck Sharp and Dome, Mundi, Novo Nordisk, Sanofi Aventis, and Vifor.

Funding

None.