Counteracting aldosterone in cardiorenal disease in type 2 diabetes through finerenone administration

Blockade of the renin angiotensin system (RAS) has been classically used as the initial treatment in patients with type 2 diabetes (T2D) with cardiorenal disease to facilitate blood pressure (BP) control and the simultaneous cardiovascular and kidney protection. Albeit the demonstration of the role of aldosterone has been extensively proven in experimental studies, the presence of elevated circulating aldosterone levels and the prevalence of primary aldosteronism in hypertensive patients with or without T2D indicate that aldosterone frequently plays a significant role promoting simultaneously cardiac and renal damage in humans that had not been properly investigated in clinical studies.^1–3 In fact, in chronic kidney disease (CKD) only data indicating an important anti-proteinuric capacity with the use of mineralocorticoid receptor antagonists (MRAs) alone or on top of RAS blockade, have been demonstrated before the data of the new non-steroidal MRA finerenone were published.³

Finerenone is a novel non-steroidal MRA with high receptor selectivity and affinity overcoming the capacities of spironolactone and eplerenone while avoiding importantly the risk of hyperkalemia.⁴ The initial trial on the effect of finerenone on albuminuria in patients with diabetic nephropathy most receiving a RAS blocker demonstrated a relevant improvement in the urinary albumin–creatinine ratio.⁵ These data open the door to the performance of two big clinical trials with 5734 and 7437 devoted, the first denominated the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial that preferentially investigated the capacity of renal protection,⁶ and the second the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial that preferentially investigated the capacity of cardiovascular protection of finerenone.⁷ The initial planning also contemplated the simultaneous analysis including the data of the two trials that originated The FInerenone in chronic kiDney diseasE and type 2 diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial programme analYsis (FIDELITY) study⁸ that in our opinion constitutes the main influence for the future use of finerenone in clinical practice. In fact, the number of published articles related to finerenone containing data from FIDELITY are more numerous.

The main findings of the FIDELIO-DKD trial demonstrated that finerenone resulted in a lower risk of CKD progression (18%) and cardiovascular events (24%) than placebo.⁶ This was accompanied by a decrease in albuminuria oscillating between 29.3 and 41.3% and by the presence of serious hyperkalemia in only 1.6% in patients treated with finerenone that exhibited an estimated glomerular filtration rate (eGFR) of 44.4 mL/min/1.73 m² with very high albuminuria.⁶ On the other hand, the main data of the FIGARO-DKD trial demonstrated that with a mean eGFR of 67.6 mL/min/1.73 m² with high and very high albuminuria, finerenone therapy improved cardiovascular outcome compared to placebo predominantly at expenses of improving in hospitalization for heart failure and death. With respect to renal outcomes there was a trend in favor of protection that did not attained statistical significance.⁷ However, when the analysis of the whole database was performed in the FIDELITY trial, it was found that finerenone reduces clinically relevant cardiovascular and kidney outcomes across the spectrum of CKD in patients with T2D.⁸

Other advantages of the use of finerenone are: (1) important reduction of hyperkalemia providing a basis for clinical use of the drug⁹; (2) prevention of atrial fibrillation¹⁰; (3) prevention of incident of heart failure¹¹; (4) primary and secondary cardiovascular prevention.⁸ On the other hand, a percentage of patients in both FIDELIO-DKD and FIGARO-DKD trials received at baseline treatment with a sodium-glucose cotransporter-2 inhibitors (SGLT2i) or glucagon-like peptide-1 agonists (GLP1a) it has been demonstrated that these drugs do not interfere at all with the positive effect of finerenone indicating that an additive effect of the combination any of these two drugs with finerenone is very probable.^12,13

T2D particularly when CKD is present is accompanied by a significant increase in BP that we need to control. In the current trials, the great majority of patients were receiving three or more drugs at baseline.⁸ In other words, many of them presented with resistant hypertension. The mean baseline systolic BP was 136.8 mmHg in FIDELITY trial that was elevated according to the goal promoted by recent hypertension guidelines (BP < 130/80 mmHg), and defended as adequate for resistant hypertension in the analysis of The Systolic Blood Pressure Intervention Trial (SPRINT) trial.¹⁴ The maximal effect of finerenone on systolic BP was −3.84 mmHg in office BP observed at month fourth.¹⁵ Apparently, this fall in systolic BP was insufficient to attain the expected goal according to hypertension guidelines, particularly whether KDIGO guidelines are considered because the goal for systolic BP in CKD is <120 mmHg.¹⁶ However, data from the substudy of ambulatory BP monitoring (ABPM) performed in the Mineralocorticoid Receptor Antagonist Tolerability Study in Diabetic Nephropathy ARTS-DN trial showed that finerenone reduced 24 h, daytime and nighttime systolic BP with a placebo adjusted change at the end of the study above −8.3 mmHg for 10, 15 and 20 mg of finerenone per day,¹⁷ clearly above the fall in BP obtained in the office in these trials.

Finally, clinicians interested in the treatment of DKD probably consider after reading the results of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial¹⁸ that a SGLT2i could be better for renal protection than finerenone (30% compares with 18%). However, the recent publication showing the comparison in the evolution of patients in FIDELITY accomplishing the entry criteria of CREDENCE trial proved that the comparison was 30% to 28%.¹⁹ These data indicate that the selection of patients in trials must accomplish similar criteria to avoid false differences in the outcome.

In conclusion, finerenone is a new drug that comes to improve the cardiorenal prognosis of patients with DKD adding its effects to those of RAS blockers, SGLT2i, and GLP1a.