In this study, investigators will compare the effect of vicadrostat combined with empagliflozin with the effect of spironolactone combined with empagliflozin on renal function and changes in protein profiles in blood and urine.

The hypothesis is that the renal and cardiac responses between vicadrostat and spironolactone differ due to mechanistic differences in their mode of action. Spironolactone is a mineralocorticoid receptor antagonist (MRA) and exerts its effect on a receptor, or a type of "receiver," found on various cells. Vicadrostat is an aldosterone synthase inhibitor (ASI) and inhibits aldosterone production. Therefore, both drugs affect aldosterone.

However, studies evaluating the differences between MRAs (such as spironolactone) and ASI (such as vicadrostat) and examining their effects on the kidneys in patients with chronic kidney disease with concurrent cardiovascular disease, and/or heart failure are still lacking.

For this study, all participants will be divided into two groups:

• Group 1. Participants in this group will receive one tablet of vicadrostat (10 mg) and one tablet of empagliflozin (10 mg) daily for 26 weeks.
• Group 2. Participants in this group will receive one tablet of spironolactone (25 mg) and one tablet of empagliflozin (10 mg) daily for the first four weeks. Participants in this group will then receive two tablets of spironolactone (50 mg) and one tablet of empagliflozin (10 mg) daily for the remaining 22 weeks. The spironolactone dosage may be adjusted during the study period (from 12.5 to 50 mg) based on blood test results.

The hypothesis is that renal and cardiac response to a mineralocorticoid receptor antagonist (MRA) differs from the response to an aldosterone synthase inhibitor (ASi) due to the mechanistic differences in action between these two compounds. However, direct head-to-head comparative studies evaluating the renal, cardiac, and systemic effects of MRAs and ASi in patients with chronic kidney disease (CKD), with concomitant cardiovascular disease (CVD) or heart failure (HF), are lacking.

The main objective of this study in patients with chronic kidney disease with either cardiovascular disease and/or or heart failure is to compare the effects of the ASi, vicadrostat, with the steroidal MRA, spironolactone, on the change in kidney function from baseline to 4 and 26 weeks.

Secondary objectives include

• Change in renal hemodynamic measurements from baseline to 4 and 26 weeks
• Changes in plasma and urinary protein profiles and associated pathways from baseline to 4 and 26 weeks

This is a mechanistic trial using an open-label, parallel-group comparative design with 1:1 randomization and blinded endpoint assessment.

Treatment with vicadrostat (Investigational Medicinal Product; IMP 10mg daily) or spironolactone (Comparator IMP; 25-50mg daily) for 26 weeks whilst on empagliflozin (Auxiliary Medicinal Product; AxMP 10mg daily). In half of the enrolled subjects (targeted 50 subjects) renal hemodynamic measurements will be performed at baseline, at 4 and at 26 weeks.

Inclusion Criteria:

1. Provided written and dated informed consent for participation prior to trial admission,

2. Age ≥18 years, female or male

3. Patients with

   • Heart failure*1 (any LVEF) and eGFR*2 between 25-90 mL/min/1.73m2 OR
   • Established cardiovascular disease*3 and eGFR between 25-60 mL/min/1.73m2 OR
   • Established cardiovascular disease and type 2 diabetes and eGFR between 25-90 mL/min/1.73m2

4. Serum potassium ≤ 5.0 mmol

5. Currently treated or eligible for treatment with Empagliflozin*4

6. Not using a MRA or AS inhibitor in the last 6 months prior to enrollment

7. On stable doses of other guideline directed medical therapies for ≥ 4 weeks prior to enroll-ment

8. Outpatient.

   • 1 HF is defined as the definition used in the most recent ESC guidelines for HF.
   • 2 eGFR as assessed by the 2009 CKD-EPI without the race coefficient
   • 3 Cardiovascular disease is defined as a history of a myocardial infarction, coronary bypass surgery, PCI, or proven coronary artery disease (e.g. by coronary angiography, CT-scan, etc.)
   • 4 If switching from another SGLT2i to Empagliflozin subjects can be enrolled directly. If the subject is not yet on SGLT2i and starts Empagliflozin enrollment can start 4 weeks later see criteria 8.

Exclusion Criteria:

1. Inability to understand and sign informed consent
2. Absolute contra-indication for aldosterone antagonist
3. Absolute contra-indication for a SGLT2-inhibitor
4. Heart failure hospitalization, acute coronary syndrome, cardiac surgery, stroke or transient is-chemic attack in the 90 days prior to enrollment
5. Women who are pregnant, breastfeeding or may be considering pregnancy during the study duration.

will be updated at a later stage