Combined SGLT-2 Inhibitor and Mineralocorticoid Receptor Antagonist Therapy: Effects on the Renin-Angiotensin-Aldosterone System in Heart Failure Treatment.
Petramala L, Caprioni Grasso L, et al. • International journal of molecular sciences • 2026
SGLT2i therapy, particularly when combined with MRAs, may favorably influence natriuresis, chloruresis, and urinary albumin excretion in patients with heart failure, while both SGLT2i and combined SGLT2i/MRA therapy were associated with activation of the renin-angiotensin-aldosterone system.
Key Findings
Results
Combined SGLT2i and MRA therapy (Group A) was associated with increased 24-hour urinary sodium and chloride excretion compared to SGLT2i alone or ongoing SGLT2i therapy.
Patients were stratified into three groups: combined SGLT2i and MRA initiation (Group A), SGLT2i initiation alone (Group B), and ongoing SGLT2i therapy for >12 months (Group C)
Hemodynamic parameters, serum and 24-hour urinary electrolytes, and hormonal parameters were assessed at admission (T0), 7 days (T1), and 30 days (T2)
Group A exhibited increased 24-hour urinary sodium and chloride excretion relative to the other groups
The study included 114 patients with heart failure admitted to the Emergency Medicine Unit of Policlinico Umberto I, Sapienza University of Rome, between March and December 2025
Results
Combined SGLT2i and MRA therapy (Group A) was associated with lower urinary albumin excretion compared to other treatment groups.
Group A exhibited lower urinary albumin excretion alongside increased natriuresis and chloruresis
Urinary albumin excretion was assessed at three time points: T0 (admission), T1 (7 days), and T2 (30 days)
This finding suggests a potential renoprotective effect of combined SGLT2i and MRA therapy in heart failure patients
Results
Both Group A (combined SGLT2i/MRA) and Group B (SGLT2i alone) showed activation of the renin-angiotensin-aldosterone system (RAAS).
RAAS activation was observed in both the newly initiated SGLT2i group and the combined SGLT2i/MRA group
Group C (ongoing SGLT2i for >12 months) did not show the same pattern of RAAS activation as Groups A and B
Hormonal parameters were assessed longitudinally at T0, T1, and T2 to track RAAS changes over 30 days
Results
Baseline 24-hour urinary glucose excretion was significantly increased in Group C (ongoing SGLT2i >12 months) compared to Groups A and B.
Group C consisted of patients already on SGLT2i therapy for more than 12 months at the time of admission
Baseline anthropometric and laboratory parameters were otherwise comparable among the three groups
Elevated urinary glucose excretion in Group C is consistent with the expected sustained glucosuric effect of long-term SGLT2i therapy
Results
Hypertension was the most prevalent comorbidity in the study population, followed by atrial fibrillation, dyslipidemia, and coronary artery disease.
Hypertension prevalence was 74% among the 114 heart failure patients studied
Atrial fibrillation was present in 49% of patients
Dyslipidemia was present in 47% of patients
Coronary artery disease was present in 39% of patients
Methods
The study was a retrospective evaluation of 114 heart failure patients admitted over a nine-month period and assessed at three time points.
The study was conducted at the Emergency Medicine Unit of Policlinico Umberto I, Sapienza University of Rome, Italy
Patient recruitment occurred between March and December 2025
Three assessment time points were used: admission (T0), 7 days (T1), and 30 days (T2)
Parameters assessed included hemodynamic measures, serum and 24-hour urinary electrolytes, and hormonal parameters
What This Means
This research studied 114 heart failure patients to understand how different treatments involving a class of diabetes drugs called SGLT2 inhibitors (like empagliflozin or dapagliflozin) affect the body's salt-water balance and hormone systems. Patients were divided into three groups: those starting a combination of an SGLT2 inhibitor and a separate drug called a mineralocorticoid receptor antagonist (MRA), those starting an SGLT2 inhibitor alone, and those who had already been on an SGLT2 inhibitor for over a year. Blood and urine measurements were taken at admission, after 7 days, and after 30 days.
This research suggests that patients who received both an SGLT2 inhibitor and an MRA together excreted more sodium and chloride in their urine (a process called natriuresis and chloruresis) and had lower levels of protein in their urine (urinary albumin), which is generally considered a favorable sign for kidney health. Both newly treated groups — those starting SGLT2 inhibitors alone and those starting the combination — showed activation of the renin-angiotensin-aldosterone system (RAAS), a hormonal system involved in blood pressure and fluid regulation. Patients who had been on SGLT2 inhibitors for more than a year showed higher urinary glucose levels, consistent with the known sustained effect of these drugs.
These findings add to the growing body of evidence that SGLT2 inhibitors can positively affect fluid balance and kidney function in heart failure patients, and that combining them with MRAs may offer additional benefits in terms of salt excretion and reducing urinary protein. Understanding how these drug combinations interact with the body's hormone systems could help guide treatment strategies for people living with heart failure, a condition where managing fluid balance is critically important.
Petramala L, Caprioni Grasso L, Calise G, Circosta F, Letizia T, Marino L, et al.. (2026). Combined SGLT-2 Inhibitor and Mineralocorticoid Receptor Antagonist Therapy: Effects on the Renin-Angiotensin-Aldosterone System in Heart Failure Treatment.. International journal of molecular sciences. https://doi.org/10.3390/ijms27198522