Efficacy and safety of non-steroidal mineralocorticoid receptor antagonist and SGLT2 inhibitor combination therapy versus SGLT2-inhibitor monotherapy in patients with chronic kidney disease with albuminuria: a systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION

Sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) and non-steroidal mineralocorticoid receptor antagonists (nsMRAs) exert complementary renoprotective effects in chronic kidney disease (CKD). However, the efficacy and safety of nsMRA plus SGLT2 inhibitor combination therapy compared with SGLT2 inhibitor monotherapy in patients with albuminuria remain uncertain.

METHODS

We systematically searched for randomized controlled trials (RCTs) comparing nsMRA plus SGLT2 inhibitor therapy with SGLT2 inhibitor monotherapy in adults with CKD with albuminuria. Outcomes included changes in albumin-creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), serum potassium, categorical ACR response (≥ 30% and ≥ 50% reduction), and short- and long-term safety outcomes, including hyperkalemia, adverse events (AEs), and serious adverse events (SAEs). Random-effects models were used to pool ratio of means (ROM), mean differences (MD), and risk ratios (RR).

RESULTS

Four RCTs including 1835 patients were analyzed. Combination therapy was associated with a greater reduction in ACR compared with monotherapy (ROM = 0.67, 95% CI 0.63-0.72), corresponding to an approximate 33% reduction. The likelihood of achieving ≥ 30% (RR = 1.36) and ≥ 50% (RR = 1.76) ACR reduction was significantly higher with combination therapy, however, with a modest increase in serum potassium (MD = 0.11 mmol/L) and a significantly higher risk of hyperkalemia both short term (RR = 1.55) and long-term. There was no overall effect on eGFR, the risk of AEs and SAEs were comparable.

CONCLUSION

In patients with CKD with albuminuria, nsMRA plus SGLT2 inhibitor therapy may provide clinically meaningful albuminuria reduction, however with an increased risk of hyperkalemia. Given reliance on surrogate endpoints, heterogeneity and limited long-term data, these findings should be interpreted cautiously and require confirmation in larger, long-term clinical outcome trials.