Mineralocorticoid receptor antagonists (MRAs) are a cornerstone drug class for
heart failure therapy. Several clinical studies have demonstrated its role in
heart failure therapy. However, due to the recommendation of
sodium-
glucose cotransporter-2 (SGLT-2) inhibitors for the treatment of
heart failure, there is a lack of sufficient evidence regarding whether MRAs can continue to play a cornerstone role in
heart failure treatment. A meta-analysis was performed on subgroups of the DAPA-HF and EMPEROR-Reduced trials. Using trial-level data, we performed a meta-analysis to assess the effects of
SGLT-2 inhibitors and MRAs on various clinical endpoints of
heart failure. The incidence of cardiovascular-related death or
heart failure hospitalization was the primary outcome. In addition, we assessed cardiovascular death, all-cause death,
heart failure hospitalization, renal outcomes, and
hyperkalemia. This study has already been registered with PROSPERO, CRD42022385023. Compared with
SGLT-2 inhibitor monotherapy, combined treatment did not demonstrate more significant advantages in terms of
heart failure or cardiovascular death (RR = 1.00; 95% CI: 0.78-1.28), cardiovascular death (RR = 0.96; 95% CI: 0.61-1.52),
heart failure hospitalization (RR = 0.92; 95% CI: 0.79-1.07), all-cause death (RR = 1.00; 95% CI: 0.63-1.59) and composite kidney endpoint (RR = 0.85; 95% CI: 0.49-1.46). Moreover, in comparison to
SGLT-2 inhibitors, combined
therapy increased the risk of moderate-severe
hyperkalemia (blood potassium > 6.0 mmol/l) (RR = 4.13; 95% CI: 2.23-7.65). In patients with HFrEF who have started MRAs treatment, the addition of an
SGLT-2 inhibitor provides significant clinical benefit. However, the addition of MRAs to
SGLT-2 inhibitors to treat
heart failure is not essential.