Mineralocorticoid Receptor Antagonists Do Not Alter SGLT2i Effects in Heart Failure

Risk for hospitalization for heart failure (HHF), cardiovascular (CV) death, and all-cause mortality are not affected by use of mineralocorticoid receptor antagonists (MRAs) with sodium-glucose co-transporter-2 inhibitors (SGLT2) in patients with HF, according to a study in the European Heart Journal.

The meta-analysis evaluated the effect of MRA use on the CV effects of SGLT2 inhibitors in patients with HF regardless of ejection fraction (EF).

Investigators search the PubMed/MEDLINE, Embase, and Web of Science databases and clinical trial registries for relevant randomized controlled trials (RCTs) or post-hoc analyses of RCTs through February 4, 2023. Eligible studies included adults (aged ≥18 years) with HF regardless of EF and diabetes status with a duration of 6 months or longer and an intervention group treated with 1 SGLT2 inhibitor as monotherapy or add-on to baseline medications and a comparator group treated with placebo. The main outcomes were the composite of HHF/CV death, HHF, and CV death.

The analysis included 5 studies with 21,947 patients who had HF. Sotagliflozin was used in 1 study and the other 4 studies were post-hoc analyses of RCTs on empagliflozin and dapagliflozin.

In the pooled analysis, randomization to SGLT2 inhibitor treatment vs placebo was associated with a decreased risk for HHF/CV death among patients with HF treated with MRAs (hazard ratio [HR], 0.75; 95% CI, 0.68-0.81) or without MRAs (HR, 0.79; 95% CI, 0.72-0.86; P =.43 for subgroup differences).

SGLT2 inhibitors had a similar decrease compared with placebo for the risk for HHF in patients with chronic HF who were or were not using MRAs at baseline (HR, 0.74; 95% CI, 0.67-0.83; vs HR, 0.71; 95% CI, 0.63-0.80; P_interaction =.53).

SGLT2 inhibitors reduced CV death compared with placebo among only patients with chronic HF treated with MRAs (HR, 0.81; 95% CI, 0.72-0.91) but not for MRA nonusers (HR, 0.98; 95% CI, 0.86-1.13). A greater relative reduction was indicated in CV death in patients with chronic HF regardless of EF who were randomly assigned to SGLT2 inhibitors and receiving MRA (P =.034 for subgroup differences).

SGLT2 inhibitors compared with placebo reduced all-cause mortality in the HF subgroup with MRA use (HR, 0.90; 95% CI, 0.81-0.99), but not in those without MRA use at baseline (HR, 0.97; 95% CI, 0.88-1.08). No subgroup differences were observed in SGLT2 inhibitor effects based on MRA use (P_interaction =.27).

For participants who received SGLT2 inhibitors, renal adverse events were comparable in MRA users vs nonusers (relative risk [RR], 0.83; 95% CI, 0.68-1.01). A similar observation occurred among patients randomly assigned to placebo (RR, 0.97; 95% CI, 0.80-1.17). SGLT2 inhibitors appeared to reduce the risk for mild hyperkalemia (P_interaction <.001) and severe hyperkalemia (P_interaction =.051) associated with use of MRA.

Among several limitations, participants were randomized for SGLT2 inhibitors use but not for MRA use. In addition, the data for previous MRA use are unavailable for patients who were not on MRAs at baseline, the analysis did not account for changes in MRA use during the follow-up, and the duration of differential use of MRAs was unknown.

“Combination of SGLT2i [inhibitors] and MRA may offer a potential disease-modifying strategy with lower risk of treatment-emergent hyperkalemia in people with chronic HF regardless of EF,” wrote the study authors. “These hypothesis-generating findings require prospective testing with adequately powered randomized controlled trials.”