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Mineralocorticoid Receptor Antagonists With SGLT2 Inhibitors in HF
Quick Takes
- This meta-analysis reports greater beneficial effects of SGLT2i on cardiovascular mortality in individuals who were using MRAs compared to those who were not using MRAs regardless of EF.
- Furthermore, SGLT2i appeared to mitigate the risk of MRA-associated treatment-emergent hyperkalemia.
- Additional prospective testing with adequately powered randomized controlled trials is indicated to assess synergistic benefits of SGLT2i plus MRA in heart failure.
Study Questions:
What are the cardiovascular effects of sodium-glucose co-transporter-2 inhibitors (SGLT2i) with concomitant mineralocorticoid receptor antagonist (MRA) use in heart failure (HF) regardless of ejection fraction (EF)?
Methods:
The investigators searched PubMed/MEDLINE, Web of Science, Embase, and clinical trial registries for randomized controlled trials/post hoc analyses evaluating SGLT2i in HF with or without MRA use (PROSPERO: CRD42023397129). The main outcomes were composite of first hospitalization or urgent visit for HF/cardiovascular death (HHF/CVD), HHF, and CVD. Others were all-cause mortality, and composite renal and safety outcomes. Hazard ratios (HRs)/risk ratios were extracted. Fixed-effects meta-analyses and subgroup analyses were performed. Additionally, to explore the impact of SGLT2i on MRA-associated hyperkalemia, the difference in the rate of occurrence of adverse events in MRA users versus MRA nonusers was calculated using the relative risk (RR) with 95% confidence interval (CI) after implementation of the Mantel-Haenszel fixed-effects model followed by a subgroup analysis based on randomized treatment with SGLT2i versus placebo.
Results:
Five eligible studies were included, pooling data from 21,947 people with HF (type 2 diabetes mellitus, n = 10,805). Compared to placebo, randomization to SGLT2i showed a similar reduction in HHF/CVD and HHF in people who were or were not using MRAs (HHF/CVD: HR, 0.75; 95% CI, 0.68–0.81 vs. HR, 0.79; 95% CI, 0.72–0.86; p for interaction = 0.43; HHF: HR, 0.74; 95% CI, 0.67–0.83 vs. HR, 0.71; 95% CI, 0.63–0.80; p for interaction = 0.53), with a suggestion of greater relative reduction in CVD in chronic HF people randomized to SGLT2i and using MRAs irrespective of EF (HR, 0.81; 95% CI, 0.72–0.91 vs. HR, 0.98; 95% CI, 0.86–1.13; p for interaction = 0.034). SGLT2i reduced all-cause mortality (p for interaction = 0.27) and adverse renal endpoints regardless of MRA use (p for interaction = 0.73) despite a higher risk of volume depletion with concomitant MRAs (p for interaction = 0.082). SGLT2i attenuated the risk of mild hyperkalemia (p for interaction < 0.001) and severe hyperkalemia (p for interaction = 0.051) associated with MRA use.
Conclusions:
The authors report a more pronounced relative reduction in CVDs in chronic HF patients regardless of EF who were randomized to SGLT2i and receiving an MRA.
Perspective:
This meta-analysis reports a greater beneficial effect of SGLT2i on cardiovascular mortality in individuals who were using MRA compared to those who were not using MRA regardless of EF. Furthermore, SGLT2i appeared to mitigate the risk of MRA-associated treatment-emergent hyperkalemia and may offer a potential disease-modifying strategy in people with chronic HF regardless of EF. Although the results of this study are quite promising, these hypothesis-generating findings require additional prospective testing with adequately powered randomized controlled trials.
Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure
Keywords: Diabetes Mellitus, Type 2, Heart Failure, Hyperkalemia, Mineralocorticoid Receptor Antagonists, Sodium-Glucose Transporter 2 Inhibitors
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