Comparative Effectiveness of Sodium-Glucose Co-transporter 2 (SGLT2) Inhibitors Versus Angiotensin Receptor-Neprilysin Inhibitors (ARNIs) in Heart Failure With Reduced Ejection Fraction: A Systematic Review.

Heart failure with reduced ejection fraction (HFrEF) remains a major cause of morbidity and mortality worldwide, despite advancements in pharmacotherapy. Among the most significant recent developments are sodium-glucose co-transporter 2 (SGLT2) inhibitors and angiotensin receptor-neprilysin inhibitors (ARNIs), both of which have demonstrated substantial improvements in clinical outcomes. This systematic review aimed to compare the efficacy, clinical outcomes, and therapeutic value of SGLT2 inhibitors versus ARNIs while also exploring their potential synergistic effects in the treatment of HFrEF. A comprehensive literature search was conducted across PubMed, Scopus, Embase, and Cochrane Central, adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and included randomized controlled trials published within the last 10 years. Five high-quality studies met the strict inclusion criteria, reflecting the limited but robust available evidence. The results suggest that both drug classes are effective in reducing cardiovascular death and heart failure hospitalizations, with emerging evidence indicating that their combined use may further enhance clinical outcomes. SGLT2 inhibitors have shown consistent benefits across key endpoints, even when used alongside ARNI therapy. The review highlights favorable safety profiles for both drug classes and supports early combination therapy in suitable patient populations. Observations regarding potential synergistic effects emerged from consistent trends across studies rather than being predefined primary outcomes. These findings reinforce current guideline recommendations advocating for multidrug strategies and emphasize the need for future direct comparative trials to optimize treatment sequencing in HFrEF.