Background: Angiotensin receptor-neprilysin inhibitor (ARNI) improves heart failure outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Similarly, sodium-glucose cotransporter 2 (SGLT2) inhibitors have also shown significant beneficial effects in this patient population. It is unclear if adding SGLT2 inhibitors to patients already using ARNI-containing regimen will have additional benefits in improving heart failure outcomes in patients with HFrEF. Methods: PubMed and MEDLINE search was performed using the search words – ARNI, SGLT2 inhibitor, and heart failure. Among the studies identified, we looked for randomized controlled, prospective, and retrospective studies on HFrEF that included patient groups using ARNI with SGLT2 inhibitors and ARNI without SGLT2 inhibitors and had heart failure outcomes. We identified three studies and performed a meta-analysis. Results: A total of 671 patients in the treatment group and 808 patients in the placebo group are included in our meta-analysis. The heart failure outcome analyzed is the composite of hospitalization for heart failure and cardiovascular death. Among the patients using ARNI without SGLT2 inhibitors, the outcome occurred in a total of 215 out of 808 patients (26.61%). In comparison, it occurred in 114 out of 671 patients (16.99%) among those who are on both ARNI and SGLT2 inhibitors. This study shows that there is a significant improvement in this heart failure outcome in patients with HFrEF taking an SGLT2 inhibitor and ARNI-containing regimen compared to those taking ARNI without an SGLT2 inhibitor with a relative risk (RR) of 0.67 and 95% confidence interval (CI) of 0.55 to 0.83 (p=0.0001). Conclusion: Though ARNI and SGLT2 inhibitors individually are known to improve heart failure outcomes, adding an SGLT2 inhibitor to ARNI significantly improves the heart failure outcome of the composite of hospitalization for heart failure and cardiovascular death in patients with HFrEF.