Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors in Non-diabetic Heart Failure: A Systematic Review of Randomized Controlled Trials and Real-World Evidence.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were initially developed to improve glycemic control in patients with type 2 diabetes. More recently, growing evidence has highlighted their cardiovascular benefits, particularly in patients with heart failure (HF), irrespective of diabetic status. This systematic review evaluates the efficacy and safety of SGLT2i, including dapagliflozin and empagliflozin, in non-diabetic patients with HF across different phenotypes, namely heart failure with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). A comprehensive literature search was conducted in PubMed, Scopus, and Embase for studies published between January 1, 2015, and January 15, 2024, in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Eligible studies included adult patients with HF, reported outcomes for non-diabetic subgroups, and assessed treatment with SGLT2i. Six studies met the inclusion criteria: four randomized controlled trials (RCTs), one pooled patient-level analysis, and one observational cohort study involving 16,264 non-diabetic patients. A pooled patient-level analysis incorporated data from DAPA-HF and DELIVER; to avoid duplication, only DAPA-HF was analyzed individually, while DELIVER was included solely within the pooled dataset. SGLT2i use was associated with lower cardiovascular mortality (hazard ratio (HR): 0.73-0.86) and reduced HF hospitalization, with consistent benefits in both HFrEF and HFpEF. Adverse events such as hypoglycemia, volume depletion, and infections were uncommon and typically mild, although genital infections were more frequent than placebo, and severe adverse events were not increased. Due to heterogeneity in study designs, outcome definitions, and HF phenotypes, quantitative meta-analysis was not feasible. A structured qualitative synthesis was performed. To our knowledge, this is one of the first systematic reviews to comprehensively evaluate the use of SGLT2i in non-diabetic patients with HF across phenotypes. The findings reinforce the role of SGLT2i as a foundational therapy in non-diabetic HF and highlight the need for broader implementation in practice.