Clinical Outcomes of SGLT2 Inhibitors in Heart Failure Patients Regardless of Diabetes Status: A Systematic Review

Abstract

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors were developed as glucose-lowering agents but have demonstrated profound cardiovascular benefits in patients with heart failure regardless of diabetes status. The landmark DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, and DELIVER trials have collectively established SGLT2 inhibitors as foundational therapy across the entire spectrum of heart failure ejection fractions. This systematic review aimed to comprehensively evaluate the clinical outcomes of SGLT2 inhibitors in heart failure patients irrespective of diabetes status.

Methods: A systematic literature search was conducted in PubMed/MEDLINE, EMBASE, Cochrane Library, and Web of Science. Randomized controlled trials, systematic reviews, and meta-analyses reporting clinical outcomes of SGLT2 inhibitors in heart failure patients, with pre-specified subgroup data by diabetes status, were eligible. Quality assessment used the Cochrane Risk of Bias tool (RoB 2.0) for RCTs and AMSTAR-2 for systematic reviews. The GRADE approach was applied to evidence certainty.

Results: Ten studies met eligibility criteria: 4 landmark RCTs (DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, DELIVER), 1 pre-specified meta-analysis of 2 HFrEF trials (Zannad et al., Lancet 2020), and 1 comprehensive meta-analysis of 5 trials (Vaduganathan et al., Lancet 2022), plus 4 additional subgroup analyses. SGLT2 inhibitors significantly reduced the composite primary outcome of cardiovascular death or worsening heart failure across all ejection fraction categories regardless of diabetes status. In HFrEF (DAPA-HF; HR 0.74; 95% CI 0.65–0.85): benefit was consistent in diabetic (HR 0.75) and non-diabetic patients (HR 0.73). In HFpEF (EMPEROR-Preserved): HR 0.79 (95% CI 0.69–0.90). The comprehensive 5-trial meta-analysis confirmed a pooled 23% relative risk reduction in CV death or HF hospitalization (HR 0.77; 95% CI 0.72–0.82; p<0.0001) with no significant diabetes-status interaction.

Conclusion: SGLT2 inhibitors provide consistent, diabetes-status-independent cardiovascular and heart failure benefits across the full ejection fraction spectrum. These agents should be considered standard of care for all eligible patients with heart failure, irrespective of the presence or absence of type 2 diabetes mellitus, consistent with current international guidelines