SGLT2 inhibitors improve cardiovascular clinical outcomes in patients undergoing anthracycline chemotherapy: a systematic review and meta-analysis of 13,333 patients

Abstract Background A growing body of preclinical and clinical studies suggests that sodium-glucose cotransporter-2 (SGLT2) inhibitors may play a protective role against anthracycline-related cardiotoxicity (1). Despite these promising findings, an updated meta-analysis addressing this hypothesis remains lacking. Purpose The aim of this systematic review was to evaluate the efficacy and safety of SGLT2 inhibitors in improving cardiovascular outcomes in patients receiving anthracycline chemotherapy. Methods A systematic search of PubMed, Web of Science, and Cochrane Library was conducted up to February 15, 2025, using keywords such as SGLT2 inhibitors, anthracyclines, cardiotoxicity, and heart failure. Only observational and randomized studies reporting all-cause mortality and a composite of new-onset heart failure (HF) or hospitalization for heart failure as primary endpoints were included. Secondary outcomes included a ≥10% reduction in left ventricular ejection fraction (LVEF), a composite of eGFR decline or acute kidney injury (AKI), a composite of atrial fibrillation (AF), atrial flutter (FLA), or clinically relevant arrhythmias, and urinary tract infections (UTIs) as a safety endpoint. Four retrospective cohort studies and one prospective randomized case-control study were deemed eligible. Results A total of 13,333 patients were included across the five studies. The mean age ranged from 56.5 to 70 years, with a male proportion varying from 29.5% to 68%. Diabetes mellitus was highly prevalent, reaching 100% in three studies. Most patients were receiving concomitant cardiovascular therapies, including statins, beta-blockers, and RAS inhibitors. SGLT2 inhibitors were associated with a significant reduction in all-cause mortality (RR: 0.38, 95% CI: 0.32–0.46, p 0.001) with no heterogeneity (I² = 0.00%), and Egger’s test did not indicate small-study effects (p = 0.765). The risk of new-onset HF or HF hospitalization was significantly lower in SGLT2 inhibitor users (RR:0.52, 95% CI: 0.42–0.66, p 0.001) with no heterogeneity (I² = 0.00%); Egger’s test suggested a potential small-study effect trend (p = 0.095). EF reduction by ≥10% from baseline was significantly less frequent in SGLT2 inhibitor users (RR: 0.21, 95% CI: 0.06–0.76, p = 0.02), as was renal injury (RR: 0.60, 95% CI: 0.51–0.72, p 0.001), AF, FLA, or clinically relevant arrhythmias (RR: 0.40, 95% CI: 0.22–0.70, p = 0.00), and UTI (RR: 0.54, 95% CI: 0.40–0.71, p 0.001), all with no heterogeneity (I² = 0.00%). Conclusions SGLT2 inhibitors significantly reduce mortality, HF hospitalization or incident HF, renal function decline, and arrhythmias in patients undergoing anthracycline chemotherapy, without increasing UTI risk. The absence of heterogeneity supports the robustness of these findings, though further randomized trials are needed to confirm these benefits.Figure 1 Figure 2