SGLT2 inhibitors prevent mortality and CTRCD in anthracycline-treated patients: first meta-analytic evidence integrating EMPACARD trial

Background Anthracycline cardiotoxicity affects ~9% of treated patients causing cancer therapy-related cardiac dysfunction (CTRCD) (1). ESC defines CTRCD as LVEF decline >10% to <50% or new symptomatic cardiomyopathy (2). While ESC guidelines recommend ACE inhibitors/β-blockers (Class IIa, Level B), they don't have SGLT2 inhibitors (SGLT2i) recommendations despite preclinical evidence and emerging clinical data (2). Prior meta-analyses reported benefits, but were limited to retrospective cohorts and did not assess CTRCD outcomes (3). Purpose We combined the first prospective trial (EMPACARD-PILOT) and propensity-matched cohorts to quantify SGLT2i efficacy in preventing mortality, heart failure (HF) and specifically structural CTRCD in anthracycline-treated patients. Methods Our analysis adhered to PRISMA guidelines. A systematic search of PubMed, Scopus, Embase, and Cochrane was performed till January 2026 to identify studies comparing SGLT-2i with standard care in cancer patients undergoing anthracycline therapy. Two independent reviewers performed data extraction and quality assessment using the ROBINS-I. Data were analyzed using RevMan 5.4.1. Adjusted Hazard Ratios (HRs) and Odds Ratios (ORs) were pooled using the Generic Inverse Variance method, while dichotomous outcomes were analyzed by calculating Risk Ratios (RRs) with 95% Confidence Intervals (CIs) using the Mantel-Haenszel method. A random-effects model was used for all analyses to account for study heterogeneity, which was assessed using Higgins’ I² statistic. Outcomes assessed included mortality, and incidence of Heart Failure (HF), arrhythmias and CTRCD as defined above. Number Needed to Treat (NNT) was calculated for statistically significant outcomes to estimate clinical impact. Results Six studies comprising 8,571 patients were included. In the pooled analysis, SGLT2i use was associated with a 48% reduction in all-cause mortality (RR 0.52, 95% CI 0.37–0.75, p=0.0004) and a significant reduction in Heart Failure events (RR 0.36, 95% CI 0.19–0.68, p=0.002). Notably, SGLT2i showed efficacy in preventing CTRCD (pooled n=460 from 3 studies; RR 0.23, 95% CI 0.14–0.40, p<0.00001). This finding was remarkably consistent across study designs (I²=0%), including the EMPACARD study and propensity matched real-world cohorts. Additionally, SGLT2i significantly reduced the risk of new-onset arrhythmias (RR 0.24, 95% CI 0.06–0.95, p=0.04). Conclusion This meta-analysis provides the strongest evidence to date that SGLT2i prevent CTRCD and shows promise as potential cardioprotective strategy in anthracycline-treated patients. The signal for CTRCD prevention is consistent (I²=0%) across prospective and propensity matched data, with a calculated NNT of 6 to prevent one case of CTRCD. Further prospective randomized studies are warranted to provide stronger evidence for guidelines.