Impact of SGLT2 Inhibition on Markers of Reverse Cardiac Remodelling in Heart Failure: Systematic Review and Meta-Analysis

INTRODUCTION: Several landmark randomized-controlled trials (RCTs) have demonstrated the efficacy of sodium-glucose co-transport 2 (SGLT2) inhibitors in reducing all-cause mortality, cardiovascular (CV) mortality and heart failure (HF) hospitalizations. Much interest surrounds their mechanism of action and whether they have direct effects on reverse cardiac remodelling. Therefore, we conducted a meta-analysis of placebo controlled RCTs evaluating the impact of SGLT2 inhibition on imaging derived markers of reverse cardiac remodelling in patients with HF. METHODS: We performed a systematic review and meta-analysis in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Statement and Cochrane Collaboration. Data interrogation of each major database including PubMed, EMBASE, MEDLINE and Cochrane Library was performed. RCTs evaluating HF patients >18 years comparing SGLT2 inhibitor versus placebo-control were included. Outcome measures included left ventricular end-diastolic volume and volume index (LVEDV/LVEDVi), left ventricular end-systolic volume and volume index (LVSDV/LVSDVi), left ventricular ejection fraction (LVEF), left ventricular mass index (LVMi), left atrial volume index (LAVi) and left ventricular global longitudinal strain (LV GLS). Studies with an HF with preserved ejection fraction population were excluded from analysis of parameters, which would be significantly affected by baseline LVEF, such as volumes and LVEF. The mean difference and standard error were extracted from each study and a random effects model used pool the mean difference and standard error across studies. A pre-specified sub-group analysis was performed to stratify results according to imaging modality used (cardiac magnetic resonance imaging and echocardiography). This study is registered on PROSPERO: CRD42023482722. RESULTS: Seven randomized, placebo-controlled trials in patients with HF comprising a total population of 657 patients were included. Overall LVEF of included studies ranged from 29 ± 8.0% to 55.5 ± 4.2%. In studies included in analysis of HFrEF parameters, baseline LVEF ranged from 29 ± 8% to 45.5 ± 12%. Pooled data demonstrated SGLT2 inhibition, compared with placebo control, resulted in significant improvements in mean difference of LVEDV -11.62 ml (95% confidence interval, CI -17.90 to -5.25; z = 3.67, P = 0.0004), LVEDVi -6.08 ml (95% CI -9.96 to -2.20; z = 3.07; P = 0.002), LVESV -12.47 ml (95% CI -19.12 to -5.82; z = 3.68; P = 0.0002), LVESVi -6.02 ml (95% CI -10.34 to -1.70; z = 2.73; P = 0.006), LVM -9.77 g (95% CI -17.65 to -1.89; z = 2.43; P = 0.02), LVMi (-3.52 g 95% CI -7.04 to 0.01; z = 1.96; P = 0.05) and LVEF +2.54 mL (95% CI 1.10 to 3.98; z = 3.62; P = 0.0005). No significant difference in GLS (n = 327) +0.42% (95%CI -0.19 to 1.02; P = 0.18) or LAVi -3.25 ml (95% CI -8.20 to 1.69; z = 1.29; P = 0.20) was noted. CONCLUSION: This meta-analysis provides additional data and insight into the effects of SGLT2 inhibition on reverse cardiac remodelling in patients with HF. Compared with placebo control, we found that treatment with a SGLT2 inhibitor produced significant improvements in several markers of reverse cardiac remodelling.