Sotagliflozin Reduces HF Events in T2DM Regardless of Baseline Characteristics, Including HF, CKD and LVEF

Abstract

The SCORED trial [1] showed that among patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) sotagliflozin versus placebo significantly reduced the heart failure (HF) composite endpoint of cardiovascular mortality (CVM) or hospitalizations and urgent visits for heart failure (HHF), while the SOLOISTWHF trial [2] showed that sotagliflozin did this among patients with T2DM and HF. However, neither of the trials [1, 2] was powered to assess the HF composite endpoint in clinically important subgroups and assess important individual endpoints such as CVM and all-cause mortality (ACM). Thus, we sought to evaluate the efficacy of sotagliflozin on the HF composite endpoint in various subgroups from the two trials [1, 2] and evaluate that on three individual outcomes, namely CVM, ACM, and HHF, by a meta-analysis incorporating the data from the two trials [1, 2]. In this meta-analysis, two authors extracted hazard ratios (HRs) and 95% confidence intervals (CIs) from various subgroups defined by 17 factors (they are detailed in Appendix 1) for analysis of HF composite endpoint (i.e., CVM or HHF), and extracted those from all randomly assigned patients for analysis of three individual outcomes using Stata/MP (version 16.0). Discrepancies between authors were resolved through discussion with a third author. An inverse-variance randomeffects meta-analysis was conducted. We examined heterogeneity via I statistic and between-group differences via metaregression analysis. Among T2DM patients with CKD or HF, sotagliflozin versus placebo did not significantly affect CVM (HR 0.88, 95% CI 0.73–1.06) and ACM (HR 0.95, 95% CI 0.81–1.11), but significantly reduced HHF (HR 0.66, 95% CI 0.56–0.77) (Fig. 1a–c). Among T2DM patients, sotagliflozin significantly reduced HF composite endpoint (HR 0.73, 95% CI 0.64–0.83), regardless of HF status, CKD status, cardiovascular disease (CVD) status (Psubgroup 0.834, 0.488, and 0.830, respectively; Fig. 1d– f), and ten other factors (Psubgroup ≥ 0.419; Fig. S1–S10). Although sotagliflozin showed a reduction in that endpoint among patients without baseline use of angiotensin receptor–neprilysin inhibitor (ARNI) (HR 0.67, 95% CI 0.56–0.80), and showed an increased trend among patients with baseline use of ARNI (HR 1.20, 95% CI 0.76–1.90; Fig. S11), the subgroup difference was not statistically significant (Psubgroup = 0.145). Among T2DM patients with HF, sotagliflozin significantly reduced that endpoint (HR 0.72, 95% CI 0.61–0.86), regardless of left ventricular ejection fraction (LVEF) level (Psubgroup ≥ 0.331; Fig. 1g–i), with a significant reduction in that endpoint among patients with LVEF ≥50% (HR 0.70, 95% CI 0.53–0.93). McGuire et al.’s meta-analysis [3] revealed that sodium–glucose cotransporter (SGLT) 2 inhibitors led to the consistent effects of favorable HHF and renal disease outcomes across various subgroups defined by CVD status, HF status, CKD status, glycated hemoglobin (HbA1c) level, and albuminuria level, although some heterogeneity was observed for the outcome of cardiovascular death. However, that meta-analysis [3], as well as any other previous studies, failed to confirm the clear benefits of SGLT 2 inhibitors on cardiorenal outcomes in patients with HF with preserved ejection fraction (HFpEF). Two ongoing trials, EMPEROR-Preserved (NCT03057951) assessing * Mei Qiu [email protected]