Commentary: Cardiovascular Outcome in Patients Treated With SGLT2 Inhibitors for Heart Failure: A Meta-Analysis

Abstract

A Commentary on Cardiovascular Outcome in Patients Treated With SGLT2 Inhibitors for Heart Failure: A Meta-Analysis by Gager, G. M, Gelbenegger, G., Jilma, B., von Lewinski, D., Sourij, H., Eyileten, C., Filipiak, K., Postula, M., Siller-Matula, J. M. (2021). Front. Cardiovasc. Med. 8:691907. doi: 10.3389/fcvm.2021.691907 In the meta-analysis of Gager et al. (1) recently published in the journal Frontiers in Cardiovascular Medicine, the authors identified that sodium-glucose co-transporter-2 (SGLT2) inhibitors could reduce heart failure (HF) events and all-cause mortality in patients with HF and that the benefit of this drug class on the primary endpoint (i.e., a composite of hospitalization for HF HHF) or cardiovascular mortality (CVM) was consistent across relevant HF subgroups defined by the following clinically important factors: the status of type 2 diabetes at baseline, type of HF (according to left ventricular ejection fraction, LVEF), cause of HF, specific SGLT2 inhibitors, gender, age, estimated glomerular filtration rate (eGFR), body mass index, and concomitant medications. However, Gager et al. (1) failed to evaluate the effect of SGLT2 inhibitors in several subgroups defined by three other clinically important factors: race, region, and baseline New York Heart Association (NYHA) class. Hence, we aimed to conduct another meta-analysis to examine whether these factors affect the efficacy of gliflozins in patients with HF or not. Moreover, Gager et al. in their meta-analysis (1), failed to include the latest EMPEROR-Preserved trial (2) assessing empagliflozin in patients with HF with an LVEF of > 40%. Since that trial (2) provided the new data in the subgroup of HF with mildly reduced LVEF (HFmrEF) and the subgroup of HF with preserved LVEF (HFpEF), we repeated the subgroup analysis according to LVEF by adding these new data, although this subgroup analysis had been performed in the meta-analysis of Gager et al. (1). We only included in this meta-analysis large cardiovascular outcome trials (CVOTs) that compared the HF outcomes of SGLT2 inhibitors with those of placebo in patients with HF. The only endpoint of interest for this meta-analysis was the composite HF outcome, which was defined as a composite of HHF or CVM. Embase and PubMed were searched (from inception to August 31st, 2021), using the following retrieval terms: “heart failure,” “HFpEF,” “HF with reduced LVEF (HFrEF),” “SGLT2 inhibitors,” “empagliflozin,” “canagliflozin,” “ertugliflozin,” “dapagliflozin,” “sotagliflozin,” and “randomized controlled trial.” Finally, we included four CVOTs (2–5) focusing on assessing gliflozins in patients with HF. We extracted trial-level survival data (i.e., hazard ratios, HRs, and 95% confidence intervals, CIs) in various subgroups of interest from included trials, and, based on them, performed a random-effects meta-analysis. Subgroup analyses were conducted according to the following four factors: region (Asia, Latin America, North America, and Europe), race (White, Asian, and Black), baseline NYHA class (Class II and Class III or IV), and LVEF at baseline (LVEF ≤ 40%, i.e., HFrEF, LVEF > 40 to P < 0.05 indicating statistical significance. We completed data analyses using Stata (version 16.0). Compared with placebo, SGLT2 inhibitors reduced the composite HF outcome by 40% in patients with HF enrolled in Asia (HR.6, 95% CI 0.50–0.73), 17% in those enrolled in Europe (HR 0.83, 95% CI 0.74–0.93), 26% in those enrolled in Latin America (HR 0.74, 95% CI 0.64–0.85), and 30% in those enrolled in North America (HR 0.7, 95% CI 0.58–0.84); and yielded more reductions in those enrolled in Asia than in the other three continents (P_subgroup = 0.03; Figure 1A). SGLT2 inhibitors yielded more reductions in that outcome in Asian patients (38% reduction, HR 0.62, 95% CI 0.52–0.74) and Black patients (36% reduction, HR 0.64, 95% CI 0.47–0.87) than in White patients (21% reduction, HR 0.79, 95% CI 0.72–0.88), with a significant subgroup difference (P_subgroup = 0.04; Figure 1B). SGLT2 inhibitors yielded more reductions in that outcome in patients with NYHA class II (31% reduction, HR 0.69, 95% CI 0.63–0.76) than NYHA classes III–IV (14% reduction, HR 0.86, 95% CI 0.77–0.97), with a significant subgroup difference (P_subgroup < 0.01; Figure 1C). SGLT2 inhibitors reduced that outcome by 24% (HR 0.76, 95% CI 0.69–0.82) whether in patients with HFmrEF, patients with HFrEF patients, or patients with HFpEF patients (P_subgroup = 0.53; Figure 1D). Figure 1. Forest plots illustrating the effect of SGLT2 inhibitors on composite HF outcome in patients with HF by four important factors. (A) Effects of SGLT2 inhibitors on composite HF outcome in HF patients by Regions. (B) Effects of SGLT2 inhibitors on composite HF outcome in HF patients by Race. (C) Effects of SGLT2 inhibitors on composite HF outcome in HF patients by Baseline NYHA class. (D) Effects of SGLT2 inhibitors on composite HF outcome in HF patients by LVEF at baseline. SGLT2, sodium-glucose co-transporter-2; HF, heart failure; CI, confidence interval; NYHA, New York Heart Association; LVEF, left ventricular ejection fraction; Composite HF outcome: defined as a composite of hospitalization for HF or cardiovascular mortality. The meta-analysis of Gager et al. (1) confirmed the consistent efficacy of SGLT2 inhibitors on the composite HF outcome (i.e., a composite of HHF/CVM) in various HF subgroups...