Efficacy of SGLT2-inhibitors across different definitions of heart failure with preserved ejection fraction

Abstract

Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been evaluated in phase 3 randomized–controlled trials (RCTs) that enrolled individuals with heart failure and preserved ejection fraction (HFpEF) based on detailed clinical, biochemical, and echocardiographic criteria (hereafter HF-RCTs), and in cardiovascular outcomes trials (CVOTs) in diabetic patients, in which the diagnosis of HFpEF relied on medical history. Methods and results We performed a study-level meta-analysis of the efficacy of SGLT2i across different definitions of HFpEF. Three HF-RCTs (EMPEROR-Preserved, DELIVER, and SOLOIST-WHF) and four CVOTs (EMPA-REG OUTCOME, DECLARE-TIMI 58, VERTIS-CV, and SCORED) were included, for a total of 14 034 patients. SGLT2i reduced the risk of cardiovascular death or heart failure hospitalization (HFH) in all RCTs pooled together [risk ratio 0.75, 95% confidence interval (95% CI) 0.63–0.89, NNT 19], in HF-RCTs (risk ratio 0.71, 95% CI 0.52–0.97, NNT 13), and in CVOTs (risk ratio 0.78, 95% CI 0.60–0.99, NNT 26). SGLT2i also decreased the risk of HFH in all RCTs (risk ratio 0.81, 95% CI 0.73–0.90, NNT 45), in HF-RCTs (risk ratio 0.81, 95% CI 0.72–0.93, NNT 37), and in CVOTs (risk ratio 0.78, 95% CI 0.61–0.99, NNT 46). By contrast, SGLT2i were not superior to placebo for cardiovascular death or all-cause death in all RCTs, HF-RCTs, or CVOTs. Results were comparable after excluding one RCT at a time. Meta-regression analysis confirmed that the type of RCT (HF-RCT vs. CVOT) did not influence the SGLT2i effect. Conclusions In RCTs, SGLT2i improved the outcomes of patients with HFpEF regardless of how the latter was diagnosed.

The complex interplay between SGLT2 inhibitors and atrial fibrillation: mechanisms and clinical implications

“…The use of SGLT2 inhibitors has shown favorable effects in patients with heart failure (HF), including reduced HF with reduced or preserved ejection fraction, and chronic kidney disease. These findings suggest that SGLT2 inhibitors may have a role in blood pressure modulation and potentially reducing the risk of AF (Vincenzo et al, 2023;Sajad et al, 2023;Ping-Fan, 2023).…”

“…• Heart failure benefits: SGLT2 inhibitors have consistently demonstrated substantial benefits in reducing heart failure hospitalizations and cardiovascular mortality. Given the frequent coexistence of AF and heart failure, improved heart failure outcomes indirectly contribute to better AF management (Khiali et al, 2023;Vincenzo et al, 2023;Omar et al, 2023;Sara, 2023).…”

Empagliflozin ameliorates ventricular arrhythmias by inhibiting sympathetic remodeling via nerve growth factor/tyrosine kinase receptor A pathway inhibition

“…They reduce the renal threshold for glucose and increase its excretion in urine by inhibiting the active glucose reabsorption by SGLT2 of the proximal renal tubules, thus lowering blood glucose safely and effectively 7 . They also significantly reduce the occurrence and progression of heart failure and cardiovascular events 8–12 . Compared with angiotensin receptor-neprilysin inhibitor (ARNI) monotherapy, ARNI combined with SGLT2is therapy could reduce hospitalization and mortality in patients with heart failure with preserved ejection fraction (HFpEF) 13 .…”

“…7 They also significantly reduce the occurrence and progression of heart failure and cardiovascular events. [8][9][10][11][12] Compared with angiotensin receptor-neprilysin inhibitor (ARNI) monotherapy, ARNI combined with SGLT2is therapy could reduce hospitalization and mortality in patients with heart failure with preserved ejection fraction (HFpEF). 13 In patients with HFrEF, compared with omecamtiv mecarbil and vericiguat, SGLT2is can significantly reduce the risk of heart failure hospitalization, and were superior to omecamtiv mecarbil for cardiovascular death and all-cause death.…”