SGLT2 inhibitors in heart failure with preserved and reduced ejection fraction: a systematic review and meta-analysis

Abstract

Background: Over the recent months, the scenery of the pharmacological treatment of heart failure has changed. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have become the protagonists, as trial after trial is revealing a prognostic benefit of their use for patients with heart failure (HF). While their clear advantage in heart failure with reduced ejection fraction (HFrEF) has resulted in the addition of SGLT2i in the most recent treatment guidelines 1, the magnitude of their impact in heart failure with preserved ejection fraction (HFpEF) is still debated. With the recent results of EMPEROR-Preserved trial shedding more light into this matter 2, concrete evidence is needed now more than ever to ascertain the role of SGLT2i in the management of HFpEF. Aims: We performed a systematic review and meta-analysis to evaluate the role of SLGT2i in the management of patients with HF. More specifically, we performed a pre-specified subgroup analysis to assess the impact of this drug class in heart failure with reduced and preserved ejection fraction separately. Methods: We conducted a systematic search of PubMed, Embase, Cochrane and Web of Science databases from inception to 15th of September. With the primary endpoint being hospitalisation for heart failure (HHF) or cardiovascular death (CVD), we identified 9,493 articles out of which 8 randomised controlled trials and 20,758 patients were included in the meta-analysis 2-9. The hazard ratios (HR) and 95% CI given in each study were used for the meta-analysis. A random-effects model with inverse-variance weights was used to combine the effect measures from all studies on a logarithmic scale. Statistical heterogeneity was assessed using the I2 statistic. The statistical analyses were conducted using the Review Manager (RevMan) software (version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Results: The use of SGLT2i was associated with a significant reduction in HHF or CVD both for the patients with heart failure and EF>40% (HR=0.78, 95%CI: 0.69, 0.87; I2 0%) and for the patients with heart failure and EF<40% (HR=0.74, 95%CI: 0.68, 0.81; I2 0%), while for the total population SGLT2i reduced the risk of HHF or CV death by 25% (HR=0.75, 95%CI: 0.70, 0.81; I2 0%) (figure 1). Additionally, a prespecified subanalysis showed that in the specific cohort of patients with heart failure and EF>50%, SGLT2i resulted in 23% lower risk of HHF or CV death (HR=0.77, 95%CI: 0.66, 0.91; I2 22%) (figure 2). Conclusion: This meta-analysis provides robust evidence that SGLT2i appear to have a prognostic benefit across the spectrum of heart failure subgroups in terms of HHF or CV death. Further large-scale randomised trials examining the role of this drug class in the management of HFpEF would be extremely valuable and might transform the field of therapeutic strategies in this challenging clinical entity. (Figure Presented).