Lessons from a pre-specified meta-analysis of sodium-glucose cotransporter-2 (SGLT2) inhibitors in heart failure: Time for new clinical recommendations

Introduction: Cardiovascular disease remains the leading cause of death worldwide with heart failure (HF) being one of the significant contributors to morbidity and mortality. The incidence of HF with preserved ejection fraction (HFpEF) is increasing, especially in young adults making it a growing public health matter. Sodium–glucose cotransporter-2 (SGLT2) inhibitors have been shown to reduce the development, progression, and mortality of heart failure in patients with reduced EF regardless of patients’ diabetes status but their clinical benefits in patients with heart failure and preserved ejection fraction are less well-established. Recent trials have shown reductions in cardiovascular death and heart failure events in patients with mildly reduced or preserved ejection fraction (EF), although with uncertainty around the consistency of clinical benefits across the classes and therapeutic effects. Study and Results: The meta-analysis used data from trials on patients with mildly reduced or preserved EF (DELIVER and EMPEROR-Preserved), reduced EF (DAPA-HF and EMPEROR-Reduced), and those hospitalized (SOLOIST-WHF). The endpoints evaluated included a composite of time to cardiovascular (CV) death or first hospitalization for heart failure, cardiovascular death, all-cause death, first and recurrent heart failure hospitalizations, and urgent heart failure visits (not requiring hospitalization). Among 12251 participants in the DELIVER and EMPEROR-Preserved trials, SGLT2 inhibitors reduced composite cardiovascular death or first hospitalization for HF (HR 0.80 [95% CI 0.73–0.87]) with consistent reductions in both components: cardiovascular death (HR 0.88 [95% CI 0.77–1.00]) and first hospitalization for HF (HR 0.74 [95% CI 0.67–0.83]). In the broader analysis of the five trials with a total of 21 947 participants, SGLT2 inhibitors reduced the risk of composite cardiovascular death or hospitalization for HF (HR 0.77 [95% CI 0.72–0.82]), cardiovascular death (0.87 [0.79–0.95]), first hospitalization for heart failure (HR 0.72 [95% CI 0.67–0.78]), and all-cause mortality (HR 0.92 [95% CI 0.86–0.99]). These treatment effects for each of the studied endpoints were consistently observed across all five trials and across the HF subgroups, including those on mildly reduced or preserved ejection fraction. Lessons learned: SGLT2 inhibitors significantly reduce the risk of mortality and worsening of heart failure and improve patient symptoms and overall health status across the full spectrum of ejection fraction. SGLT2 inhibitors should be considered foundational therapy in all patients with heart failure, irrespective of LVEF or care setting. The results presented propose an update of the recommendations for the pharmacological treatment of heart failure, to prioritize the use of SGLT2 inhibitors in patients across the full EF spectrum. Future investigations should include the long-term benefits of the use of SGLT2 inhibitors among the different HF subgroups, including the performance of SGLT2 inhibitors in those excluded from the current heart failure trials.