Consistent effects with SGLT2 inhibitors in HFrEF in meta-analysis
SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trialsLiterature - Zannad F, Ferreiro JP, Pocock SJ, et al. - The Lancet 2020 Sep 19;396:819-829. doi: 10.1016/S0140-6736(20)31824-9.
Introduction and methods
Two large clinical trials, the Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death with Chronic Heart Failure (DAPA-HF) and the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction (EMPEROR-Reduced), have shown that SGLT2 inhibition in HFrEF patients with or without type 2 diabetes improves cardiovascular outcomes. More specifically, these studies have shown a significant reduction in the combined primary endpoint of risk of CV death or hospitalization for HF [1,2]. Neither of the trials were powered to adequately assess the treatment effects on secondary outcomes, such as CV death, all-cause mortality, or serious adverse renal events, or to characterize effects in clinically important subgroups.
This study conducted a prespecified meta-analysis, to assess the effects and safety of SGLT2i treatment on CV death, HF hospitalization, renal outcomes and clinical effects on subgroups in HFrEF patients with or without T2DM. Published data from DAPA-HF and patient data from EMPEROR-Reduced were used.
8474 Symptomatic HFrEF patients with LVEF ≤40%, with or without type 2 diabetes were included in the meta-analysis. Patients enrolled in the DAPA-HF trial had higher LVEF compared to patients in the EMPEROR-Reduced trial (~31% vs. ~27%, respectively), lower NT-proBNP concentration levels (~1440 vs. ~1900 pg/mL, respectively), and higher eGFR levels (~66 vs. ~62 mL/min/1.73m², respectively). The median follow-up time in DAPA-HF was 18 months and 16 months in EMPEROR-Reduced.
The predefined primary endpoint in the meta-analysis was time to all-cause death. The CV secondary outcomes were time to CV death, first hospitalization for HF or CV death, first HF hospitalization, and recurrent hospitalization for HF or CV death, and the renal secondary outcome was a composite of ≥50% sustained decline in eGFR, end-stage renal failure (ESRD, defined as sustained eGFR lower than 15mL/min per 1.73m², chronic dialysis or a renal transplantation), or renal death. The predefined study subgroups were: T2DM, sex, ARNI treatment, New York Heart Association (NYHA) class II or III-IV, race, age (≤65 or >65 years), history of HF hospitalization, eGFR<60 or ≥60 mL/min/1.73m², BMI <30 of ≥30kg/m², and region (North America, Latin America, Europe, or Asia). The last subgroup, region, was added post-hoc to determine whether the observed treatment effects on race would reflect the results in the subgroup region.
- SGLT2 inhibition significantly reduced the risk of all-cause mortality with 13% (HR 0.87, 95% CI:0.77-0.98, P=0.018), and CV death with 14% (HR 0.86, 95% CI: 0.76-0.98, P=0.027), compared to placebo.
- SGLT2i treatment resulted in a 26% reduction in combined risk of CV death or first hospitalization for HF (HR 0.74, 95% CI: 0.68-0.82, P<0.0001), a 25% reduction in risk of first and recurrent hospitalization for HF or CV death (HR 0.75, 95% CI: 0.68-0.84, P<0.0001), and 31% decrease in first hospitalization for HF (HR 0.69, 95% CI: 0.62-0.78, P<0.0001), compared to the pooled placebo group.
- The risk of the composite of renal events was reduced with 38% (HR 0.62, 95% CI: 0.43-0.90, P=0.013).
- No differences in treatment effects were found for diabetes, sex, ARNI therapy, age, history of hospitalization, eGFR, and BMI subgroups.
- A significant treatment-by-subgroup interaction was found for NYHA functional class. The pooled HRs for patients in NYHA class II significantly differed from patients in NYHA class III-IV (HR 0.67, 95% CI:0.59-0.76 vs. HR 0.87, 95% CI: 0.75-1.01, respectively, Pinteraction=0.0087). Treatment differences were also found for race (white vs. black and Asian, Pinteraction=0.0063) and region (Europe vs. North America, Latin America and Asia, Pinteraction=0.037).
- No statistical evidence for heterogeneity of SGLT2 inhibition treatment effects between the two trails was found for any of the endpoints. Also, no heterogeneity between the two treatments within a specific subgroup was observed.
- Both SGLT2 inhibitors were well tolerated. No excess in and imbalances for adverse events were observed between SGLT2i and placebo groups.
The meta-analysis of the DAPA-HF and EMPEROR-Reduced trials revealed that SGLT2 inhibition combined with standard HF care in HFrEF patients reduced all-cause mortality and CV death, HF hospitalization and serious adverse renal events, without any heterogeneity between the two trials. The risk reductions were independent of T2DM, sex, age, or ARNI treatment.