SGLT2i reduces cardiorenal outcomes in HFrEF irrespective of baseline NT-proBNP
Prognostic Importance of NT-proBNP and Effect of Empagliflozin in the EMPEROR-Reduced Trial
Introduction and methods
In patients with HFrEF, increased levels of NT-proBNP are associated with a more decompensated hemodynamic profile, higher filling pressures, greater risk for progression of adverse cardiac remodeling, hospitalization and death [1-4]. And reduction in NT-proBNP in response to treatment for HFrEF is associated with improved outcomes [1,2,5].
Following treatment with SGLT2 inhibitors in patients with T2DM (most of whom did not have HFrEF), a reduction in NT-proBNP has been observed . But the effect of SGLT2 inhibitors on NT-proBNP levels in chronic HFrEF patients has not been fully explored.
Therefore, in this analysis using data of the EMPEROR-Reduced trial, it was examined whether baseline NT-proBNP had an effect on the efficacy of SGLT2 inhibitors in HFrEF, what the effect of SGLT2 inhibitors was on levels of NT-proBNP, and whether changes in NT-proBNP after SGLT2i treatment were associated with subsequent outcomes.
In the EMPEROR-Reduced trial, HF patients with LVEF of ≤40% and NYHA class II-IV were randomized to placebo or empagliflozin. Other inclusion criteria were: recent hospitalization (within 12 months), or elevated NT-proBNP. NT-proBNP levels were measured at baseline, and at 4,12, 52 and 100 weeks. Baseline NT-proBNP measurements were available in 3728 study participants.
- Treatment with empagliflozin reduced time to first events of CV death, hospitalization or the composite of both events across NT-proBNP quartiles without interaction with baseline NT-proBNP (P trend >0.05).
- Use of empagliflozin reduced the risk of total hospitalizations for HF in all NT-proBNP quartiles, with no heterogeneity between groups (Ptrend=0.49). Similar results were seen for all-cause mortality.
- Empagliflozin reduced the rate of eGFR decline in each quartile, with no significant treatment-by-NT-pro-BNP heterogeneity (Ptrend=0.27). In addition, rates of the renal composite endpoint were reduced by empagliflozin, without treatment interaction with NT-proBNP.
- 4 Weeks of treatment with empagliflozin resulted in lowering of NT-proBNP levels (mean % change was 5%, 1-8%, P=0.0009). The difference was observed across all timepoints with the largest difference at 52 weeks (mean % change was 13% (7-18%, P<0.001).
- Patients had a lower risk of the primary endpoint of CV death/HF hospitalization if they had NT-proBNP of <1,115 pg/mL at week 12, regardless of baseline value of NT-proBNP.
- In an adjusted model, treatment with empagliflozin resulted in a 27% (95%CI: 5.6-52.6) higher likelihood of having NT-proBNP of <1,115 pg/mL (P=0.01). In those with an NT-proBNP of ≥1,115 pg/mL at baseline, treatment with empagliflozin resulted in an adjusted 35% (95CI: 17-56) higher likelihood of achieving an NT-proBNP of <1,115 pg/mL compared to the placebo group (P<0.001).
In this pre-specified analysis of EMPEROR-Reduced in HFrEF patients, the effect of empagliflozin on reducing the risk of outcomes was similar across NT-proBNP quartiles. Furthermore, empagliflozin reduced NT-proBNP levels and achievement of levels <1,115 pg/mL of NT-proBNP was associated with lower risk of outcomes.