Latest EMPEROR-Reduced results show this SGLT2 inhibitor lowered risks for adverse HF/renal outcomes

The latest results from the EMPEROR-Reduced study show that empagliflozin reduced risks for adverse heart failure (HF) and renal outcomes independently of baseline N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentrations.

Researchers also demonstrated that patients with higher baseline NT-proBNP had greater risks for these adverse outcomes and recommended that—to better determine patient prognosis—clinicians may be better served in measuring NT-proBNP concentrations after, rather than before, treatment with empagliflozin.

Lead author James L. Januzzi, Jr., MD, of Massachusetts General Hospital, Harvard Medical School, and the Baim Institute for Clinical Research, Boston, explained the impetus behind the study—the first to gather large-scale data on serial NT-proBNP concentrations in HFrEF patients treated with empagliflozin, that is published in the Journal of the American College of Cardiology.

“The SGLT2 inhibitor class of therapies were originally developed for care of diabetes. However, early on in the studies of these drugs, we noticed they had an impact on heart failure outcomes. One of the ways to understand benefit of heart failure therapies is to evaluate how treatments affect concentrations of biomarkers known as natriuretic peptides. These circulating proteins are released from the heart in proportion to presence and severity of heart failure, so when very elevated they are associated with more severe disease and worse prognosis. In contrast, treatments with favorable effects in heart failure tend to LOWER natriuretic peptides in parallel with benefit of the treatment,” he told BreakingMED.

“In early work from the MGH Heart Center, we published data showing that SGLT2 inhibitors lowered concentrations of NT-proBNP in patients with diabetes,” Januzzi added. “After being recognized as a candidate treatment for heart failure, large programs focused on effects of SGLT2 inhibitors as a heart failure (rather than diabetes) treatment were performed. The EMPEROR-Reduced Trial evaluated impact of empagliflozin 10 mg versus placebo as a heart failure treatment among patients with heart failure and reduced ejection fraction. The study revealed a 25% reduction in the primary endpoint of cardiovascular death or heart failure hospitalization. However, mechanistically, we remain uncertain how these therapies are exerting their benefits. This motivated the current research.”

These results come on the heels of another recent study, also published in the Journal of the American College of Cardiology, in which empagliflozin was shown to improve cardiovascular and renal outcomes independently of systolic blood pressures. These findings also bolster and expand on those from recent sister trials, including EMPEROR-Pooled and EMPEROR-Preserved.

In this latest iteration of results from EMPEROR-Reduced, Jannuzzi and colleagues sought to assess the relationship between NT-proBNP and empagliflozin on patients with HFrEF who had been randomized to treatment with either empagliflozin (10 mg daily) or placebo. They measured NT-proBNP concentrations at baseline, and then again at 4, 12, 52, and 100 weeks; and classified patients according to baseline levels.

From lowest to highest, patients were classified according to the following NT-proBNP quartiles:

  • ˂1,115 pg/mL.
  • 1,115 to 1,909 pg/mL.
  • 1,910-3,479 pg/mL.
  • ≥3,480 pg/mL.

Strikingly, researchers found that patients in the highest NT-proBNP quartile had 4- to 6-fold higher incidence rates for each study outcome compared with those in the lowest quartiles. Other findings include the following:

  • Patients with higher NT-proBNP had 2- to 3-fold higher total hospitalizations compared with those in the lowest quartile.
  • Across NT-proBNP quartiles, empagliflozin effected similar reductions on the risk for major cardiorenal events (primary endpoint Pinteraction=0.94; renal composite endpoint Pinteraction=0.71).
  • Empagliflozin reduced NT-proBNP at all timepoints, and by 52 weeks, the adjusted mean difference from placebo was 13% (P˂0.001).
  • At 12 weeks, having an NT-proBNP of ˂1,115 pg/mL (the lowest quartile) was associated with lower risks for cardiovascular death or hospitalization for heart failure or renal outcomes, no matter what patients’ baseline NT-proBNP concentrations were.
  • Compared with placebo, empagliflozin effected a 27% higher adjusted odds of having NT-proBNP ˂1,115 pg/mL (P=0.01).

“What we found—that empagliflozin was associated with an early robust reduction in NT-proBNP, that treatment with empagliflozin increased the likelihood for lower NT-proBNP soon after treatment initiation, and that such reductions were strongly associated with benefits of the treatment help to confirm a strong link between NT-proBNP trends and outcomes when treated with favorable therapies in heart failure,” Januzzi told BreakingMED.

“As with other studies, NT-proBNP is strongly prognostic for adverse outcome, and the changes seen after treatment were predictive of the change in prognosis. These results are thus consistent with other studies that suggest that longitudinal change in biomarkers may help to monitor prognosis over time in chronic heart failure,” he added.

Januzzi added a few caveats: “It is worthwhile pointing out the magnitude of NT-proBNP reduction from empagliflozin treatment was more modest than that seen with treatment with other newer heart failure treatments like sacubitril/valsartan, but to be fair, the reduction from empagliflozin was larger than that seen with some other treatments.

“One open question is what the reduced NT-proBNP is telling us. Is it reduced filling pressures? Is it reverse cardiac remodeling? Unfortunately, the design of the study will not allow for an answer,” he said.

Jonathan W. Cunningham, MD, MPH, of Brigham and Women’s Hospital, and Peder L. Myhre, MD, PHD, of Akershus University Hospital and University of Oslo, Oslo, Norway, also questioned the significantly improved outcomes in light of the less significant lowering of NT-proBNP.

“What mechanisms may explain the apparent disconnect between the modest reduction in NT-proBNP and more robust reduction in clinical events from SGLT2 inhibitors? First, improvements in HF outcomes with SGLT2 inhibitors may not be due to reductions in wall stress, filling pressures, and other hemodynamic determinants of NP expression. Interestingly, empagliflozin has been shown to significantly reduce left ventricular volumes, left ventricular mass, and systolic function in HFrEF. These results suggest that SGLT2 inhibitors are beneficial beyond their diuretic effect,” they wrote in their accompanying editorial.

What is the take-away to stress for clinicians in treating HFrEF patients with empagliflozin?

“These results provide useful information that a) treatment with empagliflozin in part mediates its benefit through pathways that lower NT-proBNP, and b) that monitoring serial NT-proBNP concentrations after treatment for HF provides important prognostic information,” concluded Januzzi. “They provide important support to the recommendations from clinical practice guidelines and consensus documents to monitor NT-proBNP at routine visits and after treatment changes.”

Cunningham and Myhre agreed: “In conclusion, this important paper demonstrates that empagliflozin reduced HF events regardless of baseline NT-proBNP levels and that empagliflozin reduced NT-proBNP by 5%-13%. The dramatic clinical benefit of empagliflozin in chronic HFrEF is larger than might be expected given this more modest reduction in NT-proBNP. Smaller reductions in NT-proBNP should not dissuade clinicians from starting and continuing patients on this highly effective and safe new therapy for chronic HF.”

Study limitations include the inclusion of patients with higher NT-proBNP for those with left ventricular ejection fractions (LVEFs) of closer to 40%, while those with LVEFs of 30% and less had no such requirement.

Dr. Januzzi recently took part in Morning Commute’s podcast series on SGLT2 inhibitors.

  1. In EMPEROR-Reduced, empagliflozin improved cardiorenal outcomes irrespective of baseline NT-proBNP levels.

  2. Empagliflozin reduced NT-proBNP by 5%-13 in heart failure patients with reduced ejection fraction (HFrEF),

Liz Meszaros, Deputy Managing Editor, BreakingMED™

The EMPEROR-Reduced trial was supported by Boehringer Ingelheim and Eli Lilly and Company.

Januzzi is supported in part by the Hutter Family Professorship at Harvard Medical School; is a Trustee of the American College of Cardiology; is a board member of Imbria Pharmaceuticals; has received grant support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics; has received consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics; and participates in Clinical Endpoint Committees/ Data Safety Monitoring Boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda.

Cunningham reported no disclosures.

Myhre has served on advisory boards for AstraZeneca, Novartis, and Novo Nordisk; and has received consulting honoraria from AmGen, AstraZeneca, Boehringer Ingelheim, Novartis, and Novo Nordisk.

Cat ID: 3

Topic ID: 74,3,730,3,914,127,192,925