Empagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor, now considered a foundational treatment for chronic heart failure with reduced ejection fraction. The EMPEROR-Reduced trial showed a 25% reduction with empagliflozin 10 mg in the primary endpoint of cardiovascular death or heart failure hospitalization.
In the current study, Dr. James Januzzi of Massachusetts General Hospital in Boston and colleagues sought to assess the relationship between these benefits and NT-proBNP concentrations, which are biomarkers of heart failure severity (higher levels are associated with worse disease and prognosis).
"What we found - that empagliflozin was associated with an early robust reduction in NT-proBNP, that (it) increased the likelihood for lower NT-proBNP soon after treatment initiation, and that such reductions were strongly associated with benefits - helps to confirm a strong link between NT-proBNP trends and outcomes with favorable therapies in heart failure," Dr. Januzzi told Reuters Health by email.
"The most surprising result was the speed of NT-proBNP lowering," he said. "It really implies a very rapid effect of SGLT2 inhibitors to lower risk, something we see in the trials of these therapies - i.e., there is a rapid divergence of the survival curves between those treated with empagliflozin versus placebo."
"It was also interesting to see empagliflozin increased the likelihood for achieving lower NT-proBNP, reaching a zone that, among patients with chronic heart failure, we begin to see favorable reverse cardiac remodeling.
As reported in the Journal of the American College of Cardiology, Dr. Januzzi and colleagues analyzed data on patients with heart failure with reduced ejection fraction randomly assigned to placebo or empagliflozin 10 mg daily. NT-proBNP was measured at baseline, 4 weeks, 12 weeks, 52 weeks, and 100 weeks. Participants (mean age, about 65; about 24% women; about 70% white) were divided into quartiles of baseline NT-proBNP.
The primary outcome was the time to first event in a composite of CV death or hospitalization for HF. Secondary endpoints included heart failure hospitalizations and the slope of the change in estimated glomerular filtration rate (eGFR) during treatment.
The incidence rates for each outcome were 4- to 6-fold higher among those in the highest versus lowest NT-proBNP quartiles (3,480 or higher vs. <1,115 pg/mL) at baseline.
Those with higher NT-proBNP had 2- to 3-fold higher total hospitalizations than the lowest NT-proBNP quartile.
Empagliflozin reduced risk for major cardiorenal events across NT-proBNP quartiles, and also significantly reduced NT-proBNP at all timepoints examined; by 52 weeks, the adjusted mean difference from placebo was 13%.
Further, an NT-proBNP in the lowest quartile 12 weeks after randomization was associated with lower risk for subsequent cardiovascular death or heart failure hospitalization regardless of baseline concentrations. Empagliflozin resulted in 27% higher adjusted odds of the lowest NT-proBNP concentration by 12 weeks compared with placebo.
Dr. Januzzi said, "The results put further emphasis on the importance of post-treatment natriuretic peptide trends, which may have implications for newer drug development, using biomarker changes as indirect evidence for benefit of newer drugs."
The team currently is evaluating changes in NT-proBNP among heart failure patients with preserved ejection fraction treated with empagliflozin in the EMPEROR-Preserved trial (https://www.nejm.org/doi/full/10.1056/NEJMoa2107038).
Dr. Jonathan Cunningham of Brigham and Women's Hospital in Boston commented on the study in an email to Reuters Health. "This class of medications is a great option for patients with heart failure. The study demonstrates consistent clinical benefit with empagliflozin across the spectrum of baseline NT-proBNP values."
"The reduction in NT-proBNP with empagliflozin and other SGLT2 inhibitors appears to be less than might be expected given the clinical benefits," he noted. "This finding has interesting implications regarding the mechanism of action of these drugs. However, it should not dissuade patients and physicians from using SGLT2 inhibitors in heart failure, given the strong clinical benefits."
The EMPEROR-Reduced trial was supported by Boehringer Ingelheim and Eli Lilly and Company. Two coauthors are Boehringer employees and several have received feels from the company. Dr. Cunningham's editorial coauthor also received fees from the company.
SOURCE: https://bit.ly/3AvvXWX and https://bit.ly/3CALxB8 Journal of the American College of Cardiology, online September 20, 2021.
By Marilynn Larkin
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