Ejection fraction influences major renal event risk with empagliflozin
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The SGLT2 inhibitor empagliflozin decreased risk for major renal outcomes in patients with heart failure with reduced ejection fraction but not preserved ejection fraction, according to an analysis of two large randomized controlled trials.
In a prespecified, patient-level pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved, empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) reduced the risk for major renal events by nearly 50% among adults with HFrEF, yet had no effect on major renal events among adults with HFpEF. Empagliflozin also reduced HF hospitalization risk by approximately 30% in both trials.
“Ejection fraction influenced the effect of empagliflozin on renal events, whether the analysis was carried out between or within trials,” Milton Packer, MD, distinguished scholar in cardiovascular science at Baylor University Medical Center and chair of the executive committee for the EMPEROR program, said during a press conference at the European Society of Cardiology Congress. “These findings demonstrate the benefits of empagliflozin across a broad range of patients with HF, specifically those with an EF of less than 60% to 65%. These patients are not being effectively treated with currently available agents.”
Packer and colleagues analyzed data from 9,718 participants from EMPEROR-Reduced and EMPEROR-Preserved. The two trials, carried out in parallel with nearly identical protocols, investigative sites and administrative committees, evaluated the effects of empagliflozin 10 mg daily (n = 4,860) compared with placebo (n = 4,858) in adults with established HF with reduced and preserved EF. The primary outcome of the pooled analysis was a composite of major adverse renal outcomes, defined as profound or sustained decreases in estimated glomerular filtration rate (eGFR) or renal replacement therapy.
The findings were simultaneously published in The New England Journal of Medicine.
During a median follow-up of 21 months, 138 participants assigned empagliflozin (2.8%) and 170 assigned placebo (3.5%) developed major adverse renal outcomes (P = .016 for interaction). HRs for serious renal outcomes were 0.51 (95% CI, 0.33-0.79) in the EMPEROR-Reduced trial and 0.95 (95% CI, 0.73-1.24) in the EMPEROR-Preserved trial.
For both trials, the effect of empagliflozin was consistent across components of the primary outcome and across all prespecified subgroups — including those with and without type 2 diabetes, Packer said.
In 4,111 participants, researchers measured paired, off-treatment eGFR levels at baseline and at approximately 30 days after discontinuation of empagliflozin or placebo, enabling assessment of the long-term effects of empagliflozin that was not affected by confounding factors. In this group, the annualized decline in eGFR between the paired values was more marked in the placebo group vs. the empagliflozin group. The adjusted mean difference was nearly twice as great in EMPEROR-Reduced (1.77 mL/min/1.73 m2) than in EMPEROR-Preserved (0.94 mL/min/1.73 m2). Findings were not influenced by diabetes status.
Researchers also found that the effects of empagliflozin to reduce HF outcomes in EMPEROR-Preserved and EMPEROR-Reduced were “highly concordant,” Packer said. Empagliflozin reduced HF hospitalizations by about 30% across a broad range of EF — less than 25% to less than 65% — with attenuation of the effect at higher EF levels, Packer said.
“At an EF of 40% to 65%, the benefit appeared to be greater with empagliflozin than with sacubitril/valsartan in the PARAGON-HF trial,” Packer said.
Calling the differing renal outcomes between trials “noteworthy,” the researchers wrote that the observed lack of renal benefit in EMPEROR-Preserved contrasts with the finding that empagliflozin slowed the decline in eGFR in that trial, suggesting that eGFR slope analysis “has limitations as a surrogate” for predicting the effect of drugs on renal outcomes in adults with HF.
Packer said data from the EMPEROR program are unique, as no other trial with an SGLT2 inhibitor measured EF in a systematic way in a meaningful number of participants.
“There is parallelism between the effects of empagliflozin on HF outcomes and renal outcomes, with attenuation in both at ejection fraction of 65% and greater,” Packer said. “That raises an interesting question: Who are these patients with HF with an EF of 65% or greater? These patients are unusual. They tend to be elderly women with hypertension, very low incidence of ischemic heart disease, but with a high prevalence of atrial fibrillation. Despite that, [they have] reasonably low levels of natriuretic peptides. This is an unusual clinical picture, and we think some of these patients have dyspnea related to their AF and do not actually have underlying HF. We need to look at this much more closely. That could explain the attenuated effect.”
Reference:
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Manesh Patel, MD
When you look at this pooled analysis, it is clear that, across the spectrum of EF, you see CV benefits with empagliflozin. This study highlights that EF influences the benefit of major renal outcomes. Those patients with lower EF seem to see a bigger benefit toward reduction in renal outcomes, something not seen in EMPEROR-Preserved or at higher EF. It seems as though LVEF is a marker for the therapeutic effect on renal function and renal outcomes.
EMPEROR-Pooled adds confidence to the findings observed across the broad spectrum of patients, both for the CV benefit and also for renal benefit in those with the lowest EF.
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Packer M, et al. Hot Line: EMPEROR-Preserved/EMPEROR-Pooled. Presented at: European Society of Cardiology Congress; Aug. 27-30, 2021 (virtual meeting).
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