Advanced CKD Doesn't Derail Empagliflozin in EMPEROR-Preserved

Chronic kidney disease (CKD) had no impact on the efficacy or safety of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) for patients with heart failure with preserved ejection fraction (HFpEF) in the EMPEROR-Preserved trial, showing once again that agents in this class are appropriate for patients with heart failure even when their kidney function is severely compromised.

More than half of the nearly 6000 patients with heart failure and HFpEF enrolled in EMPEROR-Preserved had CKD (although renal function was not an enrollment criterion), including 10% with an estimated glomerular filtration rate (eGFR) that fell in the range of 20-29 mL/min/1.73m², which categorized them as having stage 4 CKD.

The results showed, in a prespecified analysis, that treatment with empagliflozin led to a consistent, significant relative risk reduction compared with placebo in the primary endpoint of cardiovascular death or hospitalization for heart failure "across the full spectrum of kidney function, down to an eGFR of 20 mL/min/1.73m²," said Faiez Zannad, MD, PhD, who presented the findings at virtual Kidney Week 2021.

Among the 46.5% of enrolled patients without CKD, empagliflozin produced a significant 20% drop in the primary outcome relative to those who received placebo. Among the 53.5% of patients with CKD at time of randomization (defined as an eGFR < 60 mL/min/1/73m² or a urinary albumin to creatinine ratio > 300 mg/g), treatment with empagliflozin was associated with a significant 25% cut in the primary endpoint compared with placebo.

Empagliflozin was also "well tolerated" by patients with HFpEF, whether or not they also had CKD, "including patients with severely impaired kidney function," said Zannad, a professor of cardiology therapeutics at the University of Lorraine in Nancy, France.

An End to "Renalism"

"This is a nail in the coffin for the concept of 'renalism,'" the erroneous notion held by many clinicians and researchers that various treatments are not as effective and potentially more likely to cause adverse effects in patients with CKD compared with those with better renal function, commented Janani Rangaswami, MD, a nephrologist who is a professor and director of the cardiorenal program at George Washington University in Washington, DC.

In addition to EMPEROR-Preserved, other large trials of agents from the SGLT2 inhibitor class bucked the premise of renalism and took the "groundbreaking step" of enrolling patients with moderate-severe CKD, noted Rangaswami in an interview. In particular, two trials took this approach when enrolling patients heart failure with reduced ejection fraction (HFrEF), EMPEROR-Reduced (which also tested empagliflozin and matched the design of EMPEROR-Preserved) and DAPA-HF (which tested the SGLT2 inhibitor dapagliflozin [Farxiga, AstraZeneca]).

"It was a huge, bold step, especially in EMPEROR-Preserved and in EMPEROR-Reduced, which both enrolled patients with eGFRs as low as 20 mL/min/1.73m²," Rangaswami said. DAPA-HF included patients with eGFRs as low as 30 mL/min/1.73m².

EMPEROR-Reduced and DAPA-HF — published earlier this year — both had similar findings as EMPEROR-Preserved as reported by Zannad: consistent benefit from empagliflozin or dapagliflozin regardless of eGFR level and no signal of increased adverse events from treatment.

In fact, all three analyses show that patients with worse renal function had the highest risk for cardiovascular death and hospitalization for heart failure, and hence, the beneficial impact from SGLT2 inhibitors is greatest in these patients.

These observations "make it easier to focus on the group with moderate-to-severe CKD," both in the routine care setting as well as in future trials, said Rangaswami.

"This is a welcome trend that paves the way to test more treatments in patients with stage 4 and even stage 5 CKD, patients...excluded from trials in the past," she said.

In addition, the consistent benefit from SGLT2 inhibitors in these three heart failure trials regardless of CKD "means there is simply no room for renalism. There is no room for clinicians to say that because a patient's eGFR is 30 mL/min/1.73m² they are worried about starting an SGLT2 inhibitor," she stressed.

More CKD-Independent Effects of Empagliflozin

Results of other new analyses from EMPEROR-Preserved, also reported by Zannad, included the finding that empagliflozin was associated with a similar slowing of loss of renal function over time compared with placebo, regardless of CKD status.

In patients with CKD, empagliflozin slowed eGFR loss by 1.4 mL/min/1.73m²/year, and in those without CKD, by 1.3 mL/min/1.73m²/year, relative to placebo.

"Even in patients without CKD, there was a relevant eGFR decline in the placebo group that was attenuated by empagliflozin," Zannad said.

At the end of the study, when empagliflozin was stopped, patients with or without CKD had their eGFR bounce back by an identical 2.4 mL/min/1.73m² relative to placebo.

Empagliflozin slowed progression to macroalbuminuria and significantly reduced the incidence of acute kidney injury by a similar amount regardless of CKD status compared with placebo.

EMPEROR-Preserved enrolled patients with function-limiting HFpEF, a left ventricular ejection fraction > 40%, and a minimum level of a reliable serum marker of heart failure, N-terminal pro-B-type natriuretic peptide (NT-proBNP). Compared with placebo, empagliflozin reduced the trial's primary outcome by an absolute 3.3 percentage points and by a significant relative risk reduction of 21% after a median 26 months of follow-up, according to a report published in October 2021.

EMPEROR-Preserved is the first prospective, randomized trial to unequivocally show the efficacy and safety of a drug for improving outcomes in patients with HFpEF.

EMPEROR-Preserved was sponsored by Boehringer-Ingelheim and Lilly, which market empagliflozin (Jardiance). Zannad has reported financial relationships with Boehringer Ingelheim as well as other companies. Rangaswami has reported being a consultant for Boehringer Ingelheim, Lilly, and AstraZeneca.

Kidney Week 2021. Presented November 5, 2021.

Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler

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