EMPA-Kidney Moves the Needle for SGLT2 Inhibitors in Kidney Disease

Mitchel L. Zoler, PhD

November 04, 2022

Dr William Herrington

ORLANDO, Florida — The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (Jardiance) significantly slowed progression of renal dysfunction or death from cardiovascular causes among patients with chronic kidney disease (CKD) who did not have diabetes or heart failure in a pivotal trial with more than 6600 patients.

This confirms the efficacy for this population that was previously seen with dapagliflozin, another agent from the same class, in the DAPA-CKD trial.

In the new trial, EMPA-Kidney, treatment with empagliflozin 10 mg daily for a median of 2.0 years led to a significant 28% relative risk reduction in the primary combined endpoint in comparison with placebo, William G. Herrington, MD, reported at Kidney Week 2022, organized by the American Society of Nephrology.

The results were simultaneously published in The New England Journal of Medicine.

In 2020, a different team of researchers running DAPA-CKD reported that during a median of 2.4 years, treatment of 4304 patients with dapagliflozin 10 mg daily resulted in a significant 39% relative risk reduction compared with placebo for an identical combined primary endpoint. Enrollment criteria for the DAPA-CKD trial were mostly similar to that of the current trial.

"Remarkably Similar" Findings

Results from EMPA-Kidney and DAPA-CKD are "remarkably similar," said Herrington during a press briefing at the meeting.

He also noted that when the EMPA-Kidney study began ― before results from DAPA-CKD were known ― "we never imagined such a large effect" on important endpoints in people with CKD.

In addition to cardiovascular death, the combined primary endpoint included the incidence of renal death, incident end-stage kidney disease, a sustained decrease in estimated glomerular filtration rate (eGFR) to less than 10 mL/min/1.73m2, or a sustained decrease in eGFR of at least 40% from baseline.

Having similar evidence from both trials "will hopefully provide people with the confidence to start to use SGLT2 inhibitors as standard care in people with CKD" who match enrollment criteria of the two trials, added Herrington, a nephrologist at the University of Oxford, United Kingdom.

The analyses he reported also showed that empagliflozin had similar efficacy for the primary endpoint regardless of whether patients had type 2 diabetes at the time of enrollment and regardless of their eGFR at entry.

To enter EMPA-Kidney, people needed to have either an eGFR of 20–44 mL/min/1.73m2 with no minimum level of albuminuria or an eGFR of 45–89 mL/min/1.73m2 with a urine albumin-to-creatinine ratio (UACR) of at least 200 mg/g.

In contrast, to enroll in DAPA-CKD, patients had to have a UACR of at least 200 mg/g. This means that for the first time, EMPA-Kidney produced data on the relationship between albuminuria severity and the impact of treatment with an SGLT2 inhibitor in the enrolled population.

A Signal of Greater Efficacy With Higher UACR

A total of 6609 patients underwent randomization in EMPA-Kidney. During a median of 2.0 years of follow-up, the primary endpoint ― progression of kidney disease or death from cardiovascular causes ― occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; P < .001).

The results "suggested that the effects [of empagliflozin] are greater in patients with higher levels of albuminuria, with statistically significant heterogeneity between this subgroup and those with a UACR of less than 200 mg/g (P = .02)," Herrington said.

Of the study population, 54% had no evidence of diabetes at enrollment.

Having data from a second large trial of an SGLT2 inhibitor that included people with isolated CKD who did not have diabetes or heart failure "will start to move the needle" on using this class of drugs in these types of patients, commented F. Perry Wilson, MD, a nephrologist at Yale school of Medicine in New Haven, Connecticut.

On the basis of the DAPA-CKD results, in April 2021 the US Food and Drug Administration expanded dapagliflozin's indications to include CKD, yet, "a lot of nephrologists consider SGLT2 inhibitors to be agents for people with diabetes or heart failure, and they defer prescribing them to endocrinologists and cardiologists," Wilson said in an interview.

"Flozinators" Rising

But Pascale H. Lane, MD, a pediatric nephrologist at the University of Oklahoma Health Sciences Center in Oklahoma City, commented that many nephrologists she knows have been prescribing dapagliflozin "widely" to their patients with CKD.

Dr Pascale Lane

"I know many adult nephrologists who use it almost universally now," Lane said. "They call themselves 'flozinators.' "

EMPA-Kidney was sponsored by Boehringer Ingelheim, the company that along with Lilly markets empagliflozin (Jardiance). Herrington, Wilson, and Lane have disclosed no relevant financial relationships.

N Engl J Med. Published online November 4, 2022. Abstract

Kidney Week 2022: American Society of Nephrology Annual Meeting: Abstract FR-OR68.

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

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