Researchers running the EMPA-KIDNEY trial that’s been testing the safety and efficacy of the SGLT2 inhibitor empagliflozin (Jardiance) in about 6600 patients with chronic kidney disease (CKD) announced on March 16 that they had stopped the trial early because of positive efficacy that met the study’s prespecified threshold for early termination.
EMPA-KIDNEY is the third major trial of an agent from the sodium-glucose co-transport 2 (SGLT2) inhibitor class tested in patients with CKD to be stopped early because of positive results that met a prespecified termination rule.
In 2020, the DAPA-CKD trial of dapagliflozin (Farxiga) stopped early, after a median follow-up of 2.4 years, because of positive efficacy results. In 2019, the same thing happened in the CREDENCE trial of canagliflozin (Invokana), with the unexpected halt coming after a median follow-up of 2.62 years.
The announcement about EMPA-KIDNEY did not include information on median follow-up, but enrollment into the trial ran from May 2019 to April 2021, which means that the longest that enrolled patients could have been in the study was about 2.85 years.
The primary efficacy endpoint in EMPA-KIDNEY was a composite of a sustained decline in estimated glomerular filtration rate (eGFR) to <10 mL/min/1.73 m2, renal death, or a sustained decline of at least 40% in eGFR from baseline, or cardiovascular death. The announcement of the trial’s early termination provided no details on the efficacy results.
EMPA-KIDNEY Enrolled a Wider Range of Patients
EMPA-KIDNEY expands the scope of types of patients with CKD now shown to benefit from treatment with an SGLT2 inhibitor. CREDENCE tested canagliflozin only in patients with type 2 diabetes and diabetic nephropathy, and in DAPA-CKD, two thirds of enrolled patients had type 2 diabetes, and all had CKD. In EMPA-KIDNEY, 46% of the 6609 enrolled patients had diabetes (including a very small number with type 1 diabetes).
Another departure from prior studies of an SGLT2 inhibitor for patients selected primarily for having CKD was that in EMPA-KIDNEY, 20% of patients did not have albuminuria, and for 34%, eGFR at entry was <30 mL/min/1,73m2, with all enrolled patients required to have an eGFR at entry of ≥20 mL/min/1.73m2. Average eGFR in EMPA-KIDNEY was about 38 mL/min/1.73m2. To be included in the trial, patients were not required to have albuminuria except those whose eGFR was ≥45 mL/min/1.73m2.
In DAPA-CKD, the minimum eGFR at entry had to be ≥25 mL/min/1.73m2, and roughly 14% of enrolled patients had an eGFR of <30 mL/min/1,73m2. The average eGFR in DAPA-CKD was about 43 mL/min/1.73m2. In addition, all patients had at least microalbuminuria, with a minimum urinary albumin-to-creatinine ratio of 200. In CREDENCE, the minimum eGFR for enrollment was 30 mL/min/1.73m2, and the average eGFR was about 56 mL/min/1.73m2. All patients in CREDENCE had to have macroalbuminuria, with a urinary albumin-to-creatinine ratio of more than 300.
According to the researchers who designed EMPA-KIDNEY, the trial enrollment criteria aimed to include adults with CKD “who are frequently seen in practice but were underrepresented in previous SGLT2 inhibitor trials.”
Indications for Empagliflozin Are Expanding
The success of empagliflozin in EMPA-KIDNEY follows its positive results in both the EMPEROR-Reduced and EMPEROR-Preserved trials, which collectively proved the efficacy of the agent for patients with heart failure regardless of their left ventricular ejection fraction and regardless of whether they also had diabetes.
These results led the US Food and Drug Administration to recently expand the labeled indication for empagliflozin to all patients with heart failure. Empagliflozin also has labeled indications for glycemic control in patients with type 2 diabetes and to reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease.
As of today, empagliflozin has no labeled indication for treating patients with CKD. Dapagliflozin received that indication in April 2021, and canagliflozin received an indication for treating patients with type 2 diabetes, diabetic nephropathy, and albuminuria in September 2019.
EMPA-KIDNEY is sponsored by Boehringer Ingelheim and Lilly, the two companies that jointly market empagliflozin (Jardiance).
Mitchel L. Zoler is a reporter with Medscape and MDedge based in the Philadelphia region. @mitchelzoler
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