Empagliflozin Effects Subside With Discontinuation

UPDATED October 31, 2024 // Editor’s note: This article was revised to include additional comments.
SAN DIEGO — The significant kidney and cardiovascular benefits people with chronic kidney disease (CKD) show over 2 years of treatment with empagliflozin begin to subside within about a year after treatment discontinuation, suggesting the need for ongoing treatment.
“We know that empagliflozin is safe we know it works and now we know we need to keep people on the treatment to maximize the benefits,” said first author William G. Herrington, MD, of the Renal Studies Group, Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University of Oxford, UK, at a press briefing at the American Society of Nephrology (ASN) Kidney Week 2024.
The study was published concurrently in The New England Journal of Medicine. 
In the EMPA-KIDNEY trial, empaglifozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, was shown to reduce the risk of kidney disease or progression in patients with a broad range of kidney disease causes and levels of kidney function and was stopped early due to efficacy observed in a formal interim analysis.
With a median follow-up of 2 years, the study showed empagliflozin reduced the primary outcome of kidney disease progression or cardiovascular death by 28% vs placebo, with no major safety concerns.
To further investigate the evolving effects of the drug after discontinuation, Herrington and colleagues evaluated data on 4891 (74%) of the 6609 active trial patients with CKD who took part in an additional 2-year post-trial observational period.
In the study, inclusion criteria specifically included adult patients with CKD-EPI estimated glomerular filtration rate (eGFR) of 20 to 45 mL/min/1.73 m2, or 45 to 90 mL/min/1.73 m2 plus urine albumin-to-creatinine of ≥ 200 mg/g. 
At randomization in the post-trial, the mean age was 63 years, 34% were female, and about 57% had no prior diabetes in both groups. The mean eGFR was 37 mL/min/1.73 m2, and about 35% in each group had a mean eGFR of less than 30 mL/min/1.73 m2.
Patients were randomly assigned to empagliflozin 10 mg once daily or a matching placebo.
No trial-related empagliflozin or placebo was administered during the post-trial period. However, patients could receive open-label SGLT2 inhibitors as prescribed by their clinicians, including empagliflozin, and open-label SGLT2 inhibitors were used in the post-trial period similarly, by 43% in the empagliflozin group and 40% in the placebo group.
“The lack of a between-group difference in SGLT2 inhibitor use post-trial enables an assessment for any carry-over effects,” Herrington noted.
In combining the effects across the active and post-trial periods, the primary outcome, a composite of kidney disease progression or cardiovascular death, occurred among 865 of 3304 patients (26.2%) in the empagliflozin group vs 1001 of 3305 patients (30.3%) in the placebo group (hazard ratio [HR], 0.79; P < .0001). 
During the post-trial period only, the hazard ratio for the primary outcome remained significant, but less so, at 0.87 (P = .04). 
In terms of other specific outcomes, the risk for kidney disease progression during the combined periods was 23.5% in the empagliflozin group and 27.1% in the placebo group; the risk for the composite of death or end-stage kidney disease was 16.9% with empagliflozin and 19.6% placebo, and the risk of cardiovascular death was 3.8% and 4.9%, respectively. 
There were no differences between the groups in terms of death from noncardiovascular causes (5.3% in both groups).
Overall, “the carry-over effect was a 13% reduction in risk for the primary outcome, less than the 28% reduction whilst taking empagliflozin during the active trial, and appeared to last for only approximately 12 months,” Herrington noted.
Empagliflozin’s effects were observed at the end of follow-up regardless of factors including the level of albuminuria, diabetes status, level of kidney function, and primary kidney diagnosis, the authors noted.
“Analyses of the long-term eGFR slope from the active-trial period have also shown that empagliflozin slowed progression in all albuminuria subgroups,” they write in the study.
Ultimately, the findings indicate that “the post-trial benefit was smaller than the benefit when taking study treatment and appeared to be temporary,” they conclude.
“To maximize the cardiorenal clinical benefits of SGLT2 inhibitors therefore requires long-term treatment of patients with CKD.”
Commenting on the study, Emily Chang, MD, an associate professor of medicine with the Division of Nephrology and Hypertension at the University of North Carolina, Chapel Hill, agreed that the findings provide important insights on the likely implications if patients discontinue empagliflozin, regardless of their disease stage.
“I think it is important to know that these are likely lifelong drugs, although in my practice at least, I have already been operating under that premise,” Chang told Medscape Medical News. “But it is good to know that this is likely the correct practice.”
In terms of similar effects with other SGLT2 inhibitors — “my guess would be that this effect would be true across SGLT2 inhibitor categories, although we can’t say for sure without the studies being done,” Chang said.
“The same thing applies that has previously applied — if a patient cannot tolerate it, this will limit use of the medicine,” she added.
“Otherwise, if tolerated, my plan is to leave these patients on this medicine lifelong.”
Further commenting on the research, Pietro Canetta, MD, an associate professor of medicine in the Division of Nephrology, Columbia University Irving Medical Center, New York, noted that although data are plentiful regarding the benefits of SGLT2 inhibitors while on treatment, “this study was striking in showing that a good chunk of benefit seemed to continue even after the study populations were no longer taking the assigned drug treatment, for up to at least a year.”
“The pronounced effect that lingered even after drug discontinuation emphasizes that there seem to be benefits beyond the immediate actions of the drug — while we cannot identify the mechanism for sure from this trial, they may be leading to beneficial remodeling or better vascular health, for example,” he said.
Canetta noted key caveats: “For example, patients had to have been on an appropriate dose of RAS [renin-angiotensin system] inhibitor, and those with recent immunosuppression or any history of ketoacidosis were excluded,” he told Medscape Medical News. 
“Additionally, it’s important to note that the benefits were not the same off-drug as they were on-drug, ” he continued.
“While the group that had originally gotten empagliflozin had superior outcomes to the one that had originally gotten placebo, the difference was more pronounced during the period that they were both receiving study drug.
“This is important because the message of the trial should not be interpreted to mean that you can stop after a year and expect the same benefits in perpetuity,” Canetta said.
“The broad message here is that this is more evidence that these drugs are a tremendous addition to our arsenal in delaying the progression of kidney disease and cardiovascular outcomes.”
The study was funded and sponsored by Boehringer Ingelheim. Herrington reported other financial support from Eli Lilly and the UK Medical Research Council. Chang reported no relevant financial relationships. 
 
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