SAN DIEGO The significant kidney and cardiovascular benefits of 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 New England Journal of Medicine published the study at the same time. Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that was discontinued early in the EMPA-KIDNEY trial because of its effectiveness in lowering the risk of kidney disease or its progression in patients with a variety of kidney disease causes and kidney function levels. The study demonstrated that empagliflozin decreased the primary outcome of kidney disease progression or cardiovascular death by 28% compared to a placebo, with no significant safety concerns, over a median follow-up of two years.

Herrington and colleagues examined data on 4891 (74 percent) of the 6609 CKD patients who participated in an extra 2-year post-trial observational period to better examine the changing effects of the medication following discontinuation. 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 were specifically included in the study. In the post-trial randomization, the average age was 63 years, 34% of the participants were female, and roughly 57% of both groups had never had diabetes before. About 35% of each group had a mean eGFR of less than 30 mL/min/1.73 m2, while the mean eGFR was 37 mL/min/1.73 m2.

Patients were randomized to receive a matching placebo or 10 mg of empagliflozin once daily. During the post-trial phase, neither placebo nor trial-related empagliflozin was given. However, open-label SGLT2 inhibitors, such as empagliflozin, were administered to patients as directed by their physicians. Similarly, during the post-trial phase, open-label SGLT2 inhibitors were utilized by 40% of the placebo group and 43% of the empagliflozin group.

Herrington stated that an evaluation for any carry-over effects is made possible by the absence of a between-group difference in SGLT2 inhibitor use after the trial. The primary outcome, a composite of kidney disease progression or cardiovascular death, was observed in 865 out of 3304 patients (26.2 percent) in the empagliflozin group compared to 1001 out of 3305 patients (30.3 percent) in the placebo group when the effects from the active and post-trial periods were combined (hazard ratio [HR], 0.79; P < .0001).

The hazard ratio for the primary outcome was still significant during the post-trial period. Still, it was less so at 0.87 (P = .04). Regarding other specific outcomes, the risk of kidney disease progression during the combined periods was 23 percent for the empagliflozin group and 27 percent for the placebo group; the risk of cardiovascular death was 3 point 8 percent and 4 point 9 percent, respectively; and the risk for the composite of death or end-stage kidney disease was 16 point 9 percent with empagliflozin and 19 point 6 percent with placebo. The percentage of deaths from noncardiovascular causes (5.3% in both groups) did not differ between the groups.

According to Herrington, the carry-over effect was only about a year long and reduced the risk for the primary outcome by 13 percent overall, which was less than the 28 percent reduction that occurred while taking empagliflozin during the active trial. According to the authors, the effects of empagliflozin were seen after the follow-up regardless of the degree of albuminuria, diabetes status, kidney function level, and primary kidney diagnosis. According to the study, analyses of the long-term eGFR slope from the active-trial period also revealed that empagliflozin slowed the progression of all albuminuria subgroups.

Finally, they conclude that the results show that the benefit after the trial was less than the benefit during the study treatment and seemed to be transient. Therefore, long-term CKD treatment is necessary to optimize the cardiorenal clinical benefits of SGLT2 inhibitors. Emily Chang, MD, an associate professor of medicine at the University of North Carolina, Chapel Hill’s Division of Nephrology and Hypertension, commented on the study and agreed that the results offer valuable information about the possible consequences for patients, irrespective of their disease stage, who stop taking empagliflozin.

Chang told Medscape Medical News, “I think it is important to know that these are probably lifelong drugs, although I have already been operating under that premise in my practice at least.”. However, knowing that this is probably the best course of action is comforting. Regarding comparable effects with other SGLT2 inhibitors, Chang speculated that this effect would hold true for all SGLT2 inhibitor classes, though we can’t be certain until more research is conducted. A patient’s ability to take the medication will be limited if they are unable to tolerate it, she continued. Otherwise, I intend to keep these patients taking this medication for the rest of their lives if it is tolerated.

Pietro Canetta, MD, an associate professor of medicine in the Division of Nephrology at Columbia University Irving Medical Center in New York, added that while there is a wealth of information about the advantages of SGLT2 inhibitors during treatment, this study was noteworthy for demonstrating that a significant portion of the benefits appeared to last for at least a year after the study populations stopped taking the prescribed medication.

Although we cannot definitively determine the mechanism from this trial, the strong effect that persisted even after stopping the drug highlights that there appear to be advantages beyond its immediate effects. For instance, he said, they might be promoting better vascular health or beneficial remodeling.

Important disclaimers were mentioned by Canetta, who told Medscape Medical News that patients with a history of ketoacidosis or recent immunosuppression were not included and that patients had to be taking an adequate dosage of an RAS [renin-angiotensin system] inhibitor. Furthermore, he added, it’s critical to remember that the advantages were different when taken off a drug than when taken on one. Although the group that initially received empagliflozin outperformed the group that initially received a placebo, the difference was more noticeable while both groups were taking the study medication.

This is significant because, according to Canetta, the trial’s message shouldn’t be taken to imply that you can quit after a year and still anticipate the same advantages indefinitely. The main takeaway from this is that there is more proof that these medications are a great addition to our toolbox for slowing the progression of kidney disease and cardiovascular consequences.

References:
https://www.medscape.com/viewarticle/empagliflozin-effects-subside-discontinuation-2024a1000jm9