SGLT2 Inhibitor Carry-Over Benefits Last How Long?

SAN DIEGO — Benefits with empagliflozin (Jardiance) for cardiovascular and renal health linger for about a year after discontinuation, as off-drug follow-up from the EMPA-KIDNEY trial showed.

During a median 2 years of post-trial follow-up, the risk of kidney disease progression or cardiovascular death remained 13% lower for patients who had been randomized to empagliflozin during the main study period compared with placebo-randomized patients (HR 0.87, 95% CI 0.76-0.99). When combined with the trial period, the hazard ratio for that primary endpoint was 0.79 (95% CI 0.72-0.87).

At 1 year post-trial, benefits slightly dipped versus the active phase of the trial (HR 0.76 vs 0.72, both statistically significant vs placebo), and significance was lost during year 2 of follow-up (HR 0.90, 95% CI 0.75-1.07) and thereafter, reported William G. Herrington, FRCP, of the University of Oxford in England, at the American Society of Nephrology Kidney Week meeting.

Of note, a similar proportion of patients in the empagliflozin and placebo groups (43% and 40%, respectively) were using an SGLT2 inhibitor during the post-trial period, they wrote in the New England Journal of Medicine, where the findings were also published.

“If we want to maximize the benefits of SGLT2 [inhibitors], we need to start patients on them early, keep them on them, and not stop the drug,” Herrington said at the late-breaking session. “To maximize benefits, we need long-term treatment.”

The EMPA-KIDNEY trial included 6,609 patients with chronic kidney disease and an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 mL/min/1.73 m² at baseline or an eGFR of 45 to 2 but with a urinary albumin-to-creatinine ratio of at least 200. For the main trial, participants were randomly assigned to receive either empagliflozin (10 mg once daily) or matching placebo and were followed for a median of 2 years.

For the post-trial phase, 4,891 (74%) surviving patients who consented were enrolled for open-label observation for 2 additional years, during which randomized trial medications were discontinued but local practitioners could prescribe open-label SGLT2 inhibitors, including empagliflozin.

During the combined active- and post-trial periods, 26.2% of the empagliflozin-randomized patients and 30.3% of the placebo-randomized patients had a primary outcome event, a composite of kidney disease progression or cardiovascular death. Kidney disease progression was defined as a sustained reduction from randomization in eGFR of at least 40%, the development of end-stage kidney disease, a sustained eGFR of less than 10 mL/min/1.73 m², or death from kidney failure.

Kidney disease progression was the predominant endpoint event, occurring in 23.5% of patients in the empagliflozin group and 27.1% of those in the placebo group, while cardiovascular death rates were 3.8% and 4.9%, respectively. Death from noncardiovascular causes occurred at a rate of 5.3% in both groups.

The mechanisms for any persisting effects of SGLT2 inhibitors could include reduced kidney disease progression and subsequent cardiovascular risks by preserving nephrons during the active-trial period, the researchers suggested.

“Some of the observed post-trial benefit on eGFR components could result from the reversal of the small acute eGFR dip when trial drug was stopped,” Herrington noted at the session. “However, that does not explain continuing benefits on risk of end-stage kidney disease.”

Subgroups, including by diabetes mellitus and albuminuria status, as well as levels of kidney dysfunction and primary kidney diagnosis, showed benefits consistent with the overall findings.

The researchers noted that the additional follow-up almost doubled the number of first primary outcomes, from 990 in the active trial to 1,866 during post-trial follow-up, which Herrington said “helps address uncertainties resulting from the short active trial period.”

The researchers acknowledged that the decision to start or continue patients on an SGLT2 inhibitor after the end of the randomized trial period was not random, pointing to the fact that patients who did not start an open-label SGLT2 inhibitor had twice the predicted risk of kidney failure as those who started an SGLT2 inhibitor post-trial.

“This phenomenon may reflect some uncertainty about the efficacy of SGLT2 inhibition in patients with more severe chronic kidney disease and inertia in changes in practice owing to the time taken for regulatory or payer approvals,” they wrote. “This prognostic imbalance implies, in particular, that any comparison of outcomes between the patients in the empagliflozin group who started an SGLT2 inhibitor post-trial and those in the placebo group who did not will be confounded and hence unreliable.”

Other limitations included a lack of data on hospitalizations after the randomized trial period ended.