Introduction In the EMPA-KIDNEY trial, the sodium–glucose cotransporter 2 (SGLT2) inhibitor empagliflozin
had positive cardiorenal effects in patients with chronic kidney disease who were
at risk for disease progression. Post-trial follow-up (PTFU) was designed to assess
how the effects of empagliflozin would evolve after the discontinuation of the trial
drug. EMPA-KIDNEY observed the cardiorenal effects of approx. 2 years of empagliflozin
and the PTFU for an additional approx. 2 years afterwards.
Methods Patients with an estimated glomerular filtration rate (eGFR) of 20 to<45; or 45 to<90;
and a urine albumin creatinine ratio (ACR) of≥200 mg/g were randomized to empagliflozin
versus placebo and provided with allocated treatment for a median of 2 year. Post-trial,
participants were prospectively observed off study treatment. Local doctors were free
to commence an open-label SGLT2 inhibitor while blinding to original treatment allocation
was maintained. The primary composite outcome was kidney disease progression or CV
death for the entire follow-up period (i.e. within-trial+PTFU periods combined).
Results Of 6609 randomized participants, 4891 (74%) entered PTFU and were followed for a
median of 2 years. During the post-trial period, any SGLT2 inhibitor use was similar
between groups (average use of empagliflozin 43% vs. placebo 40%). Over the entirety
of follow-up, a primary outcome occurred in 865/3304 participants (26.2%) in the empagliflozin
group and in 1001/3305 (30.3%) in the placebo group (HR=0.79, 95% CI 0.72-0.87). Relative
effects on the primary outcome were similar across the key subgroups (by diabetes,
eGFR & uACR). There was a 13% (HR=0.87, 95% CI 0.76-0.99) reduction in risk of the
primary outcome post-trial. This meant the absolute difference (±SE) in the primary
outcome were 57 (±14) per 1000 at the end of the within-trial period and still 45
(±14) at the end of PTFU. Allocation to empagliflozin reduced risk of kidney disease
progression (23.5% vs. 27.1%), risk of composite of death or end-stage kidney disease
(16.9% vs 19.6%), and risk of CV death (3.8% vs. 4.9%).
Conclusion EMPA-KIDNEY PTFU quantifies more completely the total effects of the short period
of 2 years of empagliflozin. Study empagliflozin continued to exert benefit on cardiorenal
outcomes for up to 12 months after its discontinuation. The post-trial benefit was
smaller than the benefit when taking study treatment and appeared to be temporary.
To maximize the cardiorenal clinical benefits of SGLT2 inhibitors therefore requires
long-term treatment of patients with CKD.
