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Long-Term Effects of Empagliflozin in Patients with Chronic Kidney Disease. BACKGROUND: In the EMPA-KIDNEY trial, empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, had positive cardiorenal effects in patients with chronic kidney disease who were at risk for disease progression. Post-trial follow-up was designed to assess how the effects of empagliflozin would evolve after the discontinuation of the trial drug. METHODS: In the active trial, patients with chronic kidney disease were randomly assigned to receive either empagliflozin (10 mg once daily) or matching placebo and were followed for a median of 2 years. All the patients had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m2 of body-surface area or an eGFR of at least 45 but less than 90 ml per minute per 1.73 m2 with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Subsequently, surviving patients who consented were observed for 2 additional years. No trial empagliflozin or placebo was administered during the post-trial period, but local practitioners could prescribe open-label SGLT2 inhibitors, including open-label empagliflozin. The primary composite outcome was kidney disease progression or cardiovascular death as assessed from the start of the active-trial period to the end of the post-trial period. RESULTS: Of the 6609 patients who had undergone randomization in the active trial, 4891 (74%) were enrolled in the post-trial period. During this period, the use of open-label SGLT2 inhibitors was similar in the two groups (43% in the empagliflozin group and 40% in the placebo group). During the combined active- and post-trial periods, a primary-outcome event occurred in 865 of 3304 patients (26.2%) in the empagliflozin group and in 1001 of 3305 patients (30.3%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.72 to 0.87). During the post-trial period only, the hazard ratio for a primary-outcome event was 0.87 (95% CI, 0.76 to 0.99). During the combined periods, the risk of kidney disease progression was 23.5% in the empagliflozin group and 27.1% in the placebo group; the risk of the composite of death or end-stage kidney disease was 16.9% and 19.6%, respectively; and the risk of cardiovascular death was 3.8% and 4.9%, respectively. There was no effect of empagliflozin on death from noncardiovascular causes (5.3% in both groups). CONCLUSIONS: In a broad range of patients with chronic kidney disease at risk for progression, empagliflozin continued to have additional cardiorenal benefits for up to 12 months after it was discontinued. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110; EuDRACT number, 2017-002971-24.).

EMPA-KIDNEY was designed and conducted by the University of Oxford in collaboration with a Steering Committee (see Supplementary Appendix). The first and senior authors wrote the first-draft manuscript, vouch for the data, and made the decision to publish. The active trial’s rationale, double-blind placebo-controlled design and main results were reported previously.3,7,8 Relevant regulatory authorities and ethics committees for each participating center approved the trial and its post-trial follow-up. Adults with a race-adjusted kidney function formula (here CKD-EPI9) eGFR of ≥20 and <45 mL/min/1.73m2 (irrespective of level of albuminuria); or an eGFR of ≥45 and <90 mL/min1.73m2 with a urinary albumin-to-creatinine ratio (uACR) ≥200 mg/g at the active trial screening visit were eligible, provided they were prescribed a clinically appropriate dose of single renin-angiotensin system (RAS) inhibitor, when indicated and tolerated. Post-trial follow-up was an optional substudy conducted at 185 of the trial’s 241 centers (77%) in 7 of the original 8 countries. All willing surviving participants from participating centers were eligible for post-trial follow-up.

e dose of single renin-angiotensin system (RAS) inhibitor, when indicated and tolerated. Post-trial follow-up was an optional substudy conducted at 185 of the trial’s 241 centers (77%) in 7 of the original 8 countries. All willing surviving participants from participating centers were eligible for post-trial follow-up. At the final active trial follow-up visit, all study drug was retrieved and local doctors informed about the trial’s conclusions. Investigators and participants remained blinded to treatment allocation, and no further study drug was provided to participants. Instead, local doctors were free to prescribe open-label SGLT2 inhibitors (where available and considered indicated) and were responsible for routine follow-up of kidney function as per local practice. Post-trial follow-up aimed to collect additional efficacy and cause-specific mortality outcome data. The main method of follow-up was medical record review supplemented with registry data in the UK and Malaysia. If medical records were unavailable, information was collected by contacting participants, a relative or carer, or local doctors. At 6 monthly reviews, details about vital status, current kidney replacement therapy status, latest local blood creatinine measurement, and any current use of relevant co-medication (limited to SGLT2 inhibitors, RAS inhibitors, and mineralocorticoid receptor antagonists) were collected directly into the trial’s custom-made IT system. Over 99% of reported ESKD was confirmed by local investigators, and reported deaths underwent central review and categorization by blinded clinician adjudicators following the same pre-specified definitions developed for the active trial.3

tor antagonists) were collected directly into the trial’s custom-made IT system. Over 99% of reported ESKD was confirmed by local investigators, and reported deaths underwent central review and categorization by blinded clinician adjudicators following the same pre-specified definitions developed for the active trial.3 The pre-specified primary post-trial assessment was the effect of allocation to empagliflozin during the original active trial on the time to the composite outcome of kidney disease progression or cardiovascular death occurring at any time during the entire follow-up period (i.e., the active trial and post-trial follow-up periods combined). Kidney disease progression was defined as a sustained ≥40% eGFR decline from randomization, ESKD, a sustained eGFR below 10 mL/min/1.73m2, or death from kidney failure.3 Confirmation of “sustained” required values on two consecutive eGFR measurements at least 30 days apart, or was assumed if it was the last eGFR value before death, withdrawal of consent or the end of a participant’s follow-up. In primary analyses, previously reported primary outcomes from the active trial period were carried over irrespective of later eGFR results collected during the post-trial period. As central samples were not collected during the post-trial follow-up period, all eGFR-based post-trial measurements were relative to the local eGFR measurement at baseline (see Supplementary Methods for more details).

l period were carried over irrespective of later eGFR results collected during the post-trial period. As central samples were not collected during the post-trial follow-up period, all eGFR-based post-trial measurements were relative to the local eGFR measurement at baseline (see Supplementary Methods for more details). The post-trial follow-up protocol pre-specified key secondary outcomes of kidney disease progression alone, and the composite of death from any cause or ESKD. The other secondary outcome was ESKD. Tertiary outcomes were death from any cause and, separately, death from cardiovascular and non-cardiovascular causes (the latter being the safety outcome for post-trial follow-up); and the primary outcome assessed by key subgroups of interest. These subgroups were by diabetes status, eGFR, uACR, and primary kidney disease at randomization (using categories pre-specified for the primary trial report3). Analyses explored the effect of empagliflozin on the primary and secondary outcomes by year, and eGFR in different follow-up windows.

ey subgroups of interest. These subgroups were by diabetes status, eGFR, uACR, and primary kidney disease at randomization (using categories pre-specified for the primary trial report3). Analyses explored the effect of empagliflozin on the primary and secondary outcomes by year, and eGFR in different follow-up windows. The analyses were performed on the original full database developed and held by the University of Oxford. Pre-specified Cox proportional hazards regression models including adjustment for categorized baseline variables specified in the minimization algorithm (age, sex, prior diabetes, eGFR, uACR, and geographical region) were used to estimate hazard ratios (HR) and 95% CIs for empagliflozin versus placebo for time-to-event analyses.10 Surviving participants who did not enter post-trial follow-up (e.g., due to attending a non-participating site or being unwilling) were censored at the end of their active trial follow-up period. Kaplan-Meier estimates for the time to each of the primary and secondary outcomes were calculated. Absolute benefits per 1000 participants allocated empagliflozin were calculated from differences in Kaplan-Meier curves between allocated groups. The eGFR-based explorations used ANCOVA to estimate the baseline-adjusted absolute difference in mean eGFR at the last local measurement overall and for the four key subgroups, and mixed model repeated measures (MMRM) approaches to estimate mean eGFR at each follow-up time point throughout the entire follow-up period using only local laboratory measurements. Supplementary materials and the Data Analysis Plan provide further details of these methods. SAS software, version 9.4 (SAS Institute, Cary NY, USA) and R v4.3.2 were used for analyses.

At the final active trial follow-up visit, all study drug was retrieved and local doctors informed about the trial’s conclusions. Investigators and participants remained blinded to treatment allocation, and no further study drug was provided to participants. Instead, local doctors were free to prescribe open-label SGLT2 inhibitors (where available and considered indicated) and were responsible for routine follow-up of kidney function as per local practice. Post-trial follow-up aimed to collect additional efficacy and cause-specific mortality outcome data. The main method of follow-up was medical record review supplemented with registry data in the UK and Malaysia. If medical records were unavailable, information was collected by contacting participants, a relative or carer, or local doctors. At 6 monthly reviews, details about vital status, current kidney replacement therapy status, latest local blood creatinine measurement, and any current use of relevant co-medication (limited to SGLT2 inhibitors, RAS inhibitors, and mineralocorticoid receptor antagonists) were collected directly into the trial’s custom-made IT system. Over 99% of reported ESKD was confirmed by local investigators, and reported deaths underwent central review and categorization by blinded clinician adjudicators following the same pre-specified definitions developed for the active trial.3

The pre-specified primary post-trial assessment was the effect of allocation to empagliflozin during the original active trial on the time to the composite outcome of kidney disease progression or cardiovascular death occurring at any time during the entire follow-up period (i.e., the active trial and post-trial follow-up periods combined). Kidney disease progression was defined as a sustained ≥40% eGFR decline from randomization, ESKD, a sustained eGFR below 10 mL/min/1.73m2, or death from kidney failure.3 Confirmation of “sustained” required values on two consecutive eGFR measurements at least 30 days apart, or was assumed if it was the last eGFR value before death, withdrawal of consent or the end of a participant’s follow-up. In primary analyses, previously reported primary outcomes from the active trial period were carried over irrespective of later eGFR results collected during the post-trial period. As central samples were not collected during the post-trial follow-up period, all eGFR-based post-trial measurements were relative to the local eGFR measurement at baseline (see Supplementary Methods for more details).

The analyses were performed on the original full database developed and held by the University of Oxford. Pre-specified Cox proportional hazards regression models including adjustment for categorized baseline variables specified in the minimization algorithm (age, sex, prior diabetes, eGFR, uACR, and geographical region) were used to estimate hazard ratios (HR) and 95% CIs for empagliflozin versus placebo for time-to-event analyses.10 Surviving participants who did not enter post-trial follow-up (e.g., due to attending a non-participating site or being unwilling) were censored at the end of their active trial follow-up period. Kaplan-Meier estimates for the time to each of the primary and secondary outcomes were calculated. Absolute benefits per 1000 participants allocated empagliflozin were calculated from differences in Kaplan-Meier curves between allocated groups. The eGFR-based explorations used ANCOVA to estimate the baseline-adjusted absolute difference in mean eGFR at the last local measurement overall and for the four key subgroups, and mixed model repeated measures (MMRM) approaches to estimate mean eGFR at each follow-up time point throughout the entire follow-up period using only local laboratory measurements. Supplementary materials and the Data Analysis Plan provide further details of these methods. SAS software, version 9.4 (SAS Institute, Cary NY, USA) and R v4.3.2 were used for analyses.

Between May 2019 and April 2021, 6609 participants were randomized, entered the active trial period and were followed for a median of 2.0 (Q1-Q3 1.5-2.4) years. Of the 6253 participants not dead or withdrawn, 1362 (22%) did not provide consent for post-trial follow-up or were from sites that could not participate for logistical reasons (including all sites in Japan), leaving 4891 who entered the post-trial follow-up period. These participants were followed post-trial for a median of 2.0 (Q1-Q3 2.0-2.1) years. By the end of post-trial follow-up vital status was missing on or after 1 April 2024 for 86 of these 4891 participants (1.8%), and 7 (0.1%) withdrew consent during post-trial follow-up (Supplementary Appendix, Figure S1).

-up period. These participants were followed post-trial for a median of 2.0 (Q1-Q3 2.0-2.1) years. By the end of post-trial follow-up vital status was missing on or after 1 April 2024 for 86 of these 4891 participants (1.8%), and 7 (0.1%) withdrew consent during post-trial follow-up (Supplementary Appendix, Figure S1). The subset of participants entering post-trial follow-up were broadly representative of the population of patients with CKD who are at risk of disease progression (Table S1), and baseline characteristics at randomization were broadly similar between the empagliflozin and placebo groups (Table 1). Mean (±SD) age of the post-trial participants at randomization was 63 (±14) years, 1664 (34%) were women, and 2784 (57%) did not have diabetes. The mean (±SD) eGFR was 36.9 (±14.1) mL/min/1.73m2 and median (Q1-Q3) uACR was 317 mg/g (44-1063), with 2393 (49%) with a uACR ≤300 mg/g. 3487 (71%) had a non-diabetic cause of CKD. Participants who entered post-trial follow-up were less likely to be Asian, slightly younger, had a slightly lower eGFR and uACR, and slightly higher risk of kidney failure when compared to survivors who did not enter post-trial follow-up (Table S2).

%) with a uACR ≤300 mg/g. 3487 (71%) had a non-diabetic cause of CKD. Participants who entered post-trial follow-up were less likely to be Asian, slightly younger, had a slightly lower eGFR and uACR, and slightly higher risk of kidney failure when compared to survivors who did not enter post-trial follow-up (Table S2). During the entire trial follow-up period, blinding to original study drug allocation was maintained in 6578 of the 6609 (>99%) participants. Average use of SGLT2 inhibitors during the active trial period was 90% in the empagliflozin group versus 2% in the placebo group. During post-trial follow-up, average use was similar between groups (43% vs. 40%, respectively; Table 2). Those participants who did not start an SGLT2 inhibitor during post-trial follow-up were more likely to be from Asia, less likely to have prior diabetes, had lower eGFR, notably higher kidney failure risk, and were less likely to be on a RAS inhibitor (Table S3). During post-trial follow-up, average use of RAS inhibitors declined over time but remained similar in both groups (68% vs. 68%) (Table S4).

were more likely to be from Asia, less likely to have prior diabetes, had lower eGFR, notably higher kidney failure risk, and were less likely to be on a RAS inhibitor (Table S3). During post-trial follow-up, average use of RAS inhibitors declined over time but remained similar in both groups (68% vs. 68%) (Table S4). During the entire follow-up period (active trial plus post-trial observation periods together), progression of kidney disease or death from cardiovascular causes occurred in 865 of 3304 patients (26.2%) in the empagliflozin group and in 1001 of 3305 (30.3%) in the placebo group (HR=0.79, 95%CI 0.72-0.87; Figure 1A). This comprised a 28% overall reduction in risk during the active trial period (0.72, 0.64-0.82; 990 outcomes) and a 13% reduction during the post-trial period (0.87, 0.76-0.99; 876 additional first primary outcomes). Much of the post-trial benefit on the primary outcome occurred early: hazard ratios for the first and second years of follow-up post-trial were 0.76 (0.60-0.96) and 0.90 (0.75-1.07) respectively, with the hazard ratio for first 6 months 0.60 (0.38-0.93) (Figure 1B). The sensitivity analyses yielded similar results (Figure S2 & Table S5).

ial benefit on the primary outcome occurred early: hazard ratios for the first and second years of follow-up post-trial were 0.76 (0.60-0.96) and 0.90 (0.75-1.07) respectively, with the hazard ratio for first 6 months 0.60 (0.38-0.93) (Figure 1B). The sensitivity analyses yielded similar results (Figure S2 & Table S5). The effect on the primary outcome during the entire follow-up period included a 21% reduction in the risk of the secondary outcomes of kidney disease progression (23.5% vs. 27.1%: 0.79, 0.72-0.87; Table 3 & Figure S3), and a 26% reduction in ESKD (9.0% vs. 11.3%: 0.74, 0.64-0.87; Table S5). During the post-trial period, the hazard ratios for kidney disease progression and ESKD were 0.89 (0.77-1.02) and 0.80 (0.66-0.98), respectively (Figure S3). During the entire follow-up period, there was a 19% reduction in the risk of the key secondary composite outcome of death from any cause or ESKD (16.9% vs. 19.6%: 0.81, 0.72-0.90), including a hazard ratio of 0.82 (0.70-0.96) for the post-trial period. In absolute terms, compared with placebo there were 57 (SE14) fewer participants with a primary outcome per 1000 participants allocated to empagliflozin at the end of the active trial period, and 45 (14) fewer at the end of the entire follow-up period. This included 26 (8) and 25 (10) fewer participants with ESKD per 1000 participants allocated to empagliflozin, respectively. There were 25 (11) and 32 (12) fewer participants per 1000 allocated to empagliflozin with the composite outcome of death or ESKD at the end of active trial and entire follow-up periods (Table S6).

s included 26 (8) and 25 (10) fewer participants with ESKD per 1000 participants allocated to empagliflozin, respectively. There were 25 (11) and 32 (12) fewer participants per 1000 allocated to empagliflozin with the composite outcome of death or ESKD at the end of active trial and entire follow-up periods (Table S6). The relative effects on the primary outcome were similar in subgroup analyses by baseline diabetes status, eGFR, uACR and primary cause of kidney disease (Figure 2). Findings were similar in post-hoc exploratory analyses assessing effects on kidney disease progression alone by key subgroups (Figure S4). During the entire follow-up period, there was a reduction in the risk of death from a cardiovascular cause by 25% (3.8% vs. 4.9%: 0.75, 0.59-0.95) and no material effect on non-cardiovascular mortality (5.3% vs. 5.3%: 0.97, 0.79-1.20), meaning there were 301 (9.1%) vs. 336 (10.2%) deaths from any cause (0.86, 0.74-1.01; Table 3 and Figure S5). Mean eGFR at last local measurement among those without ESKD was 31.4 (±0.2) mL/min/1.73m2 in the group originally allocated empagliflozin compared with 30.6 (±0.2) mL/min/1.73m2 in the placebo group, i.e., an absolute difference of 0.8 (95% CI 0.1-1.4) mL/min/1.73m2 (Table 3 and Figure S6). This absolute difference did not differ importantly in any of the key subgroups (Figure S7).

During the entire follow-up period (active trial plus post-trial observation periods together), progression of kidney disease or death from cardiovascular causes occurred in 865 of 3304 patients (26.2%) in the empagliflozin group and in 1001 of 3305 (30.3%) in the placebo group (HR=0.79, 95%CI 0.72-0.87; Figure 1A). This comprised a 28% overall reduction in risk during the active trial period (0.72, 0.64-0.82; 990 outcomes) and a 13% reduction during the post-trial period (0.87, 0.76-0.99; 876 additional first primary outcomes). Much of the post-trial benefit on the primary outcome occurred early: hazard ratios for the first and second years of follow-up post-trial were 0.76 (0.60-0.96) and 0.90 (0.75-1.07) respectively, with the hazard ratio for first 6 months 0.60 (0.38-0.93) (Figure 1B). The sensitivity analyses yielded similar results (Figure S2 & Table S5). The effect on the primary outcome during the entire follow-up period included a 21% reduction in the risk of the secondary outcomes of kidney disease progression (23.5% vs. 27.1%: 0.79, 0.72-0.87; Table 3 & Figure S3), and a 26% reduction in ESKD (9.0% vs. 11.3%: 0.74, 0.64-0.87; Table S5). During the post-trial period, the hazard ratios for kidney disease progression and ESKD were 0.89 (0.77-1.02) and 0.80 (0.66-0.98), respectively (Figure S3). During the entire follow-up period, there was a 19% reduction in the risk of the key secondary composite outcome of death from any cause or ESKD (16.9% vs. 19.6%: 0.81, 0.72-0.90), including a hazard ratio of 0.82 (0.70-0.96) for the post-trial period.

re 0.89 (0.77-1.02) and 0.80 (0.66-0.98), respectively (Figure S3). During the entire follow-up period, there was a 19% reduction in the risk of the key secondary composite outcome of death from any cause or ESKD (16.9% vs. 19.6%: 0.81, 0.72-0.90), including a hazard ratio of 0.82 (0.70-0.96) for the post-trial period. In absolute terms, compared with placebo there were 57 (SE14) fewer participants with a primary outcome per 1000 participants allocated to empagliflozin at the end of the active trial period, and 45 (14) fewer at the end of the entire follow-up period. This included 26 (8) and 25 (10) fewer participants with ESKD per 1000 participants allocated to empagliflozin, respectively. There were 25 (11) and 32 (12) fewer participants per 1000 allocated to empagliflozin with the composite outcome of death or ESKD at the end of active trial and entire follow-up periods (Table S6).

The relative effects on the primary outcome were similar in subgroup analyses by baseline diabetes status, eGFR, uACR and primary cause of kidney disease (Figure 2). Findings were similar in post-hoc exploratory analyses assessing effects on kidney disease progression alone by key subgroups (Figure S4). During the entire follow-up period, there was a reduction in the risk of death from a cardiovascular cause by 25% (3.8% vs. 4.9%: 0.75, 0.59-0.95) and no material effect on non-cardiovascular mortality (5.3% vs. 5.3%: 0.97, 0.79-1.20), meaning there were 301 (9.1%) vs. 336 (10.2%) deaths from any cause (0.86, 0.74-1.01; Table 3 and Figure S5). Mean eGFR at last local measurement among those without ESKD was 31.4 (±0.2) mL/min/1.73m2 in the group originally allocated empagliflozin compared with 30.6 (±0.2) mL/min/1.73m2 in the placebo group, i.e., an absolute difference of 0.8 (95% CI 0.1-1.4) mL/min/1.73m2 (Table 3 and Figure S6). This absolute difference did not differ importantly in any of the key subgroups (Figure S7).

The results of the active period of EMPA-KIDNEY were previously reported; empagliflozin reduced the risk of the primary composite outcome of progression of kidney disease or cardiovascular death during 2 years of active trial treatment in its population of participants with a wide range of CKD etiologies, levels of kidney function and albuminuria, with no major safety concerns.3 We now report the results of two years of post-trial prospective observation in which patients and clinicians were blinded to participants’ original treatment allocation, and during which between-group use of SGLT2 inhibitors was similar. We found that there were residual cardiorenal benefits among patients allocated empagliflozin after study drug (empagliflozin or placebo) was discontinued. Mathematically, if there had been no off-treatment effect of empagliflozin post-trial (i.e. the hazard ratio was 1.0 after study drug stopped), absolute benefits would be observed to diminish from the end of the active trial period (see supplementary methods). Instead, we observed that absolute benefits both for the primary outcome and for the key secondary outcome of death or ESKD were initially maintained. In relative terms, the carry-over effect on the primary outcome was less than the effect of taking empagliflozin during the active trial period and appeared to last for up to 12 months, with most additional benefit exerted in the first 6 months after the active trial ended. Although not demonstrated directly, this suggests that to maximize the cardiorenal clinical benefits of SGLT2 inhibitors in CKD requires long-term treatment.

during the active trial period and appeared to last for up to 12 months, with most additional benefit exerted in the first 6 months after the active trial ended. Although not demonstrated directly, this suggests that to maximize the cardiorenal clinical benefits of SGLT2 inhibitors in CKD requires long-term treatment. The mechanisms for any persisting effects of SGLT2 inhibitors still need to be elucidated. Preservation of nephron number during the active trial period might conceivably reduce hyperfiltration and risk of ESKD, and preservation of kidney function may have mediated some of the post-trial observed benefits on cardiovascular death.11 The acute eGFR dip with SGLT2 inhibition reversed within 4 weeks after discontinuation,12,13 so some of the observed post-trial benefit on eGFR components of kidney disease progression could result from reversal of the acute eGFR dip after cessation of study drug. However, that does not explain continuing benefits on ESKD.

acute eGFR dip with SGLT2 inhibition reversed within 4 weeks after discontinuation,12,13 so some of the observed post-trial benefit on eGFR components of kidney disease progression could result from reversal of the acute eGFR dip after cessation of study drug. However, that does not explain continuing benefits on ESKD. Participants who did not start an SGLT2 inhibitor had twice the predicted risk of kidney failure of participants who started an SGLT2 inhibitor post-trial. This phenomenon may reflect some uncertainty about the efficacy of SGLT2 inhibition in those with more advanced CKD, and inertia in changes in practice owing to the time taken for regulatory/payer approvals. This prognostic imbalance implies, in particular, that any comparison of outcomes between participants allocated empagliflozin who started an SGLT2 inhibitor post-trial versus those allocated placebo who remained off SGLT2 inhibition post-trial will be confounded, and hence unreliable.

n for regulatory/payer approvals. This prognostic imbalance implies, in particular, that any comparison of outcomes between participants allocated empagliflozin who started an SGLT2 inhibitor post-trial versus those allocated placebo who remained off SGLT2 inhibition post-trial will be confounded, and hence unreliable. Current international guidance on use of SGLT2 inhibitors in CKD provide recommendations of different strengths for patients who were eligible for EMPA-KIDNEY based on different levels of albuminuria.14 The almost doubling of the number of first primary outcomes from 990 in the active trial’s report to 1866 after post-trial follow-up appears to help us to address uncertainties resulting from the active trial period.3 Benefits on the post-trial follow-up primary outcome, kidney disease progression, and difference in eGFR on last measurement were similar irrespective of level of albuminuria, as well as diabetes status, level of kidney function, and primary kidney diagnosis. This is consistent with effects on eGFR-slope from the active trial phase.12,15 Our trial was designed to ensure that findings would be widely generalizable. Other key strengths of this trial were its large size and broad eligibility criteria, high levels of adherence to study drug, the high volunteer rate for post-trial follow-up, and the almost complete follow-up.3 Post-trial follow-up addresses some of the limitations of the active trial, including its low number of cardiovascular deaths.

s of this trial were its large size and broad eligibility criteria, high levels of adherence to study drug, the high volunteer rate for post-trial follow-up, and the almost complete follow-up.3 Post-trial follow-up addresses some of the limitations of the active trial, including its low number of cardiovascular deaths. Limitations of the post-trial study include the exclusion of participants from Japan (where active trial treatment effects were similar to other regions16). Doing so did not bias presented hazard ratios. Additionally, post-trial follow-up relied on locally measured creatinine levels. We do not consider this a key limitation, as results of the active trial were very similar, irrespective of whether central or local creatinine values were used.12 The lack of additional data on hospitalizations - a deliberate decision to streamline post-trial follow-up as far as possible - prevented any assessment of any effects on hospitalization during the post-trial period.3,17 In summary, post-trial follow up of our trial participants quantified more completely the total effects of a short period of two years of empagliflozin treatment, including any carry-over effect after stopping study drug. In a broad range of patients with chronic kidney disease, empagliflozin continued to exert additional cardiorenal benefits for up to 12 months after it was discontinued. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.