Characterization and implications of the initial estimated glomerular filtration rate ‘dip’ upon sodium-glucose cotransporter-2 inhibition with empagliflozin in the EMPA-REG OUTCOME trial
Authors: Bettina J. Kraus, Matthew R. Weir, George L. Bakris, Michaela Mattheus, David Z.I. Cherney, Naveed Sattar, Hiddo J.L. Heerspink, Ivana Ritter, Maximilian von Eynatten, Bernard Zinman, Silvio E. Inzucchi, Christoph Wanner, Audrey Koitka-Weber
Journal: Kidney International (2020)

Treatment with sodium-glucose co-transporter-2 inhibitors induces an initial 3–5 ml/min/1.73 m2 decline in estimated glomerular filtration rate (eGFR). Although considered to be of hemodynamic origin and largely reversible, this 'eGFR dip' may cause concern in clinical practice, which highlights the need to better understand its incidence and clinical implications. In this post hoc analysis of the EMPA-REG OUTCOME trial, 6,668 participants randomized to empagliflozin 10 mg, 25 mg or placebo with eGFR available at baseline and week four were categorized by initial eGFR change into three groups; over 10% decline ('eGFR dipper'), over 0 and up to 10% decline ('eGFR intermediate'), no eGFR decline ('eGFR non-dipper'). Baseline characteristics of 'eGFR intermediate' and 'eGFR non-dipper' were generally comparable. An initial 'eGFR dip' was observed in 28.3% of empagliflozin versus 13.4% of placebo-treated participants; odds ratio 2.7 [95% Confidence Interval 2.3–3.0]. In multivariate logistic regression, diuretic use and higher KDIGO risk category at baseline were independently predictive of an 'eGFR dip' in empagliflozin versus placebo. Safety and beneficial treatment effects with empagliflozin on cardiovascular and kidney outcomes were consistent across subgroups based on these predictive factors. The initial 'eGFR dip' did not have a major impact on the treatment effect of empagliflozin on subsequent cardiovascular death, hospitalization for heart failure, and incident or worsening kidney disease. Thus, patients with type 2 diabetes with more advanced kidney disease and/or on diuretic therapy were more likely to experience an 'eGFR dip' of over 10% with empagliflozin, but reduction in cardiovascular and kidney outcomes was not relevantly modified by such 'eGFR dip.' Treatment with sodium-glucose co-transporter-2 inhibitors induces an initial 3–5 ml/min/1.73 m2 decline in estimated glomerular filtration rate (eGFR). Although considered to be of hemodynamic origin and largely reversible, this 'eGFR dip' may cause concern in clinical practice, which highlights the need to better understand its incidence and clinical implications. In this post hoc analysis of the EMPA-REG OUTCOME trial, 6,668 participants randomized to empagliflozin 10 mg, 25 mg or placebo with eGFR available at baseline and week four were categorized by initial eGFR change into three groups; over 10% decline ('eGFR dipper'), over 0 and up to 10% decline ('eGFR intermediate'), no eGFR decline ('eGFR non-dipper'). Baseline characteristics of 'eGFR intermediate' and 'eGFR non-dipper' were generally comparable. An initial 'eGFR dip' was observed in 28.3% of empagliflozin versus 13.4% of placebo-treated participants; odds ratio 2.7 [95% Confidence Interval 2.3–3.0]. In multivariate logistic regression, diuretic use and higher KDIGO risk category at baseline were independently predictive of an 'eGFR dip' in empagliflozin versus placebo. Safety and beneficial treatment effects with empagliflozin on cardiovascular and kidney outcomes were consistent across subgroups based on these predictive factors. The initial 'eGFR dip' did not have a major impact on the treatment effect of empagliflozin on subsequent cardiovascular death, hospitalization for heart failure, and incident or worsening kidney disease. Thus, patients with type 2 diabetes with more advanced kidney disease and/or on diuretic therapy were more likely to experience an 'eGFR dip' of over 10% with empagliflozin, but reduction in cardiovascular and kidney outcomes was not relevantly modified by such 'eGFR dip.' Sodium-glucose co-transporter-2 inhibitors (SGLT2i) were developed as glucose-lowering agents but represent a new treatment option for cardiovascular (CV) and kidney disease in patients with type 2 diabetes (T2D). Improvements in CV and kidney outcomes have been observed across several SGLT2i outcomes trials.1Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (6811) Google Scholar, 2Wanner C. Inzucchi S.E. Lachin J.M. et al.Empagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375: 323-334Crossref PubMed Scopus (1935) Google Scholar, 3Neal B. Perkovic V. Mahaffey K.W. et al.Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657Crossref PubMed Scopus (2050) Google Scholar, 4Wiviott S.D. Raz I. Bonaca M.P. et al.Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2019; 380: 347-357Crossref PubMed Scopus (2762) Google Scholar, 5Mosenzon O. Wiviott S.D. Cahn A. et al.Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial.Lancet Diabetes Endocrinol. 2019; 7: 606-617Abstract Full Text Full Text PDF PubMed Scopus (350) Google Scholar, 6Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Crossref PubMed Scopus (2374) Google Scholar Owing to its renal mechanism of action, SGLT2i is associated with a transient decrease in estimated glomerular filtration rate (eGFR), also termed the 'eGFR dip,' shortly after treatment initiation.2Wanner C. Inzucchi S.E. Lachin J.M. et al.Empagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375: 323-334Crossref PubMed Scopus (1935) Google Scholar,7Heerspink H.J. Johnsson E. Gause-Nilsson I. et al.Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers.Diabetes Obes Metab. 2016; 18: 590-597Crossref PubMed Scopus (135) Google Scholar,8Heerspink H.J. Desai M. Jardine M. et al.Canagliflozin slows progression of renal function decline independently of glycemic effects.J Am Soc Nephrol. 2017; 28: 368-375Crossref PubMed Scopus (238) Google Scholar Although considered largely hemodynamic and reversible, this initial 'eGFR dip' has raised concerns in clinical practice, as it may predispose patients to acute kidney injury (AKI). Adverse event (AE) post-marketing reporting on AKI led the U.S. Food and Drug Administration to issue warnings for SGLT2i to be used with caution in patients at risk of AKI.9U.S. Food and Drug AdministrationFDA drug safety communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). [06-14-2016].https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-kidney-warnings-diabetes-medicines-canagliflozinGoogle Scholar However, data from clinical trials1Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (6811) Google Scholar,3Neal B. Perkovic V. Mahaffey K.W. et al.Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657Crossref PubMed Scopus (2050) Google Scholar,4Wiviott S.D. Raz I. Bonaca M.P. et al.Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2019; 380: 347-357Crossref PubMed Scopus (2762) Google Scholar,6Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Crossref PubMed Scopus (2374) Google Scholar and large observational cohorts10Nadkarni G.N. Ferrandino R. Chang A. et al.Acute kidney injury in patients on SGLT2 inhibitors: a propensity-matched analysis.Diabetes Care. 2017; 40: 1479-1485Crossref PubMed Scopus (108) Google Scholar, 11Ueda P. Svanström H. Melbye M. et al.Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study.BMJ. 2018; 363: k4365Crossref PubMed Scopus (201) Google Scholar, 12Patorno E. Pawar A. Franklin J.M. et al.Empagliflozin and the risk of heart failure hospitalization in routine clinical care.Circulation. 2019; 139: 2822-2830Crossref PubMed Scopus (137) Google Scholar, 13Iskander C. Cherney D.Z. Clemens K.K. et al.Use of sodium-glucose cotransporter-2 inhibitors and risk of acute kidney injury in older adults with diabetes: a population-based cohort study.CMAJ. 2020; 192: E351-E360Crossref PubMed Scopus (33) Google Scholar show a reduced AKI risk with SGLT2i.An initial 'eGFR dip' has been reported with renin-angiotensin-aldosterone system (RAAS) inhibition.14Bakris G.L. Weir M.R. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern?.Arch Intern Med. 2000; 160: 685-693Crossref PubMed Google Scholar,15Brenner B.M. Cooper M.E. de Zeeuw D. et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (6092) Google Scholar Until recently, RAAS inhibition was the sole nephroprotective treatment for patients with kidney disease, and it remains widely used. Nevertheless, the predictive value of the 'eGFR dip' associated with RAAS inhibition on CV and kidney outcomes remains controversial.16Holtkamp F.A. de Zeeuw D. Thomas M.C. et al.An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function.Kidney Int. 2011; 80: 282-287Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar, 17Clase C.M. Barzilay J. Gao P. et al.Acute change in glomerular filtration rate with inhibition of the renin-angiotensin system does not predict subsequent renal and cardiovascular outcomes.Kidney Int. 2017; 91: 683-690Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 18Ohkuma T. Jun M. Rodgers A. et al.Acute increases in serum creatinine after starting angiotensin-converting enzyme inhibitor-based therapy and effects of its continuation on major clinical outcomes in type 2 diabetes mellitus.Hypertension. 2019; 73: 84-91Crossref PubMed Scopus (33) Google Scholar, 19Fu E.L. Trevisan M. Clase C.M. et al.Association of acute increases in plasma creatinine after renin-angiotensin blockade with subsequent outcomes.Clin J Am Soc Nephrol. 2019; 14: 1336-1345Crossref PubMed Scopus (14) Google ScholarThe initial 'eGFR dip' with SGLT2i on top of RAAS inhibition may limit its clinical use, especially in patients within the lower eGFR range. Therefore, its incidence and clinical implications need to be better understood. We characterized EMPA-REG OUTCOME participants with various degrees of initial change in eGFR and investigated whether the initial 'eGFR dip' observed with empagliflozin was influenced by baseline characteristics and/or had an impact on safety and CV and kidney outcomes.MethodsThe design and methods of the double-blind, placebo-controlled, multinational EMPA-REG OUTCOME trial (ClinicalTrials.gov identifier: NCT01131676) have been described previously.1Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (6811) Google Scholar The study population included 7020 treated participants with T2D, established CV disease, and eGFR ≥30 ml/min per 1.73 m2 (MDRD; modification of diet in kidney disease). Participants were assigned at random to receive empagliflozin 10 mg or 25 mg or placebo (1:1:1) once daily, in addition to standard care. The median duration of treatment was 2.6 years, and the median observation time was 3.1 years. The primary CV outcome and prespecified secondary kidney outcome (defined as incident or worsening nephropathy) have been reported previously.1Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (6811) Google Scholar,2Wanner C. Inzucchi S.E. Lachin J.M. et al.Empagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375: 323-334Crossref PubMed Scopus (1935) Google ScholarFor this post hoc analysis, 6668 participants who received ≥1 dose of study drug and had baseline and week 4 eGFR values available were categorized by percent eGFR (equation developed by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) change from baseline at week 4 into 3 categories: >10% decline ('eGFR dipper'), >0% to ≤10% decline ('eGFR intermediate'), and no decline ('eGFR non-dipper'). This pragmatic categorization, using clinically relevant, memorable, and easy-to-apply cutoffs, resulted in 3 similar-sized groups in the empagliflozin treatment arm. For each category, we described baseline characteristics and eGFR change over time for the duration of treatment and after treatment discontinuation. Additional sensitivity analysis was performed for an eGFR decline of >30% from baseline. For all analyses, we compared placebo and pooled empagliflozin (10 mg and 25 mg) groups. Serum creatinine and albumin, and urinary albumin in spot urine, were measured in central laboratories to calculate the urine-albumin-to-creatinine ratio (UACR). Kidney Disease: Improving Global Outcomes (KDIGO) categorization was conducted according to the KDIGO heat map, a 2-dimensional classification system, identifying patients with low eGFR and higher UACR levels, who are at elevated risk of adverse kidney and CV outcomes.20Kidney Disease: Improving Global Outcomes (KDIGO)KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int. 2013; : 1-150Google Scholar For kidney function over time, we used the CKD-EPI creatinine equation. Mixed-model, repeated-measures analysis was used to evaluate changes in eGFR over time, including glycated hemoglobin (HbA1c) level and eGFR (CKD-EPI) at baseline as linear covariates and geographic region, baseline body mass index (BMI), treatment, visit, visit-by-treatment interaction, interaction between baseline HbA1c level and visit, and interaction between baseline eGFR and visit as fixed effects. Changes in eGFR per year (i.e., eGFR slope) were obtained using a random intercept/random coefficient model, as described previously.21Wanner C. Heerspink H.J. Zinman B. et al.Empagliflozin and kidney function decline in patients with type 2 diabetes: a slope analysis from the EMPA-REG OUTCOME trial.J Am Soc Nephrol. 2018; 29: 2755-2769Crossref PubMed Scopus (103) Google Scholar The model was applied by each 'eGFR dipping' category separately, and only data for participants on treatment were used. Participants who also had eGFR values available after treatment discontinuation where assessed for absolute and percent changes in eGFR between last value on treatment (LVOT) and first value after treatment discontinuation (follow-up).Baseline characteristics of the 'eGFR intermediate' and 'eGFR non-dipper' groups were generally comparable. Thus, further analyses were performed based on pooled data from these 2 categories to focus on one harmonized 'eGFR dip' event, defined as the occurrence of an 'eGFR dip' >10% from baseline at week 4. Baseline characteristics were evaluated for potential predictive effect of such an initial percent 'eGFR dip' from baseline at week 4 with empagliflozin versus placebo. We used logistic regression with baseline factors, treatment, and interaction of baseline factors with treatment to investigate potential interactions of baseline factors with treatment and hence predictive effects. Following that approach, we applied a multivariate logistic regression model using backward selection and applied significance level of P < 0.05 for interaction of each baseline factor and treatment to be retained in the model. Baseline factors with a significance level of P < 0.1 for interaction with treatment as determined from the first step were included in the multivariate model. Relevant predictive factors for an 'eGFR dip' event were calculated from the multivariate logistic regression model.To investigate the association of an 'eGFR dip' from baseline at week 4 with CV-related death, hospitalization for heart failure (HHF), or kidney outcomes after week 4 independent of treatment, we combined empagliflozin and placebo groups and used a Cox proportional hazards model with factors for treatment group, baseline variables of age, sex, BMI, HbA1c, eGFR, region, and 'eGFR dip' at week 4 and with additional adjustment for baseline values and changes from baseline at week 4 in systolic blood pressure (SBP), diastolic blood pressure (DBP), and fasting plasma glucose.While categorization by actual 'eGFR dipping' after randomization results in loss of randomization and thus does not allow for a comparison of empagliflozin treatment effect in 'eGFR dipper' versus other categories, we assessed the impact of an 'eGFR dip' at week 4 using 2 approaches. We first analyzed the effect of empagliflozin on CV and kidney outcomes across relevant predictive baseline factors for an 'eGFR dip' event. These analyses were performed using a Cox proportional hazards model with factors for treatment, age, sex, baseline BMI, baseline HbA1c, region, subgroup, and treatment-by-subgroup interaction. In addition, we assessed the 'eGFR dip' as potential mediator for the effect of empagliflozin on these outcomes. This analysis was done in accordance with the previously described concept of traditional mediation analysis proposed by Baron and Kenny,22Baron R.M. Kenny D.A. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations.J Pers Soc Psychol. 1986; 51: 1173-1182Crossref PubMed Scopus (53345) Google Scholar and similarly applied for time to occurrence of CV death.23Inzucchi S.E. Zinman B. Fitchett D. et al.How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial.Diabetes Care. 2018; 41: 356-363Crossref PubMed Scopus (427) Google Scholar We compared the treatment effect of empagliflozin on outcomes from week 4 onward from the analysis using the primary model,1Zinman B. Wanner C. Lachin J.M. et al.Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128Crossref PubMed Scopus (6811) Google Scholar with the treatment effect obtained using a model also adjusted for a >10% 'eGFR dip' at week 4. The percent mediation was calculated as follows: mediation % = 100 ∗ ([lnHR - lnHRC]/lnHR), where HR (hazard ratio) denotes a comparison of treatment groups in the model with treatment group alone and HRC denotes a comparison of treatment groups in the model adjusting for the 'eGFR dip'. To be considered a mediator, the 'eGFR dip' should have an effect on the studied outcome, and the effect of empagliflozin on outcome must be reduced in the analysis adjusted for 'eGFR dip'. Mediation was indicated if the HR for outcome between treatment groups adjusted for 'eGFR dip' was closer to unity than the HR from the model with treatment group alone (primary model). Complete mediation would be indicated by an HR of 1.0 in the model adjusted for 'eGFR dip'. A positive mediation value indicates that effect of empagliflozin on outcome was partially mediated by the 'eGFR dip,' and a negative value indicates that the effect of empagliflozin was partially diminished by the 'eGFR dip.'All analyses were performed at the nominal α level of 0.05 without correction for multiple hypothesis testing.Safety analyses of kidney and overall AEs were descriptive across predictive baseline factors for an 'eGFR dip'. Kidney AEs represent reporting of the narrow Standardised Medical Dictionary for Regulatory Activities (MedDRA) Query for acute renal failure (ARF) by study investigators, which included the preferred term AKI. Statistical analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC).ResultsThere was wide interindividual variability in the initial eGFR change among the participants. Whereas the median (IQR) eGFR change from baseline at week 4 was –0.05 (IQR, –4.04 to +4.27) ml/min per 1.73 m2 in the placebo-treated participants (–21.4 and +21.4 for the 1st and 99th percentiles, respectively), it shifted toward a median reduction of –2.69 (IQR, –7.87, +1.30) ml/min per 1.73 m2 with empagliflozin (–24.9 and +17.7 for the 1st and 99th percentiles, respectively).Baseline characteristics of 'eGFR dipping' categoriesCategorization resulted in 28.3% and 13.4% of 'eGFR dipper,' 41.1% and 39.5% of 'eGFR intermediate,' and 30.5% and 47.1% of 'eGFR non-dipper' participants in the empagliflozin and placebo groups, respectively (Figure 1a). Baseline characteristics of 'eGFR dip' categories are shown in Table 1. Among empagliflozin-treated participants, most baseline characteristics were comparable in the 'eGFR non-dipper' and 'eGFR intermediate' groups, except for SBP and eGFR, which were slightly higher in the latter group. In contrast, there were some relevant differences in baseline characteristics between empagliflozin-treated 'eGFR dippers' and 'eGFR non-dippers'; 'eGFR dippers' were older, had a longer-standing history of diabetes, and had higher rates of impaired kidney function and albuminuria and hence a higher KDIGO risk category. Hemoglobin, hematocrit, and albumin levels were slightly lower in 'eGFR dippers.' The 'eGFR dippers' were more likely to have suboptimal SBP control, even though they were taking more antihypertensive medications. In addition, more 'eGFR dippers' were treated with insulin and fewer were treated with metformin, while study participants using insulin had a lower baseline eGFR compared with nonusers, and metformin users had a higher baseline eGFR compared with nonusers.24Inzucchi S.E. Fitchett D. Jurišić-Eržen D. et al.Are the cardiovascular and kidney benefits of empagliflozin influenced by baseline glucose-lowering therapy?.Diabetes Obes Metab. 2020; 22: 631-639Crossref PubMed Scopus (49) Google Scholar Characteristics of the participant subset that experienced an initial eGFR decline of >30% on initiation of empagliflozin (1.4%; n = 64) are summarized in Supplementary Table S1. Overall, their baseline characteristics were comparable to those of the 'eGFR dippers,' but they tended to have more comorbidities and CV risk factors.Table 1Baseline characteristics for empagliflozin-treated participants according to 'eGFR dipping' categoriesCharacteristics'eGFR dipper' (>10% eGFR decline)'eGFR intermediate' (>0% to ≤10% eGFR decline)'eGFR non-dipper' (no eGFR decline)Number (%)1259 (28.3)1827 (41.1)1357 (30.5)Age, yr, mean ± SD64.6 ± 8.3cP < 0.0001 compared with the non-dipping group.62.8 ± 8.462.2 ± 8.8Male sex, n (%)875 (69.5)1316 (72.0)980 (72.2)BMI, kg/m2, mean ± SD30.9 ± 5.4bP < 0.001 compared with the non-dipping group.30.6 ± 5.2aP < 0.05 compared with the non-dipping group.30.2 ± 5.2HbA1c, %, mean ± SDdN value: 1258 for the >10% decline group.8.11 ± 0.88.04 ± 0.88.05 ± 0.9FPG, mg/dl, mean ± SDeN values: 1352, 1818, and 1257 for the no, >0 to ≤10%, and >10% decline groups, respectively.150.4 ± 44.1aP < 0.05 compared with the non-dipping group.152.7 ± 42.8153.8 ± 43.4Time since diagnosis of T2D, n (%)cP < 0.0001 compared with the non-dipping group.aP < 0.05 compared with the non-dipping group. ≤1 yr22 (1.7)51 (2.8)52 (3.8) >1 to 5 yr161 (12.8)286 (15.7)239 (17.6) >5 to 10 yr293 (23.3)457 (25.0)362 (26.7) >10 yr783 (62.2)1033 (56.5)704 (51.9)eGFR, ml/min per 1.73 m2, mean ± SD68.3 ± 18.1cP < 0.0001 compared with the non-dipping group.79.5 ± 22.9cP < 0.0001 compared with the non-dipping group.72.9 ± 20.6eGFR category, n (%)cP < 0.0001 compared with the non-dipping group.cP < 0.0001 compared with the non-dipping group. ≥90 ml/min per 1.73 m2132 (10.5)599 (32.8)272 (20.0) 60 to <90 ml/min per 1.73 m2716 (56.9)859 (47.0)731 (53.9) <60 ml/min per 1.73 m2411 (32.6)369 (20.2)354 (26.1)UACR (median, IQR)fN values: 1337, 1813, and 1245 for the no, >0 to ≤10%, and >10% decline groups, respectively.27.4 (7.1–121.1)cP < 0.0001 compared with the non-dipping group.16.8 (7.1–59.2)15.0 (6.2–55.7)UACR category, n (%)cP < 0.0001 compared with the non-dipping group. <30643 (51.1)1137 (62.2)870 (64.1) ≥30 to 300409 (32.5)513 (28.1)339 (25.0) >300193 (15.3)163 (8.9)128 (9.4)KDIGO risk category, n (%)cP < 0.0001 compared with the non-dipping group.aP < 0.05 compared with the non-dipping group. Low risk of CKD473 (37.6)961 (52.6)690 (50.8) Moderate risk of CKD391 (31.1)510 (27.9)371 (27.3) High risk of CKD246 (19.5)251 (13.7)165 (12.2) Very high risk of CKD135 (10.7)91 (5.0)111 (8.2)Hemoglobin, g/dl, mean ± SDgN values: 1356, 1826, and 1259 for the no, >0 to ≤10%, and >10% decline groups, respectively.13.5 ± 1.5cP < 0.0001 compared with the non-dipping group.13.8 ± 1.413.9 ± 1.5Hematocrit, %, mean ± SDhN values: 1353, 1821, and 1257 for the no, >0 to ≤10%, and >10% decline groups, respectively.40.6 ± 4.5cP < 0.0001 compared with the non-dipping group.41.6 ± 4.2aP < 0.05 compared with the non-dipping group.41.9 ± 4.4Albumin, g/dl, mean ± SDiN value: 1259 for the >10% decline group.4.39 ± 0.32cP < 0.0001 compared with the non-dipping group.4.43 ± 0.29aP < 0.05 compared with the non-dipping group.4.46 ± 0.31Cholesterol, mg/dl, mean ± SD HDLjN values: 1339, 1807, and 1243 for the no, >0 to ≤10%, and >10% decline groups, respectively.44.3 ± 12.144.6 ± 11.444.9 ± 12.2 LDLkN values: 1339, 1805, and 1242 for the no, >0 to ≤10%, and >10% decline groups, respectively.85.0 ± 33.7aP < 0.05 compared with the non-dipping group.85.0 ± 35.2aP < 0.05 compared with the non-dipping group.88.2 ± 38.5 TGjN values: 1339, 1807, and 1243 for the no, >0 to ≤10%, and >10% decline groups, respectively.176.8 ± 147167.8 ± 129167.4 ± 116SBP, mmHg, mean ± SD137.3 ± 17.4cP < 0.0001 compared with the non-dipping group.135.3 ± 16.4bP < 0.001 compared with the non-dipping group.133.3 ± 16.8DBP, mmHg, mean ± SD76.6 ± 9.976.8 ± 9.476.6 ± 9.8BP control, categorical, n (%)cP < 0.0001 compared with the non-dipping group.aP < 0.05 compared with the non-dipping group. SBP <140 and DBP <90 mmHg728 (57.8)1130 (61.9)898 (66.2) SBP ≥140 or DBP ≥90 mmHg531 (42.2)697 (38.1)459 (33.8)Concomitant medication, n (%) ACEi/ARB1094 (86.9)cP < 0.0001 compared with the non-dipping group.1462 (80.0)1054 (77.7) Beta-blocker853 (67.8)aP < 0.05 compared with the non-dipping group.1186 (64.9)856 (63.1) Diuretic685 (54.4)cP < 0.0001 compared with the non-dipping group.695 (38.0)539 (39.7) Loop diuretic252 (20.0)cP < 0.0001 compared with the non-dipping group.234 (12.8)178 (13.1) CCB441 (35.0)aP < 0.05 compared with the non-dipping group.581 (31.8)426 (31.4) Statin973 (77.3)1431 (78.3)1033 (76.1) ASA1068 (84.8)aP < 0.05 compared with the non-dipping group.1500 (82.1)1112 (81.9) Metformin864 (68.6)cP < 0.0001 compared with the non-dipping group.1389 (76.0)1031 (76.0) Sulfonylurea513 (40.7)aP < 0.05 compared with the non-dipping group.787 (43.1)615 (45.3) Insulin666 (52.9)cP < 0.0001 compared with the non-dipping group.858 (47.0)592 (43.6)CV high risk factor, n (%) CHD history965 (76.6)1379 (75.5)1008 (74.3) Stroke history294 (23.4)427 (23.4)307 (22.6) PAD history301 (23.9)aP < 0.05 compared with the non-dipping group.366 (20.0)270 (19.9) HF history138 (11.0)149 (8.2)135 (9.9)Race, n (%)aP < 0.05 compared with the non-dipping group. White920 (73.1)1328 (72.7)970 (71.5) Asian242 (19.2)412 (22.6)308 (22.7) Black/African-American90 (7.1)71 (3.9)64 (4.7)ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASA, acetylsalicylic acid; BMI, body mass index; CCB, calcium channel blocker; CHD, coronary heart disease; CKD, chronic kidney disease; CV, cardiovascular; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; HF, heart failure; KDIGO, Kidney Disease: Improving Global Outcomes; LDL, low-density lipoprotein; PAD, peripheral artery disease; SBP, systolic blood pressure; T2D, type 2 diabetes; TG, triglycerides; UACR, urine albumin-to-creatinine ratio.a P < 0.05 compared with the non-dipping group.b P < 0.001 compared with the non-dipping group.c P < 0.0001 compared with the non-dipping group.d N value: 1258 for the >10% decline group.e N values: 1352, 1818, and 1257 for the no, >0 to ≤10%, and >10% decline groups, respectively.f N values: 1337, 1813, and 1245 for the no, >0 to ≤10%, and >10% decline groups, respectively.g N values: 1356, 1826, and 1259 for the no, >0 to ≤10%, and >10% decline groups, respectively.h N values: 1353, 1821, and 1257 for the no, >0 to ≤10%, and >10% decline groups, respectively.i N value: 1259 for the >10% decline group.j N values: 1339, 1807, and 1243 for the no, >0 to ≤10%, and >10% decline groups, respectively.k N values: 1339, 1805, and 1242 for the no, >0 to ≤10%, and >10% decline groups, respectively. Open table in a new tab eGFR over time and after treatment discontinuation according to 'eGFR dipping' categoryThe baseline mean ± SD eGFR values in the empagliflozin-treated participants were 68.3 ± 18.1, 79.5 ± 22.9, and 72.9 ± 20.6 ml/min per 1.73 m2 for the 'eGFR dipper,' 'eGFR intermediate,' and 'eGFR non-dipper' groups, respectively. The respective mean ± SD eGFR changes from baseline at week 4 in these 3 groups were –12.6 ± 5.7, –3.3 ± 2.4, and +5.4 ± 5.7 ml/min per 1.73 m2. Few participants experienced an eGFR decline >30% at week 4 (1.4% [n = 64] on empagliflozin and 0.9% [n = 20] on placebo). Among these, 1 patient on empagliflozin and no patients on placebo discontinued the study following week 4.In participants receiving empagliflozin treatment, the mean eGFR remained stable from week 12 onward in all 'eGFR dipping' categories (Figure 1b), as well as in the subset with an initial empagliflozin-induced eGFR decline >30% (Supplementary Figure S1). In contrast, mean eGFR levels in placeb