Empagliflozin in Patients with Chronic Kidney Disease.

BACKGROUND: The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. METHODS: We enrolled patients with chronic kidney disease who 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 who had 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. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to <10 ml per minute per 1.73 m2, a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes. RESULTS: A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P<0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P = 0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. CONCLUSIONS: Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo. (Funded by Boehringer Ingelheim and others; EMPA-KIDNEY ClinicalTrials.gov number, NCT03594110; EudraCT number, 2017-002971-24.).

Efficacy and safety of aldosterone synthase inhibition with and without empagliflozin for chronic kidney disease: a randomised, controlled, phase 2 trial.

BACKGROUND: Excess aldosterone accelerates chronic kidney disease progression. This phase 2 clinical trial assessed BI 690517, an aldosterone synthase inhibitor, for efficacy, safety, and dose selection. METHODS: This was a multinational, randomised, controlled, phase 2 trial. People aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 30 to less than 90 mL/min/1·73 m2, a urine albumin to creatinine ratio (UACR) of 200 to less than 5000 mg/g, and serum potassium of 4·8 mmol/L or less, taking an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, were enrolled. Participants were randomly assigned (1:1) to 8 weeks of empagliflozin or placebo run-in, followed by a second randomisation (1:1:1:1) to 14 weeks of treatment with once per day BI 690517 at doses of 3 mg, 10 mg, or 20 mg, or placebo. Study participants, research coordinators, investigators, and the data coordinating centre were masked to treatment assignment. The primary endpoint was the change in UACR measured in first morning void urine from baseline (second randomisation) to the end of treatment. This study is registered with ClinicalTrials.gov (NCT05182840) and is completed. FINDINGS: Between Feb 18 and Dec 30, 2022, of the 714 run-in participants, 586 were randomly assigned to receive BI 690517 or placebo. At baseline, 33% (n=196) were women, 67% (n=390) were men, 42% (n=244) had a racial identity other than White, and mean participant age was 63·8 years (SD 11·3). Mean baseline eGFR was 51·9 mL/min/1·73 m2 (17·7) and median UACR was 426 mg/g (IQR 205 to 889). Percentage change in first morning void UACR from baseline to the end of treatment at week 14 was -3% (95% CI -19 to 17) with placebo, -22% (-36 to -7) with BI 690517 3 mg, -39% (-50 to -26) with BI 690517 10 mg, and -37% (-49 to -22) with BI 690517 20 mg monotherapy. BI 690517 produced similar UACR reductions when added to empagliflozin. Investigator-reported hyperkalaemia occurred in 10% (14/146) of those in the BI 690517 3 mg group, 15% (22/144) in the BI 690517 10 mg group, and 18% (26/146) in the BI 690517 20 mg group, and in 6% (nine of 147) of those receiving placebo, with or without empagliflozin. Most participants with hyperkalaemia did not require intervention (86% [72/84]). Adrenal insufficiency was an adverse event of special interest reported in seven of 436 study participants (2%) receiving BI 690517 and one of 147 participants (1%) receiving matched placebo. No treatment-related deaths occurred during the study. INTERPRETATION: BI 690517 dose-dependently reduced albuminuria with concurrent renin-angiotensin system inhibition and empagliflozin, suggesting an additive efficacy for chronic kidney disease treatment without unexpected safety signals. FUNDING: Boehringer Ingelheim.

Effects of Empagliflozin on Fluid Overload, Weight, and Blood Pressure in CKD.

SIGNIFICANCE STATEMENT: SGLT2 inhibitors reduce risk of kidney progression, AKI, and cardiovascular disease, but the mechanisms of benefit are incompletely understood. Bioimpedance spectroscopy can estimate body water and fat mass. One quarter of the EMPA-KIDNEY bioimpedance substudy CKD population had clinically significant levels of bioimpedance-derived "Fluid Overload" at recruitment. Empagliflozin induced a prompt and sustained reduction in "Fluid Overload," irrespective of sex, diabetes, and baseline N-terminal pro B-type natriuretic peptide or eGFR. No significant effect on bioimpedance-derived fat mass was observed. The effects of SGLT2 inhibitors on body water may be one of the contributing mechanisms by which they mediate effects on cardiovascular risk. BACKGROUND: CKD is associated with fluid excess that can be estimated by bioimpedance spectroscopy. We aimed to assess effects of sodium glucose co-transporter 2 inhibition on bioimpedance-derived "Fluid Overload" and adiposity in a CKD population. METHODS: EMPA-KIDNEY was a double-blind placebo-controlled trial of empagliflozin 10 mg once daily in patients with CKD at risk of progression. In a substudy, bioimpedance measurements were added to the main trial procedures at randomization and at 2- and 18-month follow-up visits. The substudy's primary outcome was the study-average difference in absolute "Fluid Overload" (an estimate of excess extracellular water) analyzed using a mixed model repeated measures approach. RESULTS: The 660 substudy participants were broadly representative of the 6609-participant trial population. Substudy mean baseline absolute "Fluid Overload" was 0.4±1.7 L. Compared with placebo, the overall mean absolute "Fluid Overload" difference among those allocated empagliflozin was -0.24 L (95% confidence interval [CI], -0.38 to -0.11), with similar sized differences at 2 and 18 months, and in prespecified subgroups. Total body water differences comprised between-group differences in extracellular water of -0.49 L (95% CI, -0.69 to -0.30, including the -0.24 L "Fluid Overload" difference) and a -0.30 L (95% CI, -0.57 to -0.03) difference in intracellular water. There was no significant effect of empagliflozin on bioimpedance-derived adipose tissue mass (-0.28 kg [95% CI, -1.41 to 0.85]). The between-group difference in weight was -0.7 kg (95% CI, -1.3 to -0.1). CONCLUSIONS: In a broad range of patients with CKD, empagliflozin resulted in a sustained reduction in a bioimpedance-derived estimate of fluid overload, with no statistically significant effect on fat mass. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03594110 ; EuDRACT: 2017-002971-24 ( https://eudract.ema.europa.eu/ ).

Methods Article for a Study Protocol: Study Design and Baseline Characteristics for Aldosterone Synthase Inhibition in Chronic Kidney Disease.

INTRODUCTION: Aldosterone synthase (AS) inhibition may overcome increased aldosterone production in response to renin-angiotensin system inhibition. BI 690517 is an AS inhibitor under investigation for chronic kidney disease (CKD). METHODS: This multinational, phase II, double-blind study (NCT05182840) investigated the efficacy and safety of daily oral BI 690517, with or without empagliflozin 10 mg, in participants with CKD. The primary endpoint was change from baseline in urine albumin:creatinine ratio (UACR) at week 14. Between February 18, 2022, and December 30, 2022, 714 adults already treated by angiotensin-converting enzyme inhibitor (30.5%) or angiotensin receptor blocker (69.8%) were randomized (1:1) to an 8-week run-in to assign background empagliflozin (n = 356) or placebo (n = 358). Participants in each group were then randomized (1:1:1:1) to a 14-week treatment period with BI 690517 (3 mg, 10 mg, or 20 mg) or placebo. Of the 714 participants who entered run-in, 586 were randomized to the treatment period. They were predominantly men (66.6%) of white race (58.4%) with a mean (standard deviation [SD]) age of 63.8 (11.3) years. Type 2 diabetes was present in 414 participants (70.6%). The baseline mean (SD) estimated glomerular filtration rate was 51.9 (17.7) mL/min/1.73 m2, and median (interquartile range) UACR was 426.3 mg/g (205.3-888.5). CONCLUSION: This study will inform dose selection for further clinical development and determine whether BI 690517, with or without background empagliflozin, has a favorable safety profile and potential for additive kidney protection in participants with CKD already treated with a renin-angiotensin system inhibitor.

Empagliflozin lowers serum uric acid in chronic kidney disease: exploratory analyses from the EMPA-KIDNEY trial.

BACKGROUND AND HYPOTHESIS: Hyperuricaemia and gout are common in chronic kidney disease (CKD). We aimed to assess the effects of sodium-glucose co-transporter-2 (SGLT2) inhibition on uric acid (urate) and gout in patients with CKD. METHODS: The EMPA-KIDNEY trial randomised 6609 patients with CKD (estimated glomerular filtration rate [eGFR] ≥20 and <90 mL/min/1.73m2) to receive either empagliflozin 10 mg daily or matching placebo over a median of two years follow-up. Serum uric acid was measured at randomisation then 2 and 18 months of follow-up and the effects of empagliflozin were analysed using a pre-specified mixed model repeated measures approach. Participant-reported gout events were analysed in Cox regression models (first events) with the Andersen-Gill extension (total events). A post-hoc composite outcome included new initiation of uric acid lowering therapy or colchicine. EMPA-KIDNEY primary and kidney disease progression outcomes were also assessed in subgroups of baseline serum uric acid. RESULTS: Baseline mean ± SD serum uric acid concentration was 431±114 µmol/L. Allocation to empagliflozin resulted in a study-average between-group difference in serum uric acid of -25.6 (95%CI -30.3,-21.0) µmol/L with larger effects in those with higher eGFR (trend P < 0.001) and without diabetes (heterogeneity P < 0.001). Compared to placebo, empagliflozin did not significantly reduce first or total gout events (HR 0.87, 95%CI 0.74-1.02 for the 595 first events, and 0.86, 0.72-1.03 for the 869 total events) with similar hazard ratios for the post-hoc composite and across subgroups, including by diabetes and eGFR. The effect of empagliflozin on the primary outcome and kidney disease progression outcomes were similar irrespective of baseline level of uric acid. CONCLUSION: SGLT2 inhibition reduces serum uric acid in patients with CKD with larger effects at higher eGFR and in the absence of diabetes. However, the effect on uric acid is modest and did not translate into reduced risk of gout in EMPA-KIDNEY.

Effects of empagliflozin in patients with chronic kidney disease from Japan: exploratory analyses from EMPA-KIDNEY.

BACKGROUND: EMPA-KIDNEY assessed the effects of empagliflozin 10 mg once daily vs. placebo in 6609 patients with chronic kidney disease (CKD) at risk of progression, including 612 participants from Japan. METHODS: Eligibility required an estimated glomerular filtration rate (eGFR) of ≥ 20 < 45; or ≥ 45 < 90 ml/min/1.73m2 with a urinary albumin-to-creatinine ratio (uACR) of ≥ 200 mg/g. The primary outcome was a composite of kidney disease progression (end-stage kidney disease, a sustained eGFR decline to < 10 ml/min/1.73m2 or ≥ 40% from randomization, or renal death) or cardiovascular death. In post-hoc analyses, we explored the effects of empagliflozin in participants from Japan vs. non-Japan regions, including additional models assessing whether differences in treatment effects between these regions could result from differences in baseline characteristics. RESULTS: Japanese participants had higher levels of albuminuria and eGFR than those from non-Japan regions. During a median of 2.0 year follow-up, a primary outcome occurred in 432 patients (13.1%) in the empagliflozin group and in 558 patients (16.9%) in the placebo group (hazard ratio [HR], 0.72, 95% confidence interval [95%CI] 0.64-0.82; P < 0.0001). Among the participants from non-Japan regions, there were 399 vs. 494 primary outcomes (0.75, 0.66-0.86), and 33 vs. 64 (0.49, 0.32-0.75; heterogeneity p = 0.06) in Japan. Results were similar when models explicitly considered treatment interactions with diabetes status, categories of eGFR/uACR, and recruitment in Japan (heterogeneity p = 0.08). Safety outcomes were broadly comparable between the two groups, and by Japanese status. CONCLUSIONS: Empagliflozin safely reduced the risk of "kidney disease progression or cardiovascular death" in patients with CKD, with consistent effects in participants from Japan.

Consistent effects of empagliflozin on cardiovascular and kidney outcomes irrespective of diabetic kidney disease categories: Insights from the EMPA-REG OUTCOME trial.

AIM: To explore the cardiovascular (CV) and kidney effects of empagliflozin in patients with different clinical phenotypes of diabetic kidney disease (DKD) (i.e. with the presence or absence of overt albuminuria) participating in the EMPA-REG OUTCOME trial. MATERIALS AND METHODS: EMPA-REG OUTCOME randomized participants (1:1:1) to empagliflozin 10 mg, 25 mg or placebo, added to standard of care. Post hoc, patients with different clinical phenotypes of DKD at baseline were categorized in three subgroups: (a) overt DKD (overt albuminuria [urinary albumin-to-creatinine ratio of >300 mg/g] with any estimated glomerular filtration rate [eGFR]; n = 769); (b) non-overt DKD (kidney impairment [eGFR < 60 mL/min/1.73 m2 ] without overt albuminuria [urinary albumin-to-creatinine ratio of ≤300 mg/g]; n = 1290); and (c) 'all others' (eGFR ≥ 60 mL/min/1.73 m2 without overt albuminuria; n = 4893). Analyses included CV (death, hospitalization for heart failure, all-cause hospitalization) and selected kidney outcomes, change in eGFR and kidney safety. Cox proportional hazards models assessed the consistency of treatment effect across subgroups. RESULTS: Empagliflozin significantly reduced the risk of CV and kidney outcomes across all subgroups (P-values for interaction >.05), consistent with the overall trial population findings. Empagliflozin also significantly reduced the yearly loss of eGFR, assessed by chronic slopes, in all subgroups. The adverse event profile of empagliflozin was similar across all subgroups. CONCLUSIONS: Empagliflozin may improve CV and kidney outcomes and slow the progression of kidney disease in type 2 diabetes patients with DKD, irrespective of its clinical form, both with or without the presence of overt albuminuria.

Kidney disease progression and all-cause mortality across estimated glomerular filtration rate and albuminuria categories among patients with vs. without type 2 diabetes.

BACKGROUND: Studies of progression of kidney dysfunction typically focus on renal replacement therapy or percentage decline in estimated glomerular filtration rate (eGFR) as outcomes. Our aim was to compare real-world patients with and without T2D to estimate progression from and to clinically defined categories of kidney disease and all-cause mortality. METHODS: This was an observational cohort study of 31,931 patients with and 33,201 age/sex matched patients without type 2 diabetes (T2D) who had a serum creatinine and urine albumin-to-creatinine ratio (UACR) or dipstick proteinuria (DP) values. We used the first available serum creatinine value between 2006 and 2012 to calculate baseline eGFR and categorized them and the corresponding UACR/DP values using the Kidney Disease Improving Global Outcomes (KDIGO) categories. To assess our primary outcomes, we extracted probabilities of eGFR progression or mortality from life-table analyses and conducted multivariable Cox regression analyses of relative risk adjusted for age, sex, race/ethnicity, smoking, ischemic heart disease, heart failure, and use of renal-angiotensin-aldosterone system inhibitors. RESULTS: Patterns of eGFR decline were comparable among patients with vs. without T2D with larger percentage declines at higher albuminuria levels across all eGFR categories. eGFR decline was generally larger among T2D patients, particularly in those with severely increased albuminuria. Across all CKD categories, risk of progression to the next higher category of eGFR was substantially increased with increasing albuminuria. For example, the risk was 23.5, 36.2, and 65.1% among T2D patients with eGFR 30-59 ml/min/1.73m2 and UACR < 30, 30-299, and > 300 mg/dL, respectively (p < 0.001). Other comparisons were similarly significant. Among patients with low eGFR and normal to mildly increased albuminuria, the relative risk was up to 8-fold greater for all-cause mortality compared with the non-CKD subgroup (eGFR> 60 ml/min/1.73m2 with normal to mildly increased albuminuria). CONCLUSIONS: Presence of albuminuria was associated with accelerated eGFR decline independent of T2D. Risk for adverse outcomes was remarkably high among patients with CKD and normal to mildly increased albuminuria levels. Independent of T2D or albuminuria, a substantial risk for adverse outcomes exists for CKD patients in a routine care setting.

Correction to: Kidney disease progression and all-cause mortality across estimated glomerular filtration rate and albuminuria categories among patients with vs. without type 2 diabetes.

An amendment to this paper has been published and can be accessed via the original article.

Carnosinase concentration, activity, and CNDP1 genotype in patients with type 2 diabetes with and without nephropathy.

This study assessed if serum carnosinase (CNDP1) activity and concentration in patients with type 2 diabetes mellitus (T2D) with diabetic nephropathy (DN) differs from those without nephropathy. In a cross-sectional design 127 patients with T2D with DN ((CTG)5 homozygous patients n = 45) and 145 patients with T2D without nephropathy ((CTG)5 homozygous patients n = 47) were recruited. Univariate and multivariate regression analyses were performed to predict factors relevant for serum CNDP1 concentration. CNDP1 (CTG)5 homozygous patients with T2D with DN had significantly lower CNDP1 concentrations (30.4 ± 18.3 vs 51.2 ± 17.6 µg/ml, p < 0.05) and activity (1.25 ± 0.5 vs 2.53 ± 1.1 µmol/ml/h, p < 0.05) than those without nephropathy. This applied for patients with DN on the whole, irrespective of (CTG)5 homozygosity. In the multivariate regression analyses, lower serum CNDP1 concentrations correlated with impaired renal function and to a lesser extend with the CNDP1 genotype (95% CI of regression coefficients: eGFR: 0.10-1.94 (p = 0.001); genotype: - 0.05 to 5.79 (p = 0.055)). Our study demonstrates that serum CNDP1 concentrations associate with CNDP1 genotype and renal function in patients with T2D. Our data warrant further studies using large cohorts to confirm these findings and to delineate the correlation between low serum CNDP1 concentrations and renal function deterioration in patients with T2D.