Empagliflozin in Patients with Chronic Kidney Disease Herrington, William G; Staplin, Natalie; Wanner, Christoph ...
New England journal of medicine/The New England journal of medicine,
01/2023, Letnik:
388, Številka:
2
Journal Article
Recenzirano
Odprti dostop
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.
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 m
of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m
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 m
, a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes.
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.
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.).
We previously demonstrated that polymorphisms in the carnosinase-1 gene (CNDP1) determine the risk of nephropathy in type 2 diabetic patients. Carnosine, the substrate of the enzyme encoded by this ...gene, is considered renoprotective and could possibly be used to treat diabetic nephropathy (DN). In this study, we examined the effect of carnosine treatment in vivo in BTBR (Black and Tan, BRachyuric) ob/ob mice, a type 2 diabetes model which develops a phenotype that closely resembles advanced human DN. Treatment of BTBR ob/ob mice with 4 mM carnosine for 18 weeks reduced plasma glucose and HbA1c, concomitant with elevated insulin and C-peptide levels. Also, albuminuria and kidney weights were reduced in carnosine-treated mice, which showed less glomerular hypertrophy due to a decrease in the surface area of Bowman's capsule and space. Carnosine treatment restored the glomerular ultrastructure without affecting podocyte number, resulted in a modified molecular composition of the expanded mesangial matrix and led to the formation of carnosine-acrolein adducts. Our results demonstrate that treatment with carnosine improves glucose metabolism, albuminuria and pathology in BTBR ob/ob mice. Hence, carnosine could be a novel therapeutic strategy to treat patients with DN and/or be used to prevent DN in patients with diabetes.
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.
The effects of the sodium-glucose co-transporter 2 inhibitor empagliflozin on renal and cardiovascular disease have not been tested in a dedicated population of people with chronic kidney disease ...(CKD).
The EMPA-KIDNEY trial is an international randomized, double-blind, placebo-controlled trial assessing whether empagliflozin 10 mg daily decreases the risk of kidney disease progression or cardiovascular death in people with CKD. People with or without diabetes mellitus (DM) were eligible provided they had an estimated glomerular filtration rate (eGFR) ≥20 but <45 mL/min/1.73 m2 or an eGFR ≥45 but <90 mL/min/1.73 m2 with a urinary albumin:creatinine ratio (uACR) ≥200 mg/g. The trial design is streamlined, as extra work for collaborating sites is kept to a minimum and only essential information is collected.
Between 15 May 2019 and 16 April 2021, 6609 people from eight countries in Europe, North America and East Asia were randomized. The mean age at randomization was 63.8 years standard deviation (SD) 13.9), 2192 (33%) were female and 3570 (54%) had no prior history of DM. The mean eGFR was 37.5 mL/min/1.73 m2 (SD 14.8), including 5185 (78%) with an eGFR <45 mL/min/1.73 m2. The median uACR was 412 mg/g) (quartile 1-quartile 3 94-1190), with a uACR <300 mg/g in 3194 (48%). The causes of kidney disease included diabetic kidney disease n = 2057 (31%), glomerular disease n = 1669 (25%), hypertensive/renovascular disease n = 1445 (22%), other n = 808 (12%) and unknown causes n = 630 (10%).
EMPA-KIDNEY will evaluate the efficacy and safety of empagliflozin in a widely generalizable population of people with CKD at risk of kidney disease progression. Results are anticipated in 2022.
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 m 2 , 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.
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.
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.
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/1.73m
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/1.73m
with normal to mildly increased albuminuria).
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.
Carnosinase 1 (CN1) has been postulated to be a susceptibility factor for developing diabetic nephropathy (DN). Although its major substrate, carnosine, is beneficial in rodent models of DN, ...translation of these findings to humans has been hampered by high CN1 activity in human serum resulting in rapid degradation of carnosine. To overcome this hurdle, we screened a protease-directed small-molecule library for inhibitors of human recombinant CN1. We identified SAN9812 as a potent and highly selective inhibitor of CN1 activity with a
K
i
of 11 nM. It also inhibited CN1 activity in human serum and serum of transgenic mice-overexpressing human CN1. Subcutaneous administration of 30 mg/kg SAN9812 led to a sustained reduction in circulating CN1 activity in human CN1 transgenic (TG) mice. Simultaneous administration of carnosine and SAN9812 increased carnosine levels in plasma and kidney by up to 100-fold compared to treatment-naïve CN1-overexpressing mice. To our knowledge, this is the first study reporting on a potent and selective CN1 inhibitor with in vivo activity. SAN9812, also called carnostatine, may be used to increase renal carnosine concentration as a potential therapeutic modality for renal diseases linked to glycoxidative conditions.
Evaluate changes in haemodynamic markers as mediators of cardiovascular (CV) and kidney benefits with empagliflozin.
Post-hoc analysis of EMPA-REG OUTCOME in patients with type 2 diabetes (T2D) and ...established CV disease receiving empagliflozin (10 and 25 mg) or placebo. Outcomes were CV death, hospitalisation for heart failure HF, HF death, incident/worsening nephropathy, new onset macroalbuminuria, and the composite of sustained estimated glomerular filtration rate decline ≥40 % from baseline, renal replacement therapy or renal death. To be considered a mediator, changes in variable (pulse pressure, mean arterial pressure and cardiac workload) over time had to be (1) affected by active treatment, (2) associated with the outcome, and (3) adjustment for changes over time must reduce treatment effect versus an unadjusted analysis. Variables were evaluated in Cox regression analyses.
Pulse pressure, mean arterial pressure and cardiac workload were significantly reduced by empagliflozin vs placebo. Using change from baseline to Week 12 or sensitivity analyses (time-dependent updated mean and current change from baseline) of these CV parameters, only small impacts on empagliflozin effect on CV and kidney outcomes were shown.
Improvements in haemodynamic parameters did not substantially mediate empagliflozin benefits on CV and kidney outcomes in patients with T2DM and established CV disease.
•Empagliflozin reduces risk of cardiovascular and kidney outcomes in type 2 diabetes.•Empagliflozin reduces pulse pressure, mean arterial pressure and cardiac workload.•Changes in these parameters did not mediate CV or kidney benefits of empagliflozin.
We evaluated the simultaneous effects of all clinically recognized categories of albuminuria and estimated glomerular filtration rate (eGFR) on cardiovascular disease (CVD) and mortality
We conducted ...a longitudinal observational study of 16,678 type 2 diabetes (T2D) patients. From the first serum creatinine value from 2006 to 2012 and a urine-albumin creatinine ratio (UACR) recorded within 6months, we applied baseline Kidney Disease: Improving Global Outcomes (KDIGO) categories of eGFR and albuminuria. We followed patients for up to 11years to calculate adjusted incidence per 1000person-years (p-y) of first CVD hospitalization and all-cause mortality.
Over 98,069p-y of follow-up, CVD hospitalization risk was greater for each higher eGFR and albuminuria category. In eGFR category G2 (60-89mL/min/1.73m2), adjusted incidence per 1000p-y was 14.1 (95% CI 12.9-15.5), 19.8 (17.2-22.8), and 22.8 (17.4-30.0) for normoalbuminuria, microalbuminuria and macroalbuminuria, respectively. For eGFR category G3a (45-59), rates were 26.7 (22.3-32.0), 40.3 (32.2-50.5), and 44.1 (28.8-67.4), respectively. Adjusted risk of all-cause mortality followed a similar pattern.
Our data underscore the importance of including detailed eGFR and UACR values in assessing CVD risk. High albuminuria and low eGFR is a potent predictor of CVD and death.
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