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The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study.

ABSTRACT: Diabetes is a common cause of chronic kidney disease (CKD), but in aggregate, non-diabetic diseases account for a higher proportion of cases of CKD than diabetes in many parts of the world. Inhibition of the renin-angiotensin system reduces the risk of kidney disease progression and treatments that lower blood pressure (BP) or low-density lipoprotein cholesterol reduce cardiovascular (CV) risk in this population. Nevertheless, despite such interventions, considerable risks for kidney and CV complications remain. Recently, large placebo-controlled outcome trials have shown that sodium-glucose co-transporter-2 (SGLT-2) inhibitors reduce the risk of CV disease (including CV death and hospitalization for heart failure) in people with type 2 diabetes who are at high risk of atherosclerotic disease, and these effects were largely independent of improvements in hyperglycaemia, BP and body weight. In the kidney, increased sodium delivery to the macula densa mediated by SGLT-2 inhibition has the potential to reduce intraglomerular pressure, which may explain why SGLT-2 inhibitors reduce albuminuria and appear to slow kidney function decline in people with diabetes. Importantly, in the trials completed to date, these benefits appeared to be maintained at lower levels of kidney function, despite attenuation of glycosuric effects, and did not appear to be dependent on ambient hyperglycaemia. There is therefore a rationale for studying the cardio-renal effects of SGLT-2 inhibition in people at risk of CV disease and hyperfiltration (i.e. those with substantially reduced nephron mass and/or albuminuria), irrespective of whether they have diabetes.

SUBMITTER: Herrington WG

PROVIDER: S-EPMC6275453 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study.

Herrington William G WG Preiss David D Haynes Richard R von Eynatten Maximilian M Staplin Natalie N Hauske Sibylle J SJ George Jyothis T JT Green Jennifer B JB Landray Martin J MJ Baigent Colin C Wanner Christoph C

Clinical kidney journal 20181025 6

Diabetes is a common cause of chronic kidney disease (CKD), but in aggregate, non-diabetic diseases account for a higher proportion of cases of CKD than diabetes in many parts of the world. Inhibition of the renin-angiotensin system reduces the risk of kidney disease progression and treatments that lower blood pressure (BP) or low-density lipoprotein cholesterol reduce cardiovascular (CV) risk in this population. Nevertheless, despite such interventions, considerable risks for kidney and CV comp ...[more]

PMID: 30524708

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Project description:IntroductionCardiac transplantation (CTx) is a life-saving operation that can improve the quality and length of a recipient's life. Immunosuppression medication, required to prevent rejection, can result in adverse metabolic and renal effects. Clinically significant complications include metabolic effects such as diabetes and weight gain, renal impairment, and cardiac disease such as allograft vasculopathy and myocardial fibrosis. Sodium glucose co-transporter 2 (SGLT2) inhibitors are a class of oral medication that increase urinary excretion of glucose. In patients with type 2 diabetes, SGLT2 inhibitors improve cardiovascular, metabolic and renal outcomes. Similar benefits have been shown in patients with heart failure and reduced ejection fraction irrespective of diabetes status. In patients with post-transplant diabetes mellitus, SGLT2 inhibitors improve metabolic parameters; however, their benefit and safety have not been evaluated in randomised prospective studies. This study will potentially provide a novel therapy to improve or prevent complications (diabetes, kidney failure and heart fibrosis) that occur with immunosuppressive medications.MethodsThe EMPA-HTx study is a randomised, placebo-controlled trial of the SGLT2 inhibitor empagliflozin 10 mg daily versus placebo in recent CTx recipients. One hundred participants will be randomised 1:1 and commence the study medication within 6-8 weeks of transplantation with treatment and follow-up until 12 months after transplantation. Demographic information, anthropomorphic measurements, pathology tests and cardiac magnetic resonance (CMR) scan will be recorded at baseline and follow-up. Patients will be reviewed monthly during the study until 12 months post-CTx and data will be collected for each patient at each study visit. The overall aim of the study is to assess the safety and efficacy of empagliflozin in CTx recipients. The primary outcome is glycaemic improvement measured as change in glycated haemoglobin and/or fructosamine. Key secondary outcomes are cardiac interstitial fibrosis measured by CMR and renal function measured by estimated glomerular filtration rate.Ethics and disseminationThis study has been approved by St Vincent's Hospital Human Research Ethics Committee (2021/ETH12184). The findings will be presented at national and international scientific meetings and published in peer-reviewed journals.Trial registration numberACTRN12622000978763.

Project description:Background Cardio/kidney composite end points are clinically relevant but rarely analyzed in cardiovascular trials. This post hoc analysis of the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial evaluated cardio/kidney composite end points by 2 statistical approaches. Methods and Results A total of 7020 patients with type 2 diabetes mellitus and established cardiovascular disease were treated with empagliflozin 10 or 25 mg (n=4687) or placebo (n=2333) on top of standard care. Cardio/kidney composite end points studied were: (1) cardiac or kidney death, kidney failure, hospitalization for heart failure, sustained decline in estimated glomerular filtration rate ≥40% from baseline, or sustained progression to macroalbuminuria; (2) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained estimated glomerular filtration rate decline ≥40% from baseline; and (3) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained doubling in serum creatinine from baseline. Cox regression using time-to-first-event analysis and win ratio (WR) using hierarchical order of events were applied. Empagliflozin reduced the risk of all cardio/kidney composites. The results varied only slightly between Cox and WR (eg, composite 1: hazard ratio, 0.56 [95% CI, 0.49-0.64]; WR, 1.76 [95% CI, 1.53-2.02]. WR prioritizes events by clinical importance; in particular, all fatal events are evaluated, whereas Cox regression ignores deaths when preceded by nonfatal events. Of the 285 cardio/kidney deaths in the analysis, 44 to 56 (15%-20%), depending on the composite, occurred after a nonfatal event and were not evaluated in Cox regression but evaluated by the WR. Conclusions By considering the clinical relevance of different event types, the WR represents an appropriate method to complement the traditional time-to-first-event analysis in cardio/kidney outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01131676.

Project description:ObjectiveTo assess the association between use of sodium-glucose co-transporter 2 (SGLT2) inhibitors and risk of serious renal events in data from routine clinical practice.DesignCohort study using an active comparator, new user design and nationwide register data.SettingSweden, Denmark, and Norway, 2013-18.ParticipantsCohort of 29 887 new users of SGLT2 inhibitors (follow-up time: dapagliflozin 66.1%; empagliflozin 32.6%; canagliflozin 1.3%) and 29 887 new users of an active comparator, dipeptidyl peptidase-4 inhibitors, matched 1:1 on the basis of a propensity score with 57 variables. Mean follow-up time was 1.7 (SD 1.0) years.ExposuresSGLT2 inhibitors versus dipeptidyl peptidase-4 inhibitors, defined by filled prescriptions and analysed according to intention to treat.Main outcome measuresThe main outcome was serious renal events, a composite including renal replacement therapy, death from renal causes, and hospital admission for renal events. Secondary outcomes were the individual components of the main outcome.ResultsThe mean age of the study population was 61.3 (SD 10.5) years; 11 108 (19%) had cardiovascular disease, and 1974 (3%) had chronic kidney disease. Use of SGLT2 inhibitors, compared with dipeptidyl peptidase-4 inhibitors, was associated with a reduced risk of serious renal events (2.6 events per 1000 person years versus 6.2 events per 1000 person years; hazard ratio 0.42 (95% confidence interval 0.34 to 0.53); absolute difference -3.6 (-4.4 to -2.8) events per 1000 person years). In secondary outcome analyses, the hazard ratio for use of SGLT2 inhibitors versus dipeptidyl peptidase-4 inhibitors was 0.32 (0.22 to 0.47) for renal replacement therapy, 0.41 (0.32 to 0.52) for hospital admission for renal events, and 0.77 (0.26 to 2.23) for death from renal causes. In sensitivity analyses in each of the Swedish and Danish parts of the cohort, the model was further adjusted for glycated haemoglobin and estimated glomerular filtration rate (Sweden and Denmark) and for blood pressure, body mass index, and smoking (Sweden only); in these analyses, the hazard ratio moved from 0.41 (0.26 to 0.66) to 0.50 (0.31 to 0.81) in Sweden and from 0.42 (0.32 to 0.56) to 0.55 (0.41 to 0.74) in Denmark.ConclusionsIn this analysis using nationwide data from three countries, use of SGLT2 inhibitors, compared with dipeptidyl peptidase-4 inhibitors, was associated with a significantly reduced risk of serious renal events.

Dataset Information

The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study.

Publications

The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study.

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