Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

Destruktivt entreprenörskap : Fusket/missbruket med assistansersättningen

Purpose: The aim is to investigate the mechanisms behind the destructive entrepreneurship in the assistance industry. Method: To investigate the destructive entrepreneurship in the assistance industry, we conducted a qualitative study in the form of semi-structured questions. In total, we interviewed four authorities and an employer organization. Theory: Theoretical framework: The study is based on Baumol's (1990) theory of productive, unproductive and destructive entrepreneurship and rent-seeking by Murphy et al (1991), but the study's principal theory that we have chosen to apply is the routine activity theory of Cohen & Felson (1979) that describes three elements that must come together in order for a crime to be committed. Conclusions and discussion: Our study shows that it is clear that there is both fraud and abuse within the assistance allowance, which can be done in different ways. Some users simulate their illness that they exaggerate their need for assistance. Some assistance providers have abused the compensation by paying lower wages and empty false wages etc. The study showed that there also exists a type of human trafficking. The fraud/abuse includes millions of kroner and it requires several people to accomplish the embezzlement. The most common form in which cheating occurs is limited but it is suspected that the abuse occurs in all forms of assistance other than the cooperative assistance form. The assistance industry is not in a position of being undermined; however, compensation levels may be slightly compressed.Syfte: Syftet är att utreda mekanismerna bakom det destruktiva entreprenörskapet i assistansbranschen. Metod: För att undersöka det destruktiva entreprenörskapet i assistansbranschen har vi genomfört en kvalitativ undersökning i form av semistrukturerade intervjuer. Totalt intervjuade vi fyra myndigheter och en arbetsgivareorganisation. Teoretisk referensram: Studien utgår ifrån Baumols (1990) teori om produktivt, improduktivt samt destruktivt entreprenörskap och privilegiejaktsteorin av Murphy med flera (1991), men studiens huvudteori som vi har valt att tillämpa är rutinaktivitetsteorin av Cohen & Felson (1979) som beskriver tre förutsättningar som måste sammanstråla för att ett brott ska kunna begås. Slutsats och Diskussion: Vår studie visar att det står klart att det förekommer både fusk och missbruk inom assistansersättningen vilket kan utföras på olika sätt. Från att vissa brukare simulerar sin sjukdom till att de överdriver sina assistansbehov. Vissa assistansanordnare har missbrukat ersättningen genom att betala lägre löner och t.o.m. falska löner mm. Studien visade att det också förekommer en typ av människohandel. Fusket/missbruket handlar om miljonbelopp och det krävs ett nätverk av personer för att åstadkomma förskingringen. Den vanligaste formen där fusket förekommer är aktiebolag men det misstänks att missbruket förekommer i alla assistansformerna utom den kooperativa assistansformen. Assistansbranschen riskerar dock inte att undermineras däremot kan ersättningsnivåerna komma att pressas något

Destruktivt entreprenörskap : Fusket/missbruket med assistansersättningen

Purpose: The aim is to investigate the mechanisms behind the destructive entrepreneurship in the assistance industry. Method: To investigate the destructive entrepreneurship in the assistance industry, we conducted a qualitative study in the form of semi-structured questions. In total, we interviewed four authorities and an employer organization. Theory: Theoretical framework: The study is based on Baumol's (1990) theory of productive, unproductive and destructive entrepreneurship and rent-seeking by Murphy et al (1991), but the study's principal theory that we have chosen to apply is the routine activity theory of Cohen & Felson (1979) that describes three elements that must come together in order for a crime to be committed. Conclusions and discussion: Our study shows that it is clear that there is both fraud and abuse within the assistance allowance, which can be done in different ways. Some users simulate their illness that they exaggerate their need for assistance. Some assistance providers have abused the compensation by paying lower wages and empty false wages etc. The study showed that there also exists a type of human trafficking. The fraud/abuse includes millions of kroner and it requires several people to accomplish the embezzlement. The most common form in which cheating occurs is limited but it is suspected that the abuse occurs in all forms of assistance other than the cooperative assistance form. The assistance industry is not in a position of being undermined; however, compensation levels may be slightly compressed.Syfte: Syftet är att utreda mekanismerna bakom det destruktiva entreprenörskapet i assistansbranschen. Metod: För att undersöka det destruktiva entreprenörskapet i assistansbranschen har vi genomfört en kvalitativ undersökning i form av semistrukturerade intervjuer. Totalt intervjuade vi fyra myndigheter och en arbetsgivareorganisation. Teoretisk referensram: Studien utgår ifrån Baumols (1990) teori om produktivt, improduktivt samt destruktivt entreprenörskap och privilegiejaktsteorin av Murphy med flera (1991), men studiens huvudteori som vi har valt att tillämpa är rutinaktivitetsteorin av Cohen & Felson (1979) som beskriver tre förutsättningar som måste sammanstråla för att ett brott ska kunna begås. Slutsats och Diskussion: Vår studie visar att det står klart att det förekommer både fusk och missbruk inom assistansersättningen vilket kan utföras på olika sätt. Från att vissa brukare simulerar sin sjukdom till att de överdriver sina assistansbehov. Vissa assistansanordnare har missbrukat ersättningen genom att betala lägre löner och t.o.m. falska löner mm. Studien visade att det också förekommer en typ av människohandel. Fusket/missbruket handlar om miljonbelopp och det krävs ett nätverk av personer för att åstadkomma förskingringen. Den vanligaste formen där fusket förekommer är aktiebolag men det misstänks att missbruket förekommer i alla assistansformerna utom den kooperativa assistansformen. Assistansbranschen riskerar dock inte att undermineras däremot kan ersättningsnivåerna komma att pressas något

Effects of empagliflozin on progression of chronic kidney disease: a prespecified secondary analysis from the empa-kidney trial

Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce progression of chronic kidney disease and the risk of cardiovascular morbidity and mortality in a wide range of patients. However, their effects on kidney disease progression in some patients with chronic kidney disease are unclear because few clinical kidney outcomes occurred among such patients in the completed trials. In particular, some guidelines stratify their level of recommendation about who should be treated with SGLT2 inhibitors based on diabetes status and albuminuria. We aimed to assess the effects of empagliflozin on progression of chronic kidney disease both overall and among specific types of participants in the EMPA-KIDNEY trial. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA), and included individuals aged 18 years or older with an estimated glomerular filtration rate (eGFR) of 20 to less than 45 mL/min per 1·73 m2, or with an eGFR of 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher. We explored the effects of 10 mg oral empagliflozin once daily versus placebo on the annualised rate of change in estimated glomerular filtration rate (eGFR slope), a tertiary outcome. We studied the acute slope (from randomisation to 2 months) and chronic slope (from 2 months onwards) separately, using shared parameter models to estimate the latter. Analyses were done in all randomly assigned participants by intention to treat. EMPA-KIDNEY is registered at ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and then followed up for a median of 2·0 years (IQR 1·5-2·4). Prespecified subgroups of eGFR included 2282 (34·5%) participants with an eGFR of less than 30 mL/min per 1·73 m2, 2928 (44·3%) with an eGFR of 30 to less than 45 mL/min per 1·73 m2, and 1399 (21·2%) with an eGFR 45 mL/min per 1·73 m2 or higher. Prespecified subgroups of uACR included 1328 (20·1%) with a uACR of less than 30 mg/g, 1864 (28·2%) with a uACR of 30 to 300 mg/g, and 3417 (51·7%) with a uACR of more than 300 mg/g. Overall, allocation to empagliflozin caused an acute 2·12 mL/min per 1·73 m2 (95% CI 1·83-2·41) reduction in eGFR, equivalent to a 6% (5-6) dip in the first 2 months. After this, it halved the chronic slope from -2·75 to -1·37 mL/min per 1·73 m2 per year (relative difference 50%, 95% CI 42-58). The absolute and relative benefits of empagliflozin on the magnitude of the chronic slope varied significantly depending on diabetes status and baseline levels of eGFR and uACR. In particular, the absolute difference in chronic slopes was lower in patients with lower baseline uACR, but because this group progressed more slowly than those with higher uACR, this translated to a larger relative difference in chronic slopes in this group (86% [36-136] reduction in the chronic slope among those with baseline uACR <30 mg/g compared with a 29% [19-38] reduction for those with baseline uACR ≥2000 mg/g; ptrend<0·0001). Interpretation: Empagliflozin slowed the rate of progression of chronic kidney disease among all types of participant in the EMPA-KIDNEY trial, including those with little albuminuria. Albuminuria alone should not be used to determine whether to treat with an SGLT2 inhibitor. Funding: Boehringer Ingelheim and Eli Lilly

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA-KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5-2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62-0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16-1·59), representing a 50% (42-58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council

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 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) 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 &lt; 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of &amp; GE;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 &lt; 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