Efficacy and Safety of Dapagliflozin in Patients with Chronic Kidney Disease across the Spectrum of Frailty

BACKGROUND: A sizeable proportion of patients with chronic kidney disease (CKD) are reported to be frail. Here we examined the safety and efficacy of dapagliflozin in patients with CKD by frailty level. METHODS: Adults with CKD, with/without type 2 diabetes, with estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m 2 and urinary albumin-to-creatinine ratio 200-5000 mg/g were randomized to dapagliflozin (10 mg/day) or placebo. The primary endpoint was composite of sustained ≥50% eGFR decline, end-stage kidney disease (ESKD) or death from kidney or cardiovascular (CV) causes. RESULTS: Frailty index (FI), assessed by Rockwood cumulative deficit approach, was calculable in 4303/4304 (99.9%) patients: 1162 (27.0%) in not-to-mildly frail(FI≤0.210), 1642 (38.2%) in moderately frail(FI 0.211-0.310), and 1499 (34.8%) in severely frail categories (FI>0.311). Dapagliflozin reduced the risk of the primary composite endpoint across all FI categories (hazard ratios [95% CI]: 0.50 [0.33-0.76], 0.62 [0.45-0.85], and 0.64 [0.49-0.83], respectively (P-interaction =0.67). Results were similar for secondary outcomes including kidney composite outcome (sustained ≥50% eGFR decline, ESKD or death from kidney cause; P-interaction=0.44), CV endpoint (heart failure hospitalization or CV death; P-interaction=0.63), and all-cause mortality (P-interaction p=0.42). Results were consistent when using FI as a continuous variable. Occurrence of serious adverse events was numerically lower in patients receiving dapagliflozin vs. placebo in all FI categories (16.9% vs. 20.1%, 26.3% vs. 30.7%, and 42.9% vs 47.8%, in not-to-mildly, moderately and severely frail categories, respectively). CONCLUSIONS: The relative benefit of dapagliflozin for all outcomes was consistent across all frailty categories, with no difference in associated safety

Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial.

BACKGROUND: Recent cardiovascular outcome trials have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors slow the progression of chronic kidney disease (CKD) in patients with type 2 diabetes at high cardiovascular risk. Whether these benefits extend to CKD patients without type 2 diabetes or cardiovascular disease is unknown. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) will assess the effect of the SGLT2 inhibitor dapagliflozin on renal and cardiovascular events in a broad range of patients with CKD with and without diabetes. METHODS: DAPA-CKD is a randomized, double-blind, placebo-controlled, trial in which ∼4300 patients with CKD Stages 2-4 and elevated urinary albumin excretion will be enrolled. The vast majority will be receiving a maximum tolerated dose of a renin-angiotensin system inhibitor at enrolment. RESULTS: After a screening assessment, eligible patients with a urinary albumin:creatinine ratio ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 are randomly assigned to placebo or dapagliflozin 10 mg/day. Enrolment is monitored to ensure that at least 30% of patients do not have diabetes and that no more than 10% have an eGFR >60 mL/min/1.73 m2. The primary endpoint is a composite of a sustained decline in eGFR of ≥50%, end-stage renal disease, renal death or cardiovascular death. The trial will conclude when 681 primary renal events have occurred, providing 90% power to detect a 22% relative risk reduction (α level of 0.05). CONCLUSION: DAPA-CKD will determine whether the SGLT2 inhibitor dapagliflozin, added to guideline-recommended therapies, safely reduces the rate of renal and cardiovascular events in patients across multiple CKD stages with and without diabetes

Isotope effect on the transition temperature TcT_c in Fe-based superconductors: the current status

The results of the Fe isotope effect (Fe-IE) on the transition temperature $T_c$ obtained up to date in various Fe-based high temperature superconductors are summarized and reanalyzed by following the approach developed in [Phys. Rev. B 82, 212505 (2010)]. It is demonstrated that the very controversial results for Fe-IE on $T_c$ are caused by small structural changes occurring simultaneously with the Fe isotope exchange. The Fe-IE exponent on $T_c$ [$\alpha_{\rm Fe}=-(\Delta T_c/T_c)/(\Delta M/M)$, $M$ is the isotope mass] needs to be decomposed into two components with the one related to the structural changes ($\alpha_{\rm Fe}^{\rm str}$) and the genuine (intrinsic) one ($\alpha_{\rm Fe}^{\rm int}$). The validity of such decomposition is further confirmed by the fact that $\alpha_{\rm Fe}^{\rm int}$ coincides with the Fe-IE exponent on the characteristic phonon frequencies $\alpha_{\rm Fe}^{\rm ph}$ as is reported in recent EXAFS and Raman experiments.Comment: 7 pages, 4 figures. The paper is partially based on the results published in [New J. Phys. 12, 073024 (2010) = arXiv:1002.2510] and [Phys. Rev. B 82, 212505 (2010) = arXiv:1008.4540

Effects of Dapagliflozin in Chronic Kidney Disease, With and Without Other Cardiovascular Medications: DAPA-CKD Trial

Background The DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial (NCT03036150) demonstrated that dapagliflozin reduced the risk of kidney and cardiovascular events in patients with chronic kidney disease and albuminuria with and without type 2 diabetes. We aimed to determine whether baseline cardiovascular medication use modified the dapagliflozin treatment effect. Methods and Results We randomized 4304 adults with baseline estimated glomerular filtration rate 25 to 75 mL/min per 1.73 m2 and urinary albumin:creatinine ratio 200 to 5000 mg/g to dapagliflozin 10 mg or placebo once daily. The primary end point was a composite of ≥50% estimated glomerular filtration rate decline, end-stage kidney disease, and kidney or cardiovascular death. Secondary end points included a kidney composite end point (primary composite end point without cardiovascular death), a cardiovascular composite end point (hospitalized heart failure or cardiovascular death), and all-cause mortality. We categorized patients according to baseline cardiovascular medication use/nonuse. Patients were required by protocol to receive a stable (and maximally tolerated) dose of a renin-angiotensin-aldosterone system inhibitor. We observed consistent benefits of dapagliflozin relative to placebo, irrespective of baseline use/nonuse of renin-angiotensin-aldosterone system inhibitors (98.1%), calcium channel blockers (50.7%), β-adrenergic antagonists (39.0%), diuretics (43.7%), and antithrombotic (47.4%), and lipid-lowering (15.0%) agents. Use of these drugs in combination with dapagliflozin did not increase the number of serious adverse events. Conclusions The safety profile and efficacy of dapagliflozin on kidney and cardiovascular end points in patients with chronic kidney disease were consistent among patients treated and not treated at baseline with a range of cardiovascular medications. Registration Information clinicaltrials.gov. Identifier: NCT03036150

The Kidney Protective Effects of the Sodium–Glucose Cotransporter-2 Inhibitor, Dapagliflozin, Are Present in Patients With CKD Treated With Mineralocorticoid Receptor Antagonists

Introduction: Mineralocorticoid receptor antagonists (MRAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce the risk of kidney failure in chronic kidney disease (CKD). We performed an analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial by baseline conventional MRA (spironolactone and eplerenone) prescription. Methods: Participants with CKD (estimated glomerular filtration rate [eGFR] 25-75 ml/min per 1.73 m2; urinary albumin-to-creatinine ratio 200-500 mg/g), with or without type 2 diabetes, were randomized 1:1 to dapagliflozin 10 mg or placebo, once daily. The primary outcome was a composite of sustained ≥50% eGFR decline, end-stage kidney disease, or kidney or cardiovascular (CV) death. A prespecified kidney-specific secondary outcome was as the primary outcome but without CV death. Hyperkalemia (serum potassium ≥6.0 mmol/l) was an exploratory end point. Time-to-event analyses (proportional hazards [Cox] regression) assessed dapagliflozin versus placebo in patient subgroups defined by baseline conventional MRA use. Results: A total of 229 of 4304 DAPA-CKD participants (5.3%) were receiving conventional MRAs at baseline (dapagliflozin n = 109, placebo n = 120). The effect of dapagliflozin on the primary outcome was consistent in participants prescribed (hazard ratio [HR] 0.76, 95% CI 0.40-1.47) and not prescribed (HR 0.60, 95% CI 0.50-0.72, P-interaction = 0.59) MRAs. This consistency was maintained for the kidney-specific outcome. The effect of dapagliflozin on hyperkalemia (HR 0.87, 95% CI 0.70-1.09) was consistent among those prescribed (HR 0.94, 95% CI 0.41-2.20) and not prescribed (HR 0.87, 95% CI 0.69-1.10, P-interaction = 0.96) MRAs. Adverse events (AEs) leading to discontinuation and serious AEs were similar between treatment groups, regardless of baseline MRA prescription. Conclusion: Dapagliflozin was similarly safe and efficacious in reducing major adverse kidney outcomes in participants with CKD who were or were not prescribed MRAs at baseline

Wide-Scale Analysis of Human Functional Transcription Factor Binding Reveals a Strong Bias towards the Transcription Start Site

We introduce a novel method to screen the promoters of a set of genes with shared biological function, against a precompiled library of motifs, and find those motifs which are statistically over-represented in the gene set. The gene sets were obtained from the functional Gene Ontology (GO) classification; for each set and motif we optimized the sequence similarity score threshold, independently for every location window (measured with respect to the TSS), taking into account the location dependent nucleotide heterogeneity along the promoters of the target genes. We performed a high throughput analysis, searching the promoters (from 200bp downstream to 1000bp upstream the TSS), of more than 8000 human and 23,000 mouse genes, for 134 functional Gene Ontology classes and for 412 known DNA motifs. When combined with binding site and location conservation between human and mouse, the method identifies with high probability functional binding sites that regulate groups of biologically related genes. We found many location-sensitive functional binding events and showed that they clustered close to the TSS. Our method and findings were put to several experimental tests. By allowing a "flexible" threshold and combining our functional class and location specific search method with conservation between human and mouse, we are able to identify reliably functional TF binding sites. This is an essential step towards constructing regulatory networks and elucidating the design principles that govern transcriptional regulation of expression. The promoter region proximal to the TSS appears to be of central importance for regulation of transcription in human and mouse, just as it is in bacteria and yeast.Comment: 31 pages, including Supplementary Information and figure

A conceptual classification of parents’ attributions of the role of food advertising in children’s diets

Background: High levels of child obesity are triggering growing concerns about the prevalence and effects of food advertising targeted at children. Efforts to address this advertising are confounded by the expanding repertoire of media and promotional techniques used to reach and attract children. The present study explored parents’ views on food marketing and the strategies parents employ when attempting to ameliorate its effects. As part of an online survey of Australian parents’ attitudes towards a range of food advertisements, respondents were invited to provide additional comment in an open-ended question. The question was optional and asked “Are there any other comments you would like to make?”. One in five of the survey respondents (18%; n = 235) elected to answer this question by discussing their views on food advertising and children’s diets. The responses were imported into NVivo10 for coding and analysis. A grounded approach was used to draw meaning from the data and develop a proposed conceptual classification of parents’ attributions relating to food advertising and its consequences.Results: The majority of responses related to the negative perceived effects of unhealthy food advertising on children’s diets, with few respondents considering such advertisements to be innocuous. The responses were classified into four conceptual categories reflecting differing attitudes to advertising (negative to neutral) and varying levels of locus of control (low to high). The typical characteristics of parents allocated to the four categories exhibited variation according to weight status, television viewing habits, education level, and family size. The largest number of responses was coded to the category characterized by a negative attitude toward food advertising and a low locus of control. Parents in this category were more likely than others to be overweight/obese and heavy television viewers. Parents in the negative attitude to advertising and high locus of control category nominated a variety of parenting practices that could form the basis of parent education interventions. Conclusions: The results suggest that many Australian parents may feel disempowered in the face of high levels of advertising for unhealthy foods. The current voluntary regulatory code appears to be inadequate in scope and coverage to address this situation

Education, sense of mastery and mental health: results from a nation wide health monitoring study in Norway

<p>Abstract</p> <p>Background</p> <p>Earlier studies have shown that people with low level of education have increased rates of mental health problems. The aim of the present study is to investigate the association between level of education and psychological distress, and to explore to which extent the association is mediated by sense of mastery, and social variables like social support, negative life events, household income, employment and marital status.</p> <p>Methods</p> <p>The data for the study were obtained from the Level of Living Survey conducted by Statistics Norway in 2002. Data on psychological distress and psychosocial variables were gathered by a self-administered questionnaire, whereas socio-demographic data were based on register statistics. Psychological distress was measured by Hopkins Symptom Checklist 25 items.</p> <p>Results</p> <p>There was a significant association between low level of education and psychological distress in both genders, the association being strongest in women aged 55–67 years. Low level of education was also significantly associated with low sense of mastery, low social support, many negative life events (only in men), low household income and unemployment,. Sense of mastery emerged as a strong mediating variable between level of education and psychological distress, whereas the other variables played a minor role when adjusting for sense of mastery.</p> <p>Conclusion</p> <p>Low sense of mastery seems to account for much of the association between low educational level and psychological distress, and should be an important target in mental health promotion for groups with low level of education.</p

Cost effectiveness of total knee arthroplasty from a health care providers' perspective before and after introduction of an interdisciplinary clinical pathway - is investment always improvement?

<p>Abstract</p> <p>Background</p> <p>Total knee arthroplasty (TKA) is an effective, but also cost-intensive health care intervention for end stage osteoarthritis. This investigation was designed to evaluate the cost-effectiveness of TKA before versus after introduction of an interdisciplinary clinical pathway from a University Orthopedic Surgery Department's cost perspective as an interdisciplinary full service health care provider.</p> <p>Methods</p> <p>A prospective trial recruited two sequential cohorts of 132 and 128 consecutive patients, who were interviewed by means of the WOMAC questionnaire. Direct process costs from the health care providers' perspective were estimated according to the German DRG calculation framework. The health economic evaluation was based on margiual cost-effectveness ratios (MCERs); an individual marginal cost effectiveness relation ≤ 100 € per % WOMAC index increase was considered as primary endpoint of the confirmatory cohort comparison. The interdisciplinary clinical pathway under consideration primarily consisted of a voluntary preoperative personal briefing of patients concerning postoperatively expectable progess in health status and optimum use of walking aids after surgery. All patients were supplied with written information on these topics, attendance of the personal briefing also included preoperative training for postoperative mobilisation by the Department's physiotherapeutic staff.</p> <p>Results</p> <p>An individual marginal cost effectiveness relation ≤ 100 €/% WOMAC index increase was found in 38% of the patients in the pre pathway implementation cohort versus in 30% of the post pathway implementation cohort (Fisher p = 0.278). Both cohorts showed substantial improvement in WOMAC scores (39 versus 35% in median), whereas the cohort did not differ significantly in the median WOMAC score before surgery (41% for the pre pathway cohort versus 44% for the post pathway cohort). Despite a locally significant decrease in costs (4303 versus 4194 € in median), the individual cost/benefit relation became worse after introduction of the pathway: for the first cohort the MCER was estimated 108 € per gained % WOMAC index increase (86 - 150 €/%) versus 118 €/% WOMAC gain (93 - 173 €/%) in the second cohort after pathway implementation. In summary, the proposed critical pathway for TKA could be shown to be significantly cost efficient, but not cost effective concerning functional outcome, when the above individual marginal cost effectiveness criterion was concentrated on.</p> <p>Conclusions</p> <p>The introduction of an interdisciplinary clinical pathway does not necessarily improve patient related outcomes. On the contrary, cost effectiveness from the health care providers' perspective may even turn out remarkably reduced in the setting considered here (functional outcome assessment after treatment by a full service health care provider).</p

Eight common genetic variants associated with serum dheas levels suggest a key role in ageing mechanisms

Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands-yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10-36), SULT2A1 (rs2637125; p = 2.61×10-19), ARPC1A (rs740160; p = 1.56×10-16), TRIM4 (rs17277546; p = 4.50×10-11), BMF (rs7181230; p = 5.44×10-11), HHEX (rs2497306; p = 4.64×10-9), BCL2L11 (rs6738028; p = 1.72×10-8), and CYP2C9 (rs2185570; p = 2.29×10-8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS