Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

A research agenda to improve incidence and outcomes of assisted vaginal birth

Access to emergency obstetric care, including assisted vaginal birth and caesarean birth, is crucial for improving maternal and childbirth outcomes. However, although the proportion of births by caesarean section has increased during the last few decades, the use of assisted vaginal birth has declined. This is particularly the case in low- and middle-income countries, despite an assisted vaginal birth often being less risky than caesarean birth. We therefore conducted a three-step process to identify a research agenda necessary to increase the use of, or reintroduce, assisted vaginal birth: after conducting an evidence synthesis, which informed a consultation with technical experts who proposed an initial research agenda, we sought and incorporated the views of women's representatives of this agenda. This process has allowed us to identify a comprehensive research agenda, with topics categorized as: (i) the need to understand women's perceptions of assisted vaginal birth, and provide appropriate and reliable information; (ii) the importance of training health-care providers in clinical skills but also in respectful care, effective communication, shared decision-making and informed consent; and (iii) the barriers to and facilitators of implementation and sustainability. From women's feedback, we learned of the urgent need to recognize labour, childbirth and postpartum experiences as inherently physiological and dignified human processes, in which interventions should only be implemented if necessary. The promotion and/or reintroduction of assisted vaginal birth in low-resource settings requires governments, policy-makers and hospital administrators to support skilled health-care providers who can, in turn, respectfully support women in labour and childbirth. [Abstract copyright: (c) 2023 The authors; licensee World Health Organization.

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Deuterium Equilibrium Time in Saliva of Newborn Infants

There is an increasing interest about the use of stable isotopes for body composition analysis in pediatrics. To ensure the success of total body water analysis by the deuterium dilution method, it is fundamental to determine the equilibrium tune (plateau) of deuterium in the body fluid studied. Objectives: We report here the equilibration time of deuterium oxide in the saliva of newborns after oral intake of the isotope. Methods: Twenty healthy term newborn infants, 10 males and 10 females, were analyzed. Saliva was collected from each newborn before the oral administration of a 100 mg/kg dose of deuterium oxide (baseline sample) and then at 1-hour intervals for 5 hours after administration. Deuterium enrichment of saliva was determined by isotope ratio mass spectrometry according to the recommendations of the International Atomic Energy Agency. Results: The plateau time of deuterium in saliva occurred 3 hours after oral administration of the stable isotope. Conclusion: These data are essential for further studies on the body composition of newborn infants. To the best of our knowledge, this is the first study regarding the equilibration time of deuterium in the saliva of term newborns. JPGN 48:471-474, 2009.International Atomic Energy Agency, Nestle NutritionCNPq (Brazilian National Research Council)FAPESP (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo

Deuterium Equilibrium Time in Saliva of Newborn Infants

There is an increasing interest about the use of stable isotopes for body composition analysis in pediatrics. To ensure the success of total body water analysis by the deuterium dilution method, it is fundamental to determine the equilibrium tune (plateau) of deuterium in the body fluid studied.Objectives: We report here the equilibration time of deuterium oxide in the saliva of newborns after oral intake of the isotope.Methods: Twenty healthy term newborn infants, 10 males and 10 females, were analyzed. Saliva was collected from each newborn before the oral administration of a 100 mg/kg dose of deuterium oxide (baseline sample) and then at 1-hour intervals for 5 hours after administration. Deuterium enrichment of saliva was determined by isotope ratio mass spectrometry according to the recommendations of the International Atomic Energy Agency.Results: The plateau time of deuterium in saliva occurred 3 hours after oral administration of the stable isotope.Conclusion: These data are essential for further studies on the body composition of newborn infants. To the best of our knowledge, this is the first study regarding the equilibration time of deuterium in the saliva of term newborns. JPGN 48:471-474, 2009.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Un programa de investigación para mejorar la incidencia y los resultados del parto vaginal asistido

Access to emergency obstetric care, including assisted vaginal birth and caesarean birth, is crucial for improving maternal and childbirth outcomes. However, although the proportion of births by caesarean section has increased during the last few decades, the use of assisted vaginal birth has declined. This is particularly the case in low- and middle-income countries, despite an assisted vaginal birth often being less risky than caesarean birth. We therefore conducted a three-step process to identify a research agenda necessary to increase the use of, or reintroduce, assisted vaginal birth: after conducting an evidence synthesis, which informed a consultation with technical experts who proposed an initial research agenda, we sought and incorporated the views of women’s representatives of this agenda. This process has allowed us to identify a comprehensive research agenda, with topics categorized as: (i) the need to understand women’s perceptions of assisted vaginal birth, and provide appropriate and reliable information; (ii) the importance of training health-care providers in clinical skills but also in respectful care, effective communication, shared decision-making and informed consent; and (iii) the barriers to and facilitators of implementation and sustainability. From women’s feedback, we learned of the urgent need to recognize labour, childbirth and postpartum experiences as inherently physiological and dignified human processes, in which interventions should only be implemented if necessary. The promotion and/or reintroduction of assisted vaginal birth in low-resource settings requires governments, policy-makers and hospital administrators to support skilled health-care providers who can, in turn, respectfully support women in labour and childbirth.L'accès aux soins obstétriques d'urgence, y compris l'accouchement vaginal assisté et la césarienne, est essentiel pour améliorer les effets de la maternité et de l'accouchement. Toutefois, bien que la proportion de césariennes ait augmenté ces dernières décennies, le recours à l'accouchement vaginal assisté a diminué. C'est particulièrement le cas dans les pays à revenu faible ou intermédiaire, bien que l'accouchement vaginal assisté soit souvent moins risqué qu'une césarienne. Nous avons donc mené un processus en trois étapes afin d'imaginer un programme de recherche qui permettrait d'augmenter le recours à l'accouchement vaginal assisté ou de le réintroduire. Après avoir réalisé une synthèse des données probantes, qui a servi de base à une consultation avec des experts techniques qui ont proposé un programme de recherche initial, nous avons sollicité et incorporé les avis des représentantes des femmes pour ce programme. Ce processus nous a permis d'imaginer un programme de recherche complet, avec des sujets classés comme suit: (i) la nécessité de comprendre la perception qu'ont les femmes de l'accouchement vaginal assisté et de fournir des informations appropriées et fiables; (ii) l'importance de la formation des prestataires de soins de santé en matière de compétences cliniques, mais aussi de respect dans les soins de santé, de communication efficace, de prise de décision partagée et de consentement éclairé; ou (iii) les obstacles à la mise en œuvre et à la durabilité et les facteurs qui les facilitent. Les réactions de femmes nous ont appris qu'il était urgent de reconnaître que l'accouchement, la naissance et le post-partum sont des processus humains intrinsèquement physiologiques et dignes au cours desquels les interventions ne devraient être mises en œuvre qu'en cas de nécessité. La promotion et/ou la réintroduction de l'accouchement vaginal assisté dans les régions à faibles ressources nécessitent que les pouvoirs publics, les décideurs politiques et les administrations d'hôpitaux soutiennent les prestataires de soins de santé qualifiés, qui pourront à leur tour soutenir respectueusement les femmes pendant l'accouchement.El acceso a la atención obstétrica de emergencia, incluido el parto vaginal asistido y el parto por cesárea, es crucial para mejorar los resultados de la maternidad y el parto. No obstante, aunque el porcentaje de partos por cesárea ha aumentado en las últimas décadas, el uso del parto vaginal asistido ha disminuido. Esto ocurre especialmente en los países de ingresos bajos y medios, a pesar de que un parto vaginal asistido suele ser menos arriesgado que un parto por cesárea. Por lo tanto, llevamos a cabo un proceso de tres pasos para identificar un programa de investigación necesario para aumentar el uso del parto vaginal asistido o volver a incorporarlo: tras realizar una síntesis de la evidencia, que sirvió de base para una consulta con expertos técnicos que propusieron un programa de investigación inicial, buscamos e integramos las opiniones de las representantes de las mujeres sobre este programa. Este proceso nos ha permitido identificar un programa de investigación exhaustivo, con temas categorizados como: (i) la necesidad de comprender las percepciones de las mujeres sobre el parto vaginal asistido, y proporcionar información adecuada y fiable; (ii) la importancia de formar a los profesionales sanitarios en habilidades clínicas, pero también en atención respetuosa, comunicación efectiva, toma de decisiones compartida y consentimiento informado; o (iii) las barreras y los facilitadores de la implementación y la sostenibilidad. A partir de las opiniones de las mujeres, nos enteramos de la urgente necesidad de reconocer las experiencias del parto, el alumbramiento y el posparto como procesos humanos inherentemente fisiológicos y dignos, en los que las intervenciones solo deben aplicarse si son necesarias. La promoción o la reincoporación del parto vaginal asistido en regiones de escasos recursos exige que los gobiernos, los responsables de formular políticas y los administradores de hospitales apoyen a los profesionales sanitarios capacitados que, a su vez, pueden ayudar a las mujeres en el trabajo de parto y el alumbramiento de manera respetuosa.https://www.who.int/publications/journals/bulletinhj2024Obstetrics and GynaecologySDG-03:Good heatlh and well-bein

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

Background: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis

BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]).CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791

Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial

Rationale & Objective: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kid-ney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagli-flozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study.Study Design: Secondary analysis of a random-ized controlled trial. Setting & Participants: Participants in the CREDENCE trial. Intervention: Participants were randomly assigned to receive canagliflozin 100 mg/d or placebo.Outcomes: Primary composite outcome of kid-ney failure, doubling of serum creatinine con-centration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Out-comes were evaluated by age at baseline (<60, 60-69, and >_70 years) and sex in the intention-to-treat population using Cox regression models.Results: The mean age of the cohort was 63.0 & PLUSMN; 9.2 years, and 34% were female. Older age and female sex were independently associ-ated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (acomposite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.4 8-0.82], and 0.89 [0.61-1.29] for ages <60, 60-69, and >_70 years, respectively; P = 0.3 for interaction) or sexes (HRs, 0.71 [95% CI, 0.5 4-0.95] and 0.69 [0.56-0.8 4] in women and men, respectively; P = 0.8 for interaction). No differences in safety outcomes by age group or sex were observed.Limitations: This was a post hoc analysis with multiple comparisons.Conclusions: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants.Funding: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical.Trial Registration: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791