Canagliflozin reduced kidney disease progression in participants with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. This analysis explored potential mediators of the effects of canagliflozin on kidney outcomes. The percent mediating effect of 18 biomarkers indicative of disease was determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the average post-randomization level of each biomarker. Multivariable analyses assessed the joint effects of biomarkers that mediated most strongly in univariable analyses. The kidney outcome was defined as a composite of 40% estimated glomerular filtration rate decline, end-stage kidney disease, or death due to kidney disease. Nine biomarkers (systolic blood pressure [8.9% of effect explained], urinary albumin:creatinine ratio [UACR; 23.9%], gamma glutamyltransferase [4.1%], hematocrit [51.1%], hemoglobin [41.3%], serum albumin [19.5%], erythrocytes [56.7%], serum urate [35.4%], and urine pH [7.5%]) individually mediated the effect of canagliflozin on the kidney outcome. In a parsimonious multivariable model, erythrocyte concentration, serum urate, and systolic blood pressure maximized cumulative mediation ( 115%). Mediating effects of UACR, but not other mediators, were highly dependent upon the baseline level of UACR: UACR mediated 42% and 7% of the effect in those with baseline UACR 30 mg/g or more and under 30 mg/g, respectively. The identified mediators support existing hypothesized mechanisms for the prevention of kidney outcomes with sodium glucose cotransporter 2 inhibitors. Thus, the disparity in mediating effects across baseline UACR subgroups suggests that the mechanism for kidney protection with canagliflozin may vary across patient subgroups.

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Aims/hypothesis An increased risk of fracture with canagliflozin vs placebo was reported from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, with heterogeneity of findings identified between the two trials that comprise the CANVAS Program, CANVAS and CANVAS-R. The objective of these analyses was to identify reasons for the possibly different effects on fracture observed between CANVAS and CANVAS-R. Methods This study was an analysis of two highly similar trials, CANVAS and CANVAS-R, conducted in 10,142 individuals with type 2 diabetes and history or high risk of cardiovascular disease who received canagliflozin (pooled 100/300 mg once daily) or placebo. Outcomes assessed in this analysis were effects on adjudicated fractures overall and by type, location, association with a fall, dose and follow-up time. Results A total of 496 participants recorded ≥1 fracture event during follow-up (15.40 vs 11.93 per 1000 patient-years with canagliflozin vs placebo; HR 1.26 [95% CI 1.04, 1.52]). There was significant heterogeneity in the effects on fracture ( p = 0.005) between CANVAS ( n = 4330: HR 1.55 [95% CI 1.21, 1.97]) and CANVAS-R ( n = 5812: HR 0.86 [95% CI 0.62, 1.19]). The between-study heterogeneity in fracture risk was not clearly explained by differences in baseline characteristics, interactions of randomised treatment with participant characteristics, dose effects, duration of follow-up, metabolic effects, adverse events related to falls or adverse events possibly causing falls. Conclusions/interpretation There was no evidence to explain clearly the fracture risk observed in the CANVAS Program or the heterogeneity in fracture risk between the two studies. The recently reported null result for fracture in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial suggests that the observed association in CANVAS is likely to be a chance finding, although an unidentified fall-related mechanism remains a possibility. Trial registration: ClinicalTrials.gov NCT01032629, NCT01989754. Electronic supplementary material The online version of this article (10.1007/s00125-019-4955-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Although much current prescriptive literature in general practice advocates the use of lay language in the consultation as a means to promote better doctor-patient partnerships, the issue of diagnosis is more complex than this. Patients attribute greater benefits to the use of medical labels for themselves and state that such medical labels are of greater benefit to the doctor.

The primary healthcare staff took ownership and responsibility for this initiative. They were creative in introducing new ways of engaging with the local armed forces community. Many veterans' and staff were unaware of veterans' entitlement to priority medical services, or the wider provisions available to them. It is probable that veterans declaring their military status within primary healthcare, or registering with a general practitioner for the first time is likely to increase. Another review will be undertaken after 12 mo, which will provide a better indication of success. There remains however an ongoing need to reach out to those veterans who never access a primary healthcare practice. This paper adds to the limited international empirical evidence undertaken to explore help-seeking behavior in an armed forces community. The positive outcomes of increased awareness and staff commitment provide a template for improvement across the UK, and will potentially stimulate similar initiatives with international colleagues.

Young soldiers presented with symptoms not in the International Classification of Disorders and older soldiers who feared being medically downgraded, sought help outside the Army Medical Services. Women found it easier to seek support, but many were inappropriately labelled as depressed. Implications include a need to address the poor understanding of military stressors; their relationships to depressive symptoms and raise higher awareness of gender imbalances with regard to access and treatment. The results have international implications for other Armed forces, and those employed in Young Men's Mental Health. The results are presented as a simple predictive model and aide memoire that can be utilised as an educational and clinical guideline. There is scope to adapt this model to international civilian healthcare practice.

Few studies have explored the predisposing factors leading to depression within the British Army, and this qualitative investigation provides a novel approach to advance knowledge in this poorly researched area. Information was provided by army mental health (MH) clinicians, with results aligned to theoretical groupings under the headings of: occupational stressors; macho culture, stigma and bullying; unhappy young soldier; relationships and gender. These issues were influenced by peacetime and operational settings; the support offered by the Army Medical Services and unit command. The results indicate that Army personnel are exposed to multi-factorial stressors that are incremental/accumulative in nature. Soldiers can cope with extreme pressures, often in hostile environments, but often cannot cope with a failing relationship. Officers were worried about the occupational implications of reporting ill, and the negative impact on their career, and might seek support from private civilian agencies, which have potentially dangerous ramifications as they may still deploy. GPs refer female soldiers more frequently for a mental health assessment because women express their emotions more openly then men. Young disillusioned soldiers who want to leave the Army form the main group of personnel accessing mental health support, although often they are not clinically depressed.

The data identified a number of factors that affected clinicians ability to provide a high standard of casualty care. The general perception of this research cohort was that despite all the obstacles, the level of trauma care was of a high nature. However, the study provides pointers to a number of areas for future exploration where patient care was not BATLS protocol compliant.