Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes.

BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed. RESULTS: A total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2±13.7 months, and the mean duration of follow-up was 39.8±9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001). CONCLUSIONS: In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months. (Funded by Novo Nordisk; SELECT ClinicalTrials.gov number, NCT03574597.).

Prophylactic tranexamic acid in patients with hematologic malignancy: a placebo-controlled, randomized clinical trial.

Evidence of the effectiveness of prophylactic use of tranexamic acid (TXA) in thrombocytopenia is lacking. To determine whether TXA safely reduces bleeding incidence in patients undergoing treatment for hematologic malignancies, a randomized, double-blind clinical trial was conducted from June 2016 through June 2020. Of 3120 screened adults, 356 patients were eligible and enrolled, and 337 patients (mean age, 53.9; 141 [41.8%] women), randomized to 1300 mg TXA orally or 1000 mg TXA through IV (n = 168) vs placebo (n = 169) thrice daily for maximum 30 days. Three hundred thirty patients were activated when their platelet counts fell below 30 000 per µL; 279 (83%) had complete outcome ascertainment. World Health Organization (WHO) grade ≥2 bleeding was observed in the 30 days following activation in 50.3% (73/145) and 54.2% (78/144) of patients in the TXA and placebo groups, with an adjusted odds ratio of 0.83 (95% confidence interval [CI], 0.50-1.34; P = .44). There was no statistically significant difference in the mean number of platelet transfusions (mean difference, 0.1; 95% CI, -1.9 to 2.0), mean days alive without grade ≥2 bleeding (mean difference, 0.8; 95% CI, -0.4 to 2.0), thrombotic events (6/163 [3.7%] TXA, 9/163 [5.5%] placebo), or deaths due to serious bleeding. Most common adverse events were: diarrhea (116/164 [70.7%] TXA and 114/163 [69.9%] placebo); febrile neutropenia (111/164 [67.7%] TXA, 105/163 [64.4%] placebo); fatigue (106/164 [64.6%] TXA, 109/163 [66.9%] placebo); and nausea (104/164 [63.4%] TXA, 97/163 [59.5%] placebo). Among patients with hematologic malignancy undergoing chemotherapy or hematopoietic stem cell transplantation, prophylactic treatment with TXA compared with placebo did not significantly reduce the risk of WHO grade ≥2 bleeding.

Familywise error for multiple time-to-event endpoints in a group sequential design.

We investigate the familywise error rate (FWER) for time-to-event endpoints evaluated using a group sequential design with a hierarchical testing procedure for secondary endpoints. We show that, in this setup, the correlation between the log-rank test statistics at interim and at end of study is not congruent with the canonical correlation derived for normal-distributed endpoints. We show, both theoretically and by simulation, that the correlation also depends on the level of censoring, the hazard rates of the endpoints, and the hazard ratio. To optimize operating characteristics in this complex scenario, we propose a simulation-based method to assess the FWER which, better than the alpha-spending approach, can inform the choice of critical values for testing secondary endpoints.

Neighbourhood context and diagnosed mental health conditions among immigrant and non-immigrant youth: a population-based cohort study in British Columbia, Canada.

PURPOSE: Evidence from systematic reviews suggests that adult immigrants living in areas of higher immigrant density (areas with a higher proportion of foreign-born residents) tend to experience fewer mental health problems-likely through less discrimination, greater access to culturally/linguistically appropriate services, and greater social support. Less is known about how such contexts are associated with mental health during childhood-a key period in the onset and development of many mental health challenges. This study examined associations between neighbourhood immigrant density and youth mental health conditions in British Columbia (BC; Canada). METHODS: Census-derived neighbourhood characteristics were linked to medical records for youth present in ten of BC's largest school districts from age 5 through 19 over the study period (1995-2016; n = 138,090). Occurrence of physician assessed diagnoses of mood and/or anxiety disorders, attention deficit hyperactivity disorder (ADHD), and conduct disorder was inferred through International Classification of Diseases (ICD) diagnostic codes in universal public health insurance records. Multi-level logistic regression was used to model associations between neighbourhood characteristics and odds of diagnoses for each condition; models were stratified by generation status (first-generation: foreign-born; second-generation: Canadian-born to a foreign-born parent; non-immigrant). RESULTS: Higher neighbourhood immigrant density was associated with lower odds of disorders among first-generation immigrant youth (e.g., adjusted odds of mood-anxiety disorders for those in neighbourhoods with the highest immigrant density were 0.67 times lower (95% CI: 0.49, 0.92) than those in neighbourhoods with the lowest immigrant density). Such protective associations generally extended to second-generation and non-immigrant youth, but were-for some disorders-stronger for first-generation than second-generation or non-immigrant youth. CONCLUSIONS: Findings suggest there may be protective mechanisms associated with higher neighbourhood immigrant density for mental health conditions in immigrant and non-immigrant youth. It is important that future work examines potential pathways by which contextual factors impact immigrant and non-immigrant youth mental health.

Evaluating group-sequential non-inferiority clinical trials following interim stopping: The HIV Prevention Trials Network 083 trial.

BACKGROUND/AIMS: The HIV Prevention Trials Network 083 trial was a group-sequential non-inferiority trial designed to compare HIV incidence under a novel experimental regimen for HIV prevention, long-acting injectable cabotegravir, with an active-control regimen of daily oral tenofovir disoproxil fumarate/emtricitabine (brand name Truvada). In March of 2020, just as the trial had completed enrollment, the COVID-19 pandemic threatened to prevent trial participants from attending study visits and obtaining study medication, motivating the study team to update the interim monitoring plan. The Data and Safety Monitoring Board subsequently stopped the trial at the first interim review due to strong early evidence of efficacy. METHODS: Here we describe some unique aspects of the trial's design, monitoring, analysis, and interpretation. We illustrate the importance of computing point estimates, confidence intervals, and p values based on the sampling distribution induced by sequential monitoring. RESULTS: Accurate analysis, decision-making and interpretation of trial results rely on pre-specification of a stopping boundary, including the scale on which the stopping rule will be implemented, the specific test statistics to be calculated, and how the boundary will be adjusted if the available information fraction at interim review is different from planned. After appropriate adjustment for the sampling distribution and overrun, the HIV Prevention Trials Network 083 trial provided strong evidence that the experimental regimen was superior to the active control. CONCLUSIONS: For the HIV Prevention Trials Network 083 trial, the difference between corrected inferential statistics and naive results was quite small-as will often be the case-nevertheless, it is appropriate to report and publish the most accurate and unbiased statistical results.

Social context factors and refugee children's emotional health.

BACKGROUND: Refugee children face numerous challenges associated with pre-migration trauma and post-migration adaptation. Much research pertaining to refugee children's well-being focuses on psychiatric symptoms. Relatively few studies have examined how social context factors-such as perceptions of peer belonging, and support from adults at home and at school-contribute to the emotional health of refugee children. Informed by social-ecological theories emphasizing dynamic interactions between the contexts in which children develop, we examined associations between social context factors and emotional health in refugee children. METHODS: Data were drawn from a population-based data linkage in British Columbia, Canada. The analytic sample included 682 grade 4 students (Mage 9.2 years; 46.3% female) with a refugee background who responded to the Middle Years Development Instrument (MDI) during the 2010/2011-2016/2017 school years. The MDI is a self-report survey of children's social and emotional competencies and social context factors completed at school. Regression analyses were used to examine associations of social context factors (school climate, supportive adults at school and at home, and peer belonging) with indicators of emotional health (life satisfaction, self-concept, optimism, and sadness). Refugee generation status (first/second) was considered through stratification and testing of interactions with social context factors. RESULTS: Perceived supportive school climate, support from adults in school and at home, and peer belonging were each independently associated with better emotional health. Results were similar for first- and second-generation children. CONCLUSION: Taken together, results suggest a unique role of the school context to refugee children's emotional health. School-based programming that promotes positive school climate can be considered as an important approach to support newcomer refugee children and their families.

Approval policies for modifications to machine learning-based software as a medical device: A study of bio-creep.

Successful deployment of machine learning algorithms in healthcare requires careful assessments of their performance and safety. To date, the FDA approves locked algorithms prior to marketing and requires future updates to undergo separate premarket reviews. However, this negates a key feature of machine learning-the ability to learn from a growing dataset and improve over time. This paper frames the design of an approval policy, which we refer to as an automatic algorithmic change protocol (aACP), as an online hypothesis testing problem. As this process has obvious analogy with noninferiority testing of new drugs, we investigate how repeated testing and adoption of modifications might lead to gradual deterioration in prediction accuracy, also known as "biocreep" in the drug development literature. We consider simple policies that one might consider but do not necessarily offer any error-rate guarantees, as well as policies that do provide error-rate control. For the latter, we define two online error-rates appropriate for this context: bad approval count (BAC) and bad approval and benchmark ratios (BABR). We control these rates in the simple setting of a constant population and data source using policies aACP-BAC and aACP-BABR, which combine alpha-investing, group-sequential, and gate-keeping methods. In simulation studies, bio-creep regularly occurred when using policies with no error-rate guarantees, whereas aACP-BAC and aACP-BABR controlled the rate of bio-creep without substantially impacting our ability to approve beneficial modifications.

Rejoinder to Discussions on "Approval policies for modifications to machine learning-based software as a medical device: A study of bio-creep".

We thank the discussants for sharing their unique perspectives on the problem of designing automatic algorithm change protocols (aACPs) for machine learning-based software as a medical device. Both Pennello et al. and Rose highlighted a number of challenges that arise in real-world settings, and we whole-heartedly agree that substantial extensions of our work are needed to understand if and how aACPs can be safely deployed in practice. Our work demonstrated that aACPs that appear to be harmless may allow for biocreep, even when the data distribution is assumed to be representative and stationary over time. While we investigated two solutions that protect against this specific issue, many more statistical and practical challenges remain and we look forward to future research on this topic.

Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes.

BACKGROUND: Degludec is an ultralong-acting, once-daily basal insulin that is approved for use in adults, adolescents, and children with diabetes. Previous open-label studies have shown lower day-to-day variability in the glucose-lowering effect and lower rates of hypoglycemia among patients who received degludec than among those who received basal insulin glargine. However, data are lacking on the cardiovascular safety of degludec. METHODS: We randomly assigned 7637 patients with type 2 diabetes to receive either insulin degludec (3818 patients) or insulin glargine U100 (3819 patients) once daily between dinner and bedtime in a double-blind, treat-to-target, event-driven cardiovascular outcomes trial. The primary composite outcome in the time-to-event analysis was the first occurrence of an adjudicated major cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) with a prespecified noninferiority margin of 1.3. Adjudicated severe hypoglycemia, as defined by the American Diabetes Association, was the prespecified, multiplicity-adjusted secondary outcome. RESULTS: Of the patients who underwent randomization, 6509 (85.2%) had established cardiovascular disease, chronic kidney disease, or both. At baseline, the mean age was 65.0 years, the mean duration of diabetes was 16.4 years, and the mean (±SD) glycated hemoglobin level was 8.4±1.7%; 83.9% of the patients were receiving insulin. The primary outcome occurred in 325 patients (8.5%) in the degludec group and in 356 (9.3%) in the glargine group (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P<0.001 for noninferiority). At 24 months, the mean glycated hemoglobin level was 7.5±1.2% in each group, whereas the mean fasting plasma glucose level was significantly lower in the degludec group than in the glargine group (128±56 vs. 136±57 mg per deciliter, P<0.001). Prespecified adjudicated severe hypoglycemia occurred in 187 patients (4.9%) in the degludec group and in 252 (6.6%) in the glargine group, for an absolute difference of 1.7 percentage points (rate ratio, 0.60; P<0.001 for superiority; odds ratio, 0.73; P<0.001 for superiority). Rates of adverse events did not differ between the two groups. CONCLUSIONS: Among patients with type 2 diabetes at high risk for cardiovascular events, degludec was noninferior to glargine with respect to the incidence of major cardiovascular events. (Funded by Novo Nordisk and others; DEVOTE ClinicalTrials.gov number, NCT01959529 .).

Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) rationale and design.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality. Although it has been widely appreciated that obesity is a major risk factor for CVD, treatments that produce effective, durable weight loss and the impact of weight reduction in reducing cardiovascular risk have been elusive. Instead, progress in CVD risk reduction has been achieved through medications indicated for controlling lipids, hyperglycemia, blood pressure, heart failure, inflammation, and/or thrombosis. Obesity has been implicated as promoting all these issues, suggesting that sustained, effective weight loss may have independent cardiovascular benefit. GLP-1 receptor agonists (RAs) reduce weight, improve glycemia, decrease cardiovascular events in those with diabetes, and may have additional cardioprotective effects. The GLP-1 RA semaglutide is in phase 3 studies as a medication for obesity treatment at a dose of 2.4 mg subcutaneously (s.c.) once weekly. Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) is a randomized, double-blind, parallel-group trial testing if semaglutide 2.4 mg subcutaneously once weekly is superior to placebo when added to standard of care for preventing major adverse cardiovascular events in patients with established CVD and overweight or obesity but without diabetes. SELECT is the first cardiovascular outcomes trial to evaluate superiority in major adverse cardiovascular events reduction for an antiobesity medication in such a population. As such, SELECT has the potential for advancing new approaches to CVD risk reduction while targeting obesity.

The Association of Residential Instability and Hospitalizations among Homeless and Vulnerably Housed Individuals: Results from a Prospective Cohort Study.

The present study examined the association of residential instability with hospitalizations among homeless and vulnerably housed individuals over a 4-year time period. Survey data were linked to administrative records on hospitalizations. Specifically, we used data from the Health and Housing in Transition study, a prospective cohort study that tracked the health and housing status of homeless and vulnerably housed individuals in Canada. Responses from Vancouver-based participants (n = 378) from baseline and 3 follow-ups were linked to their administrative health records on hospitalizations (Discharge Abstract Database - Hospital Separation Files; 2008-2012). A generalized estimating equations model was used to examine associations between the number of residential moves and any hospitalizations during each year (none versus ≥ 1 hospitalizations). Analyses included demographic and health variables. Survey data were collected via structured interviews. Hospitalizations were derived from provincial administrative health records. A higher number of residential moves were associated with hospitalization over the study period (adjusted odds ratio: 1.14; 95% confidence interval: 1.01, 1.28). Transgender, female gender, perceived social support, better self-reported mental health, and having ≥ 3 chronic health conditions also predicted having been hospitalized over the study period, whereas high school/higher education was negatively associated with hospitalizations. Our results indicate that residential instability is associated with increased risk of hospitalization, illustrating the importance of addressing housing as a social determinant of health.

Non-inferiority designs comparing placebo to a proven therapy for childhood pneumonia in low-resource settings.

BACKGROUND/AIMS: After a new treatment is recommended to be first-line treatment for a specific indication, outcome and population, it may be unethical to use placebo as a comparator in trials for that setting. Nevertheless, in specific circumstances, use of a placebo group might be warranted, for example, when it is believed that an active treatment may not be efficacious or cost-effective for a specific subpopulation. An example is antibiotic treatment for pneumonia, which may not be effective for many patients taking it due to the emergence of antibiotic-resistant strains or the high prevalence of viral and low prevalence of bacterial pneumonia. METHODS: We explore the applicability of different design options in cases where the benefit of an established treatment is questioned, with particular emphasis on issues that arise in a low-resource setting. Using the example of a clinical trial comparing the effectiveness of placebo versus amoxicillin in treating children 2-59 months of age with fast breathing pneumonia in Lilongwe, Malawi, we discuss the pros and cons of superiority versus non-inferiority designs, an intent-to-treat versus as-treated analysis and the use and interpretation of one- versus two-sided confidence intervals. RESULTS: We find that a non-inferiority design using an intent-to-treat analysis is the most appropriate design and analysis option. In addition, the presentation of one- versus two-sided confidence intervals can depend on the results but can maintain type I error. CONCLUSION: In the setting where the benefit of a previously established beneficial treatment is questioned, a non-inferiority design that includes placebo as the tested treatment option can be the most appropriate design option.

Associations of Birth Factors and Socio-Economic Status with Indicators of Early Emotional Development and Mental Health in Childhood: A Population-Based Linkage Study.

Using a linked population-based database established on healthcare, socio-economic, and survey datasets in British Columbia, Canada, we examined how biological, socio-demographic, and socio-economic status (SES) factors at birth related to children's emotional development and mental health. One analysis examined teacher-rated anxiety, hyperactivity, and aggression for kindergarten children (Mage = 5.7; n = 134,094). Another analysis examined administrative healthcare records comprising of physician-assigned diagnostic codes for mental health conditions (conduct disorder, attention deficit hyperactivity disorder, anxiety disorder and depression) from ages 5 through 15 (n = 89,404). Various factors at birth, including gestational age, birthweight, and maternal demographics, were related to emotional development and mental health in childhood. Across outcomes, low SES indicated detrimental associations with various aspects of children's emotional development and mental health (e.g., adjusted odds of mental health conditions were 25-39% higher for children of low income families versus others). Findings reinforce evidence that poverty (reduction) is a primary public health issue.

Cardiovascular safety and lower severe hypoglycaemia of insulin degludec versus insulin glargine U100 in patients with type 2 diabetes aged 65 years or older: Results from DEVOTE (DEVOTE 7).

AIMS: The aim of this study was to describe the risks of cardiovascular (CV) events and severe hypoglycaemia with insulin degludec (degludec) vs insulin glargine 100 units/mL (glargine U100) in patients with type 2 diabetes (T2D) aged 65 years or older. MATERIALS AND METHODS: A total of 7637 patients in the DEVOTE trial, a treat-to-target, randomized, double-blind trial evaluating the CV safety of degludec vs glargine U100, were divided into three age groups (50-64 years, n = 3682; 65-74 years, n = 3136; ≥75 years, n = 819). Outcomes by overall age group and randomized treatment differences were analysed for major adverse cardiovascular events (MACE), all-cause mortality, severe hypoglycaemia and serious adverse events (SAEs). RESULTS: Patients with increasing age had higher risks of CV death, all-cause mortality and SAEs, and there were non-significant trends towards higher risks of MACE and severe hypoglycaemia. Treatment effects on the risk of MACE, all-cause mortality, severe hypoglycaemia and SAEs were consistent across age groups, based on the non-significant interactions between treatment and age with regard to these outcomes. CONCLUSIONS: There were higher risks of CV death, all-cause mortality and SAEs, and trends towards higher risks of MACE and severe hypoglycaemia with increasing age after adjusting for baseline differences. The effects across age groups of degludec vs glargine U100 on MACE, all-cause mortality and severe hypoglycaemia were comparable, suggesting that the risk of MACE, as well as all-cause mortality, is similar and the risk of severe hypoglycaemia is lower with degludec regardless of age. Evidence is conclusive only until 74 years of age.

Lower rates of cardiovascular events and mortality associated with liraglutide use in patients treated with basal insulin: A DEVOTE subanalysis (DEVOTE 10).

AIM: To compare the associations between concomitant liraglutide use versus no liraglutide use and the risk of major adverse cardiovascular events (MACE) and all-cause mortality among patients receiving basal insulin (either insulin degludec [degludec] or insulin glargine 100 units/mL [glargine U100]) in the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE). MATERIALS AND METHODS: Patients with type 2 diabetes and high cardiovascular risk were randomized 1:1 to degludec or glargine U100. Hazard ratios for MACE/mortality were calculated using a Cox regression model adjusted for treatment and time-varying liraglutide use at any time during the trial, without interaction. Sensitivity analyses were adjusted for baseline covariates including, but not limited to, age, sex, smoking and prior cardiovascular disease. RESULTS: At baseline, 436/7637 (5.7%) patients were treated with liraglutide; after baseline, 187/7637 (2.4%) started and 210/7637 (2.7%) stopped liraglutide. Mean liraglutide exposure from randomization was 530.2 days. Liraglutide use versus no liraglutide use was associated with significantly lower hazard rates for MACE [0.62 (0.41; 0.92)95%CI ] and all-cause mortality [0.50 (0.29; 0.88)95%CI ]. There was no significant difference in the rate of severe hypoglycaemia with versus without liraglutide use. Multiple sensitivity analyses yielded similar results. CONCLUSIONS: Use of liraglutide was associated with significantly lower risk of MACE and death in patients with type 2 diabetes and high cardiovascular risk using basal insulin.

An apple a day: Protective associations between nutrition and the mental health of immigrants in Canada.

PURPOSE: Mental illness represents a major public health burden among Canada's large immigrant population. A burgeoning cross-sectional, longitudinal, and experimental evidence base implicates nutrition in mental health. Healthier diets (e.g., those rich in certain micro-nutrients) may benefit cognitive, social, and emotional functioning through attenuated inflammation and other bio-psychological pathways. The present study examined associations between nutrition and three markers of mental health among immigrants to Canada. METHODS: Employing cross-sectional data from immigrant respondents (n = 37,071) to a nationally representative population-based survey (the Canadian Community Health Survey: CCHS 2011-2014), we modelled associations of daily fruit and vegetable consumption with three mental health outcomes: anxiety and/or mood disorder diagnosis, being distressed (assessed via the 6-item Kessler Psychological Distress Scale), and having good self-rated overall mental health. Multivariable logistic regression analyses were employed, adjusting for various socio-demographic and lifestyle-related variables. RESULTS: Higher consumption of fruit and vegetables demonstrated significant, protective associations with odds of having a mood and/or anxiety disorder, being distressed, and self-rated good mental health. Such patterns of association were similar regardless of ethno-cultural minority status and recency of immigration. Moreover, the protective associations of nutrition and mental health were independent of socio-demographic, health, and lifestyle factors. CONCLUSIONS: Results suggested evidence of protective associations between healthy nutritional intake and mental illness among a large-scale sample of immigrants in Canada. Importantly, the protective associations of healthier diets with immigrants' mental health were independent of various markers of healthy lifestyles (e.g., general health status, physical activity, alcohol use). Healthy dietary intake may, therefore, be worth consideration in efforts to prevent mental illness among immigrants.

DEVOTE 3: temporal relationships between severe hypoglycaemia, cardiovascular outcomes and mortality.

AIMS/HYPOTHESIS: The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality. METHODS: In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population. RESULTS: There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group. CONCLUSIONS/INTERPRETATION: The results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect. TRIAL REGISTRATION: ClinicalTrials.gov NCT01959529.

Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2).

AIMS/HYPOTHESIS: The Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) was a double-blind, randomised, event-driven, treat-to-target prospective trial comparing the cardiovascular safety of insulin degludec with that of insulin glargine U100 (100 units/ml) in patients with type 2 diabetes at high risk of cardiovascular events. This paper reports a secondary analysis investigating associations of day-to-day fasting glycaemic variability (pre-breakfast self-measured blood glucose [SMBG]) with severe hypoglycaemia and cardiovascular outcomes. METHODS: In DEVOTE, patients with type 2 diabetes were randomised to receive insulin degludec or insulin glargine U100 once daily. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In this article, day-to-day fasting glycaemic variability was based on the standard deviation of the pre-breakfast SMBG measurements. The variability measure was calculated as follows. Each month, only the three pre-breakfast SMBG measurements recorded before contact with the site were used to determine a day-to-day fasting glycaemic variability measure for each patient. For each patient, the variance of the three log-transformed pre-breakfast SMBG measurements each month was determined. The standard deviation was determined as the square root of the mean of these monthly variances and was defined as day-to-day fasting glycaemic variability. The associations between day-to-day fasting glycaemic variability and severe hypoglycaemia, MACE and all-cause mortality were analysed for the pooled trial population with Cox proportional hazards models. Several sensitivity analyses were conducted, including adjustments for baseline characteristics and most recent HbA1c. RESULTS: Day-to-day fasting glycaemic variability was significantly associated with severe hypoglycaemia (HR 4.11, 95% CI 3.15, 5.35), MACE (HR 1.36, 95% CI 1.12, 1.65) and all-cause mortality (HR 1.58, 95% CI 1.23, 2.03) before adjustments. The increased risks of severe hypoglycaemia, MACE and all-cause mortality translate into 2.7-, 1.2- and 1.4-fold risk, respectively, when a patient's day-to-day fasting glycaemic variability measure is doubled. The significant relationships of day-to-day fasting glycaemic variability with severe hypoglycaemia and all-cause mortality were maintained after adjustments. However, the significant association with MACE was not maintained following adjustment for baseline characteristics with either baseline HbA1c (HR 1.19, 95% CI 0.96, 1.47) or the most recent HbA1c measurement throughout the trial (HR 1.21, 95% CI 0.98, 1.49). CONCLUSIONS/INTERPRETATION: Higher day-to-day fasting glycaemic variability is associated with increased risks of severe hypoglycaemia and all-cause mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT01959529.

A population-based analysis of life satisfaction and social support among children of diverse backgrounds in British Columbia, Canada.

PURPOSE: The Satisfaction With Life Scale adapted for Children (SWLS-C) is a self-report measure of children's quality of life and has exhibited sound psychometric properties. In light of increasing ethno-cultural diversity, it is important to understand child life satisfaction across diverse subgroups. Employing children's language background as a proxy for cultural background among children in British Columbia, Canada, we examined (a) the cross-cultural measurement equivalence of the SWLS-C; and (b) cross-cultural relations of peer support and adult support with SWLS-C. METHODS: Participants were 20,119 children (Mage 9.2; 50.2% boys) who provided data as part of a self-report child health survey (the Middle-years Development Instrument). Measurement equivalence across eight language/cultural background groups was tested via multi-group confirmatory factor analysis. Multi-level analyses were used to compare: a) SWLS-C means; and b) associations of peer support and adult support with SWLS-C scores, by language/cultural background. RESULTS: Findings supported strict measurement equivalence between the English language/cultural background group and all other language/cultural background groups for the SWLS-C. Relative to the English language background group, SWLS-C means differed for several language/cultural background groups. Within every language/cultural background group, however, peer and adult support scale scores were significant positive correlates of SWLS-C scores. CONCLUSIONS: This study provided evidence for measurement equivalence of a life satisfaction measure across children from diverse language/cultural backgrounds and identified between-group differences in the level of child life satisfaction that were generally consistent with prior theory and findings. Moreover, results provided evidence of promotive associations of adult support and peer support with life satisfaction among diverse groups of children.