Once-Weekly Dulaglutide for the Treatment of Youths with Type 2 Diabetes.

BACKGROUND: The incidence of type 2 diabetes mellitus is increasing among youths. Once-weekly treatment with dulaglutide, a glucagon-like peptide-1 receptor agonist, may have efficacy with regard to glycemic control in youths with type 2 diabetes. METHODS: In a double-blind, placebo-controlled, 26-week trial, we randomly assigned participants (10 to <18 years of age; body-mass index [BMI], >85th percentile) being treated with lifestyle modifications alone or with metformin, with or without basal insulin, in a 1:1:1 ratio to receive once-weekly subcutaneous injections of placebo, dulaglutide at a dose of 0.75 mg, or dulaglutide at a dose of 1.5 mg. Participants were then included in a 26-week open-label extension study in which those who had received placebo began receiving dulaglutide at a weekly dose of 0.75 mg. The primary end point was the change from baseline in the glycated hemoglobin level at 26 weeks. Secondary end points included a glycated hemoglobin level of less than 7.0% and changes from baseline in the fasting glucose concentration and BMI. Safety was also assessed. RESULTS: A total of 154 participants underwent randomization. At 26 weeks, the mean glycated hemoglobin level had increased in the placebo group (0.6 percentage points) and had decreased in the dulaglutide groups (-0.6 percentage points in the 0.75-mg group and -0.9 percentage points in the 1.5-mg group, P<0.001 for both comparisons vs. placebo). At 26 weeks, a higher percentage of participants in the pooled dulaglutide groups than in the placebo group had a glycated hemoglobin level of less than 7.0% (51% vs. 14%, P<0.001). The fasting glucose concentration increased in the placebo group (17.1 mg per deciliter) and decreased in the pooled dulaglutide groups (-18.9 mg per deciliter, P<0.001), and there were no between-group differences in the change in BMI. The incidence of gastrointestinal adverse events was higher with dulaglutide therapy than with placebo. The safety profile of dulaglutide was consistent with that reported in adults. CONCLUSIONS: Treatment with dulaglutide at a once-weekly dose of 0.75 mg or 1.5 mg was superior to placebo in improving glycemic control through 26 weeks among youths with type 2 diabetes who were being treated with or without metformin or basal insulin, without an effect on BMI. (Funded by Eli Lilly; AWARD-PEDS ClinicalTrials.gov number, NCT02963766.).

Long-Term Efficacy and Safety of Ultra Rapid Lispro (URLi) in Adults with Type 1 Diabetes: The PRONTO-T1D Extension.

INTRODUCTION: The PRONTO-T1D study, which evaluated the efficacy and safety of ultra rapid lispro (URLi) versus lispro in adults with type 1 diabetes (T1D), met the primary endpoint of noninferiority of HbA1c change from baseline compared to lispro at 26 weeks. We present results of an additional 26-week treatment phase evaluating long-term efficacy and safety of URLi. METHODS: In this phase 3, treat-to-target study, subjects were randomized to double-blind mealtime URLi, lispro, or open-label postmeal URLi with insulin degludec or glargine for 26 weeks. Subjects in the double-blind URLi (n = 451) and lispro (n = 442) groups continued for another 26 weeks to assess long-term efficacy and safety. RESULTS: HbA1c increased marginally during the long-term maintenance period (week 26-52) in both groups to 7.47% (URLi) and 7.54% (lispro). At week 52, there were no statistically significant treatment differences in change from baseline HbA1c with a least-squares mean treatment difference (95% confidence interval) of - 0.06% (- 0.16, 0.03). Proportions of patients with HbA1c < 7% at week 52 were similar (URLi, 26.8%; lispro, 24.5%). Self-monitored blood glucose (SMBG) showed that 1-h (9.23 versus 10.14 mmol/L) and 2-h (8.40 versus 9.53 mmol/L) postmeal daily mean glucose was statistically significantly (p < 0.001) lower with URLi than lispro. The rate and incidence of severe, documented, and postprandial hypoglycemia (< 54 mg/dl [3.0 mmol/L]) were similar between treatments, but URLi demonstrated a 31% lower rate in the period more than 4 h after meals, (p = 0.023). Injection site reactions were reported by 3.3% of patients on URLi and 0.9% on lispro. The incidence of treatment-emergent adverse events was similar between treatments. CONCLUSION: Overall glycemic control and improved postprandial glucose via SMBG were maintained after 52 weeks with URLi versus lispro, suggesting that the efficacy of URLi is preserved during long-term treatment in patients with T1D. No long-term safety issues were identified with URLi. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03214367.

Generalized causal mediation and path analysis: Extensions and practical considerations.

Causal mediation analysis seeks to decompose the effect of a treatment or exposure among multiple possible paths and provide casually interpretable path-specific effect estimates. Recent advances have extended causal mediation analysis to situations with a sequence of mediators or multiple contemporaneous mediators. However, available methods still have limitations, and computational and other challenges remain. The present paper provides an extended causal mediation and path analysis methodology. The new method, implemented in the new R package, gmediation (described in a companion paper), accommodates both a sequence (two stages) of mediators and multiple mediators at each stage, and allows for multiple types of outcomes following generalized linear models. The methodology can also handle unsaturated models and clustered data. Addressing other practical issues, we provide new guidelines for the choice of a decomposition, and for the choice of a reference group multiplier for the reduction of Monte Carlo error in mediation formula computations. The new method is applied to data from a cohort study to illuminate the contribution of alternative biological and behavioral paths in the effect of socioeconomic status on dental caries in adolescence.

Ethnically Tibetan women in Nepal with low hemoglobin concentration have better reproductive outcomes.

Background and objectives: Tibetans have distinctively low hemoglobin concentrations at high altitudes compared with visitors and Andean highlanders. This study hypothesized that natural selection favors an unelevated hemoglobin concentration among Tibetans. It considered nonheritable sociocultural factors affecting reproductive success and tested the hypotheses that a higher percent of oxygen saturation of hemoglobin (indicating less stress) or lower hemoglobin concentration (indicating dampened response) associated with higher lifetime reproductive success. Methodology: We sampled 1006 post-reproductive ethnically Tibetan women residing at 3000-4100 m in Nepal. We collected reproductive histories by interviews in native dialects and noninvasive physiological measurements. Regression analyses selected influential covariates of measures of reproductive success: the numbers of pregnancies, live births and children surviving to age 15. Results: Taking factors such as marriage status, age of first birth and access to health care into account, we found a higher percent of oxygen saturation associated weakly and an unelevated hemoglobin concentration associated strongly with better reproductive success. Women who lost all their pregnancies or all their live births had hemoglobin concentrations significantly higher than the sample mean. Elevated hemoglobin concentration associated with a lower probability a pregnancy progressed to a live birth. Conclusions and implications: These findings are consistent with the hypothesis that unelevated hemoglobin concentration is an adaptation shaped by natural selection resulting in the relatively low hemoglobin concentration of Tibetans compared with visitors and Andean highlanders.

Intakes of dairy products and calcium and obesity in Korean adults: Korean National Health and Nutrition Examination Surveys (KNHANES) 2007-2009.

BACKGROUND: The possible effects of dairy product intake against obesity have been suggested in animal studies; however, the association is still not well established in epidemiological studies. Few studies in Asian countries with relatively low intake of dairy products exist. OBJECTIVE: We investigated the association between dairy products and calcium intake and obesity in Korean population with relatively low intake of dairy products. SUBJECTS AND METHODS: Our study population consisted of adults (n = 7173) aged 19-64 among participants of the 2007, 2008 and 2009 Korean National Health and Nutrition Examination Survey who had not made any attempt of intentional weight loss. Dietary intake data from food frequency questionnaire (FFQ) and 24-hour recall were used. Dairy products included milk and yogurt in the FFQ. Obesity was defined as BMI≥25 kg/m². RESULTS: Higher frequency of dairy product intake was associated with a reduced prevalence of obesity (OR = 0.63; 95% CI = 0.45-0.89 for ≥2 times/day vs. ≤1 time/month; p for trend = 0.003) using the intake data from FFQ. Similarly, high frequency of milk or yogurt intake had an inverse association with obesity. The association between milk and yogurt intake and obesity was similar when the intake from 24-hour recall was examined. Higher calcium intake from dairy products as well as total dietary calcium intake was associated with a decreased prevalence of obesity (OR = 0.83; 95% CI = 0.71-0.98 for highest vs. lowest quintile of dairy calcium intake; p for trend = 0.02, OR = 0.78; 95% CI = 0.64-0.94 for highest vs. lowest quintile of total calcium intake; p for trend = 0.04). The associations appeared to be stronger in women than in men. CONCLUSION: These results suggest that high consumption of dairy products is associated with a lower prevalence of obesity and that calcium in dairy products may be one of the components contributing to the association. Further longitudinal studies are warranted to replicate our findings.

Living alone and cardiovascular risk in outpatients at risk of or with atherothrombosis.

BACKGROUND: Living alone, a proxy for social support, has been inconsistently linked with cardiovascular risk. METHODS: We investigated whether living alone was associated with increased mortality and cardiovascular risk in the global REduction of Atherothrombosis for Continued Health (REACH) Registry. Stable outpatients at risk of or with atherothrombosis were recruited from December 1, 2003, through December 31, 2004, and followed up to 4 years for cardiovascular events. Events were examined by living arrangement with risk adjustment for age, sex, clinical risk factors, therapy, preexisting vascular disease, and sociodemographic factors. Effect modification was tested by age, sex, employment, ethnicity, education, and geography. RESULTS: Among the 44 573 REACH participants, 8594 (19%) were living alone. Living alone was associated with higher 4-year mortality (14.1% vs 11.1%) and cardiovascular death (8.6% vs 6.8%; log-rank P < .01 for both comparisons); however, there was significant effect modification by age (P value for interaction = .03). Specifically, among younger participants, living alone compared with those living with others was associated with higher mortality (age 45-65 years: 7.7% vs 5.7%; adjusted hazard ratio [HR], 1.24 [95% CI, 1.01-1.51]; age 66-80 years: 13.2% vs 12.3%; adjusted HR, 1.12 [95% CI, 1.01-1.26]), but this was not observed among older participants (age > 80 years: 24.6% vs 28.4%; adjusted HR, 0.92 [95% CI, 0.79-1.06]). A similar trend was observed for the risk of cardiovascular death. CONCLUSIONS: In an international outpatient population with atherothrombosis aged 45 years or older, living alone was associated with increased mortality among all but the most elderly patients, although this observation warrants confirmation.

Urine arsenic concentration and obstructive pulmonary disease in the U.S. population.

Arsenic (As) is a known carcinogen commonly found in drinking water. An emerging body of evidence suggests that exposure to inorganic As may be associated with nonmalignant respiratory disease. The aim of this study was to determine whether there is an association between As exposure at levels seen in the United States and prevalence of asthma, emphysema, chronic bronchitis, and respiratory symptoms.Urinary As was collected from 5365 participants from the combined 2003-2006 National Health and Nutrition Examination Survey (NHANES) cohorts. Two methods to adjust for organic As component were incorporated into the statistical model. Linear and logistic regression models compared urinary As adjusted for organic As with diagnoses of obstructive pulmonary disease and respiratory symptoms.Geometric mean concentration of urinary As were not significantly different between participants with and those without asthma, chronic bronchitis,and emphysema. Odds of having asthma was 0.71 for participants with the highest quintile of urinary As (≥ 17.23 µg/dl) when compared to the lowest quintile (≤ 3.52 µg/dl). A significant association was found between increasing urinary As concentration and decreasing age, male gender, and non-"white" race.A significant association between urinary As and obstructive pulmonary disease and symptoms was not demonstrated in the U.S. population.