Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes.

BACKGROUND: Data are lacking on the comparative effectiveness of commonly used glucose-lowering medications, when added to metformin, with respect to microvascular and cardiovascular disease outcomes in persons with type 2 diabetes. METHODS: We assessed the comparative effectiveness of four commonly used glucose-lowering medications, added to metformin, in achieving and maintaining a glycated hemoglobin level of less than 7.0% in participants with type 2 diabetes. The randomly assigned therapies were insulin glargine U-100 (hereafter, glargine), glimepiride, liraglutide, and sitagliptin. Prespecified secondary outcomes with respect to microvascular and cardiovascular disease included hypertension and dyslipidemia, confirmed moderately or severely increased albuminuria or an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m2 of body-surface area, diabetic peripheral neuropathy assessed with the Michigan Neuropathy Screening Instrument, cardiovascular events (major adverse cardiovascular events [MACE], hospitalization for heart failure, or an aggregate outcome of any cardiovascular event), and death. Hazard ratios are presented with 95% confidence limits that are not adjusted for multiple comparisons. RESULTS: During a mean 5.0 years of follow-up in 5047 participants, there were no material differences among the interventions with respect to the development of hypertension or dyslipidemia or with respect to microvascular outcomes; the mean overall rate (i.e., events per 100 participant-years) of moderately increased albuminuria levels was 2.6, of severely increased albuminuria levels 1.1, of renal impairment 2.9, and of diabetic peripheral neuropathy 16.7. The treatment groups did not differ with respect to MACE (overall rate, 1.0), hospitalization for heart failure (0.4), death from cardiovascular causes (0.3), or all deaths (0.6). There were small differences with respect to rates of any cardiovascular disease, with 1.9, 1.9, 1.4, and 2.0 in the glargine, glimepiride, liraglutide, and sitagliptin groups, respectively. When one treatment was compared with the combined results of the other three treatments, the hazard ratios for any cardiovascular disease were 1.1 (95% confidence interval [CI], 0.9 to 1.3) in the glargine group, 1.1 (95% CI, 0.9 to 1.4) in the glimepiride group, 0.7 (95% CI, 0.6 to 0.9) in the liraglutide group, and 1.2 (95% CI, 1.0 to 1.5) in the sitagliptin group. CONCLUSIONS: In participants with type 2 diabetes, the incidences of microvascular complications and death were not materially different among the four treatment groups. The findings indicated possible differences among the groups in the incidence of any cardiovascular disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.).

Withdrawal of medications leads to worsening of OGTT parameters in youth with impaired glucose tolerance or recently-diagnosed type 2 diabetes.

BACKGROUND: The RISE Pediatric Medication Study compared strategies for preserving ß-cell function, including a 9-month follow-up after treatment withdrawal to test treatment effect durability. OBJECTIVE: Evaluate OGTT measures of glucose and ß-cell response through 12 months of intervention and 9 months of medication washout. PARTICIPANTS: Youth (n = 91) aged 10 to 19 years with BMI ≥85th percentile and impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes (T2D). METHODS: A multicenter randomized clinical trial comparing insulin glargine for 3 months followed by metformin for 9 months (G→Met) or metformin alone (Met) for 12 months. We report within-group changes from baseline to end of medication intervention (M12), baseline to 9 months post-medication withdrawal (M21), and end of medication (M12) to M21. OGTT C-peptide index [CPI] paired with 1/fasting insulin evaluated ß-cell response. RESULTS: At M12, both treatments were associated with stable fasting glucose (G→Met baseline 6.0 ± 0.1 vs M12 5.9 ± 0.2 mmol/L, P = .62; Met baseline 6.1 ± 0.2 vs M12 6.0 ± 0.2 mmol/L, P = .73) and 2-hour glucose (G→Met baseline 10.2 ± 0.4 vs M12 9.3 ± 0.5 mmol/L, P = .03; Met baseline 10.2 ± 0.4 vs M12 10.6 ± 0.6 mmol/L, P = .88). Following medication withdrawal, fasting glucose worsened (G→Met M21 8.6 ± 1.8, P = .004; Met M21 7.8 ± 0.7 mmol/L, P = .003), as did 2-hour glucose (G→Met M21 13.2 ± 1.4, P = .002; Met M21 13.1 ± 1.2 mmol/L, P = .006), associated with declines in ß-cell response. CONCLUSIONS: G→Met and Met were associated with stable glucose measures during 12 months of treatment in youth with IGT or recently diagnosed T2D. Glucose and ß-cell response worsened post-medication withdrawal, suggesting treatment must be long-term or alternative treatments pursued.

ß-cells in youth with impaired glucose tolerance or early type 2 diabetes secrete more insulin and are more responsive than in adults.

OBJECTIVE: Glycemic control deteriorates more rapidly in youth vs adults. We compared model-derived measures of ß-cell function between youth and adults with either impaired glucose tolerance (IGT) or type 2 diabetes to determine if a ß-cell defect differentiates these age groups. METHODS: This is a cross-sectional analysis of baseline data from the Restoring Insulin Secretion (RISE) Study. Youth (54 Y-IGT, 33 Y-D) and adults (250 A-IGT, 104 A-D) underwent 3-hour oral glucose tolerance tests for modeling of insulin secretion rates (ISRs), glucose sensitivity, and rate sensitivity. Insulin sensitivity was quantified as the glucose infusion rate/insulin (M/I) from a hyperglycemic clamp. RESULTS: Youth had lower insulin sensitivity despite similar body mass index. Analyses were adjusted for insulin sensitivity. Youth had higher basal ISRs (Y-IGT 200 ± 161 vs A-IGT 152 ± 74, P < .001; Y-D 245 ± 2.5 vs A-D 168 ± 115 pmol/min/m2 , P = .007) and total ISRs (Y-IGT 124 ± 86 vs A-IGT 98 ± 39, P < .001; Y-D 116 ± 110 vs A-D 97 ± 62 nmol/m2 , P = .002). Within IGT, glucose sensitivity (Y-IGT 140 ± 153 vs A-IGT 112 ± 70 pmol/min/m2 /mM, P = .004) and rate sensitivity (median[interquartile range]:Y-IGT 2271[1611, 3222] vs A-IGT 1164[685, 1565] pmol/m2 /mM, P < .001) were higher in youth, but not different by age group within diabetes. CONCLUSIONS: Model-derived measures of ß-cell function provide additional insight into the pathophysiology of type 2 diabetes in youth with higher ISRs and ß-cell secretion more responsive to glucose in youth relative to adults even after adjusting for differences in insulin sensitivity. It is unknown whether these findings in youth reflect ß-cells that are healthier or whether this is a defect that contributes to more rapid loss of function.

Impact of Glucose-Lowering Medications on Health-Related Quality of Life in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

OBJECTIVE: Diabetes is associated with reduced health-related quality of life (HRQoL). Information on the relationship between HRQoL and glucose-lowering medications in recently diagnosed type 2 diabetes (T2D) is limited. We assessed changes in HRQoL in participants with T2D receiving metformin plus one of four glucose-lowering medications in Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). RESEARCH DESIGN AND METHODS: A total of 5,047 participants, baseline mean age 57 years, with <10 years T2D duration and glycated hemoglobin level 6.8-8.5% and taking metformin monotherapy, were randomly assigned to glargine, glimepiride, liraglutide, or sitagliptin. HRQoL was evaluated at baseline for 4,885 participants, and at years 1, 2, and 3, with use of the self-administered version of the Quality of Well-being Scale (QWB-SA) and SF-36 physical (PCS) and mental (MCS) component summary scales. Linear models were used to analyze changes in HRQoL over time in intention-to-treat analyses. RESULTS: None of the medications worsened HRQoL. There were no differences in QWB-SA or MCS by treatment group at any time point. PCS scores improved with liraglutide versus other groups at year 1 only. Greater weight loss during year 1 explained half the improvement in PCS scores with liraglutide versus glargine and glimepiride. Liraglutide participants in the upper tertile of baseline BMI showed the greatest improvement in PCS scores at year 1. CONCLUSIONS: Adding liraglutide to metformin in participants within 10 years of T2D diagnosis showed improvement in the SF-36 PCS in comparisons with the other medications at 1 year, which was no longer significant at years 2 and 3. Improvement was related to weight loss and baseline BMI.

Comparative Effects of Randomized Second-line Therapy for Type 2 Diabetes on a Composite Outcome Incorporating Glycemic Control, Body Weight, and Hypoglycemia: An Analysis of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

OBJECTIVE: In Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) (5,047 participants, mean follow-up 5.0 years), differences in glycemic control were demonstrated over time among four randomized therapies added to metformin. Weight gain and hypoglycemia are also important outcomes for people with type 2 diabetes. We compared the effects of the four randomized GRADE medications on a composite outcome incorporating glycemic deterioration, weight gain, and hypoglycemia. RESEARCH DESIGN AND METHODS: The composite outcome was time to first occurrence of any of the following: HbA1c >7.5%, confirmed; ≥5% weight gain; or severe or recurrent nonsevere hypoglycemia. Secondary analyses included examination of individual components of the composite outcome, subgroup effects and potential mediators, and treatment satisfaction. Cumulative incidence was estimated with the Kaplan-Meier estimator. Cox proportional hazards models were used to assess pairwise group differences in risk of an outcome. RESULTS: Risk of reaching the composite outcome (events per 100 participants per treatment year [PTYs]) was lowest with liraglutide (19 per 100 PTYs) followed by sitagliptin (26 per 100 PTYs), glargine (29 per 100 PTYs), and glimepiride (40 per 100 PTYs); all pairwise comparisons were statistically significant. The order was the same for risk of weight gain and hypoglycemia, but risk of glycemic deterioration was lowest with glargine, followed by liraglutide, glimepiride, and sitagliptin. No significant heterogeneity in risk of composite outcome was detected across prespecified covariates. Participants who reached the composite outcome had modestly but significantly lower treatment satisfaction. CONCLUSIONS: Among participants treated with common second-line drug classes for type 2 diabetes, the liraglutide group had the lowest and glimepiride the highest risk of reaching a composite outcome encompassing glycemic deterioration, weight gain, and hypoglycemia. These findings may inform decision-making regarding type 2 diabetes therapy.

Effects of metformin and intensive lifestyle interventions on the incidence of kidney disease in adults in the DPP/DPPOS.

AIMS: We analyzed the incidence of kidney disease in the Diabetes Prevention Program Outcomes Study (DPPOS) by originally randomized treatment group assignment: Intensive Lifestyle (ILS), Metformin (MET) or Placebo (PLB). METHODS: The current analyses used a time-to-event approach in which the primary outcome was kidney disease, ascertained as urine albumin-to-creatinine ratio (ACR) ≥ 3.39 mg/mmol (30 mg/g) or eGFR <45 mL/min/1.73m2, with confirmation required at the next visit, or adjudicated end-stage kidney disease (ESKD). RESULTS: At a median of 21 years following randomization in DPP, diabetes development was reduced in both the ILS (HR 0.73 [95%CI = 0.62, 0.85]) and MET groups (HR 0.85 [0.73, 0.99]) compared to the PLB group. Although risk for developing the primary kidney disease outcome was higher among those with incident diabetes compared to those without (HR 1.81 [1.43, 2.30]), it did not differ by intervention groups (ILS vs. PLB 1.02 (0.81, 1.29); MET vs. PLB 1.08 (0.86, 1.35). There was a non-significant metformin by age interaction (p = 0.057), with metformin being beneficial for kidney disease in the younger but potentially harmful in the older participants. CONCLUSIONS: Development of kidney disease was increased in participants who developed diabetes but did not differ by original treatment group assignment. CLINICAL TRIAL REGISTRATIONS: Diabetes Prevention Program (DPP) Clinical trial reg. no. NCT00004992 DPP Outcomes Study (DPPOS) Clinical trial reg. no. NCT0038727.

Towards a consensus-based classification of childhood arterial ischemic stroke.

BACKGROUND AND PURPOSE: The implementation of uniform nomenclature and classification in adult arterial ischemic stroke (AIS) has been critical for defining outcomes and recurrence risks according to etiology and in developing risk-stratified treatments. In contrast, current classification and nomenclature in childhood AIS are often overlapping or contradictory. Our purpose was to develop a comprehensive consensus-based classification system for childhood AIS. METHODS: Using a modified-Delphi method, members of the International Pediatric Stroke Study (IPSS) developed the Childhood AIS Standardized Classification And Diagnostic Evaluation (CASCADE) criteria. Two groups of pediatric stroke specialists from the IPSS classified 7 test cases using 2 methods each: (1) classification typical of the individual clinician's current clinical practice; and (2) classification based on the CASCADE criteria. Group 1 underwent in-person training in the utilization of the CASCADE criteria. Group 2 classified the same cases via an online survey, including definitions but without training. Inter-rater reliability (IRR) was assessed via multi-rater unweighted κ-statistic. RESULTS: In Group 1 (with training), IRR was improved using CASCADE criteria (κ=0.78, 95% CI=[0.49, 0.94]), compared with typical clinical practice (κ=0.40, 95% CI=[0.11, 0.60]). In Group 2 (without training), IRR was lower than among trained raters (κ=0.61, 95% CI=[0.29, 0.77]), but higher than current practice (κ=0.23, 95% CI=[0.03, 0.36]). CONCLUSIONS: A new, consensus-based classification system for childhood AIS, the CASCADE criteria, can be used to classify cases with good IRR. These preliminary findings suggest that the CASCADE criteria may be particularity useful in the setting of prospective multicenter studies in childhood-onset AIS, where standardized training of investigators is feasible.

Genetic Architecture of Plasma Alpha-Aminoadipic Acid Reveals a Relationship With High-Density Lipoprotein Cholesterol.

Background Elevated plasma levels of alpha-aminoadipic acid (2-AAA) have been associated with the development of type 2 diabetes and atherosclerosis. However, the nature of the association remains unknown. Methods and Results We identified genetic determinants of plasma 2-AAA through meta-analysis of genome-wide association study data in 5456 individuals of European, African, and Asian ancestry from the Framingham Heart Study, Diabetes Prevention Program, Jackson Heart Study, and Shanghai Women's and Men's Health Studies. No single nucleotide polymorphisms reached genome-wide significance across all samples. However, the top associations from the meta-analysis included single-nucleotide polymorphisms in the known 2-AAA pathway gene DHTKD1, and single-nucleotide polymorphisms in genes involved in mitochondrial respiration (NDUFS4) and macrophage function (MSR1). We used a Mendelian randomization instrumental variable approach to evaluate relationships between 2-AAA and cardiometabolic phenotypes in large disease genome-wide association studies. Mendelian randomization identified a suggestive inverse association between increased 2-AAA and lower high-density lipoprotein cholesterol (P=0.005). We further characterized the genetically predicted relationship through measurement of plasma 2-AAA and high-density lipoprotein cholesterol in 2 separate samples of individuals with and without cardiometabolic disease (N=98), and confirmed a significant negative correlation between 2-AAA and high-density lipoprotein (rs=-0.53, P<0.0001). Conclusions 2-AAA levels in plasma may be regulated, in part, by common variants in genes involved in mitochondrial and macrophage function. Elevated plasma 2-AAA associates with reduced levels of high-density lipoprotein cholesterol. Further mechanistic studies are required to probe this as a possible mechanism linking 2-AAA to future cardiometabolic risk.

Weight loss and ß-cell responses following gastric banding or pharmacotherapy in adults with impaired glucose tolerance or type 2 diabetes: a randomized trial.

OBJECTIVE: The extent to which weight loss contributes to increases in insulin sensitivity (IS) and ß-cell function after surgical or medical intervention has not been directly compared in individuals with impaired glucose tolerance or newly diagnosed type 2 diabetes. METHODS: The Restoring Insulin Secretion (RISE) Study included adults in the Beta-Cell Restoration Through Fat Mitigation Study (n = 88 randomized to laparoscopic gastric banding or metformin [MET]) and the Adult Medication Study (n = 267 randomized to placebo, MET, insulin glargine/MET, or liraglutide + MET [L + M]). IS and ß-cell responses were measured at baseline and after 12 months by modeling of oral glucose tolerance tests and during arginine-stimulated hyperglycemic clamps. Linear regression models assessed differences between and within treatments over time. RESULTS: BMI decreased in all treatment groups, except placebo, at 12 months. IS increased in all arms except placebo and was inversely correlated with changes in BMI. L + M was the only treatment arm that enhanced multiple measures of ß-cell function independent of weight loss. Insulin secretion decreased in the laparoscopic gastric banding arm proportional to increases in IS, with no net benefit on ß-cell function. CONCLUSIONS: Reducing demand on the ß-cell by improving IS through weight loss does not reverse ß-cell dysfunction. L + M was the only treatment that enhanced ß-cell function.

Differential loss of ß-cell function in youth vs. adults following treatment withdrawal in the Restoring Insulin Secretion (RISE) study.

AIMS: To compare OGTT-derived estimates of ß-cell function between youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes after treatment discontinuation in RISE. METHODS: Youth (n = 89) and adults (n = 132) were randomized to 3 months glargine followed by 9 months metformin (G/M) or 12 months metformin (MET). Insulin sensitivity and ß-cell responses were estimated from 3-hour OGTTs over 21 months. Linear mixed models tested for differences by time and age group within each treatment arm. RESULTS: After treatment withdrawal, HbA1c increased in both youth and adults with a larger net increase in G/M youth vs. adults at 21 months. Among youth, ß-cell function decreased starting at 12 months in G/M and 15 months in MET. Among adults, ß-cell function remained relatively stable although insulin secretion rates decreased in G/M at 21 months. At 21 months vs. baseline ß-cell function declined to a greater extent in youth vs. adults in both the G/M and MET treatment arms. CONCLUSIONS: After treatment withdrawal youth demonstrated progressive decline in ß-cell function after stopping treatment with either G/M or MET. In contrast, ß-cell function in adults remained stable despite an increase in HbA1c over time. ClinicalTrials.gov Identifier: NCT01779375 and NCT01779362 at clinical trials.gov.

Hepatic Fat in Participants With and Without Incident Diabetes in the Diabetes Prevention Program Outcome Study.

CONTEXT: There is little information about fatty liver in prediabetes as it transitions to early diabetes. OBJECTIVE: This study is aimed at evaluating the prevalence and determinants of fatty liver in the Diabetes Prevention Program (DPP). METHODS: We measured liver fat as liver attenuation (LA) in Hounsfield units (HU) in 1876 participants at ~14 years following randomization into the DPP, which tested the effects of lifestyle or metformin interventions versus standard care to prevent diabetes. LA was compared among intervention groups and in those with versus without diabetes, and associations with baseline and follow-up measurements of anthropometric and metabolic covariates were assessed. RESULTS: There were no differences in liver fat between treatment groups at 14 years of follow-up. Participants with diabetes had lower LA (mean ± SD: 46 ± 16 vs 51 ± 14 HU; P < 0.001) and a greater prevalence of fatty liver (LA < 40 HU) (34% vs 17%; P < 0.001). Severity of metabolic abnormalities at the time of LA evaluation was associated with lower LA categories in a graded manner and more strongly in those with diabetes. Averaged annual fasting insulin (an index of insulin resistance [OR, 95% CI 1.76, 1.41-2.20]) waist circumference (1.63, 1.17-2.26), and triglyceride (1.42, 1.13-1.78), but not glucose, were independently associated with LA < 40 HU prevalence. CONCLUSION: Fatty liver is common in the early phases of diabetes development. The association of LA with insulin resistance, waist circumference, and triglyceride levels emphasizes the importance of these markers for hepatic steatosis in this population and that assessment of hepatic fat in early diabetes development is warranted.

Baseline Predictors of Glycemic Worsening in Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes in the Restoring Insulin Secretion (RISE) Study.

OBJECTIVE: To identify predictors of glycemic worsening among youth and adults with impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes in the Restoring Insulin Secretion (RISE) Study. RESEARCH DESIGN AND METHODS: A total of 91 youth (10-19 years) were randomized 1:1 to 12 months of metformin (MET) or 3 months of glargine, followed by 9 months of metformin (G-MET), and 267 adults were randomized to MET, G-MET, liraglutide plus MET (LIRA+MET), or placebo for 12 months. All participants underwent a baseline hyperglycemic clamp and a 3-h oral glucose tolerance test (OGTT) at baseline, month 6, month 12, and off treatment at month 15 and month 21. Cox models identified baseline predictors of glycemic worsening (HbA1c increase ≥0.5% from baseline). RESULTS: Glycemic worsening occurred in 17.8% of youth versus 7.5% of adults at month 12 (P = 0.008) and in 36% of youth versus 20% of adults at month 21 (P = 0.002). In youth, glycemic worsening did not differ by treatment. In adults, month 12 glycemic worsening was less on LIRA+MET versus placebo (hazard ratio 0.21, 95% CI 0.05-0.96, P = 0.044). In both age-groups, lower baseline clamp-derived ß-cell responses predicted month 12 and month 21 glycemic worsening (P < 0.01). Lower baseline OGTT-derived ß-cell responses predicted month 21 worsening (P < 0.05). In youth, higher baseline HbA1c and 2-h glucose predicted month 12 and month 21 glycemic worsening, and higher fasting glucose predicted month 21 worsening (P < 0.05). In adults, lower clamp- and OGTT-derived insulin sensitivity predicted month 12 and month 21 worsening (P < 0.05). CONCLUSIONS: Glycemic worsening was more common among youth than adults with IGT or recently diagnosed type 2 diabetes, predicted by lower baseline ß-cell responses in both groups, hyperglycemia in youth, and insulin resistance in adults.

Peanut-allergic subjects and their peanut-tolerant siblings have large differences in peanut-specific IgG that are independent of HLA class II.

We enrolled 53 peanut-allergic subjects and 64 peanut-tolerant full siblings, measured peanut-specific IgG and IgE, determined HLA class II at high resolution, and analyzed DRB1 alleles by supertypes. Peanut-specific IgG and IgE were elevated in the peanut-allergic subjects (p<0.0001) but did not stratify with HLA alleles, haplotypes, or supertypes. There were no significant differences in HLA class II between the peanut-allergic and peanut-tolerant siblings but there was an increased frequency of DRB1*0803 in both sets of siblings compared to unrelated controls (p(c)=4.5×10⁻9). Furthermore, we identified 14 sibling pairs in which the peanut-allergic and the peanut-tolerant siblings have identical HLA class II and again found an elevation of anti-peanut IgG in the peanut-allergic subjects (p<0.0001). In conclusion, although DRB1*0803 may identify a subset of families with increased risk of peanut allergy, differences in peanut-specific immunoglobulin production between peanut-allergic subjects and their peanut-tolerant siblings are independent of HLA class II.

Biomarkers of hypercoagulability and inflammation in childhood-onset arterial ischemic stroke.

OBJECTIVE: To test the hypothesis that acute elevations of biomarkers of hypercoagulability and inflammation are common in children with arterial ischemic stroke (AIS), particularly among etiologic subtypes that carry an increased risk of recurrent stroke. STUDY DESIGN: In this prospective/retrospective institutional-based cohort study of acute childhood-onset AIS (n = 50) conducted between 2005 and 2009, D-dimer, factor VIII (FVIII) activity, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were serially evaluated at the time of clinical blood sampling. Patients were classified by stroke subtype as cardioembolic, moyamoya, non-moyamoya arteriopathy, or other. RESULTS: Both D-dimer and CRP were frequently elevated in acute childhood-onset AIS and exhibited a decreasing trend with time. Acute D-dimer levels were significantly higher in cardioembolic AIS compared with noncardioembolic AIS (median, 2.04 microg/mL [range 0.54-4.54 microg/mL] vs 0.32 microg/mL [0.22-3.18 microg/mL]; P = .002). At an optimal threshold of > or = 0.50 microg/mL, the sensitivity and specificity of D-dimer for cardioembolic subtype were 78% and 79%, respectively. CONCLUSIONS: Our findings identify D-dimer and CRP as candidate biomarkers for etiology and prognosis in childhood-onset AIS. Further studies should investigate the role of these and other biomarkers of hypercoagulability and inflammation in childhood-onset AIS.

Depressive symptoms in pulmonary arterial hypertension: prevalence and association with functional status.

BACKGROUND: In patients with left-heart disease, depressive symptoms have a significant impact on functional status and quality of life. The prevalence of depressive symptoms, and their impact on patients with pulmonary arterial hypertension (PAH) is understudied. OBJECTIVE: The authors investigated the prevalence of depressive symptoms in PAH and their correlation with physical functioning. METHOD: Consecutive outpatients with PAH (idiopathic; or associated with scleroderma, congenital heart disease, or anorexiant use) seen in two university PAH clinics were screened. At two outpatient visits, 8 to 16 weeks apart, patients completed the PHQ-8, a well-validated instrument for grading severity of depressive symptoms; they were assessed for cardiac functional class (FC), and performed a 6-minute walk-distance test (6MWD). RESULTS: A group of 100 patients (88% women, 50% with idiopathic PAH) were enrolled. At baseline, 15% of subjects had symptoms suggestive of major depressive disorder; 40% had mild-to-moderate depressive symptoms; and 45% had no-to-minimal depressive symptoms. CONCLUSION: Depression is common in patients with PAH, with 55% demonstrating depressive symptoms. These results suggest that screening patients with PAH will identify a large proportion of patients who might benefit from depression therapy.

Long-term metformin adherence in the Diabetes Prevention Program Outcomes Study.

INTRODUCTION: To investigate long-term metformin adherence in the Diabetes Prevention Program Outcomes Study (DPPOS) by examining: (1) predictors of long-term adherence to study metformin and (2) whether metformin adherence was associated with incident type 2 diabetes. RESEARCH DESIGN AND METHODS: DPPOS was an open-label continuation of the randomized clinical trial (Diabetes Prevention Program (DPP)) in which eligible participants randomized to the metformin group were offered study metformin and followed over 11 years. A brief structured adherence interview was administered semiannually. Metformin adherence was assessed by pill counts. Predictors of metformin adherence were examined in multivariate regression models. Incident diabetes associated with metformin adherence and other variables was assessed in Cox proportional hazards models. RESULTS: Of 868 participants eligible to continue taking study metformin, 664 (76%) took at least some metformin over 11 years, with 478 of them reporting problems with adherence. DPPOS cumulative adherence showed significant associations of higher adherence (≥80%) with early adherence at 3 months in DPP (p<0.001) and lower depression scores during DPPOS (p<0.001); significant differences were also seen by race/ethnicity (p<0.004). Predicting adherence by multivariate modeling showed odds of adherence significantly lower for Black participants and for participants reporting more than one barrier. Odds for adherence were significantly higher for those adherent early in DPP and those reporting at least one planned strategy to improve adherence. Higher metformin adherence was significantly associated with a lower diabetes risk (p=0.04), even after adjustment for demographic variables, depression, and anxiety scores. CONCLUSIONS: In this long-term diabetes prevention study, early metformin adherence and planned strategies to promote adherence improved long-term adherence over 11 years; higher adherence to metformin was related to lower diabetes incidence. Incorporating strategies to promote adherence when initially prescribing metformin and counseling to support adherence over time are warranted.

Anticoagulation in childhood-onset arterial ischemic stroke with non-moyamoya arteriopathy: findings from the Colorado and German (COAG) collaboration.

BACKGROUND AND PURPOSE: Childhood arterial ischemic stroke treatment guidelines recommend extended anticoagulation in cardioembolism and dissection. We sought to investigate the safety of extended anticoagulation in childhood arterial ischemic stroke with nonmoyamoya arteriopathy, for which the risk of recurrent stroke is high. METHODS: Thirty-seven patients with childhood-onset arterial ischemic stroke with acute arteriopathy (excluding moyamoya) were diagnosed between 1999 and 2007 and treated with anticoagulation for at least 4 weeks. Patients were followed in hospital-based cohort studies at 2 centers and systematically assessed for bleeding episodes and recurrent events. RESULTS: Over a cumulative anticoagulation duration of 1329 patient-months, there were no major bleeding episodes and 2 clinically relevant bleeding episodes. Cumulative probability of recurrent arterial ischemic stroke at 1 year was 14%. CONCLUSIONS: Anticoagulation can be used safely for secondary arterial ischemic stroke prevention in children with acute nonmoyamoya arteriopathy. Anticoagulation is worthy of evaluation in future randomized, controlled treatment trials in this disease.

Anti-Xa stability of diluted dalteparin for pediatric use.

BACKGROUND: The low-molecular-weight heparin (LMWH) dalteparin is approved by the Food and Drug Administration for prophylaxis of venous thromboembolism (VTE) in adults and has recently received an indication for acute VTE therapy in adults with cancer. Published reports of experience with dalteparin use in European children suggest that this LMWH agent is safe and effective in the prophylaxis and treatment of VTE in the pediatric population. However, dalteparin is commonly available in the US in a concentrated form that requires dilution for accurate administration in infants and young children. OBJECTIVE: To investigate the in vitro stability of diluted dalteparin for pediatric use, as measured by serial anti-Xa activity assays over the course of 4 weeks. METHODS: At 2 clinical research pharmacies, dalteparin multidose vials (anti-Xa concentration 25,000 U/mL) of the 2 distinct lots presently available for clinical use were diluted 1:10 with preservative-free NaCl 0.9% and maintained in tuberculin syringes at 4 degrees C. Syringes were then sampled for anti-Xa activity by chromogenic assay at baseline and weekly over the course of 4 weeks. RESULTS: For each lot of dalteparin, there was strong agreement in anti-Xa activity between corresponding diluted syringes prepared at the 2 pharmacy sites. No statistically significant difference in anti-Xa activity was detected from baseline to any time point, nor was a trend of change detected in anti-Xa activity with time for either lot of dalteparin. CONCLUSIONS: These data indicate that the anti-Xa activity of diluted dalteparin for pediatric use is stable over the course of 4 weeks.

A summarization approach for Affymetrix GeneChip data using a reference training set from a large, biologically diverse database.

BACKGROUND: Many of the most popular pre-processing methods for Affymetrix expression arrays, such as RMA, gcRMA, and PLIER, simultaneously analyze data across a set of predetermined arrays to improve precision of the final measures of expression. One problem associated with these algorithms is that expression measurements for a particular sample are highly dependent on the set of samples used for normalization and results obtained by normalization with a different set may not be comparable. A related problem is that an organization producing and/or storing large amounts of data in a sequential fashion will need to either re-run the pre-processing algorithm every time an array is added or store them in batches that are pre-processed together. Furthermore, pre-processing of large numbers of arrays requires loading all the feature-level data into memory which is a difficult task even with modern computers. We utilize a scheme that produces all the information necessary for pre-processing using a very large training set that can be used for summarization of samples outside of the training set. All subsequent pre-processing tasks can be done on an individual array basis. We demonstrate the utility of this approach by defining a new version of the Robust Multi-chip Averaging (RMA) algorithm which we refer to as refRMA. RESULTS: We assess performance based on multiple sets of samples processed over HG U133A Affymetrix GeneChip arrays. We show that the refRMA workflow, when used in conjunction with a large, biologically diverse training set, results in the same general characteristics as that of RMA in its classic form when comparing overall data structure, sample-to-sample correlation, and variation. Further, we demonstrate that the refRMA workflow and reference set can be robustly applied to naïve organ types and to benchmark data where its performance indicates respectable results. CONCLUSION: Our results indicate that a biologically diverse reference database can be used to train a model for estimating probe set intensities of exclusive test sets, while retaining the overall characteristics of the base algorithm. Although the results we present are specific for RMA, similar versions of other multi-array normalization and summarization schemes can be developed.

Postmenopausal hormone therapy is associated with atherosclerosis progression in women with abnormal glucose tolerance.

BACKGROUND: Abnormal glucose tolerance (AGT; diabetes or impaired glucose tolerance) is associated with increased risk of cardiovascular disease, especially in women. Cardiovascular disease rates in women increase after menopause. The Women's Health Initiative found that postmenopausal hormone therapy (PHT) increased the risk of cardiovascular disease and that effects in diabetic women did not differ from those in women without diabetes. In this study, we hypothesized that PHT would have a worse effect on disease among women with AGT. METHODS AND RESULTS: We randomly assigned 423 postmenopausal women with angiographically defined atherosclerosis (321 women had exit angiograms) with (n=140) or without (n=181) AGT to receive estrogen, estrogen plus progestin, or a placebo for 2.8+/-0.9 years. LDL was lower and HDL and triglycerides were higher after PHT in non-AGT and AGT women, but more adverse changes occurred in C-reactive protein and fibrinogen in women with AGT (P=0.11 and P=0.02 for interactions). PHT had no effect on fasting glucose or insulin concentrations in women without AGT, but in women with AGT, fasting glucose levels, insulin concentration, and insulin resistance as assessed by the HOMA (homeostasis model) calculation decreased slightly (P=0.28, P=0.25, P=0.14 for interaction, respectively). Atherosclerotic progression was greater in women with AGT. Atherosclerotic progression in previously nondiseased segments was enhanced by PHT to a greater extent in women with AGT (P=0.11 for interaction). CONCLUSIONS: PHT is associated with a worsening of coronary atherosclerosis and exacerbation of the profile of inflammatory markers in women with AGT. Therefore, PHT is not warranted for use in diabetic women. Further study is needed to explore the improvement in insulin resistance and glycemia that appears to occur with PHT in women with AGT.