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OBJECTIVE: We examined longitudinal associations between emotional distress (specifically, depressive symptoms and diabetes distress) and medication adherence in Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), a large randomized controlled trial comparing four glucose-lowering medications added to metformin in adults with relatively recent-onset type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: The Emotional Distress Substudy assessed medication adherence, depressive symptoms, and diabetes distress in 1,739 GRADE participants via self-completed questionnaires administered biannually up to 3 years. We examined baseline depressive symptoms and diabetes distress as predictors of medication adherence over 36 months. Bidirectional visit-to-visit relationships were also examined. Treatment satisfaction, beliefs about medication, diabetes care self-efficacy, and perceived control over diabetes were evaluated as mediators of longitudinal associations. RESULTS: At baseline, mean ± SD age of participants (56% of whom were White, 17% Hispanic/Latino, 18% Black, and 66% male) was 58.0 ± 10.2 years, diabetes duration 4.2 ± 2.8 years, HbA1c 7.5% ± 0.5%, and medication adherence 89.9% ± 11.1%. Higher baseline depressive symptoms and diabetes distress were independently associated with lower adherence over 36 months (P < 0.001). Higher depressive symptoms and diabetes distress at one visit predicted lower adherence at the subsequent 6-month visit (P < 0.0001) but not vice versa. Treatment assignment did not moderate relationships. Patient-reported concerns about diabetes medications mediated the largest percentage (11.9%–15.5%) of the longitudinal link between emotional distress and adherence. CONCLUSIONS: Depressive symptoms and diabetes distress both predict lower adherence to glucose-lowering medications over time among adults with T2DM. Addressing emotional distress and concerns about anticipated negative effects of taking these treatments may be important to support diabetes treatment adherence. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To describe rescue insulin use and associated factors in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). RESEARCH DESIGN AND METHODS: GRADE participants (type 2 diabetes duration <10 years, baseline A1C 6.8%–8.5% on metformin monotherapy, N = 5,047) were randomly assigned to insulin glargine U-100, glimepiride, liraglutide, or sitagliptin and followed quarterly for a mean of 5 years. Rescue insulin (glargine or aspart) was to be started within 6 weeks of A1C >7.5%, confirmed. Reasons for delaying rescue insulin were reported by staff-completed survey. RESULTS: Nearly one-half of GRADE participants (N = 2,387 [47.3%]) met the threshold for rescue insulin. Among participants assigned to glimepiride, liraglutide, or sitagliptin, rescue glargine was added by 69% (39% within 6 weeks). Rescue aspart was added by 44% of glargine-assigned participants (19% within 6 weeks) and by 30% of non-glargine-assigned participants (14% within 6 weeks). Higher A1C values were associated with adding rescue insulin. Intention to change health behaviors (diet/lifestyle, adherence to current treatment) and not wanting to take insulin were among the most common reasons reported for not adding rescue insulin within 6 weeks. CONCLUSIONS: Proportionately, rescue glargine, when required, was more often used than rescue aspart, and higher A1C values were associated with greater rescue insulin use. Wanting to use noninsulin strategies to improve glycemia was commonly reported, although multiple factors likely contributed to not using rescue insulin. These findings highlight the persistent challenge of intensifying type 2 diabetes treatment with insulin, even in a clinical trial. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Differences in type 2 diabetes phenotype by age are described, but it is not known whether these differences are seen in a more uniformly defined adult population at a common early stage of care. We sought to characterize age-related clinical and metabolic characteristics of adults with type 2 diabetes on metformin monotherapy, prior to treatment intensification. RESEARCH DESIGN AND METHODS: In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), participants were enrolled who had type 2 diabetes duration <10 years, had HbA1c 6.8–8.5%, and were on metformin monotherapy. Participants were randomly assigned to one of four additional glucose-lowering medications. We compared baseline clinical and metabolic characteristics across age categories (<45, 45 to <55, 55 to <65, and ≥65 years) using ANOVA and Pearson χ2 tests. RESULTS: Within the GRADE cohort (n = 5,047), we observed significant differences by age, with younger adults having greater racial diversity, fewer medications for common comorbidities, lower prevalence of CVD, higher weight and BMI, and more pronounced hyperglycemia and diabetic dyslipidemia and with metabolic profile indicating lower insulin sensitivity (inverse fasting insulin [1/(fasting insulin)], HOMA of steady-state insulin sensitivity, Matsuda index) and inadequate β-cell response (oral disposition index) (P < 0.05 across age categories). CONCLUSIONS: Clinical and metabolic characteristics of type 2 diabetes differ by age within the GRADE cohort. Younger adults exhibit more prominent obesity-related characteristics, including higher obesity levels and lower insulin sensitivity and β-cell compensation. Given the increasing burden of type 2 diabetes and complications, particularly among younger populations, these age-related distinctions may inform risk factor management approaches and treatment priorities. Further study will determine whether age-related differences impact response to therapy. [ABSTRACT FROM AUTHOR]

Background: We compared HbA1c values obtained from capillary blood collection kits versus venous whole blood collections in study participants with type 1 or type 2 diabetes. Methods: A total of 122 subjects, 64 with type 2 diabetes participating in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study and 58 with type 1 diabetes from the Epidemiology of Diabetes Interventions and Complications (EDIC) Study, participated in the validation study. Capillary tubes were filled by fingerstick by the participants on the same day as the collection of venous whole blood samples in EDTA-containing test tubes and were mailed to the central laboratory. HbA1c in all samples was measured with the same high-performance liquid chromatography. GRADE participants also completed a questionnaire on the ease of performing capillary collections. Results: Participants from 22 clinical centers (GRADE n = 5, EDIC n = 17) were between 35 and 86 years of age, with 52% male and diverse race/ethnicities. Venous HbA1c results ranged between 5.4–11.9% (35.5–106.6 mmol/mol) with corresponding capillary results ranging between 4.2–11.9% (22.4–106.6 mmol/mol). The venous and capillary results were highly correlated (R2 = 0.993) and 96.7% differed by ≤0.2% (2.2 mmol/mol). Of participants surveyed, 69% indicated that the instructions and collection were easy to follow and 97% felt the collection method would be easy to do at home. Conclusions: The capillary blood HbA1c results compared well with the conventional venous whole blood results. The capillary kits can be employed in other studies to reduce interruption of critical data collection and potentially to augment clinical care when in-person visits are not possible. [ABSTRACT FROM AUTHOR]

Objective: GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) is a 36-center unmasked, parallel treatment group, randomized controlled trial evaluating four diabetes medications added to metformin in people with type 2 diabetes (T2DM). We report baseline characteristics and compare GRADE participants to a National Health and Nutrition Examination Survey (NHANES) cohort.Research Design and Methods: Participants were age ≥30 years at the time of diagnosis, with duration of T2DM <10 years, HbA1c 6.8-8.5% (51-69 mmol/mol), prescribed metformin monotherapy, and randomized to glimepiride, sitagliptin, liraglutide, or insulin glargine.Results: At baseline, GRADE's 5,047 randomized participants were 57.2 ± 10.0 years of age, 63.6% male, with racial/ethnic breakdown of 65.7% white, 19.8% African American, 3.6% Asian, 2.7% Native American, 7.6% other or unknown, and 18.4% Hispanic/Latino. Duration of diabetes was 4.2 ± 2.8 years, with mean HbA1c of 7.5 ± 0.5% (58 ± 5.3 mmol/mol), BMI of 34.3 ± 6.8 kg/m2, and metformin dose of 1,944 ± 204 mg/day. Among the cohort, 67% reported a history of hypertension, 72% a history of hyperlipidemia, and 6.5% a history of heart attack or stroke. Applying GRADE inclusion criteria to NHANES indicates enrollment of a representative cohort with T2DM on metformin monotherapy (NHANES cohort average age, 57.9 years; mean HbA1c, 7.4% [57 mmol/mol]; BMI, 33.2 kg/m2; duration, 4.2 ± 2.5 years; and 7.2% with a history of cardiovascular disease).Conclusions: The GRADE cohort represents patients with T2DM treated with metformin requiring a second diabetes medication. GRADE will inform decisions about the clinical effectiveness of the addition of four classes of diabetes medications to metformin. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We evaluated whether adding basal insulin to metformin in adults with early type 2 diabetes mellitus (T2DM) would increase emotional distress relative to other treatments. RESEARCH DESIGN AND METHODS: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) of adults with T2DM of <10 years' duration, HbA1c 6.8–8.5%, and taking metformin monotherapy randomly assigned participants to add insulin glargine U-100, sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or the dipeptidyl peptidase 4 inhibitor sitagliptin. The Emotional Distress Substudy enrolled 1,739 GRADE participants (mean [SD] age 58.0 [10.2] years, 32% female, 56% non-Hispanic White, 18% non-Hispanic Black, 17% Hispanic) and assessed diabetes distress and depressive symptoms every 6 months. Analyses examined differences at 1 year and over the 3-year follow-up. RESULTS: Across treatments, diabetes distress (−0.24, P < 0.0001) and depressive symptoms (−0.67, P < 0.0001) decreased over 1 year. Diabetes distress was lower at 1 year for the glargine group than for the other groups combined (−0.10, P = 0.002). Diabetes distress was also lower for liraglutide than for glimepiride or sitagliptin (−0.10, P = 0.008). Over the 3-year follow-up, there were no significant group differences in total diabetes distress; interpersonal diabetes distress remained lower for those assigned to liraglutide. No significant differences were observed for depressive symptoms. CONCLUSIONS: Contrary to expectations, this randomized trial found no evidence for a deleterious effect of basal insulin on emotional distress. Glargine lowered diabetes distress modestly at 1 year rather than increasing it. Liraglutide also reduced diabetes distress at 1 year. Results can inform treatment decisions for adults with early T2DM. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate whether baseline levels of depressive symptoms and diabetes-specific distress are associated with glycemic control in Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), a large randomized controlled trial comparing the metabolic effects of four common glucose-lowering medications when combined with metformin in individuals with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: The primary and secondary outcomes were defined as an HbA1c value ≥7%, subsequently confirmed, and an HbA1c value >7.5%, subsequently confirmed, respectively. Separate Cox proportional hazards models assessed the association between baseline levels of each exposure of interest (depressive symptoms measured with the eight-item Patient Health Questionnaire and diabetes distress measured with the Diabetes Distress Scale) and the subsequent risk of metabolic outcomes. RESULTS: This substudy included 1,739 participants (56% of whom were non-Hispanic White, 18% non-Hispanic Black, 17% Hispanic, and 68% male; mean [SD] age 58.0 [10.2] years, diabetes duration 4.2 [2.8] years, and HbA1c 7.5% [0.48%]). A total of 1,157 participants reached the primary outcome, with time to event of 2.1 years on average, while 738 participants reached the secondary outcome at 3 years on average. With adjustment for sex, race/ethnicity, treatment group, baseline age, duration of T2DM, BMI, and HbA1c, there were no significant associations between the depressive symptoms or diabetes distress and the subsequent risk of the primary or secondary outcomes. CONCLUSIONS: The current findings suggest that, at least for individuals with diabetes of relatively short duration, baseline levels of emotional distress are not associated with glycemic control over time. [ABSTRACT FROM AUTHOR]

We examined emotional distress in relation to metformin adherence, overall diabetes self-management, and glycemic control among adults with early type 2 diabetes (T2DM) enrolled in the GRADE study. Linear regression models examined cross-sectional associations of baseline depression symptoms and diabetes distress with adherence to metformin, self-management, and HbA1c, adjusting for covariates. Cognitive-affective (e.g., sadness) and somatic (e.g., sleep/appetite disturbance) depression symptoms and diabetes distress subscales were also examined. This substudy of 1,739 GRADE participants (56 % Non-Hispanic White, 18 % Non-Hispanic Black, 17 % Hispanic, 68 % male, mean[SD] age = 57.96[10.22] years, diabetes duration = 4.21[2.81] years, and HbA1c = 7.51[0.48]) found that the prevalence of clinically significant depression and diabetes distress was 8.7 % and 25 %, respectively. Fully adjusted models showed that depression symptoms were associated with lower self-management (p < 0.0001); this effect was only significant for somatic symptoms. Diabetes distress was associated with lower adherence (p = 0.0001) and self-management (p < 0.0001); effects were significant for all subscales, except physician-related distress. No significant relationships of total depression symptom severity or diabetes distress with HbA1c were found. Depression symptoms and diabetes distress were robustly associated with problematic diabetes self-management among participants in GRADE. These findings highlight the need for routine assessment of depression symptoms and diabetes distress early in T2DM care. [ABSTRACT FROM AUTHOR]

Objectives: The goal of this study was to determine the influence of gender on baseline characteristics, response to treatment, and prognosis in patients with heart failure (HF) and impaired left ventricular ejection fraction (LVEF).Background: Under-representation of women in HF clinical trials has limited our understanding of gender-related differences in patients with HF.Methods: The impact of gender was assessed in the Beta-Blocker Evaluation of Survival Trial (BEST) which randomized 2,708 patients with New York Heart Association class III/IV and LVEF ≤0.35 to bucindolol versus placebo. Women (n = 593) were compared with men (n = 2,115). Mean follow-up period was two years.Results: Significant differences in baseline clinical and laboratory characteristics were found. Women were younger, more likely to be black, had a higher prevalence of nonischemic etiology, higher right and left ventricular ejection fraction, higher heart rate, greater cardiothoracic ratio, higher prevalence of left bundle branch block, lower prevalence of atrial fibrillation, and lower plasma norepinephrine level. Ischemic etiology and measures of severity of HF were found to be predictors of prognosis in women and men. However, differences in the predictive values of various variables were noted; most notably, coronary artery disease and LVEF appear to be stronger predictors of prognosis in women. In the nonischemic patients, women had a significantly better survival rate compared with men.Conclusions: In HF patients with impaired LVEF, significant gender differences are present, and the prognostic predictive values of some variables vary in magnitude between women and men. The survival advantage of women is confined to patients with nonischemic etiology. [Copyright &y& Elsevier]

: ObjectivesThis was a retrospective analysis to determine the effect of diabetes on outcome in patients with advanced heart failure (HF), and to determine the effect of beta-blockade in patients with HF with and without diabetes mellitus.: BackgroundIn chronic HF the impact on clinical outcomes and therapeutic response of the prevalent comorbid condition diabetes mellitus has not been extensively investigated.: MethodsWe assessed the impact of diabetes on prognosis and effectiveness of beta-blocker therapy with bucindolol in patients with HF enrolled in the Beta-Blocker Evaluation of Survival Trial (BEST). We conducted a retrospective analysis to examine the prognosis of patients with advanced HF with and without diabetes, and the effect of beta-blocker therapy on mortality and HF progression or myocardial infarction (MI). The database was the 2,708 patients with advanced HF (36% with diabetes and 64% without diabetes) who were randomized to the beta-blocker bucindolol or placebo in BEST and followed for mortality, hospitalization, and MI for an average of two years.: ResultsPatients with diabetes had more severe chronic HF and more coronary risk factors than patients without diabetes. Diabetes was independently associated with increased mortality in patients with ischemic cardiomyopathy (adjusted hazard ratio 1.33, 95% confidence interval 1.12 to 1.58, p = 0.001), but not in those with a nonischemic etiology (adjusted hazard ratio 0.98, 95% confidence interval 0.74 to 1.30, p = 0.89). Compared with patients without diabetes, in diabetic patients beta-blocker therapy was at least as effective in reducing death or HF hospitalizations, total hospitalizations, HF hospitalizations, and MI. Ventricular function and physiologic responses to beta-blockade were similar in patients with and without diabetes.: ConclusionsDiabetes worsens prognosis in patients with advanced HF, but this worsening appears to be limited to patients with ischemic cardiomyopathy. In advanced HF beta-blockade is effective in reducing major clinical end points in patients with and without diabetes. [Copyright &y& Elsevier]

The mapping and sequencing of the human genome promises rapid growth in understanding the genetically influenced mechanisms that underlie human disease. To realize this promise fully, it is necessary to relate genetic information to clinical phenotypes. Genetic tissue banking in clinical studies provides opportunities to analyze the genetic contribution to variation in response to treatments. The challenges to progress are likely to come from the complex organizational, social, political, and ethical issues that must be resolved in order to put clinical and DNA bank information together. Concerns about subjects'' rights, informed consent, privacy, and ownership of genetic material require attention in the development of DNA banks. In this paper we describe one approach to the solution of these problems that was adopted by one clinical trials group, the Department of Veterans Affairs Cooperative Studies Program. [Copyright &y& Elsevier]

Emotional distress, including depression and diabetes-specific distress (e.g., feeling overwhelmed by living with diabetes, feelings of failure related to diabetes self-care), is a significant and prevalent problem for patients with type 2 diabetes. Both depression and diabetes distress have been associated with metabolic/glycemic control, diabetes complications, mortality, and quality of life. Recent findings further suggest that risk for emotional distress is influenced by diabetes treatment. The GRADE Study (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) is generating prospective data that will provide a unique opportunity to examine the relationships between emotional distress, diabetes treatment, and outcomes in an experimental design. The GRADE study is a randomized clinical trial that will compare the metabolic effects of four common anti-hyperglycemic drugs when combined with metformin. This sub-study recruited a subset (n = 1739) of GRADE participants and will examine patient-level variation in baseline emotional distress as a predictor of glycemic control and other health outcomes, independent of treatment effects. The study will also provide an experimental examination of treatment regimen effects on emotional distress over time as part of the overall evaluation of comparative effectiveness. Evaluation of emotional distress using validated measures will allow us to disentangle the roles of depressive symptoms and diabetes distress, factors that share significant overlap but require distinct approaches to screening and treatment. Study findings may directly influence practice decisions regarding screening and treatment for emotional distress as part of diabetes care. ClinicalTrials.gov Identifier: NCT01794143 [ABSTRACT FROM AUTHOR]

Background: GRADE enrolled 5,047 adults > 30 years, T2DM < 10 years duration, on metformin, requiring a second medication, A1C 6.8-8.5%. Age-related differences in disease phenotype may affect responses to the randomized treatments being evaluated. Objective: To evaluate whether baseline characteristics differed by age. Methods: Baseline characteristics were compared across age groups, using mean ± SD (ANOVA) or % (Pearson's chi-square). We report nominal, unadjusted p-values. Results: With the defined inclusion criteria, we enrolled a cohort with overall DM duration 4.2 ± 2.8 years, and A1c 7.5 ± 0.5%. Within this cohort, distinct clinical phenotypes by age were present. Across the age groups, older individuals had more CVD, and were on more medications for DM-related comorbidities. Younger individuals were more diverse, had higher weight, FPG, and insulin, more pronounced diabetic dyslipidemia, and were taking fewer medications for comorbidities (Table). Conclusion: Within the GRADE cohort defined by inclusion criteria representing a specific stage of glycemia, the clinical phenotype of T2DM differed by age, with older participants having greater prevalent comorbidity and younger participants having more prominent hyperglycemia and higher weight. An understanding of the distinct phenotypes by age may identify priorities and gaps in clinical care. Disclosure: V.R. Aroda: Consultant; Self; ADOCIA, AstraZeneca, Becton, Dickinson and Company, Novo Nordisk Inc., Sanofi, Zafgen, Inc. Employee; Spouse/Partner; Merck & Co., Inc. Research Support; Self; AstraZeneca, Calibra Medical, Eisai Inc., Janssen Research & Development, Novo Nordisk Inc., Sanofi, Theracos, Inc. H. Krause-Steinrauf: None. J.B. Buse: Consultant; Self; Neurimmune AG. Research Support; Self; AstraZeneca, National Center for Advancing Translational Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk A/S, Sanofi, vTv Therapeutics. Stock/Shareholder; Self; Mellitus Health, PhaseBio Pharmaceuticals, Inc., Stability Health. Other Relationship; Self; ADOCIA, AstraZeneca, Dance Biopharm Holdings Inc., Eli Lilly and Company, MannKind Corporation, NovaTarg, Novo Nordisk A/S, Senseonics, vTv Therapeutics, Zafgen, Inc. B.I. Gulanski: None. H. Florez: None. A.J. Ahmann: Advisory Panel; Self; Eli Lilly and Company, MannKind Corporation, Novo Nordisk Inc., Sanofi-Aventis. Consultant; Self; Dexcom, Inc. Research Support; Self; Dexcom, Inc., Medtronic. A. Loveland: None. A. Kuhn: None. J. Lonier: None. K.J. Mather: Advisory Panel; Self; Roche Diabetes Care. Research Support; Self; Abbott, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. D.J. Wexler: Other Relationship; Spouse/Partner; APOLO1BIO. Funding: National Institute of Diabetes and Digestive and Kidney Diseases [ABSTRACT FROM AUTHOR]

Based on self-report in the GRADE diabetes study, cumulative incidence of retinopathy was low over 5 years (3.7 %; 184 of 4098 participants) and did not differ among the 4 treatment groups (glargine 4.0 %, glimepiride 3.2 %, liraglutide 3.7 %, sitagliptin 3.8 %). There were no differences in retinopathy with specific therapies in GRADE. Clinicaltrials.gov identifier: NCT01794143 [Display omitted] • Retinopathy is linked to T2DM duration, glycemic control, and other risk factors. • Retinopathy over a 5-year period in people with T2DM < 10 years is reported. • Low prevalence and incidence of diabetes-related retinopathy no matter the treatment [ABSTRACT FROM AUTHOR]

OBJECTIVE: We report mortality outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) among people with type 2 diabetes diagnosed within 10 years and no recent history of cardiovascular events or cancer. RESEARCH DESIGN AND METHODS: Overall mortality rates and major causes of death were assessed over an average of 5 years of follow-up. Cause of death was adjudicated centrally by a committee masked to treatment assignment. We examined baseline covariates and the 10-year Framingham Risk Score for associations. RESULTS: Mortality rate was low (0.59 per 100 participant-years). Participants who died during follow-up were likely to be older, be male, have a history of hypertension, have a history of smoking, and have moderate albuminuria. The two most common underlying causes of death were "cardiovascular-cause" (a composite of underlying causes) (38.6%) and cancer (26.8%). There were no differences by treatment group. CONCLUSIONS: Among people with diabetes of relatively short duration, cause of death was varied. Attention to health risks beyond cardiovascular diseases is warranted. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes. The effects of glucose-lowering medications on cardiovascular outcomes in individuals with type 2 diabetes and low cardiovascular risk are unclear. We investigated cardiovascular outcomes by treatment group in participants randomly assigned to insulin glargine, glimepiride, liraglutide, or sitagliptin, added to baseline metformin, in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study). METHODS: A total of 5047 participants with a mean±SD age of 57.2±10.0 years, type 2 diabetes duration of 4.0±2.7 years, and low baseline prevalence of cardiovascular disease (myocardial infarction, 5.1%; cerebrovascular accident, 2.0%) were followed for a median of 5 years. Prespecified outcomes included between-group time-to-first event analyses of MACE-3 (composite of major adverse cardiovascular events: cardiovascular death, myocardial infarction, and stroke), MACE-4 (MACE-3+unstable angina requiring hospitalization or revascularization), MACE-5 (MACE-4+coronary revascularization), MACE-6 (MACE-5+hospitalization for heart failure), and the individual components. MACE outcomes and hospitalization for heart failure in the liraglutide-treated group were compared with the other groups combined using Cox proportional hazards models. MACE-6 was also analyzed as recurrent events using a proportional rate model to compare all treatment groups. RESULTS: We observed no statistically significant differences in the cumulative incidence of first MACE-3, MACE-4, MACE-5, or MACE-6, or their individual components, by randomized treatment group. However, when compared with the other treatment groups combined, the liraglutide-treated group had a significantly lower risk of MACE-5 (adjusted hazard ratio, 0.70 [95% CI, 0.54-0.91]; P=0.021), MACE-6 (adjusted hazard ratio, 0.70 [95% CI, 0.55-0.90]; P=0.021), and hospitalization for heart failure (adjusted hazard ratio, 0.49 [95% CI, 0.28--0.86]; P=0.022). Compared with the liraglutide group, significantly higher rates of recurrent MACE-6 events occurred in the groups treated with glimepiride (rate ratio, 1.61 [95% CI, 1.13-2.29]) or sitagliptin (rate ratio 1.75; [95% CI, 1.24-2.48]). CONCLUSIONS: This comparative effectiveness study of a contemporary cohort of adults with type 2 diabetes, largely without established cardiovascular disease, suggests that liraglutide treatment may reduce the risk of cardiovascular events in patients at relatively low risk compared with other commonly used glucose-lowering medications. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794143. [ABSTRACT FROM AUTHOR]

People with type 2 diabetes (T2DM) have an increased risk of cardiovascular disease (CVD). We examined depressive symptoms (DS) and diabetes distress (DD) in relation to the estimated 10-year risk of CVD in adults with T2DM enrolled in the GRADE Emotional Distress Substudy. Linear regression models examined the associations of baseline DS and DD with estimated 10-year risk of CVD using the Atherosclerotic Cardiovascular Disease (ASCVD) risk score, adjusting for age, sex, race/ethnicity, education, income, diabetes duration, diabetes-related complications, and HbA1c. A total of 1,605 GRADE participants were included: 54% Non-Latino (NL) White, 18% Latino, 19% NL-Black, 66% male, mean age 57.5 (SD = 10.25) years, diabetes duration 4.2 (SD = 2.8) years, and HbA1c 7.5% (SD = 0.5%). After incorporating covariates, only DS, especially cognitive-affective symptoms, were associated with ASCVD risk (estimate = 0.15 [95% CI: 0.04, 0.025], p = 0.006). Higher DS remained significantly associated with higher ASCVD risk when adding DD to covariates (estimate = 0.19 [95% CI: 0.07, 0.30], p = 0.002). DD was not associated with ASCVD risk when accounting for covariates. Depressive symptoms, particularly cognitive-affective symptoms, are associated with increased 10-year predicted ASCVD risk among adults with early T2DM. Diabetes distress is not significantly associated with the predicted ASCVD risk when accounting for covariates. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about a study on the use of spironolactone or placebo with a beta-blocker in patients with advanced heart failure.

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.). [ABSTRACT FROM AUTHOR]

Background: The comparative effectiveness of glucose-lowering medications for use with metformin to maintain target glycated hemoglobin levels in persons with type 2 diabetes is uncertain.Methods: In this trial involving participants with type 2 diabetes of less than 10 years' duration who were receiving metformin and had glycated hemoglobin levels of 6.8 to 8.5%, we compared the effectiveness of four commonly used glucose-lowering medications. We randomly assigned participants to receive insulin glargine U-100 (hereafter, glargine), the sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or sitagliptin, a dipeptidyl peptidase 4 inhibitor. The primary metabolic outcome was a glycated hemoglobin level, measured quarterly, of 7.0% or higher that was subsequently confirmed, and the secondary metabolic outcome was a confirmed glycated hemoglobin level greater than 7.5%.Results: A total of 5047 participants (19.8% Black and 18.6% Hispanic or Latinx) who had received metformin for type 2 diabetes were followed for a mean of 5.0 years. The cumulative incidence of a glycated hemoglobin level of 7.0% or higher (the primary metabolic outcome) differed significantly among the four groups (P<0.001 for a global test of differences across groups); the rates with glargine (26.5 per 100 participant-years) and liraglutide (26.1) were similar and lower than those with glimepiride (30.4) and sitagliptin (38.1). The differences among the groups with respect to a glycated hemoglobin level greater than 7.5% (the secondary outcome) paralleled those of the primary outcome. There were no material differences with respect to the primary outcome across prespecified subgroups defined according to sex, age, or race or ethnic group; however, among participants with higher baseline glycated hemoglobin levels there appeared to be an even greater benefit with glargine, liraglutide, and glimepiride than with sitagliptin. Severe hypoglycemia was rare but significantly more frequent with glimepiride (in 2.2% of the participants) than with glargine (1.3%), liraglutide (1.0%), or sitagliptin (0.7%). Participants who received liraglutide reported more frequent gastrointestinal side effects and lost more weight than those in the other treatment groups.Conclusions: All four medications, when added to metformin, decreased glycated hemoglobin levels. However, glargine and liraglutide were significantly, albeit modestly, more effective in achieving and maintaining target glycated hemoglobin levels. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.). [ABSTRACT FROM AUTHOR]

OBJECTIVE-The TrialNet Study Group evaluated rituximab, a B-cell-depleting monoclonal antibody, for its effect in new-onset patients with type 1A diabetes. Rituximab decreased the loss of C-peptide over the first year of follow-up and markedly depleted B lymphocytes for 6 months after administration. This article analyzes the specific effect of rituximab on multiple islet autoantibodies. RESEARCH DESIGN AND METHODS-A total of 87 patients between the ages of 8 and 40 years received either rituximab or a placebo infusion weekly for four doses close to the onset of diabetes. Autoantibodies to insulin (IAAs), GAD65 (GADAs), insulinoma-associated protein 2 (IA2As), and ZnT8 (ZnT8As) were measured with radioimmunoassays. The primary outcome for this autoantibody analysis was the mean level of autoantibodies during follow-up. RESULTS-Rituximab markedly suppressed IAAs compared with the placebo injection but had a much smaller effect on GADAs, IA2As, and ZnT8As. A total of 40% (19 of 48) of rituximab-treated patients who were IAA positive became IAA negative versus 0 of 29 placebo-treated patients (P , 0.0001). In the subgroup (n = 6) treated within 50 days of diabetes, IAAs were markedly suppressed by rituximab in all patients for 1 year and for four patients as long as 3 years despite continuing insulin therapy. Independent of rituximab treatment, the mean level of IAAs at study entry was markedly lower (P = 0.035) for patients who maintained C-peptide levels during the first year of follow-up in both rituximab-treated and placebo groups. CONCLUSIONS-A single course of rituximab differentially suppresses IAAs, clearly blocking IAAs for .1 year in insulin-treated patients. For the patients receiving insulin for .2 weeks prior to rituximab administration, we cannot assess whether rituximab not only blocks the acquisition of insulin antibodies induced by insulin administration and/or also suppresses preformed insulin autoantibodies. Studies in prediabetic non-insulin-treated patients will likely be needed to evaluate the specific effects of rituximab on levels of IAAs. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- This trial tested whether mycophenolate mofetil (MMF) alone or with daclizumab (DZB) could arrest the loss of insulin-producing β-cells in subjects with new-onset type 1 diabetes. RESEARCH DESIGN AND METHODS--A multi-center, randomized, placebo-controlled, double-masked trial was initiated by Type 1 Diabetes TrialNet at 13 sites in North America and Europe. Subjects diagnosed with type 1 diabetes and with sufficient C-peptide within 3 months of diagnosis were randomized to either MMF alone, MMF plus DZB, or placebo, and then followed for 2 years. The primary outcome was the geometric mean area under the curve (AUC) C-peptide from the 2-h mixed meal tolerance test. RESULTS -- One hundred and twenty-six subjects were randomized and treated during the trial. The geometric mean C-peptide AUC at 2 years was unaffected by MMF alone or MMF plus DZB versus placebo. Adverse events were more frequent in the active therapy groups relative to the control group, but not significantly. CONCLUSIONS -- Neither MMF alone nor MMF in combination with DZB had an effect on the loss of C-peptide in subjects with new-onset type 1 diabetes. Higher doses or more targeted immunotherapies may he needed to affect the autoimmune process. [ABSTRACT FROM AUTHOR]

Background: The immunopathogenesis of type 1 diabetes mellitus is associated with T-lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte–mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes. Methods: We conducted a randomized, double-blind study in which 87 patients between 8 and 40 years of age who had newly diagnosed type 1 diabetes were assigned to receive infusions of rituximab or placebo on days 1, 8, 15, and 22 of the study. The primary outcome, assessed 1 year after the first infusion, was the geometric mean area under the curve (AUC) for the serum C-peptide level during the first 2 hours of a mixed-meal tolerance test. Secondary outcomes included safety and changes in the glycated hemoglobin level and insulin dose. Results: At 1 year, the mean AUC for the level of C peptide was significantly higher in the rituximab group than in the placebo group. The rituximab group also had significantly lower levels of glycated hemoglobin and required less insulin. Between 3 months and 12 months, the rate of decline in C-peptide levels in the rituximab group was significantly less than that in the placebo group. CD19+ B lymphocytes were depleted in patients in the rituximab group, but levels increased to 69% of baseline values at 12 months. More patients in the rituximab group than in the placebo group had adverse events, mostly grade 1 or grade 2, after the first infusion. The reactions appeared to be minimal with subsequent infusions. There was no increase in infections or neutropenia with rituximab. Conclusions: A four-dose course of rituximab partially preserved beta-cell function over a period of 1 year in patients with type 1 diabetes. The finding that B lymphocytes contribute to the pathogenesis of type 1 diabetes may open a new pathway for exploration in the treatment of patients with this condition. (ClinicalTrials.gov number, NCT00279305.) N Engl J Med 2009;361:2143-52. [ABSTRACT FROM AUTHOR]

: ObjectivesWe sought to determine whether hormone replacement therapy (HRT) is associated with an improved prognosis in women with advanced heart failure (HF) and systolic dysfunction.: BackgroundThere are about two million postmenopausal women in the U.S. with HF. However, limited data are available to assess the effects of HRT on survival in this large group of patients.: MethodsA retrospective analysis of women age 50 years and over entered into the Beta-Blocker Evaluation of Survival Trial (BEST) was conducted using Cox regression analysis comparing survival in HRT users and non-users after correcting for baseline variables known to predict survival in women with HF and systolic dysfunction.: ResultsIn 493 women age 50 years and older, HRT was associated with a significant reduction in mortality—21% mortality in HRT users and 34% in non-users (p = 0.025). Multivariate analysis demonstrated a hazard ratio for mortality of 0.6 (95% confidence interval = 0.36 to 0.97) (p = 0.039) for HRT users. The benefits of HRT were noted only in women with a nonischemic etiology of HF (n = 237).: ConclusionsHormone replacement therapy is associated with a marked improvement in survival in postmenopausal women with advanced HF. A prospective, randomized trial of HRT should be performed in this large group of patients. [Copyright &y& Elsevier]

Objective: Type 2 diabetes is a risk factor for cognitive impairment. We examined the relation of glycemia, lipids, blood pressure (BP), hypertension history, and statin use with cognition in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).Research Design and Methods: Cross-sectional analyses from GRADE at baseline examined the association of glycemia (hemoglobin A1c [HbA1c]), LDL, systolic BP (SBP) and diastolic BP (DBP), hypertension history, and statin use with cognition assessed by the Spanish English Verbal Learning Test, letter and animal fluency tests, and Digit Symbol Substitution Test (DSST).Results: Among 5,047 GRADE participants, 5,018 (99.4%) completed cognitive assessments. Their mean age was 56.7 ± 10.0 years, and 36.4% were women. Mean diabetes duration was 4.0 ± 2.7 years. HbA1c was not related to cognition. Higher LDL was related to modestly worse DSST scores, whereas statin use was related to modestly better DSST scores. SBP between 120 and 139 mmHg and DBP between 80 and 89 mmHg were related to modestly better DSST scores. Hypertension history was not related to cognition.Conclusions: In people with type 2 diabetes of a mean duration of <5 years, lower LDL and statin use were related to modestly better executive cognitive function. SBP levels in the range of 120-139 mmHg and DBP levels in the range of 80-89 mmHg, but not lower levels, were related to modestly better executive function. These differences may not be clinically significant. [ABSTRACT FROM AUTHOR]

Background: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) study has enrolled a racially and ethnically diverse population with type 2 diabetes, performed extensive phenotyping, and randomly assigned the participants to one of four second-line diabetes medications. The continuous glucose monitoring (CGM) substudy has been added to determine whether there are racial/ethnic differences in the relationship between average glucose (AG) and hemoglobin A1c (HbA1c). CGM will also be used to compare time in target range, glucose variability, and the frequency and duration of hypoglycemia across study groups. Methods: The observational CGM substudy will enroll up to 1800 of the 5047 GRADE study participants from the four treatment groups, including as many as 450 participants from each of 4 racial/ethnic minority groups to be compared: Hispanic White, non-Hispanic White, non-Hispanic African American, and non-Hispanic Other. CGM will be performed for 2 weeks in proximity to a GRADE annual visit, during which an oral glucose tolerance test will be performed and HbA1c and glycated albumin measured. Indicators of interindividual variation in red blood cell turnover, based on specialized erythrocyte measurements, will also be measured to explore the potential causes of interindividual HbA1c variations. Conclusions: The GRADE CGM substudy will provide new insights into whether differences exist in the relationship between HbA1c and AG among different racial/ethnic groups and whether glycemic profiles differ among frequently used diabetes medications and their potential clinical implications. Understanding such differences is important for clinical care and adjustment of diabetes medications in patients of different races or ethnicities. [ABSTRACT FROM AUTHOR]

Background and purpose The National Diabetes Education Program created the 4 Steps to Manage Your Diabetes for Life ( 4 Steps) booklet to help patients with diabetes learn the basics of self-management and care recommendations. The purpose of this study is to explore the impact of 4 Steps on participants' diabetes management knowledge and self-efficacy in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). Methods A sample of 348 adults with type 2 diabetes enrolled in GRADE was included in this analysis. Participants took a pretest, were sent home with 4 Steps, then took a posttest at their next visit. The Wilcoxon signed rank test was used to detect differences in knowledge and self-efficacy between scale scores pre- and posttest. Conclusions Analyses revealed increases in participants' diabetes management knowledge ( p < .001) and self-efficacy ( p < .001) from pre- to posttest. Participants who reported no formal previous diabetes education showed a statistically significant increase in knowledge scores compared to those with previous diabetes education ( p < .05). Implications for practice Appropriate, relevant diabetes education materials may improve self-management knowledge and self-efficacy among adults with type 2 diabetes. Providers should feel confident using 4 Steps as a resource for clinical practice. [ABSTRACT FROM AUTHOR]

A correction for the article "Rationale and Design of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE)" is presented, which is published in the previous issue of the periodical.

OBJECTIVE--The epidemic of type 2 diabetes (T2DM) threatens to become the major public health problem of this century. However, a comprehensive comparison of the long-term effects of medications to treat T2DM has not been conducted. GRADE, a pragmatic, unmasked clinical trial, aims to compare commonly used diabetes medications, when combined with metformin, on glycemia-lowering effectiveness and patient-centered outcomes. RESEARCH DESIGN AND METHODS--GRADE was designed with support from a U34 planning grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The consensus protocol was approved by NIDDK and the GRADE Research Group. Eligibility criteria for the 5,000 metformin-treated subjects include <5 years' diabetes duration, ≤30 years of age at time of diagnosis, and baseline hemoglobin A1c (A1C) of 6.8-8.5% (51-69 mmol/mol). Medications representing four classes (sulfonylureas, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, and insulin) will be randomly assigned and added to metformin (minimum-maximum 1,000-2,000 mg/day). The primary metabolic outcome is the time to primary failure defined as an A1C≥7% (53 mmol/mol), subsequently confirmed over an anticipated mean observation period of 4.8 years (range 4-7 years). Other long-term metabolic outcomes include the need for the addition of basal insulin after a confirmed A1C>7.5% (58 mmol/mol) and, ultimately, the need to implement an intensive basal/bolus insulin regimen. The four drugs will also be compared with respect to selected microvascular complications, cardio-vascular disease risk factors, adverse effects, tolerability, quality of life, and cost-effectiveness. CONCLUSIONS--GRADE will compare the long-term effectiveness of major glycemia-lowering medications and provide guidance to clinicians about the most appropriate medications to treat T2DM. GRADE begins recruitment at 37 centers in the U.S. in 2013. [ABSTRACT FROM AUTHOR]

The use of mycophenolate mofetil with or without daclizumab was generally safe in treatment of early onset type 1 diabetes. Epstein-Barr virus reactivations were equally common across treatment groups, but cumulative viral burdens tended to be higher in subjects receiving double-active versus double-placebo treatment.Background. We assessed the morbidity of herpesviruses in patients with type 1 diabetes mellitus (T1D) enrolled in immunosuppressive treatment studies.Methods. Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella zoster virus (VZV) infections were monitored in 126 participants of a randomized, double-blind, placebo-controlled study of daclizumab (DZB) and mycophenolate mofetil (MMF) including DZB+MMF+, DZB−MMF+, DZB+MMF−, and DZB−MMF−. During the 2-year follow-up, herpesviral infections were monitored clinically, by serology and blood DNA polymerase chain reaction.Results. Among 57 baseline EBV-seronegative participants, 9 developed EBV primary infections, including 2 with infectious mononucleosis syndrome. There were no appreciable differences in the course of the primary EBV infections across treatment groups. Among 69 baseline EBV-seropositive participants, 22 had virologic reactivations, including 1 symptomatic DZB−MMF+ subject. Compared with 7 DZB–MMF– EBV reactivators, the 9 DZB+MMF+ reactivators tended to have more prolonged viremia (11.4 vs 4.4 months; P = .06) and higher cumulative viral burden (14.2 vs 12.5 log EBV copies/mL; P = .06). Four of 85 baseline CMV-seronegative subjects developed asymptomatic primary CMV infections. There were no CMV reactivations. Of 30 baseline HSV-seropositive subjects, 8 developed ≥1 episode of herpes labialis; 1 subject had a primary HSV infection; and 1 subject without baseline serology information had a new diagnosis of genital HSV. There were no significant differences in the incidence of HSV recurrences across treatment groups. Of 100 baseline VZV-seropositive subjects, 1 DZB–MMF– subject developed herpes zoster and 1 DZB−MMF+ subject had Bell's palsy possibly related to VZV.Conclusions. The use of DZB alone or in combination with MMF was not associated with increased morbidity due to herpesviruses.Clinical Trials Registration. NCT00100178. [ABSTRACT FROM PUBLISHER]

Interpretation of clinical trials to alter the decline in β-cell function after diagnosis of type 1 diabetes depends on a robust understanding of the natural history of disease. Combining data from the Type 1 Diabetes TrialNet studies, we describe the natural history of β-cell function from shortly after diagnosis through 2 years post study randomization, assess the degree of variability between patients, and investigate factors that may be related to C-peptide preservation or loss. We found that 93% of individuals have detectable C-peptide 2 years from diagnosis. In 11% of subjects, there was no significant fall from baseline by 2 years. There was a biphasic decline in C-peptide; the C-peptide slope was -0.0245 pmol/mL/month (95% CI -0.0271 to -0.0215) through the first 12 months and -0.0079 (-0.0113 to -0.0050) from 12 to 24 months (P < 0.001). This pattern of fall in C-peptide over time has implications for understanding trial results in which effects of therapy are most pronounced early and raises the possibility that there are time-dependent differences in pathophysiology. The robust data on the C-peptide obtained under clinical trial conditions should be used in planning and interpretation of clinical trials. [ABSTRACT FROM AUTHOR]

Type 1 diabetes mellitus is believed to be due to the autoimmune destruction of β-cells by T lymphocytes, but a single course of rituximab, a monoclonal anti-CD20 B lymphocyte Ab, can attenuate C-peptide loss over the first year of disease. The effects of B cell depletion on disease-associated T cell responses have not been studied. We compare changes in lymphocyte subsets, T cell proliferative responses to disease-associated target Ags, and C-peptide levels of participants who did (responders) or did not (nonresponders) show signs of β-cell preservation 1 y after rituximab therapy in a placebo-controlled TrialNet trial. Rituximab decreased B lymphocyte levels after four weekly doses of mAb. T cell proliferative responses to diabetes-associated Ags were present at baseline in 75% of anti-CD20- and 82% of placebo-treated subjects and were not different over time. However, in rituximab-treated subjects with significant C-peptide preservation at 6 mo (58%), the proliferative responses to diabetes-associated total (p = 0.032), islet-specific (p = 0.048), and neuronal autoantigens (p = 0.005) increased over the 12-mo observation period. This relationship was not seen in placebo-treated patients. We conclude that in patients with type I diabetes meilitus, anti-B cell mAb causes increased proliferative responses to diabetes Ags and attenuated β-cell loss. The way in which these responses affect the disease course remains unknown. [ABSTRACT FROM AUTHOR]

Sosenko JM, Mahon J, Rafkin L, Lachin JM, Krause-Steinrauf H, Krischer JP, Cuthbertson D, Palmer JP, Thompson C, Greenbaum CJ, Skyler JS, the Diabetes Prevention Trial-Type 1 and TrialNet Study Groups. A comparison of the baseline metabolic profiles between Diabetes Prevention Trial-Type 1 and TrialNet Natural History Study participants. Objective: We assessed whether differing autoantibody screening criteria for type 1 diabetes (T1D) prevention trials result in different baseline metabolic profiles of those who screen positive. Methods: Diabetes Prevention Trial-Type 1 (DPT-1) participants were screened for islet cell autoantibodies, whereas TrialNet Natural History Study (TNNHS) participants were screened for biochemical autoantibodies. In both studies, those determined to be autoantibody positive underwent baseline oral glucose tolerance tests (OGTTs) in which glucose and C-peptide were measured. Results: The percentage of those with an OGTT in the diabetic range was higher among the DPT-1 participants (10.0% of 956 vs. 6.4% of 645, p < 0.01). In a logistic regression analysis with adjustments for age and gender, the difference persisted (p < 0.01). Among those in the non-diabetic range (n = 860 for DPT-1 and n = 604 for the TNNHS), glucose levels were similar at all time points, except for higher fasting glucose levels in the TNNHS participants (p < 0.001). There was a higher percentage of impaired fasting glucose (IFG) in the TNNHS participants (10.9 vs. 6.7%, p < 0.01); however, with adjustments for age and gender, there was no longer a significant difference. There was no significant difference in the percentages with impaired glucose tolerance. C-peptide levels were much lower in the DPT-1 cohort at all OGTT time points (p < 0.001 for all). Discussion: Differing criteria for autoantibody screening can result in marked differences in the baseline metabolic profiles of prospective participants of T1D prevention trials. [ABSTRACT FROM AUTHOR]

Objective: This trial tested whether mycophenolate mofetil (MMF) alone or with daclizumab (DZB) could arrest the loss of insulin-producing beta-cells in subjects with new-onset type 1 diabetes.Research Design and Methods: A multi-center, randomized, placebo-controlled, double-masked trial was initiated by Type 1 Diabetes TrialNet at 13 sites in North America and Europe. Subjects diagnosed with type 1 diabetes and with sufficient C-peptide within 3 months of diagnosis were randomized to either MMF alone, MMF plus DZB, or placebo, and then followed for 2 years. The primary outcome was the geometric mean area under the curve (AUC) C-peptide from the 2-h mixed meal tolerance test.Results: One hundred and twenty-six subjects were randomized and treated during the trial. The geometric mean C-peptide AUC at 2 years was unaffected by MMF alone or MMF plus DZB versus placebo. Adverse events were more frequent in the active therapy groups relative to the control group, but not significantly.Conclusions: Neither MMF alone nor MMF in combination with DZB had an effect on the loss of C-peptide in subjects with new-onset type 1 diabetes. Higher doses or more targeted immunotherapies may be needed to affect the autoimmune process. [ABSTRACT FROM AUTHOR]

Objectives: TrialNet’s goal to test preventions for type 1 diabetes has created an opportunity to gain new insights into the natural history of pre-type 1 diabetes. The TrialNet Natural History Study (NHS) will assess the predictive value of existing and novel risk markers for type 1 diabetes and will find subjects for prevention trials. Research design and methods: The NHS is a three-phase, prospective cohort study. In phase 1 (screening), pancreatic autoantibodies (glutamic acid decarboxylase, insulin, ICA-512, and islet cell antibodies) are measured. Phase 2 (baseline risk assessment) includes oral glucose tolerance tests (OGTTs) in antibody-positive subjects and estimation of 5-yr diabetes risks according to the OGTT and number of confirmed positive antibody tests. Phase 3 (follow-up risk assessments) requires OGTTs every 6 months. In phases 2 and 3, samples are collected for future tests of T-lymphocyte function, autoantibody isotypes, RNA gene expression, and proteomics. The primary outcome is diabetes onset. Results: Of 12 636 relatives screened between March 2004 and December 2006, 605 (4.8%) were positive for at least one biochemical antibody. Of these, 322 were confirmed antibody positive and completed phase 2, of whom 296 subjects were given preliminary 5-yr diabetes risks of <25% (n = 132), ≥25% (n = 36), and ≥50% (n = 128) where the latter two categories represent different subjects based on number of confirmed positive antibodies (2, ≥25%; 3 or more, ≥50%) and/or an abnormal OGTT (≥50%). Conclusions: The NHS is identifying potential prevention trial subjects and is assembling a large cohort that will provide new natural history information about pre-type 1 diabetes. Follow-up to diabetes will help establish the biological significance and clinical value of novel type 1 diabetes risk markers. [ABSTRACT FROM AUTHOR]

Aims: We evaluated differences in participants with type 2 diabetes (T2DM) enrolled in the GRADE study at VA vs non-VA sites, focusing on cardiovascular risk factors and rates of diabetes care target achievements.Methods: We compared baseline characteristics between participants at VA (n = 1216) and non-VA (n = 3831) sites, stratifying analyses by cardiovascular disease (CVD) history.Results: VA and non-VA participants had similar diabetes duration (4.0 years), HbA1c (7.5%), and BMI (34 kg/m2); however, VA participants had more individuals ≥ 65 years (37.3% vs 19.8%, p < 0.001), men (90.0% vs 55.2%, p < 0.001), hypertension (75.8% vs 63.6%, p < 0.001), hyperlipidemia (76.6% vs 64.6%, p < 0.001), current smokers (19.0% vs 12.1%, p < 0.001), nephropathy (20.4% vs 17.0%, p < 0.05), albuminuria (18.4% vs 15.1%, p < 0.05), and CVD (10.4% vs 5.2%, p < 0.001). In those without CVD, more VA participants were treated with lipid (70.8% vs 59.5%, p < 0.001) and blood pressure (74.9% vs 65.4%, p < 0.001) lowering medications, and had LDL-C < 70 mg/dl (32.9% vs 24.2%, p < 0.05). Among those with CVD, more VA participants had BP < 140/90 (80.2% vs 70.1%, p < 0.05) after adjusting for demographics.Conclusion: GRADE participants at VA sites had more T2DM complications, greater CVD risk and were more likely to be treated with medications to reduce it, leading to more LDL-C at goal than non-VA participants, highlighting differences in diabetes populations and care. [ABSTRACT FROM AUTHOR]

Heterogeneity of heart failure (HF) phenotypes indicates contributions from underlying common polymorphisms. We considered polymorphisms in the β1-adrenergic receptor (β1AR), a β-blocker target, as candidate pharmacogenomic loci. Transfected cells, genotyped human nonfailing and failing ventricles, and a clinical trial were used to ascertain phenotype and mechanism. In nonfailing and failing isolated ventricles, β1-Arg-389 had respective 2.8 ± 0.3- and 4.3 ± 2.1-fold greater agonist-promoted contractility vs. β1-Gly-389, defining enhanced physiologic coupling under relevant conditions of endogenous expression and HF. The β-blocker bucindolol was an inverse agonist in failing Arg, but not Gly, ventricles, without partial agonist activity at either receptor; carvedilol was a genotype-independent neutral antagonist. In transfected cells, bucindolol antagonized agonist-stimulated cAMP, with a greater absolute decrease observed for Arg-389 (435 ± 80 vs. 115 ± 23 fmol per well). Potential pathophysiologic correlates were assessed in a placebo-controlled trial of bucindolol in 1,040 HF patients. No outcome was associated with genotype in the placebo group, indicating little impact on the natural course of HF. However, the Arg-389 homozygotes treated with bucindolol had an age-, sex-, and race-adjusted 38% reduction in mortality (P = 0.03) and 34% reduction in mortality or hospitalization (P = 0.004) vs. placebo. In contrast, Gly-389 carriers had no clinical response to bucindolol compared with placebo. Those with Arg-389 and high baseline norepinephrine levels trended toward improved survival, but no advantage with this allele and exaggerated sympatholysis was identified. We conclude that β1AR-389 variation alters signaling in multiple models and affects the β-blocker therapeutic response in HF and, thus, might be used to individualize treatment of the syndrome. [ABSTRACT FROM AUTHOR]

We sought to identify the clinical characteristics and outcomes of patients who had advanced heart failure and nonfatal myocardial infarction (MI) in the β-Blocker Evaluation of Survival Trial (BEST) and to investigate whether bucindolol alters the risk of developing nonfatal MI. Of the 2,708 patients enrolled in the study, 142 had suspected MI and 69 had confirmed MI; there were 860 deaths overall. The rate of nonfatal MI in the BEST was low over the 4.1 years of follow-up (4.8% had suspected events and 2.4% had adjudicated events) and was similar to that in high-risk populations. Cox''s proportional hazard model with 23 prespecified candidate variables associated advanced age, heart failure symptoms, male gender, ischemic etiology, diabetes, and hypertension with nonfatal MI or cardiovascular death. The 2-year mortality rate was 56% for the cohort that had suspected nonfatal MI versus 30% for the cohort that did not (p = 0.01). Likewise, the risk of hospitalization for congestive heart failure was twofold greater. Beta-blocker therapy with bucindolol resulted in a 52% decrease in suspected nonfatal MI (2.9% vs 5.5%, p = 0.001). In conclusion, nonfatal MI occurs at low rates but increases the risks for mortality and hospitalization in patients who have advanced heart failure. Beta-blocker therapy with bucindolol appears to attenuate the risk of nonfatal MI in this population. [Copyright &y& Elsevier]

Objectives: We sought to determine whether hormone replacement therapy (HRT) is associated with an improved prognosis in women with advanced heart failure (HF) and systolic dysfunction.Background: There are about two million postmenopausal women in the U.S. with HF. However, limited data are available to assess the effects of HRT on survival in this large group of patients.Methods: A retrospective analysis of women age 50 years and over entered into the Beta-Blocker Evaluation of Survival Trial (BEST) was conducted using Cox regression analysis comparing survival in HRT users and non-users after correcting for baseline variables known to predict survival in women with HF and systolic dysfunction.Results: In 493 women age 50 years and older, HRT was associated with a significant reduction in mortality-21% mortality in HRT users and 34% in non-users (p = 0.025). Multivariate analysis demonstrated a hazard ratio for mortality of 0.6 (95% confidence interval = 0.36 to 0.97) (p = 0.039) for HRT users. The benefits of HRT were noted only in women with a nonischemic etiology of HF (n = 237).Conclusions: Hormone replacement therapy is associated with a marked improvement in survival in postmenopausal women with advanced HF. A prospective, randomized trial of HRT should be performed in this large group of patients. [ABSTRACT FROM AUTHOR]

Objectives: This was a retrospective analysis to determine the effect of diabetes on outcome in patients with advanced heart failure (HF), and to determine the effect of beta-blockade in patients with HF with and without diabetes mellitus.Background: In chronic HF the impact on clinical outcomes and therapeutic response of the prevalent comorbid condition diabetes mellitus has not been extensively investigated.Methods: We assessed the impact of diabetes on prognosis and effectiveness of beta-blocker therapy with bucindolol in patients with HF enrolled in the Beta-Blocker Evaluation of Survival Trial (BEST). We conducted a retrospective analysis to examine the prognosis of patients with advanced HF with and without diabetes, and the effect of beta-blocker therapy on mortality and HF progression or myocardial infarction (MI). The database was the 2,708 patients with advanced HF (36% with diabetes and 64% without diabetes) who were randomized to the beta-blocker bucindolol or placebo in BEST and followed for mortality, hospitalization, and MI for an average of two years.Results: Patients with diabetes had more severe chronic HF and more coronary risk factors than patients without diabetes. Diabetes was independently associated with increased mortality in patients with ischemic cardiomyopathy (adjusted hazard ratio 1.33, 95% confidence interval 1.12 to 1.58, p = 0.001), but not in those with a nonischemic etiology (adjusted hazard ratio 0.98, 95% confidence interval 0.74 to 1.30, p = 0.89). Compared with patients without diabetes, in diabetic patients beta-blocker therapy was at least as effective in reducing death or HF hospitalizations, total hospitalizations, HF hospitalizations, and MI. Ventricular function and physiologic responses to beta-blockade were similar in patients with and without diabetes.Conclusions: Diabetes worsens prognosis in patients with advanced HF, but this worsening appears to be limited to patients with ischemic cardiomyopathy. In advanced HF beta-blockade is effective in reducing major clinical end points in patients with and without diabetes. [ABSTRACT FROM AUTHOR]

Background: Although beta-adrenergic-receptor antagonists reduce morbidity and mortality in patients with mild-to-moderate chronic heart failure, their effect on survival in patients with more advanced heart failure is unknown.Methods: A total of 2708 patients with heart failure designated as New York Heart Association (NYHA) functional class III (in 92 percent of the patients) or IV (in 8 percent) and a left ventricular ejection fraction of 35 percent or lower were randomly assigned to double-blind treatment with either bucindolol (1354 patients) or placebo (1354 patients) and followed for the primary end point of death from any cause.Results: The data and safety monitoring board recommended stopping the trial after the seventh interim analysis. At that time, there was no significant difference in mortality between the two groups (unadjusted P=0.16). The results presented here are based on complete follow-up at the time of study termination (average, 2.0 years). There were a total of 449 deaths in the placebo group (33 percent) and 411 deaths in the bucindolol group (30 percent; adjusted P=0.13). The risk of the secondary end point of death from cardiovascular causes was lower in the bucindolol group (hazard ratio, 0.86; 95 percent confidence interval, 0.74 to 0.99), as was the risk of heart transplantation or death (hazard ratio, 0.87; 95 percent confidence interval, 0.77 to 0.99).Conclusions: In a demographically diverse group of patients with NYHA class III and IV heart failure, bucindolol resulted in no significant overall survival benefit. [ABSTRACT FROM AUTHOR]

Aims: The Glycemia Reduction Approaches in Diabetes - A Comparative Effectiveness (GRADE) trial is a randomized clinical trial comparing glycemic effects of four diabetes medications added to metformin in type 2 diabetes (T2D). Microvascular and macrovascular diseases are secondary outcomes. We evaluated the prevalence and risk factor relationships for microvascular and macrovascular complications in the GRADE cohort at study entry.Methods: Complication prevalence and risk factors were analyzed based on data from screening in all consenting participants meeting GRADE eligibility. Logistic regression and Z-statistics were used to assess risk factor relationships with complications.Results: We enrolled 5047 T2D participants [mean age 57 years; 36% female; mean known T2D duration 4 years (all < 10 years); mean HbA1c 8.0% (∼64 mmol/mol) at screening]. Urinary albumin/creatinine ratio (ACR) ≥ 30 mg/gram was present in 15.9% participants; peripheral neuropathy (by Michigan Neuropathy Screening Instrument) in 21.5%; cardiovascular autonomic neuropathy by electrocardiography-derived indices in 9.7%; self-reported retinopathy in 1.0%. Myocardial infarction ascertained by self-report or electrocardiogram was present in 7.3%, and self-reported history of stroke in 2.0%.Conclusions: In the GRADE cohort with < 10 years of T2D and a mean HbA1c of 8.0%, diabetes complications were present in a substantial fraction of participants, more so than might otherwise have been expected. [ABSTRACT FROM AUTHOR]

Evidence for the initiation of type 1 diabetes (T1D) early in life comes from studies demonstrating 80% of children who develop this disease before the age of 12 years manifest autoantibodies prior to age 3 years. T1D prevention therefore may be most successful when treatments are begun at an early age. However, such interventions must be safe and not interfere with the growth and development of infants. A pilot feasibility trial to prevent the initiation of islet inflammation in high-risk infants has been initiated by Type 1 Diabetes TrialNet in which 90 infants from 10 clinical sites will receive docosahexaenoic acid (DHA), an omega 3 fatty acid, or a placebo. In human studies, supplementation with DHA effectively reduced inflammatory responses, e.g., IL-1b (beta) and IL-12, and blocked Th1 responses, thus targeting key immuno-pathogenie events that may block or reduce early β (beta) cell destruction. In the current study, DHA (or placebo) is either given to pregnant mothers in their third trimester of pregnancy (Group A) or administered to infants within the first 6 months after birth (Group B). In order to continue (Group A) or enter (Group B) the one year pilot trial, infants must have a family history of T1D and must express high-risk HLA alleles. The goals of the trial are; i) enroll 90 subjects in 12 months, ii) demonstrate 90/95% compliance in visits/taking supplement, iii) demonstrate DHA supplementation increases RBC DHA levels by greater than or equal to 20%, iv) demonstrate DHA supplementation reduces inflammatory cytokine production, e.g. IL-1β (beta), by greater than or equal to 20%, and v) demonstrate DHA supplementation does not interfere with immunity. Upon reaching these goals a full trial would ensue where infants will receive DHA supplements until age 3 years. Annual follow-up will occur until age 6 years with contact to age 9 years. The study endpoint will be the development of 2 persistent biochemical islet autoantibodies. AIDA-Funded Research [ABSTRACT FROM AUTHOR]

Type 1 Diabetes TrialNet is an international research consortium whose objective is to develop interventions to delay or prevent type 1 diabetes (T1D) and to slow the loss of Beta cell function once it is diagnosed. The Natural History Study (NHS) is a core element of TrialNet, since participants (relatives of T1D patients) must first be screened positive for autoantibodies (confirmation requires positivity on 2 separate samples) and are then staged for T1D risk with 2-hr OGTTs before they can be considered for entry into a prevention trial. Data are shown from the NHS regarding associations between glucose tolerance abnormalities and autoantibody number. Of 416 participants who have been confirmed positive for at least 1 of 3 biochemical autoantibodies (GAD65, ICA512, mIAA) and have undergone baseline 2-hr OGTTs, 260 have had 1 positive autoantibody (1-abpos) and 156 have had 2 positive autoantibodies (≥ 2-abpos). Participants with ≥ 2-abpos were markedly younger than those with 1-abpos (mean±SD: 11.5±9.9 years vs 22.9±14.9 years, p<0.001). Those with ≥ 2-abpos had a significantly higher percentage of glucose levels in the diabetic range (10.3% vs. 4.2%, p=0.016) than those with 1-abpos. Of those in the non-diabetic range (n=249 for 1-abpos and n=140 for ≥ 2-abpos), the percentage with impaired glucose tolerance (IGT) was also higher in those with ≥ 2-abpos (22.1% vs 14.1%, p=0.041). Conversely, there was a lower percentage of impaired fasting glucose (IFG) in those with ≥ 2-abpos (8.6% vs 15.7%, p=0.047). In a stratified analysis, this pattern of differences persisted in those <13 years of age (n=216). Thus, in that age group, those with ≥ 2-abpos had higher percentages of diabetic range glucose levels (p=0.004) and IGT (p<0.001). The lower percentage of IFG in those with ≥ 2-abpos was again apparent (p=0.028). There were no significant differences for any glucose abnormality according to number of positive autoantibodies in those ≥ 13 years. These data suggest that in younger children, glucose levels in the diabetic range and IGT are more commonly present in those with multiple positive autoantibodies than in those with a single positive autoantibody. However, in contrast, it appears that in the same age group, IFG is less common in those with multiple autoantibodies than in those with a single positive autoantibody. [ABSTRACT FROM AUTHOR]

Background: Ventilator-dependent premature infants are often treated with dexamethasone. However, the optimal timing of therapy is unknown. Methods: We compared the benefits and hazards of initiating dexamethasone therapy at two weeks of age and at four weeks of age in 371 ventilator-dependent very-low-birth-weight infants (501 to 1500 g) who had respiratory-index scores (mean airway pressure × the fraction of inspired oxygen) of >2.4 at two weeks of age. One hundred eighty-two infants received dexamethasone for two weeks followed by placebo for two weeks, and 189 infants received placebo for two weeks followed by either dexamethasone (those with a respiratory-index score of >2.4 on treatment day 14) or additional placebo for two weeks. Dexamethasone was given at a dose of 0.25 mg per kilogram of body weight twice daily intravenously or orally for five days, and the dose was then tapered. Results: The median time to ventilator independence was 36 days in the dexamethasone–placebo group and 37 days in the placebo–dexamethasone group. The incidences of chronic lung disease (defined as the need for oxygen supplementation at 36 weeks' postconceptional age) were 66 percent and 67 percent, respectively. Dexamethasone was associated with an increased incidence of nosocomial bacteremia (relative risk, 1.5; 95 percent confidence interval, 1.1 to 2.1) and hyperglycemia (relative risk, 1.9; 95 percent confidence interval, 1.2 to 3.0) in the dexamethasone–placebo group, elevated blood pressure (relative risk, 2.9; 95 percent confidence interval, 1.2 to 6.9) in the placebo–dexamethasone group, and diminished weight gain and head growth (P<0.001) in both groups. Conclusions: Treatment of ventilator-dependent premature infants with dexamethasone at two weeks of age is more hazardous and no more beneficial than treatment at four weeks of age. (N Engl J Med 1998;338:1112-8.) [ABSTRACT FROM AUTHOR]