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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 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]

Aim: To determine the potential impact of the cross‐reactivity of insulin glargine U‐100 and its metabolites on insulin sensitivity and β‐cell measures in people with type 2 diabetes. Materials and Methods: Using liquid chromatography–mass spectrometry (LC–MS), we measured concentrations of endogenous insulin, glargine and its two metabolites (M1 and M2) in fasting and oral glucose tolerance test‐stimulated plasma from 19 participants and fasting specimens from another 97 participants 12 months after randomization to receive the insulin glargine. The last dose of glargine was administered before 10:00 PM the night before testing. Insulin was also measured on these specimens using an immunoassay. We used fasting specimens to calculate insulin sensitivity (Homeostatic Model Assessment 2 [HOMA2]‐S%; QUICKI index; PREDIM index) and β‐cell function (HOMA2‐B%). Using specimens following glucose ingestion, we calculated insulin sensitivity (Matsuda ISI[comp] index) and β‐cell response (insulinogenic index [IGI], and total incremental insulin response [iAUC] insulin/glucose). Results: In plasma, glargine was metabolized to form the M1 and M2 metabolites that were quantifiable by LC–MS; however, the analogue and its metabolites cross‐reacted by less than 100% in the insulin immunoassay. This incomplete cross‐reactivity resulted in a systematic bias of fasting‐based measures. By contrast, because M1 and M2 did not change following glucose ingestion, a bias was not observed for IGI and iAUC insulin/glucose. Conclusions: Despite glargine metabolites being detected in the insulin immunoassay, dynamic insulin responses can be used to assess β‐cell responsiveness. However, given the cross‐reactivity of the glargine metabolites in the insulin immunoassay, fasting‐based measures of insulin sensitivity and β‐cell function are biased. [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]

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented. [ABSTRACT FROM AUTHOR]

Abstract: Background: Previous studies have shown that ATP-binding cassette transporter 1 (ABCA1) polymorphisms associated with increased ABCA1 expression result in increased small HDL (high-density lipoprotein) subclass particle concentration. This study examines the effect of treatment with fenofibrate, a drug known to bind peroxisome proliferator-activated receptor alpha (PPARα) which increases the expression of ABCA1 gene, on lipoprotein subclass profiles of individuals stratified by ABCA1 genotypes. Methods: Participants of Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) were treated with fenofibrate over a three week period. We analyzed six ABCA1 polymorphisms in 287 GOLDN participants with triglyceride concentrations ⩾150mg/dL and studied their associations with HDL subclass particle concentrations, as measured by nuclear magnetic resonance spectroscopy, before and after treatment. Results: Fenofibrate treatment did not result in significant changes in small HDL subclass particle concentration. When changes in HDL subclasses were stratified by ABCA1 polymorphism genotypes, there were no statistically significant associations between ABCA1 genotypes and small HDL subclasses before fenofibrate treatment. However, after fenofibrate treatment the KK genotype of R1587K (mean 4.40μmol/L; p =0.004) and the RK genotype of R219K (mean 1.60μmol/L; p =0.02) polymorphisms were associated with significantly increased small HDL. The R1587KKK genotype (mean 4.80μmol/L; p =0.0002) and the R219K KK genotype (mean 2.50μmol/L; p =0.02) were also associated with increased HDL particle concentrations. Conclusion: There is a synergistic effect between ABCA1 polymorphisms and fenofibrate. Thus, our study indirectly confirms the role of fenofibrate and genotype in increasing cholesterol efflux, as evidenced by increased small HDL particles. [Copyright &y& Elsevier]

Abstract: The cholesteryl ester transfer protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, −629C/A, Taq1B, and −2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, carotid intimal-medial thickness (IMT), and carotid artery plaque measured by ultrasonography. Carriers of the 451Q and 373P alleles have a significantly higher CETP concentration (22.4% and 19.5%, respectively; p <0.001) and activity (13.1% and 9.4%, respectively; p <0.01) and lower HDL-C (5.6% and 6.0%, respectively; p <0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p =0.006 and p =0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p =0.036). Polymorphism is associated with neither common nor internal carotid IMT. We confirmed that the −629A, Taq1B B2, and −2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p <0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p <0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p <0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD. [Copyright &y& Elsevier]