GAD65Abs Are Not Associated With Beta-Cell Dysfunction in Patients With T2D in the GRADE Study.

Context: Autoantibodies directed against the 65-kilodalton isoform of glutamic acid decarboxylase (GAD65Abs) are markers of autoimmune type 1 diabetes (T1D) but are also present in patients with Latent Autoimmune Diabetes of Adults and autoimmune neuromuscular diseases, and also in healthy individuals. Phenotypic differences between these conditions are reflected in epitope-specific GAD65Abs and anti-idiotypic antibodies (anti-Id) against GAD65Abs. We previously reported that 7.8% of T2D patients in the GRADE study have GAD65Abs but found that GAD65Ab positivity was not correlated with beta-cell function, glycated hemoglobin (HbA1c), or fasting glucose levels. Context: In this study, we aimed to better characterize islet autoantibodies in this T2D cohort. This is an ancillary study to NCT01794143. Methods: We stringently defined GAD65Ab positivity with a competition assay, analyzed GAD65Ab-specific epitopes, and measured GAD65Ab-specific anti-Id in serum. Results: Competition assays confirmed that 5.9% of the patients were GAD65Ab positive, but beta-cell function was not associated with GAD65Ab positivity, GAD65Ab epitope specificity or GAD65Ab-specific anti-Id. GAD65-related autoantibody responses in GRADE T2D patients resemble profiles in healthy individuals (low GAD65Ab titers, presence of a single autoantibody, lack of a distinct epitope pattern, and presence of anti-Id to diabetes-associated GAD65Ab). In this T2D cohort, GAD65Ab positivity is likely unrelated to the pathogenesis of beta-cell dysfunction. Conclusion: Evidence for islet autoimmunity in the pathophysiology of T2D beta-cell dysfunction is growing, but T1D-associated autoantibodies may not accurately reflect the nature of their autoimmune process.

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

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

BMI, insulin sensitivity, and cognition in early type 2 diabetes: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study.

OBJECTIVE: This study explored the association of BMI and insulin sensitivity with cognitive performance in type 2 diabetes. METHODS: A cross-sectional analysis of data from the baseline assessment of the Glycemia Reduction Approaches in Diabetes: a Comparative Effectiveness Study (GRADE) was conducted. BMI was used as a surrogate of adiposity and the Matsuda index as the measure of insulin sensitivity. Cognitive tests included the Spanish English Verbal Learning Test, the Digit Symbol Substitution Test, and the letter and animal fluency tests. RESULTS: Cognitive assessments were completed by 5018 (99.4%) of 5047 participants aged 56.7 ± 10.0 years, of whom 36.4% were female. Higher BMI and lower insulin sensitivity were related to better performance on memory and verbal fluency tests. In models including BMI and insulin sensitivity simultaneously, only higher BMI was related to better cognitive performance. CONCLUSIONS: In this study, higher BMI and lower insulin sensitivity in type 2 diabetes were cross-sectionally associated with better cognitive performance. However, only higher BMI was related to cognitive performance when both BMI and insulin sensitivity were considered simultaneously. The causality and mechanisms for this association need to be determined in future studies.

Defining Minimum Necessary Communication During Care Transitions for Patients on Antihyperglycemic Medication: Consensus of the Care Transitions Task Force of the IPRO Hypoglycemia Coalition.

INTRODUCTION: Antihyperglycemic agents are significant contributors to adverse drug events, responsible for emergency department visits, hospitalizations, and death. Nationally, the rate of serious hypoglycemic events associated with these agents remains high despite widespread efforts to improve drug safety. Transitions of care between healthcare settings can lead to communication challenges between care professionals and increase the risk of adverse drug events. System-based improvements are needed to assure the safe transitions for patients with diabetes who are on antihyperglycemic agents. The objective of this study was to develop a consensus list of requisite elements that should be communicated between care settings during transitions of patients who are prescribed antihyperglycemic agents. METHODS: The Island Peer Review Organization (IPRO) Hypoglycemia Coalition identified suboptimal transitions of care as a barrier to improving patient safety and quality of diabetes care. The Coalition formed a multidisciplinary Task Force with experts in the field of diabetes care. The Task Force created a draft list of requisite communication elements through literature review and deliberation on monthly conference calls. A blinded iterative Delphi process was subsequently performed to generate a consensus list of requisite communication elements that participating experts agreed were necessary to safely and effectively assume the management of patients with diabetes upon care transitions. RESULTS: The Task Force completed a series of four iterative polls from September 2015 to August 2016, resulting in a final list of 22 requisite communication elements (the Diabetes Management Discharge Communication List), with the elements conceptually categorized into three domains: diagnosis and treatment, factors affecting glycemic control or patient risk, and patient self-management. CONCLUSIONS: The Diabetes Management Discharge Communication List provides an initial framework for the development of diabetes-specific resources to improve clinical communication between care settings.

Islet Autoimmunity is Highly Prevalent and Associated With Diminished ß-Cell Function in Patients With Type 2 Diabetes in the Grade Study.

Islet autoimmunity may contribute to ß-cell dysfunction in type 2 diabetes (T2D). Its prevalence and clinical significance have not been rigorously determined. In this ancillary study to the Glycemia Reduction Approaches in Diabetes-A Comparative Effectiveness (GRADE) Study, we investigated the prevalence of cellular and humoral islet autoimmunity in patients with T2D duration 4·0±3·0 y, HbA1c 7·5±0·5% on metformin alone. We measured T cell autoreactivity against islet proteins, islet autoantibodies against GAD65, IA2, ZnT8, and ß-cell function. Cellular islet autoimmunity was present in 41·3%, humoral islet autoimmunity in 13·5%, and both in 5·3%. ß-cell function calculated as iAUC-CG and ΔC-peptide(0- 30)/Δglucose(0-30) from an oral glucose tolerance test was lower among T cell-positives (T+) than T cell-negatives (T-) using two different adjustments for insulin sensitivity (iAUC-CG: 13·2% [95% CI 0·3, 24·4%] or 11·4% [95% CI 0·4, 21·2%] lower; ΔC-peptide(0-30)/Δglucose(0-30)) 19% [95% CI 3·1, 32·3%] or 17·7% [95% CI 2·6, 30·5%] lower). T+ patients had 17% higher HbA1c (95% CI 0·07, 0·28) and 7·7 mg/dL higher fasting plasma glucose levels (95% CI 0·2,15·3) than T- patients. We conclude that islet autoimmunity is much more prevalent in T2D patients than previously reported. T cell-mediated autoimmunity is associated with diminished ß-cell function and worse glycemic control.

Differences in complications, cardiovascular risk factor, and diabetes management among participants enrolled at veterans affairs (VA) and non-VA medical centers in the glycemia reduction approaches in diabetes: A comparative effectiveness study (GRADE).

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.

Correction to: Suitable Use of Injectable Agents to Overcome Hypoglycemia Risk, Barriers, and Clinical Inertia in Community-Dwelling Older Adults with Type 2 Diabetes Mellitus.

The article Suitable Use of Injectable Agents to Overcome Hypoglycemia Risk, Barriers, and Clinical Inertia in Community-Dwelling Older Adults with Type 2 Diabetes Mellitus, written by Willy M. Valencia, Hermes J. Florez and Ana M. Palacio was originally published Online First without open access.

Suitable Use of Injectable Agents to Overcome Hypoglycemia Risk, Barriers, and Clinical Inertia in Community-Dwelling Older Adults with Type 2 Diabetes Mellitus.

The management of type 2 diabetes mellitus in older adults requires a comprehensive understanding of the relationship between the disease (medical) and the functional, psychological/cognitive, and social geriatric domains, to individualize both glycemic targets and therapeutic approaches. Prevention of hypoglycemia is a major priority that should be addressed as soon as its presence or risk is detected, adjusting the target and therapeutics accordingly. Nonetheless, treatment intensification should not be neglected when applicable, consistent with recommendations from organizations such as the American Geriatrics Society and the American Diabetes Association, to reduce not only long-term macrovascular and microvascular complications (individualization), but also short-term complications from hyperglycemia (polyuria, volume depletion, urinary incontinence). Such complications can negatively impact the physical and cognitive function of older adults, worsen their quality of life, and additionally affect their families and society. We emphasize individualization, utilizing the multiple classes of antihyperglycemic agents available. Metformin remains as first-line therapy, and additional agents offer advantages and disadvantages that ought to be considered when developing a patient-centric plan of care. For selected cases, injectable therapies such as long-acting basal insulin analogs and glucagon-like peptide-1 receptor agonists can offer advantages to counter hypoglycemia risk, patient-related barriers, and clinical inertia. Furthermore, some injectable agents could potentially simplify regimens while providing safe and effective glycemic control. In this review, we discuss the use of injectable therapies for selected community-dwelling older adults, barriers to transition to injectable therapy, and measures aimed at removing these barriers and assisting physicians and their teams to transition older patients to injectable therapies when appropriate.

Baseline Characteristics of Randomized Participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

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.

Relation of Diabetes to Cognitive Function in Hispanics/Latinos of Diverse Backgrounds in the United States.

Objectives:To examine the association between diabetes and cognitive function within U.S. Hispanics/Latinos of Central American, Cuban, Dominican, Mexican, Puerto Rican, and South American background. Method: This cross-sectional study included 9,609 men and women (mean age = 56.5 years), who are members of the Hispanic Community Health Study/Study of Latinos. We classified participants as having diabetes, prediabetes, or normal glucose regulation. Participants underwent a neurocognitive battery consisting of tests of verbal fluency, delayed recall, and processing speed. Analyses were stratified by Hispanic/Latino subgroup. Results: From fully adjusted linear regression models, compared with having normal glucose regulation, having diabetes was associated with worse processing speed among Cubans (ß = -1.99; 95% CI [confidence interval] = [-3.80, -0.19]) and Mexicans (ß = -2.26; 95% CI = [-4.02, -0.51]). Compared with having normal glucose regulation, having prediabetes or diabetes was associated with worse delayed recall only among Mexicans (prediabetes: ß = -0.34; 95% CI = [-0.63, -0.05] and diabetes: ß = -0.41; 95% CI = [-0.79, -0.04]). No associations with verbal fluency. Discussion: The relationship between diabetes and cognitive function varied across Hispanic/Latino subgroup.

Metabolic Syndrome Among Marijuana Users in the United States: An Analysis of National Health and Nutrition Examination Survey Data.

BACKGROUND: Research on the health effects of marijuana use in light of its increased medical use and the current obesity epidemic is needed. Our objective was to explore the relationship between marijuana use and metabolic syndrome across stages of adulthood. METHODS: An analysis of 20- to 59-year-olds (n = 8478) who completed the 2005-2010 National Health and Nutrition Examination Surveys was conducted. Marijuana use was categorized as: never used, past use (used previously but not within the last 30 days), and current use (≥1 day in the last 30 days). Metabolic syndrome was defined as ≥3 of the following: elevated fasting glucose, high triglycerides, low high-density-lipoprotein cholesterol, elevated systolic/diastolic blood pressure, and increased waist circumference. An age-stratified analysis was conducted to examine the relationship between marijuana use and metabolic syndrome among emerging adults (20-30 years), adults (31-44 years), and middle-aged adults (45-59 years). RESULTS: Fourteen percent (13.8%) of current marijuana users and 17.5% of past marijuana users presented with metabolic syndrome, compared with 19.5% of never users (P = .0003 and P = .03, respectively). Current marijuana users had lower odds of presenting with metabolic syndrome than never users (adjusted odds ratio [AOR] 0.69; 95% confidence interval [CI], 0.47-1.00; P = .05). Among emerging adults, current marijuana users were 54% less likely than never users to present with metabolic syndrome. Current (AOR 0.49; 95% CI, 0.25-0.97) and past (AOR 0.61; 95% CI, 0.40-0.91) middle-aged adult marijuana users were less likely to have metabolic syndrome than never users. CONCLUSIONS: Current marijuana use is associated with lower odds of metabolic syndrome across emerging and middle-aged US adults. Future studies should examine the biological pathways of this relationship.

Dry eye syndrome, posttraumatic stress disorder, and depression in an older male veteran population.

PURPOSE: To evaluate whether veterans with posttraumatic stress disorder (PTSD) or depression have differences in dry eye symptoms and signs compared to a population without these conditions. METHODS: Male patients aged ≥50 years with normal eyelid, conjunctival, and corneal anatomy were recruited from the Miami Veterans Affairs Eye Clinic (N = 248). We compared dry eye symptoms (determined by the Dry Eye Questionnaire 5 [DEQ5] score) to tear film indicators obtained by clinical examination (i.e., tear osmolarity, corneal staining, tear breakup time, Schirmer's, meibomian gland quality, orifice plugging, lid vascularity) between patients with PTSD or depression and those without these conditions. Student's t-tests, χ(2) analyses, and linear and logistic regressions were used to assess differences between the groups. RESULTS: DEQ5 scores were higher in the PTSD (mean = 13.4; standard error [SE] = 1.1; n = 22) and depression (mean = 12.0; SE = 0.8; n = 40) groups compared to the group without these conditions (mean = 9.8; SE = 0.4; n = 186; P < 0.01 and P = 0.02, respectively). More patients in the PTSD and depression groups had severe dry eye symptoms, defined as a DEQ5 score ≥ 12 (77% and 63% vs. 41%; P < 0.01 and P = 0.02, respectively). No significant differences in tear film indicators were found among the three groups. Multivariable logistic regression indicated that a PTSD diagnosis (odds ratio [OR] = 4.08; 95% confidence interval [CI] = 1.10-15.14) and use of selective serotonin reuptake inhibitors (OR = 2.66; 95% CI = 1.01-7.00) were significantly associated with severe symptoms. CONCLUSIONS: Patients with PTSD have ocular surface symptoms that are not solely explained by tear indicators. Identifying underlying conditions associated with ocular discomfort is essential to better understand the mechanisms behind ocular pain in dry eye syndrome.

The response of elderly veterans to daily vitamin D3 supplementation of 2,000 IU: a pilot efficacy study.

OBJECTIVES: To determine the prevalence of hypovitaminosis D (serum 25-hydroxyvitamin D<32 ng/mL; HVD) in a population of elderly veterans and conduct a preliminary assessment of the efficacy of supplementation with cholecalciferol in correcting HVD. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. SETTING: Geriatric clinic at the Bruce W. Carter Veterans Affairs Medical Center, Miami, Florida. PARTICIPANTS: Veterans aged 70 and older. INTERVENTION: Oral cholecalciferol 2,000 IU daily or placebo for 6 months. MEASUREMENTS: Serum calcium, 25-hydroxyvitamin D, parathyroid hormone, and 24-hour urinary calcium. RESULTS: Of the 34 participants who completed the study, 62% had HVD at baseline. In the treatment group, mean serum 25-hydroxyvitamin D level rose from 28.4±7.9 ng/mL at baseline to 42.7±10.5 ng/mL at the end of the trial, but levels remained less than 32 ng/mL in three of 17 (18%) of the participants. In the placebo group, the baseline level of 27.7±8.3 ng/mL remained unchanged (28.8±8.7 ng/mL). Supplementation did not alter serum or urinary calcium levels and did not result in any adverse events. CONCLUSION: These initial observations suggest that, in older veterans, cholecalciferol 2,000 IU daily for 6 months is generally safe and corrects HVD in most but not all individuals.

Risk for fractures with centrally acting muscle relaxants: an analysis of a national Medicare Advantage claims database.

BACKGROUND: In older adults, both muscle relaxants and benzodiazepines are associated with sedation and cognitive impairment. Although benzodiazepines have been linked to falls and fracture injuries, no studies have examined the risk of fracture associated with muscle relaxants. OBJECTIVE: To determine whether muscle relaxants identified in the Beers criteria are associated with an increased risk of fracture injuries and to compare this risk to that with benzodiazepine use. METHODS: We conducted a case-control study using both medical and pharmacy claims data from 1.5 million enrollees in the Medicare Advantage plans of a large health maintenance organization. We matched 8164 cases of fractures with 8164 controls based on age, sex, health plan, and comorbidities. We measured the use of muscle relaxants, short-acting benzodiazepines, and long-acting benzodiazepines. Adjusted odds ratios were estimated using conditional logistic regression. RESULTS: After adjusting demographic and clinical covariates, muscle relaxants, long-acting benzodiazepines, and short-acting benzodiazepines were associated with a high risk of fracture injuries, with odds ratios of 1.40 (95% CI 1.15 to 1.72; p < 0.001), 1.9 (95% CI 1.49 to 2.43; p < 0.001), and 1.33 (95% CI 1.15 to 1.55; p < 0.001), respectively. CONCLUSIONS: An elevated risk of fracture injuries was noted among older adults using muscle relaxants. Our findings provide evidence of an association between the risk of fractures and the use of centrally acting muscle relaxants in older adults. This association supports current recommendations advising extreme caution in prescribing muscle relaxants to older adults.

Some new food for thought: the role of vitamin D in the mental health of older adults.

Vitamin D, a multipurpose steroid hormone vital to health, has been increasingly implicated in the pathology of cognition and mental illness. Hypovitaminosis D is prevalent among older adults, and several studies suggest an association between hypovitaminosis D and basic and executive cognitive functions, depression, bipolar disorder, and schizophrenia. Vitamin D activates receptors on neurons in regions implicated in the regulation of behavior, stimulates neurotrophin release, and protects the brain by buffering antioxidant and anti-inflammatory defenses against vascular injury and improving metabolic and cardiovascular function. Although additional studies are needed to examine the impact of supplementation on cognition and mood disorders, given the known health benefits of vitamin D, we recommend greater supplementation in older adults.

Emerging therapies to treat frailty syndrome in the elderly.

Frailty syndrome (FS) has become increasingly recognized as a major predictor of co-morbidities and mortality in older individuals. Interventions with the potential to benefit frail elders include nutritional supplementation (vitamins D, carotenoids, creatine, dehydroepiandrosterone (DHEA), and beta-hydroxy-beta-methylbutyrate) and exercise modalities (tai chi and cobblestone walking). While these have not been explicitly tested for their impact on FS, vitamin D supplementation appears to offer significant promise in enhancing long-term health of the elderly. Exercise modalities such as tai chi and cobblestone walking, because of probable low risk and ease of participation, may also confer benefit. Additional studies are needed to investigate interventions that directly prevent, delay, and/or ameliorate frailty. Successful therapies may well involve multi-component approaches utilizing a combination of medication, nutritional supplementation, and exercise.