Laura A. Young

Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial

BACKGROUND The safety and effectiveness of a continuous, day-and-night automated glycaemic control system using insulin and glucagon has not been shown in a free-living, home-use setting. We aimed to assess whether bihormonal bionic pancreas initialised only with body mass can safely reduce mean glycaemia and hypoglycaemia in adults with type 1 diabetes who were living at home and participating in their normal daily routines without restrictions on diet or physical activity. METHODS We did a random-order crossover study in volunteers at least 18 years old who had type 1 diabetes and lived within a 30 min drive of four sites in the USA. Participants were randomly assigned (1:1) in blocks of two using sequentially numbered sealed envelopes to glycaemic regulation with a bihormonal bionic pancreas or usual care (conventional or sensor-augmented insulin pump therapy) first, followed by the opposite intervention. Both study periods were 11 days in length, during which time participants continued all normal activities, including athletics and driving. The bionic pancreas was initialised with only the participants body mass. Autonomously adaptive dosing algorithms used data from a continuous glucose monitor to control subcutaneous delivery of insulin and glucagon. The coprimary outcomes were the mean glucose concentration and time with continuous glucose monitoring (CGM) glucose concentration less than 3·3 mmol/L, analysed over days 2-11 in participants who completed both periods of the study. This trial is registered with ClinicalTrials.gov, number NCT02092220. FINDINGS We randomly assigned 43 participants between May 6, 2014, and July 3, 2015, 39 of whom completed the study: 20 who were assigned to bionic pancreas first and 19 who were assigned to the comparator first. The mean CGM glucose concentration was 7·8 mmol/L (SD 0·6) in the bionic pancreas period versus 9·0 mmol/L (1·6) in the comparator period (difference 1·1 mmol/L, 95% CI 0·7-1·6; p<0·0001), and the mean time with CGM glucose concentration less than 3·3 mmol/L was 0·6% (0·6) in the bionic pancreas period versus 1·9% (1·7) in the comparator period (difference 1·3%, 95% CI 0·8-1·8; p<0·0001). The mean nausea score on the Visual Analogue Scale (score 0-10) was greater during the bionic pancreas period (0·52 [SD 0·83]) than in the comparator period (0·05 [0·17]; difference 0·47, 95% CI 0·21-0·73; p=0·0024). Body mass and laboratory parameters did not differ between periods. There were no serious or unexpected adverse events in the bionic pancreas period of the study. INTERPRETATION Relative to conventional and sensor-augmented insulin pump therapy, the bihormonal bionic pancreas, initialised only with participant weight, was able to achieve superior glycaemic regulation without the need for carbohydrate counting. Larger and longer studies are needed to establish the long-term benefits and risks of automated glycaemic management with a bihormonal bionic pancreas. FUNDING National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, and National Center for Advancing Translational Sciences.

Mindfulness-Based Stress Reduction: Effect on Emotional Distress in Older Adults:

Objectives: Mindfulness training may help seniors successfully manage the physical and psychological challenges of aging in a manner that reduces distress and promotes vitality. The purpose of this retrospective analysis is to evaluate the impact of mindfulness-based stress reduction (MBSR) training on mood states in older adults. Methods: The authors identified 141 older adults (>60 years) who completed MBSR training. All participants completed the Profile of Mood States-Short Form (POMS-SF) at baseline and following 8 weeks of MBSR. Using paired t tests, the authors evaluated changes in mood following training in MBSR. In a subset analysis, the authors further examined the impact of MBSR training in individuals with the highest scores on depression and anxiety. Primary reasons cited for MBSR enrollment are also reported. Results: Overall emotional distress and all sub-scale mood measurements improved significantly following MBSR training. MBSR training resulted in >50% reduction in the number of older people reporting clinically significant depression and anxiety. Most enrolled in MBSR training to improve stress management skills. Discussion: MBSR training is a promising, group-based intervention for decreasing psychological distress in older adults. Larger randomized controlled trials are needed to confirm study findings.

A Novel Pharmacological Approach to Treating Cardiac Ischemia BINARY CONJUGATES OF A1 AND A3 ADENOSINE RECEPTOR AGONISTS

Adenosine released during cardiac ischemia exerts a potent, protective effect in the heart via activation of A1 or A3 receptors. However, the interaction between the two cardioprotective adenosine receptors and the question of which receptor is the more important anti-ischemic receptor remain largely unexplored. The objective of this study was to test the hypothesis that activation of both receptors exerted a cardioprotective effect that was significantly greater than activation of either receptor individually. This was accomplished by using a novel design in which new binary conjugates of adenosine A1 and A3 receptor agonists were synthesized and tested in a novel cardiac myocyte model of adenosine-elicited cardioprotection. Binary drugs having mixed selectivity for both A1 and A3 receptors were created through the covalent linking of functionalized congeners of adenosine agonists, each being selective for either the A1 or A3 receptor subtype. MRS 1740 and MRS 1741, thiourea-linked, regioisomers of a binary conjugate, were highly potent and selective in radioligand binding assays for A1 and A3 receptors (K i values of 0.7–3.5 nm)versus A2A receptors. The myocyte models utilized cultured chick embryo cells, either ventricular cells expressing native adenosine A1 and A3receptors, or engineered atrial cells, in which either human A3 receptors alone or both human A1 and A3 receptors were expressed. The binary agonist MRS 1741 coactivated A1 and A3 receptors simultaneously, with full cardioprotection (EC50 ∼0.1 nm) dependent on expression of both receptors. Thus, co-activation of both adenosine A1 and A3 receptors by the binary A1/A3 agonists represents a novel general cardioprotective approach for the treatment of myocardial ischemia.

Depression in Adults in the T1D Exchange Clinic Registry

OBJECTIVE Little is known about the frequency of depression in adults with type 1 diabetes (T1D) or its relationship to diabetes outcomes. The T1D Exchange clinic registry allowed us to explore depression in a large, heterogeneous sample. RESEARCH DESIGN AND METHODS Participants ≥18 years old (N = 6,172; median age 34 years; median diabetes duration 16 years; 55% female; and 89% non-Hispanic white) completed the eight-item Patient Health Questionnaire (PHQ-8), a validated, reliable measure of current depression. Probable major depression was defined in four ways: PHQ-8 ≥10, PHQ-8 ≥12, per diagnostic algorithm, and as a continuous variable. Characteristics and clinical outcomes of those with and without depression were compared using logistic and linear regression models. RESULTS A total of 4.6–10.3% of participants were classified as probable major depression depending on how defined. Participants classified as depressed were more likely female, nonwhite race/ethnicity, to have a lower household income and lower education level, to exercise less often, to miss insulin doses, and to have one or more complications (neuropathy, nephropathy, treatment for retinopathy, or cardiovascular/cerebrovascular disease) (all P < 0.01). HbA1c was higher in the depressed versus not depressed groups (8.4 ± 1.7% [68 ± 8.6 mmol/mol] vs. 7.8 ± 1.4% [62 ± 15.3 mmol/mol]; P < 0.001). Occurrence of one or more diabetic ketoacidosis events (11 vs. 4%; P < 0.001) and one or more severe hypoglycemic events (18 vs. 9%; P < 0.001) in the past 3 months was higher among depressed participants. CONCLUSIONS In the T1D Exchange clinic registry, adults with probable major depression have worse clinical outcomes than those not depressed. Whether identification and treatment of depression improves diabetes outcomes requires study. Depression is common in T1D, and better identification and treatment of this comorbid condition is needed.

Glucose Self-monitoring in Non–Insulin-Treated Patients With Type 2 Diabetes in Primary Care Settings: A Randomized Trial

Importance The value of self-monitoring of blood glucose (SMBG) levels in patients with non–insulin-treated type 2 diabetes has been debated. Objective To compare 3 approaches of SMBG for effects on hemoglobin A1c levels and health-related quality of life (HRQOL) among people with non–insulin-treated type 2 diabetes in primary care practice. Design, Setting, and Participants The Monitor Trial study was a pragmatic, open-label randomized trial conducted in 15 primary care practices in central North Carolina. Participants were randomized between January 2014 and July 2015. Eligible patients with type 2 non–insulin-treated diabetes were: older than 30 years, established with a primary care physician at a participating practice, had glycemic control (hemoglobin A1c) levels higher than 6.5% but lower than 9.5% within the 6 months preceding screening, as obtained from the electronic medical record, and willing to comply with the results of random assignment into a study group. Of the 1032 assessed for eligibility, 450 were randomized. Interventions No SMBG, once-daily SMBG, and once-daily SMBG with enhanced patient feedback including automatic tailored messages delivered via the meter. Main Outcomes and Measures Coprimary outcomes included hemoglobin A1c levels and HRQOL at 52 weeks. Results A total of 450 patients were randomized and 418 (92.9%) completed the final visit. There were no significant differences in hemoglobin A1c levels across all 3 groups (P = .74; estimated adjusted mean hemoglobin A1c difference, SMBG with messaging vs no SMBG, −0.09%; 95% CI, −0.31% to 0.14%; SMBG vs no SMBG, −0.05%; 95% CI, −0.27% to 0.17%). There were also no significant differences found in HRQOL. There were no notable differences in key adverse events including hypoglycemia frequency, health care utilization, or insulin initiation. Conclusions and Relevance In patients with non–insulin-treated type 2 diabetes, we observed no clinically or statistically significant differences at 1 year in glycemic control or HRQOL between patients who performed SMBG compared with those who did not perform SMBG. The addition of this type of tailored feedback provided through messaging via a meter did not provide any advantage in glycemic control. Trial Registration clinicaltrials.gov Identifier: NCT02033499

Mindfulness Based Stress Reduction: effect on emotional distress in diabetes

Psychological distress is common in patients with diabetes. Little is known about the impact of Mindfulness Based Stress Reduction (MBSR), a non-traditional, cognitive behavioural intervention designed to improve stress management skills, in patients with diabetes. The purpose of this retrospective analysis was to evaluate the impact of MBSR training on mood states in 25 individuals with diabetes. All participants completed the Profile of Mood States Short Form (POMS-SF) at baseline and following eight weeks of MBSR. Overall psychological distress measured by the total mood score (TMS) and six subscales - including tension/anxiety, depression/dejection, anger/hostility, fatigue/inertia, confusion/bewilderment and vigour/activity - were assessed. Overall mood, measured by the TMS, as well as all subscale mood measurements improved significantly from baseline following MBSR training. Compared to population means, those with diabetes had higher distress at baseline and similar levels of distress following MBSR training. The primary reason participants reported for enrolling in the MBSR course was to improve stress management skills. It was concluded that MBSR training is a promising, group-based intervention that can be used to decrease psychological distress in individuals with diabetes who perceive a need for training in stress management.

Mindfulness Meditation: A Primer for Rheumatologists

Over the past decade, there has been an increasing interest in meditation as a mind-body approach, given its potential to alleviate emotional distress and promote improved well being in a variety of populations. The overall purpose of this review is to provide the practicing rheumatologist with an overview of mindfulness and how it can be applied to Western medical treatment plans to enhance both the medical and psychological care of patients.

Effects of raltegravir combined with tenofovir/emtricitabine on body shape, bone density, and lipids in African-Americans initiating HIV therapy

Abstract Background: Raltegravir (RAL) plus tenofovir/emtricitabine (TDF/FTC) is a recommended initial antiretroviral regimen. A substantial proportion of persons diagnosed with HIV infection and starting antiretrovirals in the U.S. are African-American (AA); however, the effects of this regimen on metabolic parameters have largely been studied in white patients. Methods: Single-arm, open-label study of untreated AA HIV-infected patients administered RAL with TDF/FTC for 104 weeks. Changes in fasting lipids, insulin resistance, visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT), limb and trunk fat, and bone mineral density (BMD) were assessed at weeks 56 and 104. Results: Thirty (85% men) participants were included. Median entry characteristics included age of 38 years, CD4 323 cells/mm3, HIV RNA level 29 245 copies/ml, and body mass index 28.1 kg/m2. At 56 and 104 weeks, significant increases in VAT, trunk fat, limb fat, and overall fat were observed. Bone mineral density decreased by 1.5% by week 104.There were no significant changes in non-HDL-cholesterol, fasting triglycerides, or insulin resistance. A median CD4 cell count increase of 318 cells/mm3 (IQR 179, 403; full range 40, 749) (P < 0.001) was observed. Assuming missing = failure, 78 and 70% had HIV RNA levels < 40 copies/ml at weeks 56 and 104, respectively. There were no treatment-related discontinuations and no new antiretroviral resistance mutations were detected. Conclusions: In this cohort of AAs, initiation of RAL with TDF/FTC was associated with significant general increases in fat. Significant changes in lipids or insulin resistance were not observed and there was a small decline in BMD. Therapy was well tolerated and effective. These results are consistent with findings of studies of initial antiretroviral therapy in racially diverse cohorts and inform treatment selection for AA patients starting therapy for HIV infection.

Three approaches to glucose monitoring in non-insulin treated diabetes: a pragmatic randomized clinical trial protocol

BackgroundFor the nearly 75% of patients living with type 2 diabetes (T2DM) that do not use insulin, decisions regarding self-monitoring of blood glucose (SMBG) can be especially problematic. While in theory SMBG holds great promise for sparking favorable behavior change, it is a resource intensive activity without firmly established patient benefits. This study describes our study protocol to assess the impact of three different SMBG testing approaches on patient-centered outcomes in patients with non-insulin treated T2DM within a community-based, clinic setting.Methods/DesignUsing stakeholder engagement approach, we developed and implemented a pragmatic trial of patient with non-insulin treated T2DM patients from five primary care practices randomized to one of three SMBG regimens: 1) no testing; 2) once daily testing with standard feedback consisting of glucose values being immediately reported to the patient through the glucose meter; and 3) once daily testing with enhanced patient feedback consisting of glucose values being immediately reported to the patient PLUS automated, tailored feedback messaging delivered to the patient through the glucose meter following each testing. Main outcomes assessed at 52 weeks include quality of life and glycemic control.DiscussionThis pragmatic trial seeks to better understand the value of SMBG in non-insulin treated patients with T2DM. This paper outlines the protocol used to implement this study in fifteen community-based primary care practices and highlights the impact of stakeholder involvement from the earliest stages of project conception and implementation. Plans for stakeholder involvement for result dissemination are also discussed.Trial registrationClinicalTrials.gov NCT02033499, January 9, 2014.

GLP-1 receptor agonists and basal insulin in type 2 diabetes

Drug development is a slow process, and understanding how best to deploy new treatments even slower. In The Lancet, Conrad Eng and colleagues report the fi ndings from their systematic review and meta-analysis of evidence about the combination of glucagon-like peptide-1 (GLP-1) receptor agonists and basal insulin in type 2 diabetes. In 1992, two scientifi c breakthroughs led to the commercial development of GLP-1 agonists. First, GLP-1 (7-37)amide, the active fragment of GLP-1, was shown to have antihyperglycaemic activity in type 2 diabetes, against a background of insulin infusion. Second, exendin-4 was discovered in the saliva of the Gila monster, a venomous lizard, and recognised to have structural similarity to GLP-1. This xenopeptide was resistant to degradation and reduced glucose in animals, eventually becoming the fi rst GLP-1 agonist, exenatide. The initial phase 2 study of a GLP-1 agonist was done in 1999, a single-masked, 5 day random-order crossover design of exenatide or saline given twice daily. Six of the 24 patients were insulin-treated and assessed in our research unit; any insulin formulation, dose, or schedule was acceptable. Eligible participants were switched to bedtime basal insulin titrated to a fasting blood glucose value of less than 10 mmol/L for at least 3 consecutive days. When the fi rst insulin-treated patient received the initial dose of exenatide and underwent a liquid meal challenge, the bedside glucose analyser showed no change in the patient’s blood glucose for 5 h. This response in an insulin-defi cient patient was inconceivable, and it was assumed that there had been a miscalculation of meal volume or malfunction of the glucose analyser. However, the pattern was the usual response for the entire study. Exenatide twice-daily gained regulatory approval in 2005. Due to concerns that insulin-associated hypoglycaemia would raise questions about the safety of exenatide, a formal study of GLP-1 agonists with basal insulin was not started until 2008. Participants were treated with optimised insulin glargine plus exenatide or placebo twice daily. Compared with the placebo group, patients in the exenatide group had a 0·7% greater reduction in glycated haemoglobin (HbA1c), similar rates of hypoglycaemia, and weight loss as opposed to weight gain. Since that report in 2011, there has been an explosion of interest in the combination of GLP-1 receptor agonists with insulin and eventual regulatory approval as documented by Eng and colleagues. Of the 2905 studies identifi ed, the investigators assessed 15, which together enrolled 4348 participants. Compared with basal insulin alone, a GLP-1 agonist plus basal insulin provided substantially greater HbA1c lowering (–0·44% vs basal insulin; 95% CI –0·60 to –0·29) with similar rates of hypoglycaemia and a mean reduction in weight of –3·22 kg (–4·90 to –1·54). Compared with full basal-bolus insulin regimens, a GLP-1 agonist plus basal insulin gave a clinically insignifi cant reduction in HbA1c (–0·1% [–0·17 to –0·02]), but with a lower relative risk of hypoglycaemia (0·67 [0·56–0·80]) and a reduction in mean weight of –5·66 kg (–9·8 to –1·51). Eng and colleagues appropriately point out many limitations to the available studies; that said, the consistency of the fi ndings suggests a robust conclusion. Several questions remain. First, do shorter-acting GLP-1 agonists with their unparalleled effi cacy on postprandial glucose provide unique advantages over long-acting GLP-1 agonists combined with basal insulin? There are no adequate trials to answer this question, but it seems that the diff erences are probably small. A second issue tangential to the focus of the systematic review is whether there is a role for long-acting GLP-1 agonists combined with prandial insulin (injected or inhaled). Findings from the AWARD-4 study suggest that onceweekly dulaglutide, a GLP-1 agonist, combined with a Published Online September 12, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)61409-4