Functional impairment outcomes in clinical trials of different ADHD medications:post hoc responder analyses and baseline subgroup analyses

Several recent phase 3 clinical trials of attention-deficit/hyperactivity disorder (ADHD) medications have used the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P). Here, we assess WFIRS-P response in individual patients in two pivotal trials of lisdexamfetamine dimesylate (LDX) and guanfacine extended release (GXR). We also analysed pooled WFIRS-P data from seven phase 3 studies of ADHD medications to shed light on factors associated with baseline functional impairment. The proportion of patients with a change in WFIRS-P score that exceeded the minimal important difference (MID) criteria for response was greater for LDX than placebo in the Family, Learning and School, and Risky Activities domains, and was greater for GXR than placebo in the Social Activities, Learning and School, and Family domains. Responders had significantly worse baseline scores in all WFIRS-P domains (all p < 0.001) than non-responders. In the pooled analyses, baseline WFIRS-P scores in all domains were significantly worse in participants with oppositional defiant disorder (ODD) than in those without ODD. Having combined type or hyperactive-impulsive type ADHD, being enrolled into a study in Europe, being male and being younger also had modest negative effects on baseline WFIRS-P scores. The present analysis of WFIRS-P response shows that previously reported group-level improvements in WFIRS-P functional impairment score translated into clinically relevant improvements in many individual participants. Functional impairment is a diverse and subjective construct that is influenced by multiple factors. Optimal management of individuals with ADHD should involve monitoring improvements in functioning and quality of life, as well as symptomatic improvement

Stimulation of map kinases and S6 kinases by sodium selenate and vanadyl sulphate

Insulin has a wide range of biological effects on mammalian cells including both metabolic and mitogenic actions. A phosphorylation cascade originating at the insulinreceptor and involving a number of different serine/threonine-protein kinases is believed to mediate, at least in part, some of these effects. The two best studied kinases within this phosphorylation cascade, MAP kinases and S6 kinases, are believed to play pivotal roles in insulin signal transduction. Both selenium and vanadium compounds have been shown to have insulin-mimetic effects on isolated rat adipocytes. In providing further evidence for their insulin-mimetic properties, their effects on the activity of MAP kinases and S6 kinases in isolated rat adipocytes were examined by measuring the phosphorylation of myelin basic protein (MBP) and Ribosomal S6 Protein, respectively. Both MBP kinases and Ribosomal Protein S6 kinases were shown to be activated in response to insulin treatment of adipocytes thus confirming the suitability of this system for the investigation of insulin-mimetic agents. Sodium selenate and vanadyl sulphate treatment of cells led to dose and time-dependent stimulation of both MBP kinases and Ribosomal Protein S6 kinases. Maximal stimulation ofMBP kinases by sodium selenate was ∽2-fold control while Ribosomal Protein S6 kinases were stimulated to over 8-fold control. Vanadyl sulphate treatment led to higher levels of stimulation with MBP kinase activity being ∽5-fold control and Ribosomal Protein S6 kinase activity reaching levels that were greater than 16- fold control. Anion-exchange chromatography of the crude cell extracts revealed several distinct peaks of MBP and Ribosomal Protein S6 kinase activity corresponding to previous reports in the literature, however no distinct kinase families were conclusively identified using immunological techniques. Our results further confirm the insulin-mimetic properties of selenium and vanadium compounds. Both were shown to stimulate kinases within the signal transduction cascade of insulin to a greater degree than insulin itself. The distinct families of MAP- and S6 kinases stimulated by these agents were not identified although the presence more than one family for each group of kinases was indicated.Medicine, Faculty ofAnesthesiology, Pharmacology and Therapeutics, Department ofGraduat

Health Technology Assessment (HTA) of Roux-en-Y Gastric Bypass compared to Sleeve Gastrectomy in obese type 2 diabetic adults

The purpose of this project was to assess the value of Laproscopic Roux-en-Y Gastric Bypass (RYGB) as a treatment option in obese type 2 diabetic adults in comparison to Laparoscopic Sleeve Gastrectomy (SG). A search of the biomedical literature (2008-14) for studies comparing RYGB and SG and the effectiveness of RYGB in the treatment of obese type 2 diabetics was conducted. RYGB and SG showed statistically significantly greater weight loss, glycemic control, and diabetes remission rates than medical treatment in combination with life-style modifications. Clinical and observational studies reported statistically significant long-term favorable outcomes for RYGB compared to SG. These included bodyweight reduction, glycemic control, diabetes remission, lower diabetes relapse, lower diabetes medication use, and lower overall medication use. Bariatric quality of life, health and activities index, and patient satisfaction were also statistically significantly higher for RYGB patients. Overall complication rates were higher in RYGB than SG but there were no statistically significant differences for major complication between the two procedures. Diabetes remission was related to body mass index reduction and to the duration of diabetes. No cost-effectiveness studies of SG in comparison to RYGB were identified but RYGB cost-effectiveness studies versus laparoscopic adjustable gastric banding were used to demonstrate the cost-effectiveness of RYGB and to make a qualitative assessment of RYGB and SG. Conclusions: Bariatric surgery is the most effective option for the morbidly obese for losing weight and countering obesity-related type 2 diabetes. Among common bariatric procedures with acceptable safety profiles, RYGB provides the greatest effectiveness in long-term weight loss and diabetes remission. The cost-effectiveness of RYGB is below the commonly used willingness to pay threshold of $50,000/QAL, especially for longer time horizons, Presentation: 49 minute

Assessment of the relationship between diabetes treatment intensification and quality measure performance using electronic medical records.

AIMS:Assess the relationship between timely treatment intensification and hemoglobin A1C (HbA1C) control quality-of-care performance measures, i.e., HbA1C levels, among patients with uncontrolled type 2 diabetes. MATERIALS AND METHODS:Electronic medical records and diabetes registry data from a large, accountable care organization (ACO) were used to isolate a sample of adult patients with type 2 diabetes who received at least one oral antidiabetes agent and had at least one HbA1C level measurement ≥8.0% (64 mmol/mol; i.e., uncontrolled diabetes) between 7/1/2011 and 6/30/2015. Treatment intensification status was evaluated for each patient during a 120-day treatment intensification window following the index HbA1c measure. Two-level hierarchical generalized linear models, with patients aggregated at the physician level, were used to assess the association between treatment intensification and achieving HbA1C quality performance measures. RESULTS:547 patients met study selection criteria and 480 patients had at least one HbA1C test after the treatment intensification window and were used for the statistical analyses. About 40% of patients who had uncontrolled diabetes received treatment intensification during the 120-day window. Greater index HbA1C, greater patient body mass index, and fewer unique pre-index oral antidiabetes agents were significantly associated with greater likelihood of receiving timely treatment intensification. The odds of receiving treatment intensification were about 1.8 times higher (P = 0.0027) among patients with poor index HbA1C control (HbA1c level >9.0% [75 mmol/mol]) compared to other patients (index HbA1c 8.0% - 9.0%). Hispanic patients (compared to White patients) were significantly more likely to exhibit poor control after treatment intensification (odds ratio [OR] 2.91, P = 0.0304), underscoring the difficulty of controlling diabetes in this vulnerable group. In contrast, being male and being treated primarily by an internist (compared to primary treatment by a family medicine specialist) were both significantly associated with achieving superior control (HbA1c level <8.0%) after treatment intensification (OR 0.53 [P = 0.0165]; OR 0.41 [P = 0.0275], respectively). CONCLUSIONS:Timely treatment intensification was significantly associated with greater likelihood of patients achieving superior HbA1C control (<8.0%) and better HbA1C control quality performance for the practice. Even in an ACO with resources dedicated to diabetes control, it is incumbent upon clinicians to readily identify and open dialogues with patients who may benefit from closely supervised, individualized attention

Economic burden of comorbid chronic kidney disease and diabetes

<p><b>Objective:</b> To estimate real-world healthcare utilization and expenditures across the spectrum of chronic kidney disease (CKD), as determined by estimated glomerular filtration rate (eGFR) categories in patients with diabetes.</p> <p><b>Methods:</b> This study employed a retrospective cohort study design using the Truven Healthcare and Claims Dataset from 2009–2012. Index date was defined as the first eGFR value during a continuous enrollment period of 24 months. Cohorts of patients were stratified by Kidney Disease: Improving Global Outcomes CKD stage based on eGFR (stages 1: ≥90 mL/min/1.73 m²; 2: 60–89; 3A: 45–59; 3B: 30–44; 4: 15–29; 5: <15). Healthcare expenditures (total patient and payer paid claims) and utilization (number of claims or visits) were estimated 12-months post-index date using generalized linear modeling and negative binomial modeling, respectively, after adjusting for baseline characteristics.</p> <p><b>Results:</b> Of 130,098 patients with an index eGFR value and 24-months continuous enrolment, 64,521 (49.59%) were in stage 1 CKD, 47,816 (36.75%) were in stage 2, 13,377 (10.28%) were in stage 3A, 3,217 (2.47%) were in stage 3B, 898 (0.69%) were in stage 4, and 269 (0.21%) were in stage 5. Patients in stages 3A, 3B, and 4 CKD had 1.32 (95% CI = 1.22–1.43), 1.59 (95% CI = 1.41–1.80), and 2.65 (95% CI = 2.23–3.14) times higher rates of diabetes-associated inpatient visits, respectively, compared with stage 1 CKD patients. Patients in stages 3A, 3B, and 4 CKD had increased incremental total annual healthcare expenditures of $1,732 (95$1,109–$2,356),$2,632 (95% CI = $1,647–$3,619), and $6,949 (95$5,466–$8,432), respectively, compared with stage 1 CKD patients.</p> <p><b>Limitations:</b> The claims data were generated for billing and reimbursement, not for research purposes.</p> <p><b>Conclusions:</b> These real-world data suggest an incremental and significant increase in economic burden in diabetes as kidney function declines, starting with moderate (stage 3A) CKD.</p

Study design and timeframe.

<p>Study design and timeframe.</p

Selection flow diagram demonstrating identification and derivation of the final patient cohorts.

<p>Selection flow diagram demonstrating identification and derivation of the final patient cohorts.</p

Physician and patient characteristics associated with type 2 diabetes treatment intensification.

<p>Physician and patient characteristics associated with type 2 diabetes treatment intensification.</p