Important differences in the durability of glycaemic response among second-line treatment options when added to metformin in type 2 diabetes: a retrospective cohort study.

IMPORTANCE: There is limited information about the durability of glycaemic control when different oral glucose-lowering therapies (GLTs) are used as add-on treatments to metformin (MET) in patients with type 2 diabetes mellitus (T2DM). OBJECTIVE: To compare time to treatment failure between different classes of oral GLT when used as second line (add-on) treatments to MET monotherapy at HbA1c ≥ 7.5%. DESIGN, SETTING AND PARTICIPANTS: A retrospective cohort study on 20,070 patients who were newly treated with a sulphonylurea (SU), dipeptidyl-peptidase-4 (DPP-4) inhibitor or thiazolidinedione (TZD) following MET therapy failure (2007-2014). Patients' data was sourced from UK General Practices via The Health Improvement Network (THIN) database. The risk of dual therapy failure was compared between three treatment groups: MET + SU (reference group, n = 15,508), MET + DPP-4 inhibitor (n = 3,080) and MET + TZD (n = 1,482). Follow-up was until treatment substitution or intensification with a 3rd GLT, or for up to 5 years (totalling 46,430 person-years). Propensity score weighting and Cox proportional hazard regression analyses were employed. MAIN OUTCOMES AND MEASURES: Risk of dual therapy failure was compared between treatment groups while adjusting for baseline covariates. RESULTS: Unadjusted survival analysis showed the incidence of dual therapy failure at 1 year was 15% with SU, 23% with DPP-4 inhibitor and 8% with TZD. Corresponding failure rates at 2 years were 26, 38 and 12%, respectively. Adjusted multivariate models showed that, compared to the SU group, adding a DPP-4 inhibitor was associated with an increased risk of treatment failure (adjusted hazard ratio, aHR, 1.58; 95% CI: 1.48-1.68), while adding a TZD was associated with a reduced hazard (aHR, 0.45; 95% CI: 0.41-0.50). Baseline parameters associated with an increased hazard of intensification included HbA1c, diabetes duration, gender, smoking status and the use of statins. CONCLUSIONS AND RELEVANCE: In routine clinical practice, adding a DPP-4 inhibitor to MET is associated with an increased, earlier requirement for treatment intensification compared to adding an SU or TZD. Adding a TZD to MET resulted in the most durable glycaemic response. Key messages The Agency for Healthcare Research and Quality has suggested that the durability of glycaemic response after treatment intensification is best investigated using well-designed long-term observational studies. In routine clinical practice, among patients with T2DM receiving a second line glucose lowering treatment as add-on to MET, the addition of a Thiazolidinediones is associated with the most durable glycaemic response, followed by a Sulfonylurea and then a DPP-4 inhibitor. Factors associated with earlier dual therapy failure included concomitant use of statin therapy, being female, a smoker, those with longer diabetes duration and higher baseline HbA1c levels. The addition of a Thiazolidinediones was associated with significant weight gain (1.8 kg, p < 0.001), while add-on DPP-4 inhibitor produced a significant weight reduction (-1.8 kg, p < 0.001). A very small reduction in body weight was observed with the SU (-0.2 kg, p < 0.001)

The effects of dual-therapy intensification with insulin or dipeptidylpeptidase-4 inhibitor on cardiovascular events and all-cause mortality in patients with type 2 diabetes: A retrospective cohort study.

PURPOSE: To compare time to a composite endpoint of non-fatal acute myocardial infarction, non-fatal stroke or all-cause mortality in patients with type 2 diabetes mellitus who had their treatment intensified with a dipeptidylpeptidase-4 inhibitor or insulin following dual-therapy (metformin plus sulfonylurea) failure. METHODS: A retrospective cohort study was conducted on 5238 patients newly treated with either a dipeptidylpeptidase-4 inhibitor or insulin following dual-therapy failure (2007-2014). Data were sourced from UK General Practices. The risk of the composite outcome was compared between two treatment groups: metformin + sulfonylurea + insulin ( n = 1584) and metformin + sulfonylurea + dipeptidylpeptidase-4 inhibitor ( n = 3654), while adjusting for baseline covariates. Follow-up was for up to 5 years. Propensity score matching analysis and Cox proportional hazard models were employed. RESULTS: Overall, 123 and 171 composite outcome events occurred among patients who added insulin versus dipeptidylpeptidase-4 inhibitor, respectively (44.5 vs 14.6 events per 1000 person-years). Addition of insulin was associated with a significantly higher hazard ratio versus the addition of a dipeptidylpeptidase-4 inhibitor (adjusted hazard ratio = 2.6, 95% confidence interval: 1.9-3.4; p < 0.01), an effect that was more pronounced in obese (body mass index: 30-34.9 kg/m2) patients (corresponding adjusted hazard ratio 3.6, 95% confidence interval: 2.3-5.6; p < 0.01). CONCLUSION: In routine clinical practice, intensification of metformin + sulfonylurea therapy by adding insulin is associated with increased risk of cardiovascular events and death compared with adding a dipeptidylpeptidase-4 inhibitor. These findings are in line with suggestions from previous studies regarding the cardiovascular safety of insulin in type 2 diabetes mellitus, but should be interpreted with caution

Knowledge-based Methods for Evaluation of Engineering Changes.

Engineering Changes (ECs) are an integral part of a product's lifecycle. A proposed EC can affect several lifecycle-wide components. Detailed evaluation of each proposed EC or its effect is time-consuming and inefficient. Therefore, enterprises plan detailed evaluation of only those EC effects that might have a high cost impact. Currently, domain experts decide which effects should undergo a detailed evaluation process. Such an approach relies heavily on personal experience and is less reliable. To address this problem, this research develops a systematic knowledge-based method for determining whether a proposed EC effect has high impact and would require a detailed evaluation. Only some of the large number of EC attributes are important for retrieving past EC, which can be used to evaluate the impact of a proposed EC. This research formulates the problem of determining important EC attributes as a multi-objective optimization problem. Information-theoretic concepts are used to define measures for quantifying importance of an attribute subset. The domain knowledge and the information in EC database are combined to estimate probability distributions, which are required in computation of measures. An Ant Colony Optimization based search approach is developed for efficiently locating the important attribute set. Utilizing past EC knowledge to predict the impact of proposed EC effect requires an approach to compute similarity between EC. The second part of this research presents an approach to compute similarity between EC that are defined using disparate attributes. Since the available information is probabilistic, the measures of information are utilized for defining measures to compute similarity between two attribute values or EC. The semantics associated with attribute values are utilized to compute similarity between attribute values. In the last part of this research, an approach is developed to predict impact of proposed EC effect based on the similar past ECs. The approach incorporates a technique to quantify differences between important attribute values in proposed EC and a similar past EC. The Bayes' rule is used to determine differences in impact value from the differences in attribute values. The probability values required in the Bayes' rule are determined based on the minimum cross entropy principle.Ph.D.Mechanical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/78926/1/mehtacr_1.pd

Determinants of Glycemic Response to Add-On Therapy with a Dipeptidyl Peptidase-4 Inhibitor: A Retrospective Cohort Study Using a United Kingdom Primary Care Database.

BACKGROUND: Apart from baseline glycated hemoglobin (HbA1c), little is known about clinical parameters that affect glycemic response to a dipeptidyl peptidase-4 (DPP4) inhibitor when used in routine clinical practice. We aimed to use a large primary care database to assess the variability in response to a DPP4 inhibitor when used as add-on therapy. MATERIALS AND METHODS: Data on 25,386 patients with type 2 diabetes, newly treated with a DPP4 inhibitor (2007-2013), were sourced from a United Kingdom general practice database via the Health Improvement Network database. Baseline clinical parameters of patients (n = 13,525) for whom a DPP4 inhibitor was added because of suboptimal glucose control (HbA1c >7%) were compared with 12-month follow-up data. An optimum response to the DPP4 inhibitor was defined as an HbA1c level of <7.0% at 12 months. Descriptive analyses and unadjusted comparisons using χ(2) and t tests were carried out to ascertain glycemic and body weight responses to treatment intensification with a DPP4 inhibitor. Predictor of response analyses were performed using multivariate logistic regression. RESULTS: Overall, 1,708 (13%) of our study population achieved an HbA1c level of <7%. Intensification with a DPP4 inhibitor was associated with significant reductions in HbA1c (-0.5%), body weight (-0.9 kg), and total cholesterol (-0.1 mmol/L) (P < 0.001). Independent predictors of achieving optimal HbA1c target of <7% included the use of metformin (adjusted odds ratio [OR] = 2.58; 95% confidence interval [CI], 2.18-3.04) and use of metformin plus sulfonylurea (1.42; 95% CI, 1.21-1.68) as opposed to no use. The independent predictors of suboptimal glucose control included a higher baseline HbA1c level (OR = 0.64; 95% CI, 0.61-0.68) (i.e., 1% increase in HbA1c was associated with a 36% reduced likelihood of response), longer diabetes duration (per every year increase) (OR = 0.85; 95% CI, 0.83-0.88), and intensification therapy below 9 months compared with 9-12 months. CONCLUSIONS: There is a significant variability in glycemic response to a DPP4 inhibitor in routine practice. The best effect is achieved as add-on to metformin and metformin plus sulfonylurea, but responses are significantly lower with increased diabetes duration and among patients with high HbA1c levels at baseline

Comparative Efficacy of Adding Sitagliptin to Metformin, Sulfonylurea or Dual Therapy: A Propensity Score-Weighted Cohort Study.

INTRODUCTION: The aim of this study was to assess the efficacy of co-administering sitagliptin to patients with inadequate glycemic control following treatment with metformin (MET), sulfonylurea (SU), or MET + SU. METHODS: A cohort of 25,386 patients with type 2 diabetes mellitus (hemoglobin A1c [HbA1C] >53 mmol/mol or 7%), newly treated with sitagliptin between 2007 and 2013, was sourced from UK general practices via The Health Improvement Network database. Among these, eligible patients were segregated into three groups: MET (n = 3364), SU (n = 509), or MET + SU therapy (n = 5929). The relative efficacy of sitagliptin added to SU or MET + SU compared with sitagliptin added to MET monotherapy was assessed with regards to HbA1c and body weight changes from baseline up to 52 weeks. The glycemic efficacy was a measure of average treatment effects obtained from multivariable linear regression models and propensity score-matching analysis. RESULTS: A total of 9802 patients were included in the study. Overall, addition of sitagliptin 100 mg once daily resulted in 5.5 mmol/mol (0.5%) HbA1c reduction (P 9% receiving MET + SU therapy, adding sitagliptin, as a third agent, conferred minimal benefit

Cardiovascular events and all-cause mortality with insulin versus glucagon-like peptide-1 analogue in type 2 diabetes.

OBJECTIVES: To analyse time to cardiovascular events and mortality in patients with type 2 diabetes (T2D) who received treatment intensification with insulin or a glucagon-like peptide-1 (GLP-1ar) analogue following dual therapy failure with metformin (MET) and sulphonylurea (SU). METHODS: A retrospective cohort study was conducted in 2003 patients who were newly treated with a GLP-1ar or insulin following dual therapy (MET+SU) failure between 2006 and 2014. Data were sourced from The Health Improvement Network database. Risks of major adverse cardiovascular events (MACE) (non-fatal myocardial infarction, non-fatal stroke and all-cause mortality) were compared between MET+SU+insulin (N=1584) versus MET+SU+GLP-1ar (N=419). Follow-up was for 5 years (6614 person-years). Propensity score matching analysis and Cox proportional hazard models were employed. RESULTS: Mean age was 52.8±14.1 years. Overall, the number of MACE was 231 vs 11 for patients who added insulin versus GLP-1ar, respectively (44.5 vs 7.7 per 1000-person-years adjusted HR (aHR): 0.27; 95% CI 0.14 to 0.53; p30 kg/m(2)) there were 84 vs 11 composite outcomes (38.6 vs 8.1 per 1000 person-years; aHR: 0.31; 95% CI 0.16 to 0.61; p=0.001) in the insulin and GLP-1ar groups, respectively. CONCLUSIONS: In this cohort of obese people with T2DM, intensification of dual oral therapy by adding GLP-1ar analogue is associated with a lower MACE outcome in routine clinical practice, compared with adding insulin therapy as the third glucose-lowering agent

Choosing which ear to implant in adult candidates with functional residual hearing

This study examined whether audiologists consider the potential benefits of contralateral hearing aid use following cochlear implantation when recommending which ear to implant in UK adult candidates with residual hearing. Thirty-four audiologists from providers of adult implantation services completed a decision-choice experiment. Clinicians were willing to consider recommending that the poorer ear be implanted, provided it had been aided continuously, suggesting that their decision making seeks to preserve access to residual hearing in the non-implanted ear where possible. Future approaches to determining candidacy should therefore consider that a sub-set of patients may obtain additional benefit from this residual hearing following implantation

Assessing the impact of the introduction of an electronic hospital discharge system on the completeness and timeliness of discharge communication: a before and after study

Background: Hospital discharge summaries are a key communication tool ensuring continuity of care between primary and secondary care. Incomplete or untimely communication of information increases risk of hospital readmission and associated complications. The aim of this study was to evaluate whether the introduction of a new electronic discharge system (NewEDS) was associated with improvements in the completeness and timeliness of discharge information, in Nottingham University Hospitals NHS Trust, England. Methods: A before and after longitudinal study design was used. Data were collected using the gold standard auditing tool from the Royal College of Physicians (RCP). This tool contains a checklist of 57 items grouped into seven categories, 28 of which are classified as mandatory by RCP. Percentage completeness (out of the 28 mandatory items) was considered to be the primary outcome measure. Data from 773 patients discharged directly from the acute medical unit over eight-week long time periods (four before and four after the change to the NewEDS) from August 2010 to May 2012 were extracted and evaluated. Results were summarised by effect size on completeness before and after changeover to NewEDS respectively. The primary outcome variable was represented with percentage of completeness score and a non-parametric technique was used to compare pre-NewEDS and post-NewEDS scores. Results: The changeover to the NewEDS resulted in an increased completeness of discharge summaries from 60.7% to 75.0% (p < 0.001) and the proportion of summaries created under 24 h from discharge increased significantly from 78.0% to 93.0% (p < 0.001). Furthermore, five of the seven grouped checklist categories also showed significant improvements in levels of completeness (p < 0.001), although there were reduced levels of completeness for three items (p < 0.001). Conclusion: The introduction of a NewEDS was associated with a significant improvement in the completeness and timeliness of hospital discharge communication

Identifying 'avoidable harm' in family practice: A RAND/UCLA Appropriateness Method consensus study

BackgroundHealth care-related harm is an internationally recognized threat to public health. The United Kingdom’s national health services demonstrate that upwards of 90% of health care encounters can be delivered in ambulatory settings. Other countries are transitioning to more family practice-based health care systems, and efforts to understand avoidable harm in these settings is needed.MethodsWe developed 100 scenarios reflecting a range of diseases and informed by the World Health Organization definition of ‘significant harm’. Scenarios included different types of patient safety incidents occurring by commission and omission, demonstrated variation in timeliness of intervention, and conditions where evidence-based guidelines are available or absent. We conducted a two-round RAND / UCLA Appropriateness Method consensus study with a panel of family practitioners in England to define “avoidable harm” within family practice. Panelists rated their perceptions of avoidability for each scenario. We ran a k-means cluster analysis of avoidability ratings.ResultsPanelists reached consensus for 95 out of 100 scenarios. The panel agreed avoidable harm occurs when a patient safety incident could have been probably, or totally, avoided by the timely intervention of a health care professional in family practice (e.g. investigations, treatment) and / or an administrative process (e.g. referrals, alerts in electronic health records, procedures for following up results) in accordance with accepted evidence-based practice and clinical governance. Fifty-four scenarios were deemed avoidable, whilst 31 scenarios were rated unavoidable and reflected outcomes deemed inevitable regardless of family practice intervention. Scenarios with low avoidability ratings (1 s or 2 s) were not represented by the categories that were used to generate scenarios, whereas scenarios with high avoidability ratings (7 s 8 s or 9 s) were represented by these a priori categories.DiscussionThe findings from this RAND/UCLA Appropriateness Method study define the characteristics and conditions that can be used to standardize measurement of outcomes for primary care patient safety.ConclusionWe have developed a definition of avoidable harm that has potential for researchers and practitioners to apply across primary care settings, and bolster international efforts to design interventions to target avoidable patient safety incidents that cause the most significant harm to patients