Spectrum of Diabetes Research does not Reflect Patients' Scientific Preferences: A Longitudinal Evaluation of Diabetes Research Areas 2010-2013 vs. a Cross-sectional Survey in Patients with Diabetes.

OBJECTIVE: To compare the proportions and trends in the distribution of research topics as presented during the annual meetings 2010-2013 of the European Association for the Study of Diabetes (EASD) to patients' preferences. METHODS: Longitudinal evaluation of EASD research areas 2010-2013 divided into 9 main categories and compared with a cross-sectional survey in 918 people (652 with patients with diabetes, 205 relatives, 61 others interested), who had allocated their preferences to the same 9 topics. RESULTS: "Development, pathophysiology and prevention of diabetes" was the primary category of interest for 25% of patients, 19% preferred "transplantation and cell therapy" and 16% "blood glucose measurement, devices and artificial pancreas". During the 4 years of abstract investigation 50% or more of total research activities was constantly dedicated to "pathophysiology and prevention of diabetes", less than 2% to "transplantation and cell therapy" and 2.8-4.3% to "blood glucose measurement, devices and artificial pancreas". The average proportion of EASD research related to "blood-glucose lowering therapy without insulin" and "insulin therapy" corresponded with the proportion of research patients would like to see (12.0 vs. 12.5%, and 6.9 vs. 4.7%, respectively). The majority, however, was commercially funded. Non-commercial research was not closer correlated to patients' preferences. CONCLUSION: The distribution of research topics over the last 4 years as measured by the distribution of accepted EASD abstracts does not reflect what patients and their relatives want to have investigated. Better patient involvement and a reassessment of non-commercial funding strategies might help create more valuable research.

How do patients' preferences compare to the present spectrum of diabetes research?

OBJECTIVE: To compare patients' preferences in diabetes research to the current scientific research spectrum as presented during annual meetings of the European Association for the Study of Diabetes (EASD). METHODS: After dividing all scientific activities in diabetes research into 9 main fields, a questionnaire was published in a popular German weekly news magazine, inviting diabetic patients to express their research preferences. Thereafter, all abstracts accepted for publication at 2 recent EASD meetings were allocated to one of these research fields. RESULTS: In May and July 2011 the questionnaire was answered by 652 patients with diabetes, 205 relatives and 61 other persons interested. The most important research fields were "development, pathophysiology and prevention of diabetes" (25.6%), "transplantation and cell therapy" (19.4%) and "blood glucose measurement and artificial pancreas" (16.5%). The most often covered topic of the 2,645 EASD abstracts was "development, pathophysiology and prevention" (46.3%), followed by "diabetes complications in man" (17.5%) and "special situations, training, psychology, treatment- and care structures" (10.5%). CONCLUSION: Views of diabetic patients and their relatives regarding their preferred research fields may differ when compared to current scientific activity in diabetology. Diabetic patients and their relatives should be involved in the weighting and selection of research topics more often.

Screening for diabetes: hope and despair.

This commentary discusses whether screening for type 2 diabetes or earlier normalisation of blood glucose levels or initiation of non-antihyperglycaemic agents or any other diabetes-specific treatment can help reduce the excess associated risks for macrovascular morbidity and mortality. The available data indicate that screening with the sole aim of decreasing the lead time between diagnosis and treatment is very unlikely to reduce these risks. In contrast to macrovascular complications, some microvascular events such as background retinopathy could theoretically be prevented by earlier diagnosis and better glycaemic control, particularly in relatively young type 2 diabetic patients. This, however, remains to be shown in controlled prospective intervention trials.

[The methods within the evaluation of disease management programmes in control-group designs using the example of diabetes mellitus - a systematic literature review]. / Die Methoden der Evaluation von Disease Management Programmen im Kontrollgruppendesign am Beispiel Diabetes mellitus - Eine systematische Übersicht.

BACKGROUND: Disease management programmes (DMPs) were implemented in Germany in 2002. Their evaluation is required by law. Beyond the mandatory evaluation, a growing number of published studies evaluate the DMP for diabetes mellitus type 2 in a control-group design. As patients opt into the programme on a voluntary basis it is necessary to adjust the inherent selection bias between groups. The aim of this study is to review published studies which evaluate the diabetes DMP using a control-group design with respect to the methods used. METHODS: A systematic literature review of electronic databases (PUBMED, Cochrane Library, EMBASE, MEDPILOT) and a hand search of reference lists of the relevant publications was conducted to identify studies evaluating the DMP diabetes mellitus in a control-group design. RESULTS: 8 studies were included in the systematic literature review. 4 studies gathered retrospective claims data from sickness funds, one from physician's records, one study used prospective data from ambulatory care, and 2 studies were based on one patient survey. Methods used for adjustment of selection bias included exact matching, matching using propensity score methods, age-adjusted and sex-separated analysis, and adjustment in a regression model/analysis of covariance. One study did not apply adjustment methods. The intervention period ranged from 1 day to 4 years. Considered outcomes of studies (surrogate parameter, diabetes complications, mortality, quality of life, and claim data) depended on the database. CONCLUSION: In the evaluation of the DMP diabetes mellitus based on a control-group design neither the database nor the methods used for selection bias adjustment were consistent in the available studies. Effectiveness of DMPs cannot be judged based on this review due to heterogeneity of study designs. To allow for a comprehensive programme evaluation standardised minimum requirements for the evaluation of DMPs in the control group design are required.

Life prolonging of disease management programs in patients with type 2 diabetes is cost-effective.

AIM: Our objective was to examine the cost-effectiveness of disease management programs (DMPs) for type 2 diabetes mellitus (T2DM) taking into account their life prolonging effect. METHODS: We compared real life costs in 19,888 propensity score matched pairs of T2DM DMP participants and T2DM patients in routine care (RC) according to sickness funds data. We estimated mean annual costs for survivors, last year of life costs for decedents, the influence of ageing on costs, incremental cost-effectiveness ratio and effects on hospitalization. RESULTS: Annual costs for survivors were 3,318€ (DMP) and 3,570€ (RC). The mean costs in the last year of life were 16,911€ (DMP) and 15,763€ (RC). Ageing had a cost triggering effect for survivors (30€/36€ per year in DMP-/RC-group; p<0.001) and a cost decreasing effect in the last year of life (546€/483€ per year in DMP-/RC-group; p<0.001). The incremental cost-effectiveness ratio of the DMP vs. RC was -1396€ per life-year gained. Hospitalizations increased with age in case of survival and decreased with age in case of death but were always lower in the DMP-group. CONCLUSION: Despite increase in costs due to longer life DMPs are cost-effective.

Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study.

AIMS/HYPOTHESIS: The aim of this cohort study was to investigate the risk of malignant neoplasms and mortality in patients with diabetes treated either with human insulin or with one of three insulin analogues. METHODS: Data were provided by the largest German statutory health insurance fund (time-frame: January 1998 to June 2005 inclusive), on patients without known malignant disease who had received first-time therapy for diabetes mellitus exclusively with human insulin, aspart, lispro or glargine. The primary outcome was the diagnosis of a malignant neoplasm. Data were analysed by multiple Cox regression models adjusting for potential confounders. RESULTS: A total of 127,031 patients were included, with a mean follow-up time of 1.63 (median 1.41, maximum 4.41) years. A positive association between cancer incidence and insulin dose was found for all insulin types. Because patients receiving combined therapy with insulin analogues and human insulin were excluded, the mean daily dose was much lower for glargine than for human insulin, and a slightly lower cancer incidence in the glargine group was found. After adjusting for dose, a dose-dependent increase in cancer risk was found for treatment with glargine compared with human insulin (p < 0.0001): the adjusted HR was 1.09 (95% CI 1.00 to 1.19) for a daily dose of 10 IU, 1.19 (95% CI 1.10 to 1.30) for a daily dose of 30 IU, and 1.31 (95% CI 1.20 to 1.42) for a daily dose of 50 IU. No increased risk was found for aspart (p = 0.30) or lispro (p = 0.96) compared with human insulin. CONCLUSIONS/INTERPRETATION: Considering the overall relationship between insulin dose and cancer, and the lower dose with glargine, the cancer incidence with glargine was higher than expected compared with human insulin. Our results based on observational data support safety concerns surrounding the mitogenic properties of glargine in diabetic patients. Prospective long-term studies are needed to further evaluate the safety of insulin analogues, especially glargine.

[Patient-relevant end points: present state of the discussion at the Institute for Quality and Cost-Effectiveness in Public Health]. / Patientenrelevante Endpunkte - Stand der Diskussion im Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG).

In addition to an exact definition, correct measurement of any patient-relevant value is important. Assessing the value of medical interventions is mainly made difficult by the uncertain interpretation of a study's end points, among others caused by the use of invalid surrogate parameters, the clinically unreasonable combination of end points or the arbitrary POST HOC combination of end points as well as the premature termination of studies because of unclear evidence of superiority. As numerous errors can be made when measuring patient-relevant end points, it is the task of the Institute for Quality and Cost-Effectiveness in Health Care not only to describe patient-relevant value in general (and particular for different cases), but also to point out measurement errors in this regard, so that they can be avoided in future.

[Aspects of economic evaluation in health care]. / Aspekte zur gesundheitsökonomischen Bewertung im Gesundheitssystem.

Health economists use models to estimate comparative costs and usage of interventions in health care. However the concepts and methods used have inherent weaknesses, especially in the determination of relevant and exact effect sizes. Health economic methodologies do not replace sociopolitical decision making, but they can play an important role in rational decision making about necessary changes to our social and health system if the instruments themselves are neither over- nor underestimated.

Impact of smoking on the metabolic action of subcutaneous regular insulin in type 2 diabetic patients.

BACKGROUND AND AIMS: Smoking has repeatedly been associated with alterations in both insulin sensitivity and insulin absorption in type 2 diabetes, which should lead to differences in the pharmacokinetic (PK) and pharmacodynamic (PD) properties of regular insulin (RI). However, a direct comparison of the PK/PD-effects of RI has never been performed in these patients. Therefore, the aim of this exploratory study was to investigate the time-action profile of RI in a small group of smoking and matching non-smoking patients with type 2 diabetes using the euglycemic glucose clamp technique, which is seen as the gold standard for PD/PK investigations. MATERIAL AND METHODS: Nine smokers (more than 10 cigarettes per day) and nine non-smokers matched for gender, age, and BMI (without significant differences in HbA (1c), diabetes duration or blood pressure) were enrolled in the study. Patients' blood glucose was stabilized overnight at 7.2 mmol/l using a Biostator. Smokers were required to smoke one cigarette within ninety minutes prior to injection of 18 U RI s. c. in the morning. Glucose infusion rates (GIR) were registered for the subsequent 480 min. RESULTS: Injection of 18 U of RI resulted in significantly higher insulin concentrations in smokers compared to non-smokers, in particular in the later part of the experiment (Insulin-AUC (240-480) 10.5 +/- 2.3 (mean +/- SD) vs. 7.8 +/- 1.6 microU/ml/min, p < 0.05). This was also reflected in the PD results with a higher metabolic effect in smokers in the last four hours of the experiment (GIR-AUC (240-480) 0.9 +/- 0.4 vs. 0.6 +/- 0.3 g/kg, p < 0.05). Pharmacokinetic analyses revealed a trend towards a lower insulin clearance in smokers (1.1 +/- 0.2 vs. 1.4 +/- 0.4 l/min, p = 0.08). CONCLUSIONS: This pilot study conducted in a small group of patients with type 2 diabetes shows that regular insulin exhibits a longer-lasting rise in insulin concentrations and a higher metabolic effect four to eight hours after injection in smokers compared to non-smokers. This suggests that hyperinsulinemia in smoking type 2 diabetic patients is at least partly caused by a deterioration in insulin clearance.

Meta-analysis of short-acting insulin analogues in adult patients with type 1 diabetes: continuous subcutaneous insulin infusion versus injection therapy.

AIMS/HYPOTHESIS: This study aimed to compare the effect of treatment with short-acting insulin (SAI) analogues versus structurally unchanged short-acting insulin (regular insulin) on glycaemic control and on the risk of hypoglycaemic episodes in type 1 diabetic patients using different insulin treatment strategies. METHODS: We performed a meta-analysis of 27 randomised controlled trials that compared the effect of SAI analogues with regular insulin in patients with type 1 diabetes mellitus. The treatments were administered either via continuous subcutaneous insulin infusion (CSII) or by conventional intensified insulin therapy (IIT) with short-acting insulin injections before meals and basal insulin administered once or twice daily in most cases. RESULTS: HbA(1)c levels were reported for 20 studies. For studies using CSII, the weighted mean difference between values obtained using SAI analogues and regular insulin was -0.19% (95% CI: -0.27 to -0.12), whereas the corresponding value for injection studies was -0.08% (95% CI: -0.15 to -0.02). For the analysis of overall hypoglycaemia, we used the results from nine studies that reported the mean frequency of hypoglycaemic episodes per patient per month. For studies using CSII, the standardised mean difference between SAI analogues and regular insulin was -0.07 (95% CI: -0.43 to 0.28), whereas for IIT studies the corresponding value was -0.04 (95% CI: -0.24 to 0.16). CONCLUSIONS/INTERPRETATION: Taking into consideration the low quality of the trials included, we can conclude that use of a short-acting insulin analogue in CSII therapy provides a small, but statistically significant improvement in glycaemic control compared with regular insulin. An even smaller effect was obtained with the use of ITT. The rate of overall hypoglycaemic episodes was not significantly reduced with short-acting insulin analogues in either injection regimen.

Acarbose for prevention of diabetes, hypertension and cardiovascular events? A critical analysis of the STOP-NIDDM data.

INTRODUCTION: Cardiovascular morbidity and mortality is a major and still unresolved threat to patients with reduced glucose tolerance and Type 2 diabetes mellitus. In epidemiological studies, in non-diabetic subjects, post-prandial glycaemia is positively associated with the risk of diabetes, hypertension and cardiovascular events. If this epidemiological association is causal, Acarbose, which reduces post-prandial blood glucose concentrations, should result in a decrease in the risk of these events. The STOP-NIDDM trial investigated whether Acarbose reduces the risk of diabetes, hypertension and cardiovascular events. Consequently, the validity of the results of this trial is of major importance for future treatment in non-diabetic and diabetic patients. METHODS: We searched various databases and the Internet for publications of the design and the results of the STOP-NIDDM trial. A systematic review of these publications was done with respect to information about potential sources of bias and contradictory information in the articles. RESULTS: We found several serious flaws in the STOP-NIDDM study, especially selection bias, inadequate blinding, bias in data analysis and reporting, and potential sponsoring bias. CONCLUSIONS: The validity of the results of the STOP-NIDDM trial is seriously flawed. The clinical benefit of Acarbose and of the reduction of post-prandial glycaemia is unproven.

Centrality dependence of charged-hadron transverse-momentum spectra in d+Au collisions at sqrt[s(NN)]=200 GeV.

We have measured transverse momentum distributions of charged hadrons produced in d+Au collisions at sqrt[s(NN)]=200 GeV. The spectra were obtained for transverse momenta 0.25

Significance of the fragmentation region in ultrarelativistic heavy-ion collisions.

We present measurements of the pseudorapidity distribution of primary charged particles produced in Au+Au collisions at three energies, sqrt[s(NN)]=19.6, 130, and 200 GeV, for a range of collision centrali-ties. The distribution narrows for more central collisions and excess particles are produced at high pseudorapidity in peripheral collisions. For a given centrality, however, the distributions are found to scale with energy according to the "limiting fragmentation" hypothesis. The universal fragmentation region described by this scaling grows in pseudorapidity with increasing collision energy, extending well away from the beam rapidity and covering more than half of the pseudorapidity range over which particles are produced. This approach to a universal limiting curve appears to be a dominant feature of the pseudorapidity distribution and therefore of the total particle production in these collisions.