Cross-border flow of health information: is 'privacy by design' enough? Privacy performance assessment in EUBIROD.

BACKGROUND: The EUBIROD project aims to perform a cross-border flow of diabetes information across 19 European countries using the BIRO information system, which embeds privacy principles and data protection mechanisms in its architecture (privacy by design). A specific task of EUBIROD was to investigate the variability in the implementation of the EU Data Protection Directive (DPD) across participating centres. METHODS: Compliance with privacy requirements was assessed by means of a specific questionnaire administered to all participating diabetes registers. Items included relevant issues e.g. patient consent, accountability of data custodian, communication (openness) and complaint procedures (challenging compliance), authority to disclose, accuracy, access and use of personal information, and anonymization. The identification of an ad hoc scoring system and statistical software allowed an overall quali-quantitative analysis and independent evaluation of questionnaire responses, automated through a dedicated IT platform ('privacy performance assessment'). RESULTS: A total of 18 diabetes registers from different countries completed the survey. Over 50% of the registers recorded a maximum score for accountability, openness, anonymization and challenging compliance. Low average values were found for disclosure and disposition, access, consent, use of personal information and accuracy. A high heterogeneity was found for anonymization, consent, accuracy and access. CONCLUSIONS: The novel method of privacy performance assessment realized in EUBIROD may improve the respect of privacy in each data source, reduce overall variability in the implementation of privacy principles and favour a sound and legitimate cross-border exchange of high quality data across Europe.

An in-depth assessment of diabetes-related lower extremity amputation rates 2000-2013 delivered by twenty-one countries for the data collection 2015 of the Organization for Economic Cooperation and Development (OECD).

BACKGROUND: International comparisons of diabetes-related lower extremity amputation rates are still hampered by different criteria used for data collection and analysis. We aimed to evaluate trends and variation of major/minor amputations, using agreed definitions adopted by the Organization for Economic Cooperation and Development in 2015. METHODS: Direct age-sex standardized rates were calculated per 100,000 subjects per year between 2000 and 2013, using major/minor amputations with diabetes diagnosis as numerators and the total population or number of people with diabetes as denominators. Longitudinal trends were investigated using generalized estimating equations. RESULTS: Twenty-one countries reported major amputations referred to the general population, showing a mean reduction from 10.8 to 7.5 per 100,000 (- 30.6%). Eleven countries also reported major amputations among people with diabetes, showing a mean reduction from 182.9 to 128.3 per 100,000 (- 29.8%). Minor amputations remained stable over the study period. Longitudinal trends showed a significant average annual decrease of - 0.19 per 100,000 in the general population (95% CI - 0.36 to - 0.02; p = .03) and - 4.52 per 100,000 among subjects with diabetes (95% CI - 6.09 to - 2.94; p < .001). The coefficient of variation of major amputation rates between countries was fairly high (64%-in the total population, 67% among people with diabetes). CONCLUSIONS: The study highlighted a clinically significant reduction of major amputations, in both the general population and among people with diabetes. The use of standardized definitions, while increasing the comparability of multinational data, highlighted remarkable differences between countries. These results can help identifying and sharing best practices effectively on a global scale.

Cost-effectiveness of pioglitazone in type 2 diabetes patients with a history of macrovascular disease: a German perspective.

BACKGROUND: The aim of this study was to project health-economic outcomes relevant to the German setting for the addition of pioglitazone to existing treatment regimens in patients with type 2 diabetes, evidence of macrovascular disease and at high risk of cardiovascular events. METHODS: Event rates corresponding to macrovascular outcomes from the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) study of pioglitazone were used with a modified version of the CORE Diabetes Model to simulate outcomes over a 35-year time horizon. Direct medical costs were accounted from a healthcare payer perspective in year 2005 values. Germany specific costs were applied for patient treatment, hospitalization and management. Both costs and clinical benefits were discounted at 5.0% per annum. RESULTS: Over patient lifetimes pioglitazone treatment improved undiscounted life expectancy by 0.406 years and improved quality-adjusted life expectancy by 0.120 quality-adjusted life years (QALYs) compared to placebo. Direct medical costs (treatment plus complication costs) were marginally higher for pioglitazone treatment and calculation of the incremental cost-effectiveness ratio (ICER) produced a value of euro13,294 per QALY gained with the pioglitazone regimen versus placebo. Acceptability curve analysis showed that there was a 78.2% likelihood that pioglitazone would be considered cost-effective in Germany, using a "good value for money" threshold of euro50,000 per QALY gained. Sensitivity analyses showed that the results were most sensitive to changes in the simulation time horizon. After adjustment for the potential stabilization of pancreatic beta-cell function with pioglitazone treatment, the ICER was euro6,667 per QALY gained for pioglitazone versus placebo. CONCLUSION: The findings of this modelling analysis indicated that, for patients with a history of macrovascular disease, addition of pioglitazone to existing therapy reduces the long-term cumulative incidence of diabetes-complications at a cost that would be considered to represent good value for money in the German setting.

Quality and behavior of glimepiride generics versus amaryl under stressed conditions.

BACKGROUND: The use of generic versions of drugs, such as those for glimepiride [Amaryl, Amarel, Solosa (sanofi-aventis, Paris, France)], a third-generation sulfonylurea, can reduce healthcare costs. However, the quality and performance of these generics should be carefully evaluated. METHODS: We compared the quality and behavior of 23 marketed generic forms with Amaryl (all 2 mg) under stressed conditions. Deblistered samples were stored at 60 degrees C for 21 days in order to mimic temperature-stressed conditions. Samples were analyzed at Days 0, 7, and 21 for content of active compound, levels of impurities, levels of residual solvent (Day 0 only), and dissolution profile, and results were compared against Amaryl specifications. RESULTS: Levels of the degradation product GS [corrected] were < or = 1% in all products at Day 0; however, GS levels [corrected] increased to above Amaryl specifications [corrected] in two generics at Day 7 (Dolcyl and GLA-DM) [corrected] and in four generics at Day 21 [Dolcyl, GLA-DM, glimepiride (Hanni), and glimepirida (Esterlina)] (Fig. 2) [corrected] Total levels of other impurities and levels of residual solvents were above Amaryl specifications (1,400 ppm, respectively) in two generics at Day 0. At Day 0, the dissolution of 12 generics (52%) failed to meet Amaryl specifications (>or=85% dissolved in 15 min); this trend was confirmed at Day 21. Overall, 74% (17 of 23) of the generics were not of equivalent quality or performance compared with Amaryl. CONCLUSIONS: This study indicates that a relevant percentage of glimepiride generics may offer reduced quality and performance when compared with the original drug.

Clinical validation of a new control-oriented model of insulin and glucose dynamics in subjects with type 1 diabetes.

BACKGROUND: The development of an artificial pancreas requires an accurate representation of diabetes pathophysiology to create effective and safe control systems for automatic insulin infusion regulation. The aim of the present study is the assessment of a previously developed mathematical model of insulin and glucose metabolism in type 1 diabetes and the evaluation of its effectiveness for the development and testing of control algorithms. METHODS: Based on the already existing "minimal model" a new mathematical model was developed composed of glucose and insulin submodels. The glucose model includes the representation of peripheral uptake, hepatic uptake and release, and renal clearance. The insulin model describes the kinetics of exogenous insulin injected either subcutaneously or intravenously. The estimation of insulin sensitivity allows the model to personalize parameters to each subject. Data sets from two different clinical trials were used here for model validation through simulation studies. The first set had subcutaneous insulin injection, while the second set had intravenous insulin injection. The root mean square error between simulated and real blood glucose profiles (G(rms)) and the Clarke error grid analysis were used to evaluate the system efficacy. RESULTS: Results from our study demonstrated the model's capability in identifying individual characteristics even under different experimental conditions. This was reflected by an effective simulation as indicated by G(rms), and clinical acceptability by the Clarke error grid analysis, in both clinical data series. CONCLUSIONS: Simulation results confirmed the capacity of the model to faithfully represent the glucose-insulin relationship in type 1 diabetes in different circumstances.

PROactive 07: pioglitazone in the treatment of type 2 diabetes: results of the PROactive study.

Patients with type 2 diabetes face an increased risk of macrovascular disease compared to those without. Significant reductions in the risk of major cardiovascular events can be achieved with appropriate drug therapy, although patients with type 2 diabetes remain at increased risk compared with non-diabetics. The thiazolidinedione, pioglitazone, is known to offer multiple, potentially antiatherogenic, effects that may have a beneficial impact on macrovascular outcomes, including long-term improvements in insulin resistance (associated with an increased rate of atherosclerosis) and improvement in the atherogenic lipid triad (low HDL-cholesterol, raised triglycerides, and a preponderance of small, dense LDL particles) that is observed in patients with type 2 diabetes. The recent PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) study showed that pioglitazone can reduce the risk of secondary macrovascular events in a high-risk patient population with type 2 diabetes and established macrovascular disease. Here, we summarize the key results from the PROactive study and place them in context with other recent outcome trials in type 2 diabetes.

Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.

BACKGROUND: Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes. METHODS: We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993. FINDINGS: Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups. INTERPRETATION: Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.

Changing targets in the treatment of type 2 diabetes.

BACKGROUND: While correction of hyperglycemia remains central to the management of type 2 diabetes, current management approaches address an integrated constellation of disorders that predispose patients to the risk of microvascular and macrovascular complications. SCOPE: This paper reviews glycemic control targets and associated cardiovascular disease risk management in type 2 diabetes, as recommended by the American Diabetes Association (ADA), the International Diabetes Federation (IDF), and the UK National Institute for Clinical Excellence (NICE). It is based upon MEDLINE literature searches from January 1995 to April 2006. FINDINGS: Current guidelines recommend glycated hemoglobin (HbA1c) target levels of approximately 6.0-7.5%. However, European and US data suggest that HbA1c targets are achieved by only approximately one-third of patients with type 2 diabetes. Progression from pre-diabetic impaired glucose tolerance to type 2 diabetes has recently become a target for early intervention with pharmacological agents. The aggressive treatment of dyslipidemia towards defined target levels of triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol is recommended. The ADA and IDF recommend blood pressure targets of 130/80 mmHg in type 2 diabetes, and the use of aspirin for secondary cardiovascular disease prevention and primary prevention in patients at increased risk. Although inflammatory biomarkers, such as C-reactive protein, may predict type 2 diabetes risk, their role remains unclear. CONCLUSIONS: Concerted efforts are necessary to increase the proportion of patients achieving current treatment targets. Such measures must aim to educate patients and physicians, remove barriers due to health care organization and access, and improve the monitoring of cardiovascular disease risk indicators. The poly-pharmacy 'pill burden' may be alleviated through the use of drugs that are effective against multiple aspects of the metabolic syndrome, and by co-formulation of agents with established efficacy.

Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes.

OBJECTIVE: Insulin glargine (LANTUS) is a once-daily basal insulin analog with a smooth 24-h time-action profile that provides effective glycemic control with reduced hypoglycemia risk (particularly nocturnal) compared with NPH insulin in patients with type 2 diabetes. A recent "treat-to-target" study has shown that more patients on insulin glargine reached HbA(1c) levels < or =7.0% without confirmed nocturnal hypoglycemia compared with NPH insulin. We further assessed the risk for hypoglycemia in a meta-analysis of controlled trials of a similar design for insulin glargine versus once- or twice-daily NPH insulin in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: All studies were 24-28 weeks long, except one 52-week study, for which interim 20-week data were used. RESULTS: Patient demographics were similar between the insulin glargine (n = 1,142) and NPH insulin (n = 1,162) groups. The proportion of patients achieving target HbA(1c) (< or =7.0%) was similar between insulin glargine-and NPH insulin-treated patients (30.8 and 32.1%, respectively). There was a consistent significant reduction of hypoglycemia risk associated with insulin glargine, compared with NPH insulin, in terms of overall symptomatic (11%; P = 0.0006) and nocturnal (26%; P < 0.0001) hypoglycemia. Most notably, the risk of severe hypoglycemia and severe nocturnal hypoglycemia were reduced with insulin glargine by 46% (P = 0.0442) and 59% (P = 0.0231), respectively. CONCLUSIONS: These results confirmed that insulin glargine given once daily reduces the risk of hypoglycemia compared with NPH insulin, which can facilitate more aggressive insulin treatment to a HbA(1c) target of < or =7.0% in patients with type 2 diabetes.

The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients.

OBJECTIVE: The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) assesses the effect of pioglitazone, a peroxisome proliferator-activated receptor agonist, with anti-inflammatory and vascular properties, on the secondary prevention of macrovascular events in type 2 diabetes. RESEARCH DESIGN AND METHODS: PROactive is an on-going randomized, double-blind outcome study in patients with type 2 diabetes managed with diet and/or oral blood glucose-lowering drugs (combination of oral agents with insulin is permitted) who have a history of macrovascular disease. Patients are randomized to receive pioglitazone (forced titration from 15 to 30 to 45 mg, depending on tolerability) or placebo in addition to existing therapy. The primary end point is the time from randomization to occurrence of a new macrovascular event or death. Follow-up is estimated to span 4 years. RESULTS: A total of 5238 patients have been randomized from 19 countries. At entry into the study, patients enrolled are a mean age of 61.8 years, with type 2 diabetes for a mean of 9.5 years; 60.9 and 61.5% are taking metformin or a sulfonylurea, respectively; and 33.6% are using insulin in addition to oral glucose-lowering drugs. The majority of patients are men (66.1%). Patients are required to meet one or more of entry criteria, as follows: >6 months' history of myocardial infarction (46.7%); coronary artery revascularization (30.8%), stroke (18.8%), or acute coronary syndrome for >3 months (13.7%); other evidence of coronary artery disease (48.1%); or peripheral arterial occlusive disease (19.9%). One-half (48.5%) of the patients have two or more of these risk factors. Three-quarters (75.4%) have hypertension, and 58.8% are current or previous smokers. CONCLUSIONS: The cohort of patients enrolled in PROactive is a typical type 2 diabetic population at high risk of further macrovascular events. The characteristics of this population are ideal for assessing the ability of pioglitazone to reduce the cardiovascular risk of patients with type 2 diabetes.

Glimepiride in type 2 diabetes mellitus: a review of the worldwide therapeutic experience.

BACKGROUND: Sulfonylureas (SUs) have been used for many years as first-line therapy for patients with type 2 diabetes mellitus whose blood glucose levels have not been effectively controlled by diet and exercise alone. Glimepiride is a once-daily SU that was introduced in 1995. Since then, a considerable body of evidence has been amassed regarding its use in type 2 diabetes. OBJECTIVE: This review provides a comprehensive summary of available data on the pharmacology, pharmacokinetics, efficacy, and safety profile of glimepiride in the treatment of type 2 diabetes. It also examines the use of glimepiride to achieve and maintain good glycemic control in patients with type 2 diabetes in current clinical practice. METHODS: Relevant articles were identified through a search of MEDLINE for English-language studies published from 1990 to 2002. The search terms used were glimepiride, sulfonylureas, and type 2 diabetes mellitus. The manufacturer of glimepiride provided additional information. RESULTS: Glimepiride differs from other SUs in a number of respects. In clinical studies, glimepiride was generally associated with a lower risk of hypoglycemia and less weight gain than other SUs. Results of other studies suggest that glimepiride can be used in older patients and those with renal compromise. There is evidence that glimepiride preserves myocardial preconditioning, a protective mechanism that limits damage in the event of an ischemic event. Glimepiride can be used in combination with other oral antidiabetic agents or insulin to optimize glycemic control. CONCLUSION: Based on the evidence to date, glimepiride is an effective and well-tolerated once-daily antidiabetic drug and provides an important treatment option for the management of type 2 diabetes.

Closing the loop: the adicol experience.

The objective of the project Advanced Insulin Infusion using a Control Loop (ADICOL) was to develop a treatment system that continuously measures and controls the glucose concentration in subjects with type 1 diabetes. The modular concept of the ADICOL's extracorporeal artificial pancreas consisted of a minimally invasive subcutaneous glucose system, a handheld PocketPC computer, and an insulin pump (D-Tron, Disetronic, Burgdorf, Switzerland) delivering subcutaneously insulin lispro. The present paper describes a subset of ADICOL activities focusing on the development of a glucose controller for semi-closed-loop control, an in silico testing environment, clinical testing, and system integration. An incremental approach was adopted to evaluate experimentally a model predictive glucose controller. A feasibility study was followed by efficacy studies of increasing complexity. The ADICOL project demonstrated feasibility of a semi-closed-loop glucose control during fasting and fed conditions with a wearable, modular extracorporeal artificial pancreas.

The costs of type 2 diabetes mellitus in Italy: a CODE-2 sub-study.

AIM: To estimate the direct, indirect, and intangible costs associated with type 2 diabetes mellitus in Italy in 1998. To evaluate the economic impact of diabetic complications, and to investigate drug treatment patterns and associated costs in patients with type 2 diabetes. METHODS: The Italian arm of an international study (COsts of Diabetes in Europe--Type 2 [CODE-2], a descriptive, cross-sectional survey) was set up to collect information retrospectively by means of questionnaires from a sample of 1263 patients. Resource use was measured in monetary terms using a set of costs and tariffs. Intangible costs were estimated using the EuroQol questionnaire. RESULTS: The average yearly cost for medical resources for a patient with type 2 diabetes was 2991 Euro, whereas the estimated cost for the whole population with type 2 diabetes was about 5170 million Euro. This corresponds to 6.65% of the total healthcare expenditure (public and private) in Italy. Of direct costs, 29% was spent for the treatment of diabetes and 39% for the treatment of diabetic complications; while the remaining 32% was spent for healthcare not related to diabetes. Quality of life score in patients with type 2 diabetes (EuroQoL overall average score) was 0.68. CONCLUSIONS: Type 2 diabetes has a high cost to society. The major cost component is due to the care of diabetic complications, not to the treatment of the illness itself; in particular, drug costs represent a relatively small proportion of such treatment cost.

Nonlinear model predictive control of glucose concentration in subjects with type 1 diabetes.

A nonlinear model predictive controller has been developed to maintain normoglycemia in subjects with type 1 diabetes during fasting conditions such as during overnight fast. The controller employs a compartment model, which represents the glucoregulatory system and includes submodels representing absorption of subcutaneously administered short-acting insulin Lispro and gut absorption. The controller uses Bayesian parameter estimation to determine time-varying model parameters. Moving target trajectory facilitates slow, controlled normalization of elevated glucose levels and faster normalization of low glucose values. The predictive capabilities of the model have been evaluated using data from 15 clinical experiments in subjects with type 1 diabetes. The experiments employed intravenous glucose sampling (every 15 min) and subcutaneous infusion of insulin Lispro by insulin pump (modified also every 15 min). The model gave glucose predictions with a mean square error proportionally related to the prediction horizon with the value of 0.2 mmol L(-1) per 15 min. The assessment of clinical utility of model-based glucose predictions using Clarke error grid analysis gave 95% of values in zone A and the remaining 5% of values in zone B for glucose predictions up to 60 min (n = 1674). In conclusion, adaptive nonlinear model predictive control is promising for the control of glucose concentration during fasting conditions in subjects with type 1 diabetes.

Treatment of type 2 diabetes with combined therapy: what are the pros and cons?

Type 2 diabetes is a progressive syndrome that evolves toward complete insulin deficiency during the patient's life. A stepwise approach for its treatment should be tailored according to the natural course of the disease, including adding insulin when hypoglycemic oral agent failure occurs. Treatment with insulin alone should eventually be considered in a relevant number of cases. Experience has shown the protective effects of insulin on beta-cell survival and function, resulting in more stable metabolic control. On the contrary, treatment with most insulin secretagogues has been associated with increased beta-cell apoptosis, reduced responsiveness to high glucose, and impairment of myocardial function during ischemic conditions. In addition, macrovascular complications are associated with postprandial hyperglycemia, indicating the need for tight glycemic control. Insulin treatment, especially with rapid-acting analogs, has been demonstrated to successfully control postprandial glucose excursions. Finally, a reason for concern with regard to combined therapy is represented by the evidence that polipharmacy reduces compliance to the treatment regimen. This can be particularly relevant in patients with type 2 diabetes usually taking drugs for complications and for concomitant diseases with consequent deterioration not only of metabolic control but also of other conditions. In conclusion, therapy with insulin alone immediately after hypoglycemic oral agent failure may be a useful and safe therapeutic approach in type 2 diabetes.

The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study.

OBJECTIVES: This analysis from the PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) study assesses the effects of pioglitazone on mortality and macrovascular morbidity in patients with type 2 diabetes and a previous myocardial infarction (MI). BACKGROUND: People with type 2 diabetes have an increased incidence of MI compared with the general population. Those with diabetes and MI have a worse prognosis than nondiabetic patients with cardiovascular disease. METHODS: The PROactive study was a prospective, multicenter, double-blind, placebo-controlled trial of 5,238 patients with type 2 diabetes and macrovascular disease. Patients were randomized to either pioglitazone or placebo in addition to their other glucose-lowering and cardiovascular medication. Treatment of diabetes, dyslipidemia, and hypertension was encouraged according to the International Diabetes Federation guidelines. Patients were followed for a mean of 2.85 years. The primary end point was the time to first occurrence of macrovascular events or death. Of the total cohort, the subgroup of patients who had a previous MI (n = 2,445 [46.7%]; n = 1,230 in the pioglitazone group and n = 1,215 in the placebo group) was evaluated using prespecified and post-hoc analyses. RESULTS: Pioglitazone had a statistically significant beneficial effect on the prespecified end point of fatal and nonfatal MI (28% risk reduction [RR]; p = 0.045) and acute coronary syndrome (ACS) (37% RR; p = 0.035). There was a 19% RR in the cardiac composite end point of nonfatal MI (excluding silent MI), coronary revascularization, ACS, and cardiac death (p = 0.033). The difference in the primary end point defined in the main PROactive study did not reach significance in the MI population (12% RR; p = 0.135). The rates of heart failure requiring hospitalization were 7.5% (92 of 1,230) with pioglitazone and 5.2% (63 of 1,215) with placebo. Fatal heart failure rates were similar (1.4% [17 of the 92] with pioglitazone versus 0.9% [11 of the 63] with placebo). CONCLUSIONS: In high-risk patients with type 2 diabetes and previous MI, pioglitazone significantly reduced the occurrence of fatal and nonfatal MI and ACS. (PROspective pioglitAzone Clinical Trial In macroVascular Events; http://www.clinicaltrials.gov/ct/show/NCT00174993?order = 1; ISRCTN NCT00174993).

Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: data from the PROactive study (PROactive 08).

OBJECTIVE: PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) enrolled patients with type 2 diabetes and preexisting cardiovascular disease. These patients were at high risk for heart failure, so any therapeutic benefit could potentially be offset by risk of associated heart failure mortality. We analyzed the heart failure cases to assess the effects of treatment on morbidity and mortality after reports of serious heart failure. RESEARCH DESIGN AND METHODS: PROactive was an outcome study in 5,238 patients randomized to pioglitazone or placebo. Patients with New York Heart Association Class II-IV heart failure at screening were excluded. A serious adverse event of heart failure was defined as heart failure that required hospitalization or prolonged a hospitalization stay, was fatal or life threatening, or resulted in persistent significant disability or incapacity. Heart failure risk was evaluated by multivariate regression. RESULTS: More pioglitazone (5.7%) than placebo patients (4.1%) had a serious heart failure event during the study (P = 0.007). However, mortality due to heart failure was similar (25 of 2,605 [0.96%] for pioglitazone vs. 22 of 2,633 [0.84%] for placebo; P = 0.639). Among patients with a serious heart failure event, subsequent all-cause mortality was proportionately lower with pioglitazone (40 of 149 [26.8%] vs. 37 of 108 [34.3%] with placebo; P = 0.1338). Proportionately fewer pioglitazone patients with serious heart failure went on to have an event in the primary (47.7% with pioglitazone vs. 57.4% with placebo; P = 0.0593) or main secondary end point (34.9% with pioglitazone vs. 47.2% with placebo; P = 0.025). CONCLUSIONS: Although the incidence of serious heart failure was increased with pioglitazone versus placebo in the total PROactive population of patients with type 2 diabetes and macrovascular disease, subsequent mortality or morbidity was not increased in patients with serious heart failure.

National survey on the execution of the oral glucose tolerance test (OGTT) in a representative cohort of Italian laboratories.

BACKGROUND: Recently revised diagnostic criteria for diabetes mellitus and the lack of universal agreement on the methodology for the screening and diagnosis of gestational diabetes mellitus (GDM) still generate inconsistency in execution of the oral glucose tolerance test (OGTT). The aim of the present survey was to evaluate the adherence of Italian laboratories to the internationally accepted guidelines in carrying out the OGTT for the diagnosis of diabetes in the general population and for the screening of GDM. METHODS: A questionnaire was designed to investigate the following issues related to the OGTT: 1) the relationship between laboratories and diabetes centres for the definition of standard protocols; 2) the amount of glucose administered; 3) the number and timing of blood samples; 4) the procedures used for the screening and diagnosis of GDM; and 5) reference to WHO guidelines for the interpretation of the results. The questionnaire was administered to 400 specialists in laboratory medicine working in public or private laboratories nationwide participating in the "Italian External Evaluation of Quality in Laboratory Medicine" Study Group. RESULTS: The survey was completed in the period from June to September 2003. In the observation period, 241 questionnaires were returned by specialists working in laboratories scattered throughout 15 out of the 20 Italian regions. Only 50% of the laboratories performed the OGTT according to protocols defined in agreement with local reference diabetes centres. OGTT using 75 g of glucose in adults and 1.75 g/kg for children as recommended by WHO was performed by 87.1% of the laboratories. WHO indications to collect samples at baseline and at 120 min were followed by 33.2% of the centres. Higher variability was highlighted with respect to the methodology for GDM screening: 49.8% of the laboratories always adopted the two-step procedure consisting of a glucose challenge test (GCT) and subsequent OGTT in positive cases; 4.9% performed the 100-g OGTT with four blood samples; 1.6% the 75-g OGTT with two blood samples; and 2.7% the 75-g OGTT with four blood samples. More than 30% of the centres referred to different diagnostic schemes, 62% of which used individually chosen procedures amongst those reported above, 19% used only the GCT and no subsequent OGTT in positive cases, and 18.4% used a variety of completely different, arbitrarily chosen methods. Finally, only 25.6% of the laboratories referred to the WHO limits for interpretation of the results. CONCLUSIONS: For the Italian laboratories investigated, relevant variability was highlighted for performance of the OGTT in general and GDM screening in particular. A variable relationship between laboratories and diabetes centres was also detected, which might represent a relevant indicator for the need for rationalisation or standardisation of the method for performing an OGTT. These data highlight the need for greater collaboration between these different bodies. We suggest that other similar investigations should be carried out in other countries within the framework of the IFCC Global Campaign on Diabetes Mellitus.

The artificial pancreas.

In type 1 diabetes an absolute deficiency of insulin secretion requires exogenous insulin supply to guarantee the patient's life avoiding ketoacidotic coma and to prevent the chronic complications of diabetes. In order to obtain a more physiological replacement therapy different approaches have been pursued since the early 70s to create an artificial wearable pancreas able to deliver insulin according to the blood glucose values as determined by continuous monitoring. Four components are considered essential for the realisation of an artificial pancreas: the sampling system, the glucose sensor, the mathematical models and the related algorithms for the calculation of the insulin doses and the infusion system for the insulin delivery. At present the still unsolved issues are mainly represented by the availability of reliable continuous glucose monitor and control algorithms, while the new technologies allow for the miniaturisation of the system.