Artificial Pancreas Systems for People With Type 2 Diabetes: Conception and Design of the European CLOSE Project.

In the last 10 years tremendous progress has been made in the development of artificial pancreas (AP) systems for people with type 1 diabetes (T1D). The pan-European consortium CLOSE (Automated Glu cose Contro l at H ome for People with Chronic Disea se) is aiming to develop integrated AP solutions (APplus) tailored to the needs of people with type 2 diabetes (T2D). APplus comprises a product and service package complementing the AP system by obligatory training as well as home visits and telemedical consultations on demand. Outcome predictors and performance indicators shall help to identify people who could benefit most from AP usage and facilitate the measurement of AP impact in diabetes care. In a first step CLOSE will establish a scalable APplus model case working at the interface between patients, homecare service providers, and payers in France. CLOSE will then scale up APplus by pursuing geographic distribution, targeting additional audiences, and enhancing AP functionalities and interconnectedness. By being part of the European Institute of Innovation and Technology (EIT) Health public-private partnership, CLOSE is committed to the EIT "knowledge triangle" pursuing the integrated advancement of technology, education, and business creation. Putting stakeholders, education, and impact into the center of APplus advancement is considered key for achieving wide AP use in T2D care.

Performance Comparison of CGM Systems: MARD Values Are Not Always a Reliable Indicator of CGM System Accuracy.

BACKGROUND: The ongoing progress of continuous glucose monitoring (CGM) systems results in an increasing interest in comparing their performance, in particular in terms of accuracy, that is, matching CGM readings with reference values measured at the same time. Most often accuracy is evaluated by the mean absolute relative difference (MARD). It is frequently overseen that MARD does not only reflect accuracy, but also the study protocol and evaluation procedure, making a cross-study comparison problematic. METHODS: We evaluate the effect of several factors on the MARD statistical properties: number of paired reference and CGM values, distribution of the paired values, accuracy of the reference measurement device itself and the time delay between data pairs. All analysis is done using clinical data from 12 patients wearing 6 sensors each. RESULTS: We have found that a few paired points can have a potentially high impact on MARD. Leaving out those points for evaluation thus reduces the MARD. Similarly, accuracy of the reference measurements greatly affects the MARD as numerical and graphical data show. Results also show that a log-normal distribution of the paired references provides a significantly different MARD than, for example, a uniform distribution. CONCLUSIONS: MARD is a reasonable parameter to characterize the performance of CGM systems when keeping its limitations in mind. To support clinicians and patients in selecting which CGM system to use in a clinical setting, care should be taken to make MARD more comparable by employing a standardized evaluation procedure.

Current Trends in Continuous Glucose Monitoring.

The market introduction of systems for continuous glucose monitoring (CGM) some 15 years ago did not immediately revolutionize the treatment of diabetes; however, for a given group of patients, it would almost be inconceivable nowadays to imagine life without CGM. One day the development of insulin pumps together with CGM could culminate in an artificial pancreas system. The performance of the glucose sensors used for glucose measurement in the interstitial fluid in the subcutaneous tissue and the algorithms employed to analyze these data have improved so much over the past decade that current CGM systems by far outperform those of the first generations. This commentary discusses a number of aspects about what we have learned since CGM systems entered the market and what current trends exist in their usage. Some of these are major hurdles facing a more widespread usage of CGM.

What Are the Next Steps in Continuous Glucose Monitoring?

The development of glucose sensors for continuous glucose monitoring (CGM) is likely still in its early days. A number of novel approaches-along with many attempts to improve current CGM systems-are in development. The next generation of glucose sensors (NGGS) will also enable, for example, reliable glucose measurement in the low glycemic range. NGGS systems represent an important step forward for closed-loop systems. This commentary discusses a number of aspects that are relevant in this context.

Assessing the analytical performance of systems for self-monitoring of blood glucose: concepts of performance evaluation and definition of metrological key terms.

Reliability of blood glucose (BG) measurements is a prerequisite for successful diabetes management. Publications on the evaluation of self-monitored glucose values, however, are frequently characterized by a confusion in terminology. We provide an inventory of key terms such as accuracy, trueness, precision, traceability, calibration, and matrix effect to avoid future misunderstanding. Definitions are taken from the metrological literature and international norms and explained in a language intended for nonspecialists in metrology. The terms are presented in light of the need to apply generally accepted definitions. In addition, a description of requirements and components for a sound evaluation of BG measurement systems is presented. These factors will also enable improvement in future comparisons of study results.

Adiponectin in coronary heart disease and newly diagnosed impaired glucose tolerance.

OBJECTIVE: Adiponectin is produced by adipose tissue and regarded as protective hormone for diabetes and coronary heart disease (CHD). Its role in heart failure is discussed controversially. METHODS: In this study, 1015 consecutive patients admitted for acute (n = 149) or elective (n = 866) coronary angiography were enrolled. Patients with known diabetes mellitus (DM) were excluded. All patients were classified by oral glucose tolerance test (oGTT) according to World Health Organization (WHO) criteria and by the results of coronary angiography as no/minor coronary heart disease (CHD), single-vessel disease (1-VD), double-vessel disease (2-VD) or triple-vessel disease (3-VD), by New York Heart Association (NYHA) criteria and by echocardiography for heart failure. Adiponectin and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were measured in all patients. RESULTS: Adiponectin was higher in patients with normal glucose tolerance (NGT) (13.65 ± 10.31 mg/l) compared to impaired glucose tolerance (IGT) (11.12 ± 7.5, p < 0.001) or diabetes (11.22 ± 7.63, p < 0.001). There was a stepwise decrease in adiponectin from no CHD (18.16 ± 12.49 mg/L) to minor CHD (16.01 ± 11.42) to 1-VD (12.18 ± 8.8, p < 0.001 to no/minor CHD) to 2- and 3-VD (10.68 ± 7.5, p < 0.001 to no/minor CHD, p = 0.004 to 1-VD). Patients with heart failure NYHA III (17.4 ± 10.27) had higher adiponectin levels compared to NYHA II (12.94 ± 9.41, p < 0.001 to NYHA III) and NYHA I (10.3 ± 7.75, p < 0.001 to NYHA III/II). In this line, adiponectin levels were positively correlated to NT-proBNP levels (r = 0.303), and patients with ejection fraction (EF) < 50% had higher adiponectin levels than those with EF > 50% (14.96 ± 4.35 to 11.78 ± 3.71, p = 0.006). CONCLUSION: Adiponectin levels are inversely correlated to progressing CHD and glucose intolerance but positively correlated to increasing heart failure.

Accuracy in blood glucose measurement: what will a tightening of requirements yield?

Nowadays, almost all persons with diabetes--at least those using antidiabetic drug therapy--use one of a plethora of meters commercially available for self-monitoring of blood glucose. The accuracy of blood glucose (BG) measurement using these meters has been presumed to be adequate; that is, the accuracy of these devices was not usually questioned until recently. Health authorities in the United States (Food and Drug Administration) and in other countries are currently endeavoring to tighten the requirements for the accuracy of these meters above the level that is currently stated in the standard ISO 15197. At first glance, this does not appear to be a problem and is hardly worth further consideration, but a closer look reveals a considerable range of critical aspects that will be discussed in this commentary. In summary, one could say that as a result of modern production methods and ongoing technical advances, the demands placed on the quality of measurement results obtained with BG meters can be increased to a certain degree. One should also take into consideration that the system accuracy (which covers many more aspects as the analytical accuracy) required to make correct therapeutical decisions certainly varies for different types of therapy. At the end, in addition to analytical accuracy, thorough and systematic training of patients and regular refresher training is important to minimize errors. Only under such circumstances will patients make appropriate therapeutic interventions to optimize and maintain metabolic control.

Myocardial infarction and stroke in early years after diagnosis of type 2 diabetes: risk factors and relation to self-monitoring of blood glucose.

BACKGROUND: The natural course of macrovascular events in patients with type 2 diabetes was analyzed: what are the risk factors, and what is the relationship to the use of self-monitoring of blood glucose (SMBG)? METHODS: Data were retrieved from ROSSO-a German retrospective observational study-which followed 3,268 patients from diagnosis of type 2 diabetes for 6.5 +/- 1.6 years. We compared patients with or without a nonfatal macrovascular event (myocardial infarction or stroke) and patients using or not using SMBG. RESULTS: At baseline, worse glycemic control and higher body mass index were not risk factors for macrovascular events. Moreover, there was no association with classic risk factors like blood pressure or total cholesterol. Overall, there was a higher incidence of stroke than of myocardial infarction (0.78% vs. 0.51%). Myocardial infarction was positively associated with male sex, and stroke with age (P < 0.001 for each). Patients using SMBG compared to patients not using SMBG had fewer myocardial infarctions (2.0% vs. 4.0%, P = 0.002) and strokes (3.6% vs. 5.7%, P = 0.005), experienced a stroke later after diagnosis of type 2 diabetes (5.1 +/- 1.9 vs. 3.8 +/- 2.1 years, P < 0.001), and had a higher mean hemoglobin A1c in the years before a myocardial infarction (7.8 +/- 1.8% vs. 6.8 +/- 1.1%, P = 0.003) or a stroke (8.0 +/- 1.8% vs. 7.1 +/- 1.2%, P = 0.003). However, classic cardiovascular risk factors did not differ between patients using or not using SMBG. CONCLUSIONS: In patients with type 2 diabetes SMBG was associated with a lower event rate of myocardial infarction (-50%) and stroke (-37%), although at baseline the classic risk factors for macrovascular events were not different in both groups.

Are type 2 diabetes patients who self-monitor blood glucose special? The role of confounders in the observational ROSSO study.

BACKGROUND: In the German multicenter, retrospective cohort study (ROSSO), those patients with type 2 diabetes who performed self-monitoring of blood glucose (SMBG) had a better long-term clinical outcome. We analyzed whether confounders accounted for the lower rate of clinical events in the SMBG cohort. METHODS: ROSSO followed 3268 persons from diagnosis of type 2 diabetes for a mean of 6.5 years. Data were retrieved from patient files of randomly contacted primary care practices. RESULTS: In total, more than 60 potential confounders were documented, including nondisease-associated parameters such as patient's health insurance, marital status, habitation, and characteristics of diabetes centers. There were only modest differences for these parameters between groups with versus without SMBG, and multiple adjustments did not weaken the association of SMBG use with better outcome (odds ratio 0.65, 95% confidence interval 0.53-0.81, p < .001). This was also true for subgroups of patients defined by type of antidiabetes treatment. Propensity score analysis confirmed the association of SMBG use with outcome. Using key baseline parameters, 813 matching pairs of patients were identified. The analysis again showed a better long-term outcome in the SMBG group (hazard ratio 0.67 p = .004). CONCLUSION: An influence of nonrecognized confounders on better outcome in the SMBG group is rendered improbable by similar results obtained with adjustments for disease-associated or disease-independent parameters, by the analysis of patient subgroups, by propensity score analysis and by performing a matched-pair analysis. The higher flexibility in pharmacological antidiabetes treatment regimens in the SMBG cohort suggests a different attitude of treating physicians and patients in association with SMBG.

Cost impact of blood glucose self-monitoring on complications of type 2 diabetes: a Swiss perspective (ROSSO study No.11).

QUESTION UNDER STUDY: despite the increasing prevalence of type 2 diabetes, its financial burden on the Swiss healthcare system remains unclear. Our aim was to determine the cost of self-monitoring of blood glucose (SMBG) in reducing diabetic complications by comparing the direct costs to the Swiss statutory health insurance system of diabetic complications in SMBG users vs. nonusers. METHOD: matched pair analysis of the average annual total cost of diabetes monitoring, treatment-related services, complications and followup in the RetrOlective Study Self-Monitoring of Blood Glucose and Outcome in Patients with Type 2 Diabetes (ROSSO) study cohort, updated to 2005 from the year of occurrence or diagnosis of diabetes, applying an annual inflation rate of 5%. RESULTS: in those patients treated with oral antidiabetic drugs only, total annual costs were CHF 5,140 in SMBG users and CHF 5,654 in non - users. In those patients treated with oral antidiabetic drugs plus insulin, total annual costs were CHF 8,254 and CHF 11,776, respectively. SMBG accounted for 1.6% to 1.7% of total costs. CONCLUSION: cost analysis indicates that SMBG provides a rapid return on initial investment.

Interrelations between diabetes therapy, self-monitoring of blood glucose, blood glucose and non-fatal or fatal endpoints in patients with type 2 diabetes / results of a longitudinal cohort study (ROSSO 5).

The ROSSO study is a retrospective, longitudinal cohort study performed to obtain epidemiological data on self-monitoring of blood glucose (SMBG) in patients with type 2 diabetes and to investigate the impact of SMBG on disease-related morbidity and mortality. 3,268 patients from 192 doctor's practices in Germany were included and their data from diabetes diagnosis (between 1995 and end of 1999) till drop-out (120 died, 17 drop-outs) or end of 2003 were collected from the medical records. The mean observational time was 6.5 years; total patient years of follow-up were 21.266 years. Based on these population data, questions about the motivation of patients with type 2 diabetes to start with SMBG, the changes in diabetes therapy and blood glucose associated with SMBG and the relationship of SMBG with non-fatal or fatal events during follow-up were evaluated. Use of SMBG is significantly associated with personal and baseline conditions. Patients using SMBG are more frequently treated by an internist, more often male, have more frequently a private health insurance, exhibit less frequently arterial hypertension, are younger, have lower systolic blood pressure and higher values of fasting blood glucose (FBG), HbA1c and triglycerides at diagnosis. The start of SMBG is preceded by a steady increase in blood glucose levels. It is accompanied by an intensification of diabetes therapy and followed by a significant reduction of blood glucose in the year after start of SMBG. 67% of the patients treated with diet only before SMBG began with antidiabetic medication concomitantly with SMBG (48% with oral antidiabetic agents (OAD), 9% with insulin and 10% with OAD and insulin) and 30% of the patients treated with OAD started on additional insulin treatment in parallel with SMBG. Switching from no antidiabetic medication to OAD reduced the mean FBG levels significantly from 9.31 to 8.70 mmol/l, from no medication to insulin from 10.05 to 6.93 mmol/l and from no medication to OAD and insulin from 10.85 to 8.92 mmol/l. Similar reductions of mean FBG levels were observed for switching from OAD to insulin therapy. Patients who stayed on OAD therapy also showed a significant reduction of FBG concentrations after the start of SMBG. The hazard for non-fatal events (particularly myocardial infarction and stroke) or overall mortality was significantly reduced for patients who performed SMBG during follow-up (p<0.001). SMBG-associated changes of antidiabetic therapy may contribute to the better clinical outcome of patients with SMBG.

Altered disease course after initiation of self-monitoring of blood glucose in noninsulin-treated type 2 diabetes (ROSSO 3).

BACKGROUND: Patients with noninsulin-treated type 2 diabetes were documented from diagnosis to determine whether patients taking up self-monitoring of blood glucose (SMBG) are distinct by baseline characteristics, exhibit a different natural disease course, and are treated differently. METHODS: The German multicenter, retrospective cohort study (ROSSO) followed 3268 persons from diagnosis of type 2 diabetes for a mean of 6.5 years. During follow-up, 1912 persons received oral antidiabetic agents (OAD) for at least 1 year, but no insulin. Data were retrieved from patient files of randomly contacted primary care practices. RESULTS: During follow-up, 742 patients (38.8%) began with SMBG prior to an end point. Initiation of SMBG was followed by improved glycemic control. Patients in the SMBG cohort were treated more often by an internist, younger by a mean of 3 years, and more often male (p < 0.001, each). A higher percentage of persons in the SMBG cohort were treated with metformin (74.7% vs 65.0%, p < 0.001) or changed OAD therapy (66.3% of patients vs 48.3% of patients, p < 0.001). SMBG was not accompanied by more comedication. In the SMBG cohort, 68 persons had a clinical end point (myocardial infarction, stroke, foot amputation, blindness, hemodialysis, or all-cause mortality) (9.2%) compared to 155 persons (13.2%) in the cohort without SMBG (p = 0.04 after multivariate adjustments). CONCLUSION: This first large documentation of OAD-treated persons from diagnosis for 6.5 years indicates that the use of SMBG is associated with younger age at diagnosis, a higher prescription rate of metformin, more frequent changes of oral therapy, and a lower risk of a clinical end point.

Self-measurement of blood glucose in patients with type 2 diabetes: a health economic assessment.

BACKGROUND: The clinical role and the potential benefit of self-measurement of blood glucose (SMBG) for patients with type 2 diabetes are still under discussion. Even less information is available on the cost-effectiveness of performing SMBG by this patient group. The goal of this study was to establish cost-effectiveness ratios of performing SMBG by patients afflicted by this disease. METHODS: We assessed the benefit and cost-effectiveness of SMBG in type 2 diabetes from a third-party payer perspective based on results of both a large epidemiologic cohort study reflecting the reality of care, and a Markov model calculation. RESULTS: Analysis of cohort study data revealed that total costs cumulated over the observation period of 8 years were lower in the SMBG group than in the non-SMBG group according to savings of euro 1'714 [oral antidiabetic drugs (OAD) only] and euro 13'815 (OAD + insulin) per patient. Several scenarios were considered in the model-based calculation. The cost-effectiveness ratio varied from euro 20'768/life year gained to domination of SMBG use compared to nonusers in OAD treated patients and from euro 59'057/life year gained to domination of SMBG use compared to nonusers in OAD + insulin treated patients. CONCLUSION: Results indicate that SMBG in type 2 diabetes offers an excellent opportunity to get a high investment-outcome ratio in the treatment of this pandemic disease.

Continuous glucose monitoring with glucose sensors: calibration and assessment criteria.

Continuous glucose monitoring (CM) by means of minimally invasive or noninvasive glucose sensors can help to further optimize metabolic control in patients with diabetes without need for frequent capillary blood glucose measurements. Most glucose sensors measure glucose concentration in the interstitial fluid (ISF). Because of the varying conditions in this compartment, a general in vitro calibration ( = factory calibration) by the manufacturer appears not to be possible. Therefore, calibration of the sensor signal must be performed by the patient himself repeatedly. The calibration procedure can be performed by means of conventional capillary blood glucose measurements in order to transform the sensor signals obtained from the specific compartment (e.g., ISF) into "blood" glucose values. A number of aspects can influence the validity of this procedure. The relationship between changes in blood glucose and in ISF glucose, in both time and concentration dimensions, is not well understood, especially during dynamic changes. The physical lag time, which critically depends on the glucose sensor technology used, can also introduce a systematic calibration error. After the first calibration, usually performed some hours after the application of a given glucose sensor, recalibration at certain intervals is necessary. Therefore, patients should critically assess the values displayed by a CM system. In the case of implausible glucose values they should verify the results by means of a conventional capillary glucose measurement. Up to now there is no consensus on assessment criteria to be used for evaluation of CM system performance and calibration quality. Existing methods of displaying CM values against corresponding reference values, including linear regression analysis and error grid analysis, as well as numeric criteria such as System Error, Predicted Error Sum of Squares (in %), and Mean Absolute Deviation are not generally applicable to CM. It appears as if they do not allow sufficient description of data obtained with CM systems. There is a pressing need to develop novel adequate assessment criteria enabling a better characterization of CM system performance. If these were used uniformly by all manufacturers and scientists assessing CM systems, this would allow a fair comparison of the performance of different systems.

Hypoglycemia warning signal and glucose sensors: requirements and concepts.

Hypoglycemia is the most feared side effect of diabetes therapy with blood glucose-lowering agents. The fear of hypoglycemia often contributes to poor metabolic control of patients with diabetes. Therefore, integration of a hypoglycemia warning signal into continuous glucose monitoring systems represents an important additional help for patients with diabetes. The warning signal can be triggered at a preset level based on the current glucose values (as provided with the presently available glucose monitoring systems) or on prospective trend analysis offering the possibility to predict the risk of a hypoglycemic event in an anticipatory manner. Using the approach of a "Finite State Machine," such a more advanced warning system can completely be described as a finite collection of four states and possible transitions in-between. Most of the currently available glucose monitoring systems measure glucose in the interstitial fluid (ISF) of the dermal or subcutaneous tissue but are calibrated to blood glucose levels. This requires a number of factors to be taken into account: precision and accuracy of the glucose measurements, physiological and physical lag time, and calibration of the glucose monitoring system. From our point of view, the analytical performance of the system should be such that the majority of all hypoglycemic episodes are correctly diagnosed (>75%). Inconsistent findings regarding physiological discrepancies between blood and ISF glucose, which usually are described as a physiological lag time, range from some seconds up to 15 min. They can be observed especially during dynamic blood glucose changes (>3 mg/dL/min) and may represent major challenges for the development of a reliable hypoglycemia warning signal. In addition to possible physiological time lags, device-inherent physical lag times must be considered when selecting the threshold for the warning signal. Despite these problems, most probably all patients with diabetes who are treated with blood glucose-lowering agents will benefit from such a system since their safety and quality of life can be greatly improved, including an optimized metabolic control and lowered diabetes-related mortality. The benefit will be greatest for patients with hypoglycemia unawareness or impaired perception of hypoglycemic symptoms. The risks related to the use of a hypoglycemia warning signal seem to be low if certain precautionary measures are taken. In any case, additional clinical-experimental studies in healthy subjects as well as long-term clinical studies in diabetic patients are necessary to further evaluate the efficacy, benefits, and risks of different hypoglycemia warning concepts implemented in the different continuous glucose monitoring systems.

The SCGM1 System: subcutaneous continuous glucose monitoring based on microdialysis technique.

The SCGM1 System is designed to allow continuous glucose monitoring in the subcutaneous interstitial fluid for up to 120 h. The system is based on the microdialysis technique and is composed of three components: (1) a disposable Cassette, which contains the microdialysis catheter (with the necessary tubes), an electrochemical flow-through sensor for glucose measurement, and the fluid reservoirs for both the microdialysis perfusate and a reagent solution containing glucose oxidase; (2) the Sensor Unit, which houses the Cassette and is worn by the patient using a belt pack; and (3) the Data Manager, with an integrated blood glucose meter for the calibration of the glucose signal. The Data Manager also has the option of displaying the continuous glucose signal. The Sensor Unit and Data Manager exchange glucose data and calibration data by radio transmission. In vitro precision was assessed by measurements of two standard glucose solutions (90 mg/dL, 3.4%; 360 mg/dL, 2.4%) over a time course of 4 days. The mean difference (+/- SD) between SCGM1 System devices (n = 11) and 15 glucose standard solutions with different concentrations was 1.4 +/- 3.5 mg/dL. The mean relative difference and the mean absolute relative difference ranged from - 0.6% to 3.7% and from 0.2% to 3.8%, respectively. The inherent physical lag time was 31 +/- 2 min (n = 10). The interference on the glucose signal of ascorbic acid, acetaminophen, and uric acid at the highest physiological concentrations was below 4%. The SCGM1 System showed a reliable and precise performance under in vitro conditions.

Continuous glucose monitoring: reliable measurements for up to 4 days with the SCGM1 system.

Continuous glucose monitoring allows patients with diabetes to check their metabolic status throughout the day, including rarely monitored time periods, such as postprandial and nocturnal periods. The performance of a prototype of the novel SCGM1 System (Roche Diagnostics GmbH, Mannheim, Germany) employing the microdialysis technique was evaluated. Forty-two patients with type 1 diabetes participated in the study [29 males/13 females, age 34 +/- 9 years, duration of diabetes 16 +/- 11 years, glycated hemoglobin 7.7 +/- 1.2% (mean +/- SD)]. Forty-seven experiments were performed at four different investigational sites. A microdialysis catheter was inserted into the subcutaneous tissue of the patient's abdominal wall. Glucose was extracted from the interstitial fluid, and glucose levels were determined and stored by the SCGM1 System continuously for the duration of the experiment. Capillary blood glucose was measured frequently (at least 10 times per day) and used for linear retrospective calibration. The patients were instructed to maintain their normal diet and insulin therapy. Thirty experiments (mean duration 103 +/- 18 h) were analyzed in detail. The mean deviation of the calibrated glucose sensor values from the capillary blood glucose values (expressed as percent predicted error sum of squares) was <12.5% in 25 and <20% for all of the 30 experiments analyzed. The percent median absolute difference between the calibrated values and the reference values was <10% in 28 experiments, with a median of 5.8% for all 30 experiments. The error grid analysis of all 30 experiments showed that 99.5% of all 1,195 pairs' values were in zones A and B with only 0.2% in zone C and 0.3% in zone D. Thus the microdialysis technique employed by the SCGM1 System allows precise and accurate continuous glucose monitoring over prolonged periods of time. It appears also that effective monitoring of acute metabolic deteriorations is possible.