Stefan Pleus

System Accuracy Evaluation of 43 Blood Glucose Monitoring Systems for Self-Monitoring of Blood Glucose according to DIN EN ISO 15197

Background: The accuracy of systems for self-monitoring of blood glucose is important, as reliable measurement results are a prerequisite for therapeutic decisions. Methods: This system accuracy evaluation study was performed according to DIN EN ISO 15197:2003 for 43 Conformité Européenne (CE)-labeled blood glucose (BG) monitoring systems. Measurement results of each system were compared with results of the designated comparison method (manufacturers measurement procedure): glucose oxidase method (YSI 2300 glucose analyzer) or hexokinase method (Hitachi 917/ cobas 501). Results: Complete assessment according to the International Organization for Standardization (ISO) standard was performed for 34 out of 43 systems, and 27 (79.4%) meet the requirements of the standard, i.e., ≥95% of their results showed at least the minimum acceptable accuracy. For 9 of the 43 systems, complete accuracy assessment was not performed due to an oxygen sensitivity (manufacturers labeling). The bias (according to Bland and Altman) of all 43 evaluated systems ranged from −14.1% to +12.4%. Conclusions: From the 34 systems completely assessed, 7 systems did not fulfill the minimal accuracy requirements of the ISO standard. The CE mark apparently does not guarantee that all BG systems provide accuracy according to the standard. Because inaccurate systems bear the risk of false therapeutic decisions, regular and standardized evaluation of BG meters and test strips should be requested in order to ensure adherence to quality standards.

Lot-to-Lot Variability of Test Strips and Accuracy Assessment of Systems for Self-Monitoring of Blood Glucose according to ISO 15197

Background: Accurate and reliable blood glucose (BG) measurements require that different test strip lots of the same BG monitoring system provide comparable measurement results. Only a small number of studies addressing this question have been published. Methods: In this study, four test strip lots for each of five different BG systems [Accu-Chek® Aviva (system A), FreeStyle Lite® (system B), GlucoCheck XL (system C), Pura™/mylife™ Pura (system D), and OneTouch® Verio ™ Pro (system E)] were evaluated with procedures according to DIN EN ISO 15197:2003. The BG system measurement results were compared with the manufacturers measurement procedure (glucose oxidase or hexokinase method). Relative bias according to Bland and Altman and system accuracy according to ISO 15197 were analyzed. A BG system consists of the BG meter itself and the test strips. Results: The maximum lot-to-lot difference between any two of the four evaluated test strip lots per BG system was 1.0% for system E, 2.1% for system A, 3.1% for system C, 6.9% for system B, and 13.0% for system D. Only two systems (systems A and B) fulfill the criteria of DIN EN ISO 15197:2003 with each test strip lot. Conclusions: Considerable lot-to-lot variability between test strip lots of the same BG system was found. These variations add to other sources of inaccuracy with the specific BG system. Manufacturers should regularly and effectively check the accuracy of their BG meters and test strips even between different test strip lots to minimize risk of false treatment decisions.

Performance Evaluation of Three Continuous Glucose Monitoring Systems: Comparison of Six Sensors Per Subject in Parallel

Background: This study is aimed at comparing the performance of three continuous glucose monitoring (CGM) systems following the Clinical and Laboratory Standards Institutes POCT05-A guideline, which provides recommendations for performance evaluation of CGM systems. Methods: A total of 12 subjects with type 1 diabetes were enrolled in this study. Each subject wore six CGM systems in parallel, two sensors of each CGM system [FreeStyle Navigator™ (Navigator), MiniMed Guardian® REAL-Time with Enlite sensor (Guardian), DexCom™ Seven® Plus 3rd generation (Seven Plus)]. Each sensor was used for the lifetime specified by the manufacturer. To follow POCT05-A recommendations, glucose excursions were induced on two separate occasions, and venous and capillary blood glucose (BG) concentrations were obtained every 15 min for five consecutive hours. Capillary BG concentrations were measured at least once per hour during the day and once at night. Parameters investigated were CGM-to-BG differences [mean absolute relative difference (MARD)] and sensor-to-sensor differences [precision absolute relative difference (PARD)]. Results: Compared with capillary BG reference readings, the Navigator showed the lowest MARD, with 12.1% overall and 24.6% in the hypoglycemic range; for the Guardian and the Seven Plus, MARD was 16.2%/34.9% and 16.3%/32.7%, respectively. PARD also was lowest for the Navigator (9.6%/9.8%), followed by the Seven Plus (16.7%/25.5%) and the Guardian (18.1%/20.2%). During induced glucose excursions, MARD between CGM and BG was, again, lowest for the Navigator (14.3%), followed by the Seven Plus (15.8%) and the Guardian (19.2%). Conclusions: In this study, two sensors of each of the three CGM systems were compared in a setting following POCT05-A recommendations. The Navigator CGM system achieved more accurate results than the Guardian or the Seven Plus with respect to MARD and PARD. Performance in the hypoglycemic range was markedly worse for all CGM systems when compared with BG results.

Evaluation of the Performance of a Novel System for Continuous Glucose Monitoring

Background: The performance of a continuous glucose monitoring (CGM) system in the early stage of development was assessed in an inpatient setting that simulates daily life conditions of people with diabetes. Performance was evaluated at low glycemic, euglycemic, and high glycemic ranges as well as during phases with rapid glucose excursions. Methods: Each of the 30 participants with type 1 diabetes (15 female, age 47 ± 12 years, hemoglobin A1c 7.7% ± 1.3%) wore two sensors of the prototype system in parallel for 7 days. Capillary blood samples were measured at least 16 times per day (at least 15 times per daytime and at least once per night). On two subsequent study days, glucose excursions were induced. For performance evaluation, the mean absolute relative difference (MARD) between CGM readings and paired capillary blood glucose readings and precision absolute relative difference (PARD), i.e., differences between paired CGM readings were calculated. Results: Overall aggregated MARD was 9.2% and overall aggregated PARD was 7.5%. During induced glucose excursions, MARD was 10.9% and PARD was 7.8%. Lowest MARD (8.5%) and lowest PARD (6.4%) were observed in the high glycemic range (euglycemic range, MARD 9.1% and PARD 7.4%; low glycemic range, MARD 12.3% and PARD 12.4%). Conclusions: The performance of this prototype CGM system was, particularly in the hypoglycemic range and during phases with rapid glucose fluctuations, better than performance data reported for other commercially available systems. In addition, performance of this prototype sensor was noticeably constant over the whole study period. This prototype system is not yet approved, and performance of this CGM system needs to be further assessed in clinical studies.

Clinical Performance of Three Bolus Calculators in Subjects with Type 1 Diabetes Mellitus: A Head-to-Head-to-Head Comparison

BACKGROUND Insulin pump systems now provide automated bolus calculators (ABCs) that electronically calculate insulin boluses to address carbohydrate intake and out-of-range blood glucose (bG) levels. We compared the efficacy of three ABCs (Accu-Chek(®) Combo [Roche Insulin Delivery Systems (IDS), Inc., Fishers, IN, a member of the Roche Group], Animas(®) 2020 [Animas Corp., West Chester, PA, a Johnson and Johnson company], and MiniMed Paradigm Bolus Wizard(®) [Medtronic MiniMed, Northridge, CA]) to safely reduce postprandial hyperglycemia in type 1 diabetes mellitus (T1DM). METHODS T1DM subjects (n = 24) were recruited at a single center for a prospective, triple crossover study. ABCs with the programmed target range (80-140 mg/dL) were used in random order. Postprandial hyperglycemia was induced by reducing the calculated bolus by 25%. Two hours after test meals, the ABCs were allowed to determine whether a correction bolus was needed. Differences between 6-h bG values after test meals that achieved 2-h postprandial hyperglycemia and the mean of the target range (110 mg/dL) were determined. RESULTS The mean difference between 6-h bG levels following test meals and the 110 mg/dL bG target with the MiniMed device (47.4 ± 31.8 mg/dL) was significantly higher than the Animas (17.3 ± 30.9 mg/dL) and Roche IDS (18.8 ± 33.8 mg/dL) devices (P = 0.0022 and P = 0.0049, respectively). The number of meals with 2-h postprandial hyperglycemia and bG levels at 2 h was similar. Roche IDS and Animas devices recommended correction boluses significantly (P = 0.0001 and P = 0.0002, respectively) more frequently than the MiniMed device. ABC use was not associated with severe hypoglycemia. There was no significant difference in the rate of mild hypoglycemia (bG <60 mg/dL not requiring assistance) among the three groups (Roche IDS and Animas, n = 2; MiniMed, n = 0). CONCLUSIONS In this study, the Roche IDS and Animas devices were more efficacious in controlling postprandial hyperglycemia than the MiniMed device. This may be due, in part, to differences in ABC setup protocols and algorithms. Use of ABCs can assist in controlling postprandial glycemia without significant hypoglycemia.

Performance of Blood Glucose Meters in the Low-Glucose Range: Current Evaluations Indicate That It Is Not Sufficient From a Clinical Point of View

System accuracy requirements for blood glucose (BG) meters (BGMs) are defined in standards (1) or guidance documents (2). In 2013, International Organization for Standardization (ISO) 15197:2013 stated that BGMs are acceptably accurate if ≥95% of their measurement results are found within ±15 mg/dL (0.83 mmol/L) or ±15% (whichever is larger) of reference results (1). The 2014 U.S. Food and Drug Administration (FDA) draft guidance for over-the-counter BGMs requires ≥95% of results within ±15% and ≥99% of results within ±20% across the whole glycemic range (2). Thus, if a patient’s BG true concentration is 60 mg/dL (3.33 mmol/L), acceptably accurate results range from 45 to 75 mg/dL (2.50 to 4.16 mmol/L) according to the ISO limits and from 51 to 69 mg/dL (2.83 to 3.83 mmol/L) according to the FDA criteria. Two questions arise: 1. Do current BGMs fulfill these criteria? 2. If a BGM …

Performance Evaluation of a Continuous Glucose Monitoring System under Conditions Similar to Daily Life

Background: This study aimed at evaluating and comparing the performance of a new generation of continuous glucose monitoring (CGM) system versus other CGM systems, under daily lifelike conditions. Methods: A total of 10 subjects (7 female) were enrolled in this study. Each subject wore two Dexcom G4™ CGM systems in parallel for the sensor lifetime specified by the manufacturer (7 days) to allow assessment of sensor-to-sensor precision. Capillary blood glucose (BG) measurements were performed at least once per hour during daytime and once at night. Glucose excursions were induced on two occasions. Performance was assessed by calculating the mean absolute relative difference (MARD) between CGM readings and paired capillary BG readings and precision absolute relative difference (PARD), i.e., differences between paired CGM readings. Results: Overall aggregate MARD was 11.0% (n = 2392). Aggregate MARD for BG >70 mg/dl was 13.7%; for BG between 70 and 180 mg/dl, MARD was 11.4%; and for BG >180 mg/dl, MARD was 8.5%. Aggregate PARD was 7.3%, improving from 11.6% on day 1 to 5.2% on day 7. Conclusions: The Dexcom G4 CGM system showed good overall MARD compared with results reported for other commercially available CGM systems. In the hypoglycemic range, where CGM performance is often reported to be low, the Dexcom G4 CGM system achieved better MARD than that reported for other CGM systems in the hypoglycemic range. In the hyperglycemic range, the MARD was comparable to that reported for other CGM systems, whereas during induced glucose excursions, the MARD was similar or slightly worse than that reported for other CGM systems. Overall PARD was 7.3%, improving markedly with sensor life time.

Rate-of-Change Dependence of the Performance of Two CGM Systems During Induced Glucose Swings

Introduction: The accuracy of continuous glucose monitoring (CGM) systems is often assessed with respect to blood glucose (BG) readings. CGM readings are affected by a physiological and a technical time delay when compared to BG readings. In this analysis, the dependence of CGM performance parameters on the BG rate of change was investigated for 2 CGM systems. Methods: Data from a previously published study were retrospectively analyzed. An established CGM system (Dexcom G4, Dexcom, San Diego, CA; system A) and a prototype system (Roche Diagnostics GmbH, Mannheim, Germany; system B) with 2 sensors each were worn by 10 subjects in parallel. Glucose swings were induced to achieve rapidly changing BG concentrations. Mean absolute relative differences (MARD) were calculated in different BG rate-of-change categories. In addition, sensor-to-sensor precision was assessed. Results: At BG rates of change of –1 mg/dl/min to 0 mg/dl/min and 0 mg/dl/min to +1 mg/dl/min, MARD results were 12.6% and 11.3% for system A and 8.2% and 10.0% for system B. At rapidly changing BG concentrations (<–3 mg/dl/min and ≥+3 mg/dl/min), higher MARD results were found for both systems, but system B was less affected (system A: 24.9% and 29.6%, system B: 10.6% and 16.3%). The impact of rate of change on sensor-to-sensor precision was less pronounced. Conclusions: Both systems were affected by rapidly changing BG concentrations to some degree, although system B was mostly unaffected by decreasing BG concentrations. It would seem that technological advancements in CGM systems might allow for a more precise tracking of BG concentrations even at rapidly changing BG concentrations.

System Accuracy Evaluation of Four Systems for Self-Monitoring of Blood Glucose Following ISO 15197 Using a Glucose Oxidase and a Hexokinase-Based Comparison Method

Background: The standard ISO (International Organization for Standardization) 15197 is widely accepted for the accuracy evaluation of systems for self-monitoring of blood glucose (SMBG). Accuracy evaluation was performed for 4 SMBG systems (Accu-Chek® Aviva, Contour®XT, GlucoCheck XL, GlucoMen® LX PLUS) with 3 test strip lots each. To investigate a possible impact of the comparison method on system accuracy data, 2 different established methods were used. Methods: The evaluation was performed in a standardized manner following test procedures described in ISO 15197:2003 (section 7.3). System accuracy was assessed by applying ISO 15197:2003 and in addition ISO 15197:2013 criteria (section 6.3.3). For each system, comparison measurements were performed with a glucose oxidase (YSI 2300 STAT Plus™ glucose analyzer) and a hexokinase (cobas® c111) method. Results: All 4 systems fulfilled the accuracy requirements of ISO 15197:2003 with the tested lots. More stringent accuracy criteria of ISO 15197:2013 were fulfilled by 3 systems (Accu-Chek Aviva, ContourXT, GlucoMen LX PLUS) when compared to the manufacturer’s comparison method and by 2 systems (Accu-Chek Aviva, ContourXT) when compared to the alternative comparison method. All systems showed lot-to-lot variability to a certain degree; 2 systems (Accu-Chek Aviva, ContourXT), however, showed only minimal differences in relative bias between the 3 evaluated lots. Conclusions: In this study, all 4 systems complied with the evaluated test strip lots with accuracy criteria of ISO 15197:2003. Applying ISO 15197:2013 accuracy limits, differences in the accuracy of the tested systems were observed, also demonstrating that the applied comparison method/system and the lot-to-lot variability can have a decisive influence on accuracy data obtained for a SMBG system.

Partial Pressure of Oxygen in Capillary Blood Samples from the Fingertip

Many people with diabetes routinely measure their blood glucose (BG) on capillary blood samples from the fingertip. Beside other interfering factors, the blood samples’ partial pressure of oxygen (pO2) can affect BG measurements, particularly in systems based on glucose oxidase (GOx) enzyme reactions on test strips.1,2 Indeed, many of the available home-use systems for self-monitoring of blood glucose (SMBG) utilize the GOx enzyme reaction, which is prone to oxygen interference; however, in the literature, poor information is available concerning physiological pO2 values and possible variations in capillary blood from the fingertip in people with diabetes. In this investigation, the pO2 of capillary blood samples obtained from fingertips was determined in 110 subjects (55 female, 31 with type 1 diabetes mellitus, 69 with type 2 diabetes mellitus, 10 without diabetes; mean age 61 years, from 19 to 78 years); most of them were expected to perform SMBG regularly. The subjects had no acute serious diseases. They participate regularly in SMBG system evaluation studies at the Institute for Diabetes-Technology GmbH at Ulm University, Ulm, Germany. The study protocol was approved by the Ulm University Ethics Committee. Capillary blood samples were obtained by skin puncture, and the pO2 was analyzed on a blood gas analyzer (OPTI™ CCA-TS Analysator, OPTI Medical System Inc., Roswell, GA). Maintenance, handling, and quality control of the blood gas analyzer were performed according to the manufacturer’s labeling. Regular internal and external quality control measurements were performed, as required by German national guidelines. Sample collection and pO2 measurements were performed by trained clinical personnel. The 110 subjects showed a mean pO2 of 71.1 mmHg (standard deviation ± 6.9 mmHg), ranging from 49 to 86 mmHg. Female and male subjects showed similar mean pO2 values (72.5 and 69.8 mmHg, respectively). Ninety-four subjects (~85%) showed pO2 values between >60 and ≤80 mmHg, 6 subjects (~5%) showed pO2 values ≤60 mmHg, and 10 subjects (~9%) showed pO2 values >80 mmHg (Figure 1). Lowest pO2 values (53 and 49 mmHg) were found in two subjects with stable chronic respiratory disease. Figure 1. Relative number of subjects with pO2 values within the respective category. Our results indicate that a broad range of capillary pO2 values occur among a population of healthy people and people with diabetes without acute serious diseases. In a previous study using venous blood samples adjusted to different pO2 levels, we observed remarkable measurement deviations with some GOx systems. Particularly at pO2 ≤45 mmHg, we found considerably overestimated measurements.2 Decreased pO2 values can occur in patients with respiratory diseases, such as chronic obstructive pulmonary disease,3 which is described as being associated with type 2 diabetes.4 At high altitudes or also during long-distance flights, up to ~40% decreased pO2 is reported for arterial blood samples;5 a similar behavior can also be expected for capillary blood samples from the fingertip. In conditions with decreased pO2 values in capillary blood, measurements with oxygen-sensitive systems could be affected, and hypoglycemic events might not be detected adequately. Further investigations should be performed focusing on pO2 variations in capillary blood from fingertips in people with diabetes and the possible impact on glucose measurement results obtained with oxygen-sensitive systems.