Sanja Ramljak

Dynamic electrochemistry corrects for hematocrit interference on blood glucose determinations with patient self-measurement devices.

Background: It has been demonstrated that dynamic electrochemistry can be used to correct blood glucose measurement results for potentially interfering conditions, such as humidity, hematocrit (HCT) variations, and ascorbic acid. The purpose of this laboratory investigation was to assess the potential influence of hematocrit variations on a variety of blood glucose meters applying different measurement technologies. Methods: Venous heparinized whole blood was drawn, immediately aliquoted, and manipulated to contain three different blood glucose concentrations (80, 155, and 310 mg/dl) and five different hematocrit levels (25%, 37%, 45%, 52%, and 60%). After careful oxygenation to normal blood oxygen pressure, each of the resulting 15 different samples was measured 8 times with the following devices: BGStar, Contour, Accu-Chek Aviva, Accu-Chek Aviva Nano, Breeze 2, Precision Xceed, OneTouch Ultra 2, OneTouch Verio, FreeStyle Freedom Lite, Glucocard G+, GlucoMen LX, GlucoMen GM, and StatStrip [point-of-care (POC) device]. Cobas (Roche Diagnostics, glucose hexokinase method) served as laboratory plasma reference method. Stability to hematocrit influence was assumed when less than 10% bias occurred between the highest and lowest hematocrit levels when analyzing mean deviations for all three glucose concentrations. Results: Besides the POC StatStrip device, which is known to measure and correct for hematocrit (resulting in <2% bias), four self-test meters also showed a stable performance in this investigation: Dynamic electrochemistry, BGStar (8%), and static electrochemistry, Contour (6%), Glucocard G+ (2%), and OneTouch Verio (6%). The other meters failed this test: Colorimetry, FreeStyle Freedom Lite (16%), and static electrochemistry, Accu-Chek Aviva (23%), Accu-Chek Aviva Nano (18%), Breeze 2 (36%), OneTouch Ultra 2 (34%), Precision Xceed (34%), GlucoMen LX (24%), and GlucoMen GM (31%). Conclusions: As hematocrit variations occur in daily routine (e.g., because of smoking, exercise, hypermenorrhea, pregnancy, stay in mountains, and hemodialysis), our results may encourage use of meters with stable performance under these conditions. Dynamic electrochemistry as used in the BGStar device (sanofi-aventis) appears to be an effective technology to correct for potential hematocrit influence on the meter results.

Hematocrit Interference of Blood Glucose Meters for Patient Self-Measurement

Background: Abnormal hematocrit levels may interfere with glucose readings of patient self-assessment blood glucose (BG) meters. The aim of this laboratory investigation was to assess the potential influence of hematocrit variations on a variety of BG meters applying different measurement technologies. Methods: Venous heparinized blood was manipulated to contain three different BG concentrations (50–90, 120–180, and 280–350 mg/dl) and five different hematocrit levels (25%, 35%, 45%, 55%, and 65%). After careful oxygenation to normal blood oxygen pressure (65–100 mmHg), each sample was measured (eight times) with the following devices: Accu-Chek® Aviva, Nano, and Active, Breeze®2 and Contour®, FreeStyle Freedom Lite®, GlucoDr. auto™, Glucofix® mio Plus, GlucoLab™, GlucoMen® LX Plus, Nova Max® Link, Nova Max® Plus, OneTouch® Ultra®2 and Verio®, On Call® Plus and Platinum, Optium Xceed®, Precision Xceed®, and TaiDoc Fora TD-4227. A YSI 2300 STAT Plus™ glucose analyzer served as reference method. Stability to hematocrit influence was assumed, with <10% mean glucose result bias between the highest and lowest hematocrit levels. Results: Six of the investigated meters showed a stable performance in this investigation: Accu-Chek Active (7%), Glucofix mio Plus (5%), GlucoMen LX Plus (4%), NovaMax Plus (4%), Nova Max Link (7%), and OneTouch Verio (3%). All other meters failed this hematocrit interference test, with FreeStyle Freedom Lite (11%), and On Call Platinum 12%) being the better devices and On Call Plus (68%), GlucoLab (51%), TaiDoc Fora TD-4227 (39%), and Breeze 2 (38%) showing the worst performance. Conclusions: Hematocrit may affect BG meter performance in daily routine. In case of interference, low hematocrit values (<35%) result in too high readings. Our results encourage use of meters that are not affected by hematocrit interference.

Determination of Hematocrit Interference in Blood Samples Derived from Patients with Different Blood Glucose Concentrations

Background: We performed a blood glucose meter hematocrit (HCT) interference test with lower sample manipulation requirements by using blood samples from patients with different blood glucose (BG) levels. Methods: Blood from five patients with different BG levels (2.8, 5.6, 8.3, 13.9, 19.4 mmol/liter) was manipulated to contain five different HCT concentrations (35/40/45/50/55%). Each sample was measured three times in parallel with 14 BG testing devices (reference method: YSI 2300 STAT Plus™ Glucose Analyzer). The largest mean deviations in both directions from the reference method (normalized to 100% at 45% HCT) were added as a measure for hematocrit interference factor (HIF). A HIF >10% was considered to represent clinically relevant HCT interference. Results: Few devices showed no clinically relevant HCT interference at high/low BG levels: BGStar® (7.2%, 7.3%), iBGStar® (9.0%, 8.6%), Contour® (10.0%, 4.6%), OneTouch® Verio™ 2 (10.0%, 5.2%), and GlucoMen® LX (7.2%, 5.1%). Other devices showed interference at one or both glucose ranges: ACCU-CHEK® Aviva (12.6%, 10.7%), Aviva Nano (7.2%, 10.5%), Breeze2 (3.6%, 30.2%), GlucoCard G+ (12.6%, 7.0%), OneTouch® Ultra®2 (12.6%, 25.6%), FreeStyle Freedom Lite® (9.0%, 11.0%), Precision Xceed (16.2%, 15.3%), and MediTouch® (19.8%, 28.0%). The deviations in all devices were less pronounced in the HCT range of 35–50%. Conclusions: The results of this trial with less sample manipulation (HCT only) confirmed previous examinations with HCT and glucose manipulation. The same devices showed HCT stability as previously observed. Artificial sample manipulation may be less crucial than expected when evaluating HCT interference.

Evaluation of Hematocrit Interference With MyStar Extra and Seven Competitive Devices

Background: In previous studies, meters employing dynamic electrochemistry (DE), have been shown to correct for hematocrit (HCT) interference. This laboratory investigation assessed the HCT stability of MyStar Extra (Sanofi) in comparison to 7 competitive devices (Accu-Chek Aviva Nano & Accu-Chek Performa, Roche Diagnostics; Contour XT and Contour Link, Bayer; FreeStyle Freedom Lite, Abbott; MyLife Pura, Ypsomed; OneTouch Verio Pro, LifeScan). Method: Venous heparinized blood was freshly drawn, immediately aliquoted, and manipulated to contain 3 different blood glucose concentrations (50-80 mg/dL, 150-180 mg/dL, and 350-400 mg/dL) and 5 different HCT levels (20-25%, 30-35%, 40-45%, 50-55%, and 60-65%). After careful oxygenation to normal blood oxygen pressure, each of the 15 different samples was measured 8 times with 2 devices and 2 strip lots of each meter (32 measurements/meter/sample). YSI Stat 2300 served as laboratory reference method. Next to determination of the mean absolute relative deviation (MARD), stability to HCT influence was assumed, when less than 10% difference occurred between the highest and lowest mean glucose deviations in relation to HCT over all tested glucose ranges (HIF: hematocrit interference factor). Results: Four of the devices showed stable performance: Contour XT (MARD: 1.3%/HIF: 6.1%), MyStar Extra (4.7%/7.1%), OneTouch Verio Pro (4.5%/7.3%), and Contour Link (6.3%/9.3%). The 4 other meters were influenced by HCT (Accu-Chek Performa: 4.7%/20.9%, Accu-Chek Aviva Nano: 4.5%/22.4%, FreeStyle Freedom Lite: 4.8%/24.5%; MyLife Pura: 6.4%/28.7%). Conclusions: In this study, all meters showed a good accuracy, but only 50% of them, including MyStar Extra, were shown to reliably correct for potential hematocrit influence on the meter results.

Evaluation of the Effects of Insufficient Blood Volume Samples on the Performance of Blood Glucose Self-Test Meters

Background: Accuracy of blood glucose readings is (among other things) dependent on the test strip being completely filled with sufficient sample volume. The devices are supposed to display an error message in case of incomplete filling. This laboratory study was performed to test the performance of 31 commercially available devices in case of incomplete strip filling. Methods: Samples with two different glucose levels (60–90 and 300–350 mg/dl) were used to generate three different sample volumes: 0.20 μl (too low volume for any device), 0.32 μl (borderline volume), and 1.20 μl (low but supposedly sufficient volume for all devices). After a point-of-care capillary reference measurement (StatStrip, NovaBiomedical), the meter strip was filled (6x) with the respective volume, and the response of the meters (two devices) was documented (72 determinations/meter type). Correct response was defined as either an error message indicating incomplete filling or a correct reading (±20% compared with reference reading). Results: Only five meters showed 100% correct responses [BGStar and iBGStar (both Sanofi), ACCU-CHEK Compact+ and ACCU-CHEK Mobile (both Roche Diagnostics), OneTouch Verio (LifeScan)]. The majority of the meters (17) had up to 10% incorrect reactions [predominantly incorrect readings with sufficient volume; Precision Xceed and Xtra, FreeStyle Lite, and Freedom Lite (all Abbott); GlucoCard+ and GlucoMen GM (both Menarini); Contour, Contour USB, and Breeze2 (all Bayer); OneTouch Ultra Easy, Ultra 2, and Ultra Smart (all LifeScan); Wellion Dialog and Premium (both MedTrust); FineTouch (Terumo); ACCU-CHEK Aviva (Roche); and GlucoTalk (Axis-Shield)]. Ten percent to 20% incorrect reactions were seen with OneTouch Vita (LifeScan), ACCU-CHEK Aviva Nano (Roche), OmniTest+ (BBraun), and AlphaChek+ (Berger Med). More than 20% incorrect reactions were obtained with Pura (Ypsomed), GlucoCard Meter and GlucoMen LX (both Menarini), Elite (Bayer), and MediTouch (Medisana). Conclusions: In summary, partial and incomplete blood filling of glucose meter strips is often associated with inaccurate reading. These findings underline the importance of appropriate patient education on this aspect of blood glucose self-monitoring.

The precision study: examining the inter- and intra-assay variability of replicate measurements of BGStar, iBGStar and 12 other blood glucose monitors.

OBJECTIVE Self-monitoring of blood glucose is a key element in diabetes management. Accurate and precise performance of blood glucose monitors (BGMs) ensures that valid values are obtained to guide treatment decisions by patients and physicians. BGStar and iBGStar are hand-held BGMs that use dynamic electrochemistry to correct for potential interferences and thereby minimize system errors. RESEARCH DESIGN AND METHODS A single-center, in vitro diagnostic device performance evaluation with heparinized oxygenated venous blood samples (intra-assay precision) and control solutions (interassay precision) was performed in a laboratory setting, comparing BGStar and iBGStar with 12 competitors. MAIN OUTCOME MEASURES The primary outcome was the coefficient of variation percent (CV%) of the BGMs investigated. RESULTS In inter-assay precision analyses, all but GlucoMen LX had a CV <5%, and in intra-assay precision analyses, 10 of the 14 devices tested had CV <5%. BGStar and iBGStar had a CV <5% in both the inter- and intra-assay precision analyses. The smallest variation was found in the near-normoglycemic glucose range (5.3 - 8.0 mmol/l) for both BGStar and iBGStar in the inter-assay precision analysis. CONCLUSIONS BGStar and iBGStar were proven to have very good inter-assay and high intra-assay precision, demonstrating low scattering of replicate measurements with both clinical samples and control solutions.

Elevated Intact Proinsulin Levels During an Oral Glucose Challenge Indicate Progressive ß-Cell Dysfunction and May Be Predictive for Development of Type 2 Diabetes

Background: Elevated fasting intact proinsulin is a biomarker of late-stage ß-cell-dysfunction associated with clinically relevant insulin resistance. In this pilot investigation, we explored the potential value of measuring intact proinsulin as a functional predictor of ß-cell exhaustion during an oral glucose tolerance test (OGTT). Methods: The study was performed with 31 participants, 11 of whom were healthy subjects (7 female, age: 59 ± 20 years), 10 had impaired glucose tolerance (IGT, 6 female, 62 ± 10 years), and 10 had known type 2 diabetes (T2DM, 5 female, 53 ± 11 years, HbA1c: 7.0 ± 0.6%, disease duration: 8 ± 5 years). During OGTT, blood was drawn after 0 hours, 1 hour, and 2 hours for determination of glucose and intact proinsulin. Five years later, patients were again contacted to assess their diabetes status and the association to the previous OGTT results was analyzed. Results: The OGTT (0 hours/1 hour/2 hours) results were as follows: healthy subjects: glucose: 94 ± 8 mg/dL/140 ± 29 mg/dL/90 ± 24 mg/dL, intact proinsulin: 3 ± 2 pmol/L/10 ± 7 pmol/L/10 ± 5 pmol/L); IGT: glucose: 102 ± 9 mg/dL/158 ± 57 mg/dL/149 ± 34 mg/dL, intact proinsulin: 7 ± 4 pmol/L/23 ± 8 pmol/L/28 ± 6 pmol/L; T2DM: glucose: 121 ± 20 mg/dL/230 ± 51 mg/dL/213 ± 34 mg/dL; intact proinsulin: 7 ± 7 pmol/L/26 ± 9 pmol/L/27 ± 10 pmol/L). Five years later, all of the IGT and 2 of the healthy subjects had developed T2DM and one had devloped IGT. All of them had elevated 2-hour proinsulin values in the initial OGTT, while patients with normal intact proinsulin results did not develop diabetes. Conclusions: Elevated 2-hour intact proinsulin levels during OGTT were predictive for later type 2 diabetes development. Further studies need to confirm our findings in larger populations.

Impact of Xylose on Glucose-Dehydrogenase-Based Blood Glucose Meters for Patient Self-Testing:

The pentose xylose is enriched in edible algae, and is increasingly used as a slowly metabolized carbohydrate in functional food. It is known to interfere with glucose-dehydrogenase-based (GDH) blood glucose measurement systems for patients self-testing. The aim of our study was to investigate the extent of xylose interference in commercially available blood glucose meters. A heparinized whole blood sample was manipulated to contain 3 different glucose concentrations (50-80 mg/dL, 130-160 mg/dL, and 250-300 mg/dL) and 4 different xylose concentrations (0 mg/dL, 25 mg/dL, 50 mg/dL, and 100 mg/dL). Each sample was measured 3 times with 2 different strip lots per test meter (AccuChek Aviva, AccuChek Connect, Contour Next, FreeStyle Freedom Lite, FreeStyle Insulinx, MyStar Extra, OneTouch Verio IQ, and Wellion Calla, reference: YSI GlucoStat analyzer). For analysis, we calculated the xylose capture rate, that is, the xylose amount wrongly displayed as glucose. No xylose interference was seen with 4 meters: AccuChek Aviva (mean capture rate 0%), AccuChek Connect (–2%), MyStar Extra (10%), and Wellion Calla (8%). In contrast, substantial interference was observed with Contour Next (100%), FreeStyle Freedom Lite (104%), FreeStyle Insulinx (120%), and OneTouch Verio IQ (162%). We observed xylose interference in several GDH-based meters. This may become important with increased use of xylose in dietary and functional food products, in particular in products designed for weight loss. Our findings may affect the meter selection for patients who are consuming such food products as part of their lifestyle treatment regimen.

Evaluation of System Accuracy of the GlucoMen LX Plus Blood Glucose Monitoring System With Reference to ISO 15197:2013.

The new ISO15197:2013 norm, defining more stringent system accuracy quality standards, was published in Europe in May 2013. After enforcement of this new regulation, all new meters for patient self-monitoring of blood glucose (SMBG) need to show deviations from a reference method of less than ±15 mg/dl (±0.83 mmol/l) for values below or equal to 100 mg/dl (5.6 mmol/l) and ±15% for values above 100 mg/dl in 95% of the cases as assessed by a standardized clinical protocol requiring 3 strip lots to be tested. A transition period of 3 years has been granted to all SMBG manufacturers prior to implementing the new accuracy criteria as essential and mandatory part of the conformity process required to obtain the CE mark for new devices. The GlucoMen LX Plus meter (A. Menarini Diagnostics) is a self-testing device that measures glucose and ß-hydroxybutyrate in capillary blood and has already been introduced in Europe in 2011. Previous clinical and laboratory evaluations with this system have shown excellent accuracy and stability against hematocrit interference. The system is employing an amperometric glucose-oxidase-based technology with integrated correction algorithms, and is specifically designed for measurement in whole blood samples Purpose of our clinical study was to identify the number of blood glucose results falling within the range of the new ISO criteria. The study was performed in January/February 2013 at the laboratories that today belong to Pfützner Science & Health Institute, Mainz, Germany, in compliance with the German Medical Device Act and approved by the responsible Ethics Committee and the Federal Institute of Drugs and Medical Devices. The protocol was designed in compliance with the system accuracy procedure set forth in the ISO15197:2013 norm, in particular with respect to glucose ranges and number of devices and tests strip lots (100 subjects, 3 strip lots, 6 meters). The tested materials including the meters, the control solutions, and strip lots 3211269249 (exp 9/30/2013), 3211325249 (exp 11/30/2013), and 3211334249 (exp 11/30/2013) were provided by the manufacturer. A YSI 2300 STAT Plus glucose analyzer (Yellow Springs Instruments, Yellow Springs, OH, USA) served as reference method for this analysis. Statistical analyses were performed as defined in the ISO guidelines. All 3 strip lots were successfully tested demonstrating compliance with the new ISO criteria as shown in Table 1. The combined system accuracy results for the strip lots tested were falling within 97% to 99% of the ISO criteria. Clinical accuracy was evaluated by means of the Parkes’s consensus error grid. The overall vast majority of data pairs (628/630, 99.7%) of all values were within zone A of the CGA indicating “clinical accurate measurements with no effect on clinical action”, and 2/630 (0.3%) were in zone B (“altered clinical action with little or no effect on clinical outcome”). No values were seen in the zones C, D, or E, which represent clinically inacceptable values. In conclusion, all 3 lots of the GlucoMen LX Plus glucose meter system were compliant with ISO1597:2013 accuracy criteria.