A Brief Review of Non-invasive Systems for Continuous Glucose Monitoring

In recent years, meters for continuous monitoring of interstitial fluid glucose have been introduced to help people with type 1 diabetes mellitus (T1DM) to achieve better control of their disease. The objective of this project was to summarise the evidence on the clinical effectiveness and cost-effectiveness of the MiniMed(®) Paradigm™ Veo system (Medtronic Inc., Northridge, CA, USA) and the Vibe™ (Animas(®) Corporation, West Chester, PA, USA) and G4(®) PLATINUM CGM (continuous glucose monitoring) system (Dexcom Inc., San Diego, CA, USA) in comparison with multiple daily insulin injections (MDIs) or continuous subcutaneous insulin infusion (CSII), both with either self-monitoring of blood glucose (SMBG) or CGM, for the management of T1DM in adults and children. A systematic review was conducted in accordance with the principles of the Centre for Reviews and Dissemination guidance and the National Institute for Health and Care Excellence Diagnostic Assessment Programme manual. We searched 14 databases, three trial registries and two conference proceedings from study inception up to September 2014. In addition, reference lists of relevant systematic reviews were checked. In the absence of randomised controlled trials directly comparing Veo or an integrated CSII + CGM system, such as Vibe, with comparator interventions, indirect treatment comparisons were performed if possible. A commercially available cost-effectiveness model, the IMS Centre for Outcomes Research and Effectiveness diabetes model version 8.5 (IMS Health, Danbury, CT, USA), was used for this assessment. This model is an internet-based, interactive simulation model that predicts the long-term health outcomes and costs associated with the management of T1DM and type 2 diabetes. The model consists of 15 submodels designed to simulate diabetes-related complications, non-specific mortality and costs over time. As the model simulates individual patients over time, it updates risk factors and complications to account for disease progression. Fifty-four publications resulting from 19 studies were included in the review. Overall, the evidence suggests that the Veo system reduces hypoglycaemic events more than other treatments, without any differences in other outcomes, including glycated haemoglobin (HbA1c) levels. We also found significant results in favour of the integrated CSII + CGM system over MDIs with SMBG with regard to HbA1c levels and quality of life. However, the evidence base was poor. The quality of the included studies was generally low, often with only one study comparing treatments in a specific population at a specific follow-up time. In particular, there was only one study comparing Veo with an integrated CSII + CGM system and only one study comparing Veo with a CSII + SMBG system in a mixed population. Cost-effectiveness analyses indicated that MDI + SMBG is the option most likely to be cost-effective, given the current threshold of £30,000 per quality-adjusted life-year gained, whereas integrated CSII + CGM systems and Veo are dominated and extendedly dominated, respectively, by stand-alone, non-integrated CSII with CGM. Scenario analyses did not alter these conclusions. No cost-effectiveness modelling was conducted for children or pregnant women. The Veo system does appear to be better than the other systems considered at reducing hypoglycaemic events. However, in adults, it is unlikely to be cost-effective. Integrated systems are also generally unlikely to be cost-effective given that stand-alone systems are cheaper and, possibly, no less effective. However, evidence in this regard is generally lacking, in particular for children. Future trials in specific child, adolescent and adult populations should include longer term follow-up and ratings on the European Quality of Life-5 Dimensions scale at various time points with a view to informing improved cost-effectiveness modelling. PROSPERO Registration Number CRD42014013764. The National Institute for Health Research Health Technology Assessment programme.

Currently, patients with diabetes may choose between two major types of system for glucose measurement: blood glucose monitoring (BGM) systems measuring glucose within capillary blood and continuous glucose monitoring (CGM) systems measuring glucose within interstitial fluid. Although BGM and CGM systems offer different functionality, both types of system are intended to help users achieve improved glucose control. Another area in which BGM and CGM systems differ is measurement accuracy. In the literature, BGM system accuracy is assessed mainly according to ISO 15197:2013 accuracy requirements, whereas CGM accuracy has hitherto mainly been assessed by MARD, although often results from additional analyses such as bias analysis or error grid analysis are provided. The intention of this review is to provide a comparison of different approaches used to determine the accuracy of BGM and CGM systems and factors that should be considered when using these different measures of accuracy to make comparisons between the analytical performance (ie, accuracy) of BGM and CGM systems. In addition, real-world implications of accuracy and its relevance are discussed.

The history of the development of glucose sensors is synonym of the history of biosensor research. Glucose sensors created the past and current largest market in the industrialized biosensors. The most of the commercially available glucose sensors have been dedicated to the disposable sensor strips for self-monitoring of blood glucose (SMBG), thereby diabetic patients know which treatments and amounts of treatments to self-administer and to learn how activities affect their blood glucose levels. Currently, continuous glucose monitoring (CGM) systems have been recognized as the ideal monitoring systems for glycemic control of diabetic patients, expecting the replacement of SMBG sensors. Glucose monitoring using SMBG sensors requires taking tiny blood sample using a “lancet” to prick your finger or some other alternate sites for testing, whereas CGM systems monitor glucose level at interstitial fluid (ISF) where CGM sensor is inserted. At present, the glucose concentration in blood and ISF samples are recognized as the clinically relevant values. In 2018, the U.S. Food and Drug Administration (FDA) approved a medical device comprising CGM system, a continuous subcutaneous insulin infusion pump and a control algorithm that can supply an appropriate amount of basal insulin based on the CGM results as an artificial pancreas. Consequently, it became possible to automatically and continuously control the blood glucose level. In 2019, synthetic receptor employing long-term implantable CGM system, was approved as the prescription device, which realized up to 90 days (180 days in Europe) operation. These technological achievements boosted up CGM systems and sensors as the flagship technologies in the biosensor research.In this presentation, I will overview the current status and future perspectives of sensors for CGM systems.

Diabetes is a chronic and incurable metabolic disorder, necessitating rigorous blood glucose management as the cornerstone of effective treatment. Maintaining blood glucose levels within the normal range is critical for mitigating the risk of microvascular complications. Continuous glucose monitoring (CGM) systems represent a transformative advancement in glucose monitoring technology, enabling automated, real-time tracking of glycemic fluctuations by measuring interstitial fluid (ISF) glucose concentrations and converting these readings into blood glucose values.This paper provides a comprehensive overview of the development of CGM systems, reviewing their functional characteristics, target populations, and current technological advancements. Additionally, it examines the clinical evaluation framework for CGM systems and analyzes their application across diverse scenarios. Finally, the study highlights future directions and challenges in CGM technology, offering insights to guide further innovation and optimize clinical implementation.This review aims to serve as a valuable reference for researchers and clinicians in advancing next-generation CGM systems and enhancing their practical utility in diabetes management.

This study is aimed at comparing the performance of three continuous glucose monitoring (CGM) systems following the Clinical and Laboratory Standards Institute's POCT05-A guideline, which provides recommendations for performance evaluation of CGM systems. 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)]. 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%). 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.

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. 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. 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. 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.

Diabetes technology and devices transform the lives of people with diabetes.

Continuous glucose monitoring (CGM) systems have been available for more than 15 years by now. However, market uptake is relatively low in most countries; in other words, relatively few patients with diabetes use CGM systems regularly. One major reason for the reluctance of patients to use CGM systems is the costs associated (i.e., in most countries no reimbursement is provided by the health insurance companies). In case reimbursement is in place, like in the United States, only certain patient groups get reimbursement that fulfills strict indications. This situation is somewhat surprising in view of the mounting evidence for benefits of CGM usage from clinical trials: most meta-analyses of these trials consistently show a clinically relevant improvement of glucose control associated with a reduction in hypoglycemic events. More recent trials with CGM systems with an improved CGM technology showed even more impressive benefits, especially if CGM systems are used in different combinations with an insulin pump (e.g., with automated bolus calculators and low glucose suspend features). Nevertheless, sufficient evidence is not available for all patient groups, and more data on cost-efficacy are needed. In addition, good data from real-world studies/registers documenting the benefits of CGM usage under daily life conditions would be of help to convince healthcare systems to cover the costs of CGM systems. In view of the ongoing improvements in established needle-type CGM systems, the fact that new CGM technology will come to the market soon (e.g., implantable sensors), that CGM-like systems are quite successfully at least in certain markets (like the flash glucose monitoring systems), and that the first artificial pancreas systems will come to the market in the next few years, there is a need to make sure that this major improvement in diabetes therapy becomes more widely available for patients with diabetes, for which better reimbursement is essential.

Objective To evaluate the effect of continuous glucose monitoring system(CGMS) in improving the current status of type 1 diabetes mellitus(T1DM) control and reducing the economic burden of the patients. Methods One hundred and fifteen patients with T1DM were randomly assigned to the CGMS group and the self-monitoring of blood glucose(SMBG) group respectively. The patients in CGMS group were on 72 h CGMS every 6 months, while SMBG group only with SMBG to guide the insulin dose adjustment. The levels of blood glucose and the statistics of the number of hypoglycemia and diabetic ketoacidosis were taken as the main observational indexes every 6 months. The chronic complication and the statistics of the number of hospitalizations and the total cost of treatment were made as the secondary observational index every 12 months. Results 2 h postprandial plasma glucose(2hPG) and mean blood glucose(MBG) in the CGMS group were lower than those in the SMBG group [(10.7±1.9 vs 11.5±2.7) mmol/L, (9.7±0.5 vs 10.6±0.7) mmol/L, P<0.05] in the clinical follow-up visit after 6 months. The per capita number of hypoglycaemia in the CGMS group was lower than that in the SMBG group[(7.9±2.6 vs 9.2±3.4) times, P<0.05]. In the outpatient follow-up re-visit to the patients after 6 months, fasting plasma glucose(FPG), 2hPG, MBG, and HbA1C of the patients in the CGMS group were lower than those in the SMBG group(t=4.71~9.75, P<0.05), the per capita numbers of hypoglycemia and DKA in the CGMS group were lower than those in the SMBG group(t=3.61~4.37, P<0.05). Conclusion The application of real-time continuous glucose monitoring in T1DM outpatient management may reduce the whole-day blood glucose of the patients, decrease the incidence risk of hypoglycemia, and improve the compliance of the treatment while without increasing the economic burden of the disease. (Chin J Endocrinol Metab, 2017, 33: 367-371) Key words: Real-time continuous glucose monitoring system; Diabetes mellitus, type 1; Outpatient management system; Control status; Economic burden of disease

The goal of this paper is to describe the metrics used for the evaluation of accuracy of blood glucose (BG) meters for self-monitoring of blood glucose (SMBG) and continuous-glucose monitoring (CGM) system and their limitations and to discuss the current status of SMBG and CGM accuracy. SMBG measurement is used by patients for therapy control and for calculation of appropriate insulin doses for approximately 30 years. The minimum accuracy criteria for SMBG meters are currently defined by ISO 15197:2003 (at least 95 % of results within \(\pm \)20 % or \(\pm \)15 mg/dL of the comparison method measurement results for BG concentrations above or below 75 mg/dL, respectively). In 2013, these accuracy limits were revised in the standard ISO 15197:2013: at least 95 % of results within \(\pm \)15 % or \(\pm \)15 mg/dL for BG above or below 100 mg/dL, respectively. SMBG systems are also used by patients for calibration of CGM systems. Therefore, precision and trueness of the SMBG system are influencing the accuracy of the CGM results. The timing of the BG measurement used for calibration has to be taken into account because, during rapid glucose changes, a time lag exists between BG and the tissue glucose that is measured by CGM systems. The accuracy of CGM devices is often reported by the mean absolute relative deviation (MARD) between CGM results and BG comparison results. This parameter is influenced by different factors like study procedures, glucose fluctuations during the study, and distribution of comparison BG measurements. It is important to define standard study procedures and evaluations to be able to compare MARD results from different studies. For the correct prediction of glucose concentrations, the specific prediction method as well as the accuracy of the CGM system, which may be affected by the accuracy of the SMBG system used for calibration, and the timing of the calibration are important aspects.

This pilot prospective study reports the feasibility, management and cost of the use of a continuous glucose monitoring (CGM) system in critically ill adult horses and foals. We compared the glucose measurements obtained by the CGM device with blood glucose (BG) concentrations. Neonatal foals (0-2 weeks of age) and adult horses (> 1 year old) admitted in the period of March-May 2016 with clinical and laboratory parameters compatible with systemic inflammatory response syndrome (SIRS) were included. Glucose concentration was monitored every 4 hours on blood samples with a point-of-care (POC) glucometer and with a blood gas analyzer. A CGM system was also placed on six adults and four foals but recordings were successfully obtained only in four adults and one foal. Glucose concentrations corresponded fairly well between BG and CGM, however, there appeared to be a lag time for interstitial glucose levels. Fluctuations of glucose in the interstitial fluid did not always follow the same trend as BG. CGM identified peaks and drops that would have been missed with conventional glucose monitoring. The use of CGM system is feasible in ill horses and may provide clinically relevant information on glucose levels, but there are several challenges that need to be resolved for the system to gain more widespread usability.

This pilot prospective study reports the feasibility, management and cost of the use of a continuous glucose monitoring (CGM) system in critically ill adult horses and foals. We compared the glucose measurements obtained by the CGM device with blood glucose (BG) concentrations. Neonatal foals (0–2 weeks of age) and adult horses (> 1 year old) admitted in the period of March-May 2016 with clinical and laboratory parameters compatible with systemic inflammatory response syndrome (SIRS) were included. Glucose concentration was monitored every 4 hours on blood samples with a point-of-care (POC) glucometer and with a blood gas analyzer. A CGM system was also placed on six adults and four foals but recordings were successfully obtained only in four adults and one foal. Glucose concentrations corresponded fairly well between BG and CGM, however, there appeared to be a lag time for interstitial glucose levels. Fluctuations of glucose in the interstitial fluid did not always follow the same trend as BG. CGM identified peaks and drops that would have been missed with conventional glucose monitoring. The use of CGM system is feasible in ill horses and may provide clinically relevant information on glucose levels, but there are several challenges that need to be resolved for the system to gain more widespread usability.

Continuous glucose monitoring systems - Current status and future perspectives of the flagship technologies in biosensor research -

BackgroundContinuous glucose monitorings (CGMs) have been used to manage diabetes with reasonable glucose control amongst patients with type 2 diabetes (T2D) in recent decades. CGMs measure interstitial fluid glucose levels to provide information about glucose levels, which identify fluctuation that would not have been identified with conventional self-monitoring. Self-monitoring of blood glucose (SMBG) is a classical tool to measure glycaemic changes. However, the effectiveness of glucose control, hypoglycemia, weight change, quality of life and user satisfaction, are needed to evaluate and compare CGMs and SMBG amongst adults with T2D.MethodsThe review will compare the various forms of CGM systems (i.e flash CGM, real-time CGM, retrospective CGM) versus SMBG or usual intervention regarding diabetes management amongst adults with T2D. The following databases will be searched: Cochrane Library, PubMed, EMBASE, CINAHL, PsycINFO, Scopus and grey literature (ClinicalTrials.gov, PsycEXTRA, ProQuest Dissertations, Google Scholar and Theses Global) for the identification of studies. The studies involving adults (aged ≥ 18 years old) will be included. We will only include and summarise randomised clinical trials (RCTs) with respect to authors, publication type, year, status and type of devices. Studies published in English between February 2010 and March 2020, will be included as the field of CGMs amongst T2D patients has emerged over the last decade. Primary outcomes will be HbA1c (glycosylated haemoglobin level) (mmol/L), body weight (kg), time spent with hypoglycaemia (< 70 mg/dl) or hyperglycaemia (≥ 180 mg/dl), blood pressure (< 140/90 mmHg is considered as good management) and quality of life (understanding and feeling of living situation based on culture and value system). Secondary outcome measures will be user satisfaction (patient or treatment/intervention satisfaction or satisfaction scale) and barriers (physical and mental difficulties or issues). Study selection, data extraction and risk of bias assessment will be conducted independently by at least two reviewers. A third reviewer will determine and resolve discrepancies. Moreover, the quality of the evidence of the review will be assessed according to the Grading of Recommendations Assessment, Development and Evaluation tool (GRADE).DiscussionThe review will synthesise evidence on the comparison between using CGMs and SMBG. The results will support researchers and health professionals to determine the most effective methods/technologies in the overall diabetes management.Systematic review registrationPROSPERO CRD42020149212

Introduction: Diabetes management has evolved through the introduction of self-monitoring blood glucose (SMBG) and continuous glucose monitoring (CGM) systems, enabling real-time patient feedback.[1] Of these, CGM systems, capable of prolonged, continuous monitoring, hinge upon the dependable performance of the enzymes to maintain precise measurements and long-term sensing capabilities. Current CGM systems utilize fungi-derived glucose oxidase (GOx) to catalyze the reaction with glucose. This enzyme is able to record glucose values within the physiological range with high accuracy; however, this enzyme also creates hydrogen peroxide during continuous operation leading to self-inactivation via radical oxygen species(ROS) formation. Our group has been involved in the characterization and functional engineering of a FAD-dependent glucose dehydrogenase enzyme derived from Burkholderia cepacia (BcGDH) which is capable of direct electron transfer (DET) with an electrode.[2, 3] By eliminating the need for hydrogen peroxide or toxic external mediators—as are common with 1st and 2nd generation CGM sensors, respectively—we are able to simplify our sensing platform and create the ideal sensing modality. Additionally, we have improved the thermal stability of BcGDH by introducing inter-subunit disulfide bonds which has greatly improved the in vitro half-life of our enzyme.[4] Although we have been able to engineer our BcGDH to have a much greater half-life in vitro than the wild type BcGDH or GOx, we observe uncharacteristic inactivation during continuous applied potential electrochemistry experiments. This study focuses on the elucidation of the electrochemical inactivation mechanism of a DET-type BcGDH enzymatic sensor. Materials & Methods: BcGDH engineered enzyme, from the introduction of inter-subunit disulfide bonds was recombinantly produced and purified. A ϕ=2mm gold disk electrode was polished and electrochemically cleaned before functionalized with dithiobis(succinimidyl hexanoate) to form a self-assembled monolayer(SAM). The purified BcGDH mutant was then immobilized to the SAM. Variations in potentials (none, 100mV or 400mV vs Ag/AgCl), glucose concentration (none or 20mM), and oxygen (argon purged or ambient oxygen) were used for the incubation conditions. Every three hours (0 to 9 hours) calibration curves were investigated unilaterally at 45°C, 400mV vs Ag/AgCl applied potential, ambient oxygen, and varying concentrations from 0 to 20mM glucose. Results & Discussion: The disulfide bond stabilized BcGDH engineered enzyme was stable at more than 80°C confirming its thermal stability and extended half-life at supraphysiological temperatures. However, when utilized in a sensor format at 45°C, engineered enzyme was inactivated much more rapidly than expected. The largest rate of inactivation was revealed to be due to application of a high over-potential (+400mV vs Ag/AgCl) coupled with hyper-physiological glucose levels with ambient oxygen showing a sensor half-life of 2.89±0.74 hours at 45°C. The impact of oxygen-purging the system by utilizing argon gas was shown to improve the sensor half-life to 35.04±6.17 hours at 45°C. Additionally, without the high over-potential, the hyper-physiological glucose concentrations had no detriment to the sensor and no sensor inactivation was observed. . The high over-potential combined with hyper-physiological glucose and ambient oxygen were assumed to produce radical oxygen species (ROS) which are responsible for the inactivation of the enzyme. Conclusions: We demonstrate the ability to use this DET-type GDH electrochemical sensor to investigate the factors which accelerate its inactivation. While hyper-physiological glucose levels do not significantly inactivate the enzyme-sensor, the high over-potential incubation inactivates the sensor much faster—likely due to the formation of ROS from generation of H2O2 at the cathode. By removing oxygen from the system via an Argon purge, the conversion of oxygen to hydrogen peroxide is thwarted. In the future, studies should be done to mitigate the ROS generation as glucose levels cannot be controlled. This strategy may be done by applying a lower over-potential to the sensor would minimize the formation of ROS even in the presence of hyper-physiological glucose.