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In Pursuit of an Ideal – A Perspective on Non-Invasive Continuous Glucose Monitoring


to glucose, the level of HbA1c in a blood sample provides a glycaemic history of the previous 120 days, the average lifespan of an


erythrocyte. The test, however, provides no information about glycaemic excursions. So, an individual could have numerous excursions that, in essence, cancel each other out to deliver an


acceptable HbA1c value. Such a situation would put that individual at risk of developing diabetes-related complication.2–5,11


Even SMBG


provides only a spot measurement of an individual’s glucose level, with no information about rate or direction of change. Unless performed every 15–30 minutes, which is impractical given requirements for finger-stick blood samples and cost of test strips, SMBG simply cannot provide enough information about direction, magnitude, duration, frequency and cause of glucose fluctuations to provide a complete picture of glucose dynamics over time. Without complete information about time spent hyper-, hypo- and euglycaemic, it is difficult for an individual to achieve tight glycaemic control.


Overcoming Barriers – Continuous Glucose Monitoring Improved Glycaemic Control


Real-time CGM (RT-CGM) became available around 2006. It provides a complete picture of glucose levels over time and in the context of daily activities. Since then, a large number of studies have shown that RT-CGM can improve glycaemic control with reduced risk of hypoglycaemia.27–39


A recent review of 19


randomised controlled trials (RCTs) concluded that RT-CGM lowered HbA1c in adults with type 1 diabetes.40


In addition, of nine RCTs


focused on the use of RT-CGM data verified by SMBG data to make dynamic therapeutic adjustments for people with diabetes,32,41–45


seven


demonstrated benefit. Four showed improved glycaemic excursions, reduced glycaemic variability, decreased time spent in hypo- and hyperglycaemia, and improved HbA1c with RT-CGM;41,43–45 similar conclusions but did not evaluate HbA1c;32 improved HbA1c with frequent use of RT-CGM.27,46


one reached


and two showed Although the three


remaining studies did not find a significant benefit of RT-CGM on metabolic control, one noted decreased use of CGM due to skin irritation42


and the other two involved less than daily use of CGM,47,48 which could have affected results. Finally, several studies have observed that RT-CGM can improve glycaemic control when used as part of an insulin pump regimen if used at least 70 % of the time.8,49,50


Furthermore, the benefit of RT-CGM extends to type 2 diabetes. A recent review of published studies concluded that RT-CGM can improve glycaemic control in individuals with type 2 diabetes.51


expectations, invasiveness, cost, pain, discomfort, risk of infection and the degree to which it is perceived to interfere with daily life.60 These issues have limited willingness to begin CGM as well as frequency of CGM use once started. Since clinical studies have shown a linear relationship between increased use of CGM and lowered HbA1c,29,61


lack of adoption and infrequent use are serious concerns. All current CGM devices are invasive, requiring insertion of a needle catheter into the subcutaneous adipose tissue to measure glucose in the interstitial fluid. The insertion injures the local microvasculature, extracellular matrix of structural proteins and adipose cells, and the wound fills with red blood cells, platelets, coagulation proteins and cellular debris which can compromise sensor performance.62–64


Both


the warm-up period required for sensor stability and sensor performance depend to a large degree on the extent of tissue injury, with more extensive injury requiring more frequent sensor recalibration to ensureaccuracy.62


Sensor insertion and implantation can also result in pain or discomfort, and can pose a risk of infection.


In addition, current CGM devices require calibration against blood glucose values as often as twice a day. As a result, the cost associated with current CGM devices can be high, including the CGM device and sensors as well as consumables for SMBG calibration of the device. Similarly, overall accuracy of current CGM is subject not only to the accuracy of the CGM device, but also the accuracy of the SMBG device used to calibrate it as well as the ability of the individual to use both devices proficiently.65


Of note


is the fact that blood glucose meters are calibrated based on a laboratory reference, but current CGM devices are calibrated against a blood glucose meter, putting them one step away from calibration against a laboratory reference. So, despite the tremendous technological advance that current CGM devices represent, they are not ideal glucose monitoring solutions, which begs the question: what is an ideal solution?


Toward an Ideal – Non-Invasive Continuous Glucose Monitoring


When asked about the characteristics of an ideal glucose monitor, healthcare professionals and individuals with diabetes often start by stating the device must be non-invasive, non-intrusive and pain-free. It would, of course, accurately monitor glucose levels continuously, warn of impending glycaemic excursions and be small enough to be worn discreetly. So, how would those characteristics translate into a new medical device?


And,


two RCTs of CGM in type 2 diabetes drew similar conclusions,52,53 suggesting that RT-CGM might benefit a wider range of individuals with diabetes than previously thought. Other studies have shown CGM to be useful for modifying diet and exercise to improve glycaemic control51,54 complications.51,55,56


postprandial hyperglycaemia12,57


and reduce risk factors for diabetes-related Real-time CGM has also been used to detect and determine postprandial


This is of particular benefit given the prominent role that postprandial hyperglycaemia can play in the development of vascular complications of diabetes.59


glycaemic profiles following ingestion of meals of different composition.58


Limited Adoption and Use


Despite the benefit of RT-CGM, it has not been wholeheartedly embraced for reasons such as complexity, inappropriate


EUROPEAN ENDOCRINOLOGY


Accuracy to Support Tight Glycaemic Control Targets It goes without saying that an ideal glucose monitor must be accurate. The question is: how accurate? Current CGM devices have mean absolute relative differences (MARD) around 13–25 %,66–70 and a recent study of seven SMBG devices reported MARDs ranging from 6.5–12 %.71


A non-invasive monitor with a MARD


towards the low end or below current CGM devices would certainly offer improvement, and one that approached the MARD of SMBG devices would be closer to ideal. Further, a CGM device that required no user calibration would eliminate one common source of inaccuracy.


Continuous Information to Drive Optimal Lifestyle, Diet and Treatment


The value of RT-CGM is clear: it provides a complete picture of glucose dynamics over time, including all peaks and valleys, enabling


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