Blood Glucose Monitoring

Abstract

Glucose monitoring is the integral part of diabetes management. We have over the years moved from qualifying sugars in urine to identifying glucose alone in the interstitial tissue. Even more we are anow able to identify and use minute to minuet glucose fluctuations and use them to avoid the dangers and unpleasantries of hypoglycemia. We look at the development of glucose monitoring methods. The development of classic basic glucose monitors as well as the development of continuous glucose monitors. Basic principles of function, advantages, and disadvantages, as well as areas of actual and projected use are mentioned. We name some of the patient groups that have proven to get most advantage of glucose monitoring. He need for individual approach an patient activation as well as for alert diabetes health care provided is necessary for optimal use of technology for glucose monitoring.

1. Introduction

Diabetes mellitus is group of metabolic diseases, resulting from absent or defective insulin secretion and/or action and manifested by high blood glucose levels. We think of diabetes as of a chronic long and progressive disease that requires a complex multifaceted treatment.

At the time of insulin discovery, identification, and quantification of glucose was a demanding laboratory task. Today, glucose in blood is the most frequently analyzed parameter in a clinical chemistry laboratory. The value of global blood glucose monitoring systems market size in 2021. in the US was estimated at 14.78 billion dollars and with a projected to grow to over 31 billion dollars by 2029.

While it was the discovery of insulin, 100 years ago, that most profoundly shifted the perspective of diabetes form a lethal, relatively quickly progressive disease to a chronic progressive disease which increases risk for micro- and/or macrovascular complications, it was the availability of simple, easy to use, reliable glucose testing that has made diabetes, with its acute and chronic events (mostly hyperglycemia but also hypoglycemia), closer to every patient and living with diabetes more predictable. Glucose monitoring has, together with development of diabetes education programs, contributed to aiming the complex diabetes patient at being a “patient centered care” where “… patient values guide all clinical decisions”.

It is the development of glucose monitoring systems that has made the health care providers and researchers focus again to the fact that glucose control is a continuum- diabetes with glucose swings and inappropriate glucose control is a disease of deviant homeostasis, where insulin plays the main, but not the only role. It may be that our approach to hyperglycemia and hypoglycemia will be changed in future, again, due to the observations got through glucose monitoring systems and our interventions.

The way to modern glucose monitoring equipment was not short and was not easy.

It was necessary with development of basal natural sciences to get form the intuitive to the quantitative and beyond…

1.1 The glucose molecule

The first glucose molecule was isolated from raisins in 1747 by Andreaas Marggraf. The name (glycos- sweet) was established and used in 1838 by Jean Baptiste Dumas.

Glucose is classified as a monosaccharide- simple sugar. The molecular formula C6H12 O2.

Glucose qualifies as a hexose, because it contains 6 carbon atoms. It an aldose- meaning that it contains an aldehyde group that is easily oxidized [1].

Friederich August Kekule proposed also the name dextrose, being aware of the ability of glucose water solution to turn the plane of polarized light to the right. The metabolically active glucose is D (+) glucose.

In 1902 the Nobel Prize for chemistry was given to Emil Fisher who explained the cyclic structure of glucose: Biologically active glucose is mostly in cyclic structure.

A few chemical properties are of significance when defining glucose, but the most important is borne by the aldehyde group. That redox capacity can translate in a subset of reactions leading to formation of colored substrates or electrochemical reaction.

1.2 Glucose, laboratory identification

It was in 1838, that George Rees, a physician at Guy’s Hospital, London, isolated sugar and in excess from blood of a diabetic patient [2].

Monitoring of glucose was at first done through monitoring of glucose in the urine. That was not an easy task and it was of little clinical significance: the finding of glucose in the urine signified advanced disease. Hypoglycemia could not be verified. The technique was complicated. The method was at most semiquantitative. Basis for use lies in the classical Fehling and Benedict reaction:

In 1848. The German chemist Herman Von Fehling developed a test that was able to differentiate reducing (sugars with aldehyde group) from nonreducing (sugars with keto group). Reducing sugar (such as glucose is) would be reducing a cuprous ion that than changes color and precipitates. The reaction requires a temperature of almost 60°C.

Stanley Benedict developed a modified copper reagent urine glucose test in 1908. The test uses the same principle as Fehling `s test but was easier to perform. The test was the basic glucose-monitoring test for almost 50 years. Urinary test based on Benedict reaction was introduced for home use in 1925. Test tube was given at the doctor’s office, with the required reagents measured and dispensed by the physician. But it was basically the first test that the patients could use at home [3].

Benedict test, as a semiquantitative method, was a cornerstone of glucose monitoring in over 50 years and can be thought of the ground self-monitoring test.

In 1925, 26-year-old Danish botanist Detlev Muller discovered glucose oxidase [4]. The discovery was overshadowed by the work of Otto Warburg og Christian Walter who in 1932–1933 discovered glucose 6 phosphate dehydrogenase, the first discovered flavoenzyme. That the reaction produces color is of significance for further development of analytics. Warburg got, else, the Nobel prize for discovery of the nature and mode of action of respiratory enzyme).

Today’s glucose monitoring techniques, quantitative, are mostly based on enzymatic reactions- glucose oxidase, hexokinase, or glucose dehydrogenase. The enzyme changes (oxidizes) glucose, and the transfer of electrons causes chromogenic reaction. The change in color is detected photometrically. The electron flow can also be measured electrochemically [5]. The methods are quantitative.

None of these methods, that we, regardless of many analytical problems, think of as an acceptable and reliable (also accurate and precise) reflection of blood glucose [6], would be in use had it not been for the basic chemical and physicochemical research done from the 1800.

2. Glucose monitoring: moving towards the patient

Benedict’s reaction was developed in 1908. In 1925. we had a test for elf testing of glucose in the urine. It was a test that could be done home, but it was long from practical and it was necessary that the doctor gives the necessary equipment. In 1945, Ames (Elkhart, IN) developed a tablet with modified copper reagent, Clinitest. The method was also based on Benedicts reaction, but it was easier to perform. The method was semiquantitative and estimated the level of urinary glucose by comparison to the color chart.

By the late e1940 ies Hellen Fee (Mile’s laboratories – which was known for producing Alca Selzer) developed the “dip and read” urine test – known as Clinistix. This was a huge step forward in clinical laboratory – the reagents for complete oxidative chain of reactions were set on a filter paper strip and could instantly identify glucose.

In 1957 Kohn showed that Clinistix could also give approximate results for blood glucose [7].

Dry chemistry came in to stay. In 1964, Boehringer Ingelheim introduced first Combur test that could identify glucose, protein, pH in the urine, and later Ketostix that could also identify ketones.

The first test strip for blood glucose was introduced in 1964: Ames -Mile’s laboratories presented Dextrostix. Earnest C Adams was the developer. The test was based on glucose oxidase reaction. It included a semipermeable membrane that allowed glucose, but not the red blood cells to get to the reagent. The method was semiquantitative. It was meant for use at the doctor’s office. The strips were widely used by the health care personnel at different points of health care, regardless that there were too many steps in the procedure ant too many steps that could lead to an inaccurate result. Stix limitations have been the trigger to develop automatic electronic glucose test strip reader, with standardized precision and quantitative results.

2.1 Glucose monitoring- glucometers come

Therefore, the first glucometer came. It was in 1970. It used Dextrostix. High cost, weight at 1,2 kg and only available at the doctor’s office. Even the lighter and improved version produced by the Japanese in 1972, was a long way from what we think of as glucometer. It required repeated calibration, operator training and continuing practice, but with imminent insecurity about precision and variability.

It was developed further to a Glucometer 1, that came in 1981, as a first portable lightweight glucometer. It used again Dextrostix, and it was recommended for bedside monitoring of blood glucose. Glucometer 1 used a hexokinase-based glucose method.

In 1987. Came also the first blood glucose biosensor system. It used glucose oxidase strip. The electron transfer, stepwise, generated a current detected by amperometic sensor. It was the third generation of blood glucose monitoring systems. This was the final step that enabled the development of improved and easily used precise blood glucose monitoring instruments.

By the 1990 we have so moved from large instruments that required many analytical steps and the required blood volume for analysis was significantly reduced. Analytical time was reduced. High requirements for accuracy and precision are well met - while the first tests had variability of up to 40%, todays requirements today are less than 5% between meters and laboratory methods [8]. The development of software allows for keeping the measurements and eventually can make them available for analysis.

As much as chemistry and technology advanced, it is also the knowledge about diabetes that was pushing to test that would be reliable easy to use and available.

3. Continuous glucose monitoring (CGM): the principle

Continuous glucose measurement systems measure glucose in the interstitial fluid by a device that is inserted subcutaneously. The CGM system contains the sensor, a transmitter and a receiver or monitor.

The components have undergone significant changes from the first presented CGM system.

The first ever CGM system was approved by the FDA in 1999. It was produced by Medtronic (Medtronic guardian RT).

The device was measuring glucose in the interstitial fluid every 5 minutes. Glucose sensing electrode was inserted subcutaneously in the abdomen or in the arm. Glucose was measured electrochemically. The sensor lasted for 3 days. The results were stored and could be analyzed at the doctor’s office. The data was not real time data ant the patient did not have access to data self. The patient could not get information about imminent hypoglycemia/hyperglycemia. The system needed calibration by fingerstick glucose measurements every 6–12 hours. The sensor and the receiver were physically connected by a cable that transmitted the measurements. The CGM could collect data in a three-day period [9]. Also, far away from the CGM systems that we know today.

The revolutionary, however, was that the glucose was measured often (1–5 minutes). The number of fingerstick was reduced – to calibration and eventually to check the results. The first generations of CGMS were basically only for professional use: the patients did not have insight into the glucose levels in the observation period. The first CGMs had an exceptionally large glucose variability, something that, naturally, was not wanted.

3.1 Continuous glucose monitoring (CGM): some important steps

The first real time CGM was the Glucowatch biographer (Cygnos, Redwood CA), The device used reversed iontophoresis for measuring interstitial glucose. It was noninvasive, worn as a wristwatch. However, it caused a lot of local irritation and was not a commercial success.

In 2004, Medtronic introduced wireless transmitting from sensor to receiver. It was possible to give alerts on high low glucose: that was significant improvement and became industry standard.

In 2006 Medtronic comes with Guardian REAL time CGM system with alerts on high and low glucose. By 2006 integrated pump and sensor was released.

Dexcom introduced its first real time sensor STS in 2006. The device needs calibration. The device needed calibration. The sensor lasted for 72 hours. It could be programmed to alert high and low values. The results could, however, not be used for clinical decisions- dvs that every result had to be checked by usual SBGM before change In insulin dosage.

In 2008 Abbott came with Free Style Navigator. The main advantage was longevity of the sensor – up to 5 days. But the equilibration (warm-up) time was up to 10 hours. The receiver had also a function as a glucometer: it was again necessary to check the result before changing the treatment.

In 2012 Dexcom G4 was available, now with a 7-day wear period. In 2015 it got FDA approval for use as aa CGM in patients ages 2–17. The same year A Dexcom G5 mobile platform was launched. That allowed for the CGM data to be transmitted to a compatible mobile device – users cell phone.

The last generation Dexcom G6 is a device that does not need calibration, lasts for 10 days and requires no confirmatory finger sticks. In 2018. Dexcom 6 became the first CGM to be approved by the FDA for integration in automated insulin dosing systems.

In 2016, Abbott introduced a new GCM device, Free Style Libre Pro Flash CGM, the first that does not require calibration. Initially, the system was indicated only for use by health care professionals and for use in the adult patients. The sensor could store the glucose data for up to 14 days. Glucose measurements were registered at 15 min intervals. But the system could not give real time data. The system was further upgraded to Free Style Libre 1 and 2, such that the patient can scan and get to know glucose levels. The system is allowed fro use in children older tah 4 years and in pregnant women.

In May 2016, Eversense introduced a CGM that included the only implantable glucose sensor with a 90 day lifespan. In 2017, Eversense XL was launched – with a lifespan of 180 days. To this day it is the CGM with the long- lasting glucose sensor available on the market.

Medtronic works in this period more on the integration of glucose sensor and insulin pump. In 2013 came MiniMed 530G sensor, the first pump with threshold suspends for hypoglycemia. Integration of CGM and insulin pump required also significant advantage in software, insulin algorithms and mobile technology. Today, integration of CGM with insulin infusion pumps includes both threshold and predictive low glucose suspend, as well as hybrid- and fully automated closed loop systems using either insulin alone or insulin and glucagon. The goal is to make an insulin pump that delivers insulin in accordance to sensed glucose, with truly little need for manual control of the device.

4. Glucose monitoring - what we do

Glucose monitoring is of proven clinical benefit in diabetes patients and it is the standard of diabetes medical care [10, 11, 12]. The possibility to move to capillary glucose measurement was significant for patient understanding of glucose variations, response to daily activities and effect of choices they make.

To summarize, we have several options that the health care provider and, more important, the patient can choose to follow with blood glucose levels.

• Glucometers-measure capillary blood glucose using fingerstick.

• Flash glucose monitors- measure interstitial fluid glucose by scanning of sensing device, intermittently.

• Continuous glucose monitors- a sensing device is continuously registering interstitial glucose levels. The data is sent to a device with real time check for viewing. Such devices can be integrated into insulin pumps.

We are aware of the classic glucose laboratory test is also in use and most used tests in modern laboratory medicine and are reference to accuracy, reproducibility and reliability of other methods.

It is also good to remember of some laboratory finesses that can be of significance if not observant in diagnosing diabetes.

Glucose can be measured in the whole blood, plasma or serum samples. Concentration of glucose is approximately 15% lower than in plasma or serum. Blood glucose cannot be decided accurately on postmortem specimens. Glucometers use capillary blood – also full blood that has a lower concentration of glucose than plasma. However, capillary blood has a higher concentration (up to 20%) than venous blood. Glucose concentration in samples that wait long for analysis are lower -because of glycolysis (and of course if not properly stored).

None of the devices is perfect and we must be aware of their limits. Not all the new devices are appropriate for all diabetes patients.

4.1 Blood glucose monitoring (BMG): self-blood glucose monitoring (SBGM)

Self-blood glucose monitoring is performed buy a glucometer. Capillary blood glucose is analyzed, using glucose oxidase or hexokinase methods.

It is the standard recommended glucose monitoring for most diabetes patients today.

Regular blood glucose monitoring (BGM) has been associated with improved glycemic control in T1D patients [10, 13]. Higher frequency of measurements is associated with lower HbA1c [14]. Evidence on the role of BGM in achieving optimal glucose control in patients with type 2 diabetes (especially the patients that are not using insulin) is limited [15, 16, 17]. It does, however, give BGM a significant new role in empowering the patient to live with diabetes.

4.2 Blood glucose monitoring: glucometers - glucose monitors

Glucose measuring devices analyze capillary blood glucose. The devices we use today give a reliable insight in glucose levels. Although great improvements since the first one that was in use, one must be aware that there are some analytical limitations of the devices (and not being sensitive enough in the low glucose range, is one of the most significant).

The accuracy of a glucometer is the parameter that is most important when deciding which ne to recommend and use. The question of accuracy and standardization is ongoing [18].

The highest standards are given by ISO and FDA. Standards vary depending on whether the device will be used by a professional or at home.

Marketed monitors in Europe must meet the following standard to be certified as accurate (dvs that the results can be used to make a therapeutic decision):

95% of the results must be within 15% of the reference method for blood glucose >100 mg/dl.

95% must be within 15 mg/dl for blood glucose <100 mg/dl.

For a glucometer to be certified by FDA, for use in diabetes patients, it is necessary that 95% of the results should be within 15% of the comparator method and 99% of results should be within +/−20% of the comparator across the entire claimed measuring range.

It is also necessary to perform adequately in the low glucose range: professional devices (used in the hospital) should achieve 95% of results within +/−12% of the comparator method for blood glucose levels >75 mg/dl (4,1 mmol/l) and within +/−12 mg/dl for levels under 75 mg/dl, they should achieve 98% of values within +/−15% of the comparator method for blood glucose levels >75 mg/dl and +/−15 mg/dl for levels <75 mg/dl across the entire claimed measuring range [19, 20].

BGM today is performed through a few simple steps. No matter how easy the steps may seem and no matter how accurate the system is, it is still possible to get a result that is inaccurate, because of the pre- or postanalytical errors. Some of the preanalytical errors are – poor skin preparation (having lotion or food rests on the skin, feks) or use of test strips that are incorrectly stored or expired. Postanalytical errors are mostly connected to registration of results, missing the values in the log, use of incorrect glucose units etc.

It is also estimated that only 7–13% of errors may occur during the analytical phase – if the patient is taking ascorbic acid or acetaminophen that will influence the results. Monitors that use glucose oxidase strips can give unreliable results when used bedside in patients that have oxygenation problems: low oxygen saturation will lead to false higher glycemia, while higher oxygen tensions in pat using oxygen may result I false ow glycemia. Monitors have also optimal range of working temperature. Test strips are most sensitive (again) to oxidation during improper or too long storage.

4.3 Blood glucose monitoring: the patient

One of the great changes in modern medicine, is moving from doctor- and medicine centered follow up of chronic diseases, towards patient empowered and disease mastering patient treatment. BGM is essential in such treatment concept in diabetes.

BGM is a standard of care and basic necessity for all patients with diabetes [21, 22, 23].

The significance of BGM is different in different groups of diabetes patients.

Also, the significance that BGM has for a patient is completely individual and are depending mostly on patient’s motivation to integrate BGM in diabetes treatment plan.

4.3.1 Insulin treated diabetes type 1 patients

T1D patients on intensified insulin (multiple daily injections or CSII) treatment have, as previously mentioned, the greatest use of BGM based on their insulin regimen. It is recommended with monitoring in context of insulin dosage, postprandial, in mistaken hypoglycemia or hypoglycemia unawareness, after treating hypoglycemia, prior to exercise, prior to activity that requires normoglycemia (such as driving) or in the context of acute illness.

BGM with multiple daily monitoring in children and adolescents has special significance [24].

4.3.2 Gestational diabetes mellitus

Pregestational and gestational BGM is reduces HbA1c, but also the complications of diabetes pregnancies [25]. The recommendations ad requirements here are high:

Patients with known diabetes should plan pregnancy. In the pregestational period it is recommended that glucose monitoring be intense: pre breakfast, 2 h after all meals and at Bedtime.

Insulin dose should be titrated to achieve blood glucose.

4,0–5,8 mmol/l before breakfast.

>7,8 mmol/l post meal.

And 6-8 mmol/l at bedtime.

Once pregnancy is diagnosed intensive blood glucose monitoring is started, with the same glucose levels wanted): treatment is changed accordingly.

Pregnancy is surely the only glucose monitoring chapter with low tolerance for inconsistency.

How many times a day and in what order glucose should be monitored, is variable and has to be individualized also depending on what the goal is. In T1D patients on intensified insulin regime it is mainly insulin dosage that is the result of such monitoring. The intensity of BGM can also differ at different times, depending on patients specific needs at the time and patients goals at the time.

4.3.3 Diabetes type 2

Recommendations for patients that have T2D are a bit different: patients that use intensified insulin treatment should follow the recommendations as T1D patients.

Patients that use conventional treatment with basal insulin only can use BGM to titrate insulin dosage, but do, generally, not need intensified BGM.

Patients that do not use hypoglycemic drugs can have some help av. BGM, especially when adjusting diet, medications, level of activity or as a part of (introductory) diabetes treatment program.

Patients with prediabetes do not require self-blood glucose monitoring.

4.3.4 High accuracy

It is important to insist on devices with high accuracy (point of care requirements) glucose monitor in patients who [26].

1. Have a history of severe hypoglycemia or hypoglycemia unawareness

2. Are pregnant

3. Receive insulin therapy

4. Are otherwise at risk for hypoglycemia (feks use sulphonylureas).

5. Have occupations that enhance possible risks from hypoglycemia (fex driving or operating hazardous machinery).

6. Are using CGM device that uses calibration.

Its is necessary that all patients get god information and be educated to optimally use glucose meters, having in mind the major causes o eventually unreliable result.

4.4 Glucose monitoring: glucose monitors: what more is needed

Individual approach to every patient is important so that the recommendation on BGM (most of all structure of the measurements) leads to improved glucose control, but also improved feeling of diabetes control in patient self. It is important that the glucose value can be related to insulin dosage, meals, activity, illness, stress, new condition and that the patient/health care provider can get insight in glucose/diabetes dynamics, but also that they be able to conclude with a reasonable change. All the diabetes associations give some guidelines on number of necessary glucose measurements. But the number of required measurements must be in relation to patients needs. Gestational diabetes is maybe the only type of diabetes where the demand for BGM must be uncompromised.

But we must mention that it is often that the patient cannot follow with the requirements with BGM- it is not unusual to have patients that do not check blood glucose or do inconsequently. There are also patients who are not able to take appropriate self-management actions based on acquired data.

To motivate the patient for use of BGM can be a very complex and not always a successful job: although finger sticking can be the most intuitive hinder to multiple daily glucose measurements, it is not the main problem- BGM is a behavior and behavior is difficult to change without a structured plan and motivation [27, 28, 29].

BGM is the cornerstone of optimal diabetes management. It is important because it gives the patient direct insight into glycemia. It helps relate the symptoms to the number (hyper or hypoglycemia). It helps identifies hypoglycemia. The patterns and effects of different daily choices is obvious for the patient and health care provider. But, BGM gives us at discontinuous glycemic picture- there are periods of time that we do know nothing about blood glucose movements, periods with hypoglycemia or short postprandial hyperglycemia etc. That is an obstacle and hidden reason for patients’ symptoms, daily function and obviously parameters of glucose control.

We hope that that is overcome today by the continuous glucose monitors.

5. Continuous glucose monitoring (CGM): significance

Continuous glucose monitor is, as previously mentioned, a device that can register interstitial glucose at short intervals. The results are sent o the receiver and are further used – stored or/and displayed for the patient. The device is a system of glucose sensor, transmitter, and receiver.

The use of CGM has brought the (patho) physiological glucose continuum in focus - there where it belongs. CGM today can provide real time glucose data 24 h/day, give alerts on imminent hypo- and hyperglycemia, show the rate of glucose level change. With help av. different algorithms the glucose levels can be used to show glucose change dynamics, periods with hypoglycemia TIR and so on.

From the first study where real time CGM was proved to reduce HbA1c and time spent in hypoglycemia [30], data is consistent. The use of CGM in patients on intensified insulin regime (with MII or insulin pumps) is associated with better HbA1, less time spent in hypoglycemia, less acute hypoglycemic events, and generally better satisfaction of patients. That covers many patient groups, also including diabetes type, gender, and age differences [30, 31, 32, 33, 34, 35].

From the basic concept of CGM and first study it was clear that the CGM is most sensitive and useful in detecting and preventing hypoglycemia and time in hypoglycemic/near hypoglycemic range.

5.1 Continuous glucose monitoring - types

CGM devices can display real time data (CGM measures in short periods of time, presents real time data on the monitor, but also continuously stores data). Or CGM can continuously measure and store data, but gives the glucose level upon request, dvs when scanning the sensor.

CGM can be owned/used continuously by the patient intended for personal use. CGM can also be used by a professional- meaning that the CGM system is owned by the health care institution/provider: the patient gets the CGM over a period of time (7–14 days). The results may or may not be available for the patient at the time of use: the data are sent and stored at the doctor’s office and analyzed retrospectively. Such short CGM periods can be useful for detecting daily patterns, vulnerable periods with hyper−/hypoglycemia.

The CGM measures glucose in the interstitial fluid. That means that the results we get are estimates- the numbers we get are somewhat “late” compared to the blood glucose. The greater rate of glucose level change in the circulation the greater “time lag”, meaning also greater difference I the glucose level we get from CGM and BGM taken at the same time. That discrepancy is ameliorated by calibration or by integrated CGM algorithm. Not all the systems require calibration. But still, all the patients that have and use CGM, should have a blood glucose monitor available at all times- for eventual check on the CGM results (warm up periods, suspect hypoglycemia, lack of clinical correlation to hypo- alarm, fast change in glucose levels, lack of contact with the sensor etc..).

Some of the CGM (Dexcom G6- real time CGM and Free style Libre 2 - intermittently scanned CGM) can be integrated into insulin pumps. These CGM require no calibration.

5.2 Continuous glucose monitoring: some technicalities we have to consider

The sensitivity and accuracy of the CGMs is the subject of continuous improving. The mean absolute relative difference (MARD) is currently the most common metric used to assess the performance of CGM systems. MARD is the average of the absolute error between all CGM values and matched reference values. A small percentage indicates that the CGM readings are close to the reference glucose value, whereas a larger MARD percentage indicates greater discrepancies between the CGM and reference glucose values. MARD of <10% is considered sufficient to allow for therapeutic decision (insulin dose change).

CGM systems are sophisticated but it is not only the technical part that is responsible for eventual dysfunction. We are aware that the CGM is a foreign material that can cause allergic reactions. CGM must be inserter into the connective tissue. The actual connective tissue can be of different biological quality, variably circulated, the insertion is rarely the same etc. A sensor/glucose electrode can cause host response - irritation, immune reaction or inflammatory reaction or infection – the local process, no matter how complex, can change the sensitivity of the sensor. Sometimes it is only press on the sensor while sleeping that can provoke false alarm/unreliable result.

Clinical situations that are associated with large body fluid shifts – dehydration, hypotension, hyperosmolality states, ketosis are not good ground for CGM function.

One must also be observant on substances that influence the glucose oxidase/dehydrogenase systems.

The use of CGM should also be registered before major radiographic diagnostics.

CGM are expensive instruments and not evenly reimbursed. Optimal use of CGM requires a good educated health provider, a motivated and good educated patient and that of course implies a lot of time, not always available at the local doctor’s office. Technical support, analyzing av. stored data (the need for compatible software, problems with personal safety when transmitting data etc. can also be a challenge [36, 37].

Patient motivation to understand the benefits and accept to wear CGM is also one of the critical factors for optimal use of CGM.

All this maybe explains that high quality CGMs are in use in about 50–75 pediatric endocrine practices and 35–50% in adult endocrine practices for individuals with T1DM [38].

5.3 CGM: The patient “who is capable of using devices safely”

The amount of data gathered on CGM was such that the ADA, in its Standards of care I 2020. states:

“when used properly, real time and intermittently scanned continuous glucose monitors in conjunction with insulin therapy are useful tools to lower A1c level and/or reduce hypoglycemia in adults with T1D who are not meeting glycemic targets, have hypoglycemia unawareness, and/or have episodes of hypoglycemia—and in conjunction to insulin therapy .. to lower A1C levels and/or reduce hypoglycemia in adults with type 2 diabetes who are not meeting glycemic targets” [39].

The 2022. Standards of Care recommend the use of real time continuous glucose monitoring (evidence level A) intermittently scanned continuous glucose monitoring (B) should be offered for diabetes management

• In adult patients with diabetes managed with multiple daily injections or CSII, who can use devices safely

• In youth with type 1 diabetes on multiple daily injections or CSII who are able to use the device safely 8 either alone or with a caregiver).

• In youth with diabetes type 2 on multiple daily injections or CSII who are capable of using the devices safely.

CGM, real time can be used for diabetes management in adults with diabetes on basal insulin who are capable on using the device safely.

Continuous glucose monitoring in adjunct to pre- and postprandial glucose monitoring can help achieve HBA1c targets in gestational diabetes.

Real time CGM should be used “as close to daily as possible” in patients using multiple daily injections or CSII for maximal benefit. Intermittent scanned CGMs should be scanned frequently, at least every 8 h.

The choice of CGM should be made based on patents “circumstances, desires and needs”.

5.3.1 Gestational diabetes

The latest NICE guidelines do not differ significantly [40]. However, realtimeCGM should be offered to all pregnant women with type 1 diabetes, to help them meet pregnancy glucose targets an improve neonatal outcomes.

RT CGM should be considered for pregnant women that are on insulin therapy, not diabetes type 1, but have sever hypoglycemia (with or without impaired awareness of hypoglycemia). Or if they have unstable blood glucose levels. If CGM is already in use furthermore education and support should be provided by the antenatal/diabetes team [41].

As previously mentioned, the patient using CGM should always have a BGM available.

A large group of diabetes patients that have the need and desire for better glucose control can benefit for CGM. The patients who are, because of comorbidities, age etc., at increased risk for hypoglycemia or have poorly managed diabetes are candidates for real time or intermittent CGM, even periodically. But both the patient and the health care provider should be educated in use of CGM and both must be clear about the goals of CGM use. The patient (or, as nicely defined by the standards of care, caregiver) must be motivated to follow the message that CGM is sending and be able to respond properly. That would be the basis of GCM safety [42].

Of notice when considering safety is that the most advanced CGM are approved for use in children older than 2 years (Dexcom G6).

5.4 Continuous glucose monitoring: new glucose control parameters

Traditional methods of describing glucose control (HbA1c, BGM) are, now that we have a large amount of data from CGMs, not quite enough to fully describe glucose control and in most patients on intensified insulin regimes [43], not always enough to choose a proper therapeutic strategy.

5.4.1 Hypoglycemia

Hypoglycemia prevention and reduction of hypoglycemic episodes is one of the main advantages CGM can provide. But hypoglycemia in diabetes patient is sometimes difficult to define. The level of glucose, the rate of glucose level change and the duration of event is of significance. Originating form, the classic definition of hypoglycemia, CGMs register hypoglycemic events through two major intervals:

1. 3,9–3,0 (<70-54 mg/dl) mmol/l; That would be Level 1 hypoglycemia-hypoglycemia alert).

2. < 3,0mmoL/l (<54 mg/dl); that would be Level 2 hypoglycemia-clinically significant hypoglycemia, requiring immediate attention.

When defining hypoglycemia under CGM use, one should register the percentage of values below the named threshold (dvs percent of time with glycemia <3,9 mmol/l and percent of time spent under 3 mmol/, the later weighing heavier for the estimate); or the number of minutes/hours below the threshold. The number of such event should be reported. A significant event must last at least 15 minutes. Time spent in hypoglycemia should not exceed 1% for levels <3 mmol/l in adults with T1D, 4% for levels under 3,9 mmol/l.

In older adults time with hypoglycemia under 3,9 mmol/l should not exceed 1%.

5.4.2 Glucose variability

CGM has given us insight into different glucose patterns. Glycemic variability which reflects the amplitude frequency and duration of glucose fluctuation, is also a parameter that indicates the level of glucose control and is associated also with increased mortality in the ICU [44, 45, 46].

5.4.3 Time in range

Time in range is the time glucose measurements are in individual’s target (“wanted”) glucose range. TIR is giving some orientation about the time in eventual significant hyperglycemia or hypoglycemia. Such periods cannot be seen through HbA1c and discontinued capillary blood glucose measurements. Acceptable TIR for adults with type 1 diabetes is >70%, in older and high-risk patients >50%. Clinical benefits come with every 5% increment in TIR [47].

So, for complete insight in level of glucose control, optimal use av. data from CGM and right therapeutic decision we need to analyze far more parameters than HbA1c and the results of self-blood glucose monitoring, if any presented. Sufficient data is the data is 70–80% of possible CGM readings obtained for 2 weeks.

Here is a consensus on the parameters we should be aware of/analyze when analyzing CGM data.

(From: Battelino T, DanneT, Begenstal RM et al. Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international Consensus on time in range: Diabetes care 2019; 42 [8]:1593–1603)

Standardized CGM metrics

1. Number of days CGM worn

2. Percentage of time CGM is active

3. Mean glucose

4. Estimated A1C

5. Glycemic variability (%CV or SD)

6. Time > 250 mg/dL (>13.9 mmol/L)

7. Time > 180 mg/dL (>10.0 mmol/L)

8. Time 70–180 mg/dL (3.9–10.0 mmol/L)

9. Time < 70 mg/dL (<3.9 mmol/L)

10. Time < 54 mg/dL (<3.0 mmol/L)

11. LBGI and HBGI (risk indices)

12. Episodes (hypoglycemia and hyperglycemia) 15 min

13. Area under the curve

14. Time blocks (24-h, day, night)

Use of Ambulatory Glucose Profile (AGP) for CGM report.

CV, coefficient of variation; LBGI, low blood glucose index; HBGI, high blood glucose index.

We believe that with such range of data to be considered, will the estimate of glucose control in diabetes patient is more adequate. If such analysis and, consequently estimate will be easier to get a therapeutic decision on, it is something that has to be seen. It is probably on the the next important mission, on GCMs integration with insulin pumps that the answer awaits.

6. Conclusion

It is difficult to imagine modern diabetes management without glucose monitoring. A number of devices help us get insight into diabetes of each and every patient and makes us intervene accordingly, for the short term and long-term benefit of the patient. It is only to expect that with constant improvement, glucose monitoring will continue to connect the patient, diabetes health care provider, but also the army of researchers, hardware and software developers, investors and people with great courage and ideas.

Although the advantages of glucose monitoring are beyond doubt, and are recommended clinical practice, there are still some obstacles to the broad and universal use of the different devices (lately the CGM devices). One of the main obstacles is certainly the cost of the devices. The reimbursement is variable. Availability is different in different parts of the world. The cost benefit is probably not considered from all levels of healthcare.

To optimally use glucose monitoring is not enough only to have the newest device. The educated health care provider (the choice and performances of devices, the analysis of data feks) and motivated and educated patient are also necessary to choose optimal way to use glucose monitoring. Enough time to educate, to obtain the data, to do the adequate analysis can be difficult to find in a busy practice and with an impatient patient.

Blood glucose monitoring is a daily task: although the devices and necessary routines are trending towards small, simple to use, easy to wear, easy to manipulate, easy to understand, “does it itself”, it is necessary that the patient possesses a certain level of literacy and numeracy as well as knowledge on the method, so that the message on the monitor is understood and applied. Training in understanding and using the results to optimize glycemic management is necessary.

But, despite these impediments, the fact is that glucose monitoring has evolved and so has our understanding of diabetes and diabetes treatment. Technical advances are impressive.

There is a large diabetes population that expects to become free from multiple daily injections, bolus insulin dosage, fear for hypoglycemia and hypoglycemia. Integrating CGM in fully automated closed loop system, with insulin or combination with glucagon is maybe a way to open a new chapter in diabetes understanding and treatment. The high initial cost of implementing technology in everyday life of a diabetes patient and diabetes healthcare provider is still incomparable to the liberty such technology can give to the patient and to the satisfaction precisely tailored individualized successful treatment gives to both.