Glucose Monitoring and Control Testing in Patients with Type 1 or Type 2 diabetes

Key words

diabetes, self-management, glucose, monitoring

Overview

Regular glucose measurements are indispensable for monitoring the progress of diabetes therapy and are used either to make immediate decisions on the appropriate dosage of antidiabetic medication or on the intake of carbohydrates. The retrospective analysis of the metabolic situation using the HbA1c measurement serves mainly to assess the long-term risk for microvascular and macrovascular complications. New statistical parameters for evaluation, such as the times in the different glucose ranges (time-in-range (TiR), time-below-range (TbR), time-above-range (TaR) or the coefficient of variation (CV)) of the tissue glucose monitoring systems, can be used to further specify the quality of diabetes control.

The classic method for self-monitoring has been capillary blood glucose measurement (SMBG). Over time, some blood glucose measurement systems have been able to achieve a measurement accuracy that comes close to that of laboratory systems. Blood glucose measurements display the current glucose level. Information on the trend from the past and in the imminent future is possible with continuous glucose monitoring (CGM). Systems for CGM in interstitial tissue fluid (ISF) have been available since 1999: While measurements with SMBG systems under everyday conditions were performed on average 4–7 times daily in adults with type 1 diabetes, CGM systems provide a complete 24-hour overview and deliver measured values at 1–5 min intervals (depending on the system). The registered CGM profiles visualize the glucose trend, i. e., they display fluctuations in glucose concentrations. Although satisfactory glucose control is possible in many patients who perform sufficiently frequent SMBG measurements, CGM can promote participation in life and reduce psychological stress. This applies in particular to children with type 1 diabetes who are not yet able to identify physical symptoms, e. g. hypoglycaemia. The number of blood glucose measurements required daily was often more than 20 – which often places a high burden on both children and parents. This can be drastically reduced when using a CGM (e. g. only in the case of suspected differences between the displayed value and the how the patient feels, especially in the case of rapidly decreasing values). Furthermore, the most commonly-used CGM systems can send the data to the parent’s/caregiver's smartphone and thus significantly increase the safety in dealing with the child. CGM systems are also a technical innovation, as they enable the establishment of automated insulin delivery (Automated Insulin Delivery (AID) systems) that match current glucose levels.

The current generations of CGM systems have considerably improved measurement accuracy compared to systems of earlier generations. There is currently no standard procedure for determining the accuracy of CGM systems as there is for blood glucose monitoring systems. Irrespective of this, there may be deviations between the measured concentrations in the two compartments of blood and tissue glucose due to a physiological time lag, especially in the case of rapid increases and decreases in the glucose trend. A bias of the systems can also be caused by factory calibration, if different references are used, or by own calibration in case of faulty behaviour during blood glucose measurement or if inaccurate blood glucose measurement systems are used.

Long-term metabolic optimisation requires continuous use of CGM systems, although how patients use CGM systems in reality has not been well studied so far. However, initial studies suggest that without appropriate comprehensive and specialised CGM training and qualified supervision, the possibilities of CGM systems are insufficiently used and thus do not lead to any improvement in glucose control. In an US study, it was shown, especially among adolescents with type 1 diabetes, that there was an increase in the HbA1c value after these technologies were introduced, which may be due, among other things, to a lack of training in the USA. In Germany, the CGM-TRAIN study showed that the SPECTRUM training programme resulted in an increase in CGM knowledge among participants – both in theoretical knowledge and practical implementation. In our view, this is evidence that the provision of the technical options per se is not sufficient, but that patients and diabetes teams need to be adequately trained in the proper use of this diagnostic option. Furthermore, regular retrospective data analysis is necessary to adjust therapy in order to achieve a sustained improvement in glucose control. Manufacturers support this process with increasingly better software solutions for CGM data analyses. Such analyses can provide concrete indications for the adjustment of diabetes therapy. Overall, the patient should have an “active” view on the glucose values and “work” with them. Likewise, diabetologists and their teams should regularly support the patient with a constructive and structured data analysis.

In the following, the various options for glucose measurement using a uniform structure are explained. The decision tree in ([Fig. 1]) provides a quick overview of which glucose measurement system is best suited for which individual patient.

Fig. 1 Decision tree for the various glucose measurement options. SMBG: self-measurement of capillary blood glucose concentration; CGM: continuous glucose monitoring; ICT: intensified conventional insulin therapy; OAD: oral antidiabetics; AID: automated insulin delivery.

The decision as to which system fits the patient best should be guided primarily by medical and social indications (e. g. hypoglycaemia, pregnancy, professional life and private life), not by economic aspects. SMBG is the first level that every patient should master and use. Only then should a change to CGM take place. The decision depends on the individual conditions of the patient, e. g. the planned use of a specific AID system (AID: automated insulin delivery). Intensive training in the selected form of diabetes therapy is a prerequisite for CGM use and is required as an accompaniment. Not adhering to CGM should lead to ending the use of these systems.

Nowadays, children usually receive a CGM system at manifestation or shortly thereafter. Younger children are routinely treated with an AID system shortly after the onset of diabetes. In some cases, schoolchildren and adolescents still start with an ICT and CGM system and switch to an AID system as soon as possible.

AID pumps with a high degree of automation of insulin therapy benefit toddlers and school children, adolescents and adults alike for whom such a system is approved, as well as their parents, partners or caregivers. Forwarding CGM alarms, CGM trends or mirroring the entire pump display to a follower app makes it easier to monitor remotely and advise caregivers.

Statements on the therapeutic use of the glucose monitoring values obtained by various patient groups are published in the respective DDG (German Diabetes Society/Deutsche Diabetes Gesellschaft) clinical practice guidelines.

These clinical practice guidelines do not mention product names for SMBG systems, although there is a clear need for a positive list. Similarly, no information is provided on the technical details of specific products, as their further development is too rapid (see the manufacturers̓ homepages).

This clinical practice guideline does not deal with an evidence-based S3 guideline. For this reason, the statements are not supported by literature references. The guidelines are based on the clinical and practical experience of the authors and the evidence derived from studies for the purpose of the achieving the best possible usability in everyday life. As well, no statements are made on the diabetes diagnosis and the use of glucose measurement systems to do so (see the corresponding clinical practice recommendation).

The authors of this clinical practice guideline are members of the Working Group for Diabetes and Technology/AG Diabetes & Technologie e. V. (AGDT) and/or the Pediatric Diabetology Working Group/Arbeitsgemeinschaft für Pädiatrische Diabetologie e.V. (AGPD), which are working groups under the umbrella of the DDG.

Self-measurement of capillary blood glucose concentration (SMBG)

Goals/indications

In order to achieve the therapy goals, e. g. a HbA1c value set with the treating physician, properly-trained patients with diabetes mellitus regularly measure the glucose concentration in capillary blood samples (information on the correctly performing the measurement is presented in [Table 1]). Blood glucose measurements are also used to detect acute dysglycaemia (hypoglycaemia or hyperglycaemia).

Table 1 Procedure for capillary blood glucose measurement.

Preparation

Wash and dry hands before measuring, as food residues, skin cream or disinfectants can falsify the measurement. If this is not possible, wipe off the first drop of blood and use the second drop for the measurement.

After lancing the fingertip to obtain a drop of blood, the measurement should be performed quickly. All material should therefore be ready beforehand.

Lancing

Lance the side of the fingertip:

The fingertip is particularly sensitive and scarring damages the sense of touch.

Do not prick index finger or thumb.

Press the lancing device firmly into place. Start with the smallest penetration depth of the lancing device. Check which penetration depth results in a sufficiently large blood drop.

Change the lancet of the lancing device for each measurement.

Lancets are disposable articles; they become dull due from puncture and damage the skin when reused.

Measurement

Know the special features of the respective SMBG system, e. g.:

How and where should the blood sample be applied to the test strip?

Can blood be added subsequently if the amount of blood was insufficient?

Which drugs can interfere with the measurement?

In which temperature range can measurements be made? (Important when outdoor temperatures are low or high.)

Test strips are sensitive.

When measuring, do not touch or press down on the test strip, fold or bend it.

Always store test strips in closed tube/package and keep it dry and away from light.

Observe storage temperature (especially important in case of heat or frost).

Measurement results

Measurement results must be documented, values must be recorded in a diary or electronic documentation options must be used.

The patient and doctor can only discuss the quality of glucose control and possible therapeutic changes if the measured values are documented. Coordinate target values, measurement frequency and measurement times with the physician.

Do not blindly trust measured values.

Despite correct execution of the measurement procedure, the measurement result may be incorrect! Patient symptoms are more important than a measurement value, repeat the measurement in case of discrepancies.

Derive action for therapy management from the measurement result.

SMBG systems

Due to further technical development and damage to the device caused by use, SMBG systems should be replaced every few years.

If several/different SMBG systems are used at the same time, note the differences in operation. Systematic differences between the systems may occur in the measurement results.

SMBG: Self-measurement of capillary blood glucose concentration.

Table 2 Recommendations on using SMBG for the different diabetes types and therapies.

Diabetes	Therapy	Measurement frequency	Measurement situation Preprandial: before the meal Postprandial: 1.5 h after meal	Measurement interval	Test strip requirement
Type 1	ICT	At least 4×daily	Preprandial and possibly postprandial, before going to bed	On a daily basis	>4 strips daily at least 500 strips per quarter
			At night (2:00 a.m. to 4:00 a.m.)	Every 2–3 weeks
			In special situations (suspected hypoglycaemia, sport, illness, before driving, etc..)	When required
Type 1 children and adolescents	ICT	At least 10×daily	Preprandial, postprandial, before going to bed, at night	On a daily basis	>10 strips daily at least 1000 strips per quarter
			In special situations (before/at/after sports	When required
			During infectious diseases, etc..)	Every 2–3 h
Type 1	Insulin pump	At least 5×daily	Preprandial and possibly postprandial	On a daily basis	>5 strips daily at least 600 strips per quarter
			Before going to bed at night (2:00 a.m. to 4:00 a.m.)	Every 2–3 weeks
			In special situations (suspected hypoglycaemia, sport, illness, before driving, technical issues, etc..)	When required
Type 1 children and adolescents	Insulin pump	At least 12×daily	Preprandial, postprandial, before going to bed, at night	On a daily basis	>12 strips daily at least 1200 strips per quarter
			In special situations (before/at/after sports	When required
			During infectious diseases, technical issues, etc.)	Every 2–3 h
Type 1 with hypoglycaemia unawareness	ICT/insulin pump	At least 8×daily	Preprandial and postprandial, before going to bed	On a daily basis	>8 strips daily at least 800 strips per quarter
			At night (2:00 a.m. to 4:00 a.m.)	Every 2 weeks
			In special situations (suspected hypoglycaemia, sport, illness, before driving, technical issues, etc..)	When required
Type 1 with CGM	Insulin pump	At least 2×daily	When changing the sensor (calibration, if necessary or possible), if the algorithm requires BG measurement, in special situations (sports, no sensor available, pregnancy), in case of infectious diseases and in case of discrepancy between well-being and displayed sensor value	When required	>2 strips daily at least 300 per quarter
Type 2	ICT	At least 4×daily	Preprandial and possibly postprandial, before going to bed	On a daily basis	>4 strips daily at least 500 strips per quarter
			At night (2:00 a.m. to 4:00 a.m.)	Every 2–3 weeks
			In special situations (suspected hypoglycaemia, sport, illness, before driving, etc..)	When required
Type 2	CT	At least 2×daily	Preprandial (before injection)	On a daily basis	>2 strips daily at least 250 strips per quarter
			At night (2:00 a.m. to 4:00 a.m.)	Every 2–3 weeks
			In special situations (suspected hypoglycaemia, sport, illness, before driving, etc..)	When required
Type 2	Bedtime insulin (BOT)	At least 2×daily	Preprandial fasting, before going to bed	On a daily basis	>2 strips daily at least 200 strips per quarter
			At night (2:00 a.m. to 4:00 a.m.)	Every 2–3 weeks
			In special situations (suspected hypoglycaemia, sport, illness, before driving, etc..)	When required
Type 2 with hypoglycaemia risk	Insulinotropic oral antidiabetics (sulfonylureas, glinides)	At least 2×per week	Preprandial fasting, before going to bed	1×per week	>1–2 strips daily at least 50 strips per quarter
			At night (2:00 a.m. to 4:00 a.m.)	Every 2–3 weeks
			In special situations (suspected hypoglycaemia, sport, illness, before driving, etc..)	When required
Type 2 without hypoglycaemic risk	Oral therapy		In special situations (manifestation, for training purposes, failure to achieve the therapy goals, etc..)	When required	At least 50 strips per quarter
Type 1/type 2 Pregnancy	ICT/insulin pump	At least 7×daily	Preprandial and postprandial, before going to bed	On a daily basis	>7 strips daily at least 700 strips per quarter
			At night (2:00 a.m. to 4:00 a.m.)	On a weekly basis
			In special situations (suspected hypoglycaemia, sport, illness, before driving, technical issues, etc..)	When required
Gestational diabetes	Nutrition	At least 15×per week	Fasting,	On a daily basis	At least 350 strips per quarter
			Preprandial and postprandial, before going to bed	3×per week
Gestational diabetes	Insulin	At least 7×daily	Preprandial and postprandial, before going to bed	On a daily basis	>7 strips daily at least 700 strips per quarter
			At night (2:00 a.m. to 4:00 a.m.)	Every 2 weeks
			In special situations (suspected hypoglycaemia, sport, illness, before driving, technical issues, etc..)	When required

ICT: Intensified conventional insulin therapy; CT: conventional insulin therapy, SMBG: Self-measurement of capillary blood glucose concentration, CGM: continuous glucose monitoring.

With different therapy approaches (oral therapy, bedtime insulin administration, conventional insulin therapy (CT), intensified insulin therapy (ICT), insulin pump therapy (CSII)) and different diabetes types (type 1, type 2 with and without insulin therapy, pancreatic diabetes mellitus, gestational diabetes and others), different times and frequencies for measuring blood glucose concentrations are common and objectively indicated ([Table 2]). The glucose measurement results are used to adjust the insulin dose or other antidiabetic drugs, modify exercise to the current glucose situation or carbohydrate intake for an (imminent) hypoglycaemia.

There is a clear indication for SMBG in patients with type 1 or insulin-dependent type 2 diabetes. Measuring glucose not only involves proper patient training on how to correctly perform the glucose measurements, but it is also necessary to have an understanding of how the measurement results are transferred into therapeutic steps. The ability to perform SMBG correctly is essential even if a CGM system is used. Blood glucose test strips therefore still must continuously be prescribed. Only then can patients check unexplained glucose values when needed or have an alternative therapy control in case of technical problems with the CGM system. Furthermore, some CGM systems need to be calibrated.

Frequency of measurements without CGM?

Most patients with type 1 diabetes can use a CGM system. If this is not possible patients with type 1 diabetes and with multiple insulin injections daily (ICT) or an insulin pump should measure blood glucose concentration at least 4 times daily (preprandial and before bedtime) and every 2–3 weeks during the night. In addition, measurements may be taken in special situations, e. g. to check the effects of meals, in suspected hypoglycaemia, sport, illness, holidays, etc. This results in an average need for at least 5 glucose test strips for SBMG per day ([Table 2]). Patients with type 1 diabetes and hypoglycemia unawareness form a special group. In addition to the measurement times already described, measurements are carried out before driving a car, during physical activity, during sport and during everyday work. This results in a quarterly requirement of at least 800 test strips. The need for test strips in children, especially toddlers, increases even further as children cannot reliably express themselves regarding the symptoms of hypoglycaemia or hyperglycaemia and are also more prone to much faster and more intense glucose fluctuations than adults with type 1 diabetes. This is why younger children receive a CGM system already at diabetes onset. Currently, children diagnosed under 2 years of age must calibrate approved CGM systems several times a day.

Patients with insulin-dependent type 2 diabetes with ICT should also determine preprandial and occasionally postprandial glucose levels and measure them before bedtime. The daily requirement is at least 4–5 test strips, which corresponds to at least 500 test strips per quarter. Patients with insulin-dependent type 2 diabetes and CT or bedtime therapy (BOT) require at least 2 measurements per day; this results in a quarterly requirement of at least 200 test strips.

Patients with non-insulin-dependent type 2 diabetes undergoing therapy with insulinotropic oral antidiabetics (sulfonylureas, glinides) require test strips for detecting hypoglycaemia. Practical experience shows a requirement of at least 50 test strips per quarter. It makes medical sense to provide all patients with type 2 diabetes and oral antidiabetic therapy with at least 50 test strips per quarter in case of manifestation or for training purposes or if the therapy goals are not achieved.

Pregnant women with a pre-existing type 1 or type 2 diabetes perform preprandial and postprandial glucose measurements, resulting in a requirement of at least 7 test strips per day, i. e., at least 700 test strips per quarter. Women with gestational diabetes should always measure fasting blood glucose and postprandial glucose 2–3 times per week. In cases of insulin dependence, regular preprandial and postprandial glucose measurements are necessary which leads to a requirement of at least 7 test strips per day.

Another group of patients with a regular need for test strips are users of CGM systems and AID systems. In this case, the CGM system should be regularly checked by means of a measurement in blood.

Measurement method

In the SMBG systems commonly used by patients, the enzyme used is either glucose oxidase (GOD) or glucose dehydrogenase (GDH). The glucose oxidase method is susceptible to substance and drug interferences (e. g. ascorbic acid, paracetamol, blood oxygen content). As well, relevant interferences must be taken into account, especially in patients with multimorbidities (interferences caused by medications, uric acid, etc.). For patients with high or low haematocrit values, the respective SMBG system should be checked (manual/test strip package insert) for compatibility to the patient ([Fig. 2]).

Fig. 2 Factors that have an influence on the SMBG measurement result. SMBG: Self-measurement of capillary blood glucose concentration.

Available systems

There are many different SMBG systems currently available from various suppliers. Overviews of the properties of these SBMG systems are primarily based on the information provided by the manufacturers, however, there are no official lists of the measurement quality of the various systems. Many modern SMBG systems have additional functions, such as data storage and readout, marking of values as preprandial or postprandial, colour coding of displayed values for better assessment, a light at the test strip slot to facilitate handling, bolus calculators, calculation of an estimated HbA1c value or the possibility of transmitting data to an app/cloud (connectivity).

Specifications for measurement quality/standards

Like all medical devices, SBMG systems have CE markings. The CE marking is not a mark of quality; the SMBG systems on the market must, however, fulfil the ISO Standard 15197:2015. There is no systematic evaluation of the measurement quality of SMBG systems after their introduction to market. Over time, many independent evaluations have shown that some systems on the market exhibit inadequate measurement quality.

Costs/refund of expenses

Health insurance covers the costs for SMBG systems (device, test strips and lancing device) for patients with type 1 diabetes and patients with insulin-dependent type 2 diabetes. Patients with type 2 diabetes who do not undergo drug therapy or who take oral antidiabetics without a hypoglycaemic risk are only covered by statutory health insurance in special situations (unstable metabolic conditions, readjustment or change with an increased risk of hypoglycaemia).

The prescribing physician determines the number of test strips deemed appropriate for the given insulin-dependent patient. An exact indication is important. For example, a manifestation or pregnancy in a type 1 or type 2 diabetes patient has a significantly higher test strip consumption ranking than in CT does. In reality, the prescribability of blood glucose test strips is regulated by a Federal Joint Committee/Gemeinsamer Bundesausschuss (G-BA) decision and is laid down in the Pharmaceutical Directives/Arzneimittel Richtlinien Annex III (Overview of prescription restrictions and exclusions/Übersicht über Verordnungseinschränkungen und -ausschlüsse). The Association of Statutory Health Insurance Physicians/Kassenärztliche Vereinigungen (KV) regulates the prescription of blood glucose meters and test strips. A joint guiding framework, agreements and contracts were completed between the health insurance companies and the Associations of Statutory Health Insurance Physicians. This leads to “Recommendations” issued by the Associations of Statutory Health Insurance Physicians (KVs) together with statutory health insurance companies with regards to which costs will be covered for the types of diabetes and therapy. These recommendations are, however, not binding.

Quality control (internal and external/interlaboratory tests)

Quality control for personal glucose measurement systems can be performed by the patient with a system-specific control solution; these are offered by manufacturers of SMBG systems for their products. Ideally, the patient should carry out quality controls of the measurement quality of the SMBG system at home every time a new test strip package is opened and for the situations specified in the operating instructions.

According to the German Medical Association guidelines (Rili-BAEK), systems used in laboratories, clinics, practices and in other institutions (retirement homes) where medical personnel measures glucose in patients must meet the requirements for internal quality control (control solution measurements) but not those for external quality control (interlaboratory comparisons). The internal quality control for SMBG systems in use must be carried out regularly in every practice. The implementation of external quality control by participating in interlaboratory comparisons can provide additional information on measurement quality.

Safety issues/side effects

An incorrect SMBG measurement results in the administration of an incorrect insulin dose, which can have immediate and significant consequences such as severe hypoglycaemia. Therefore, when training patients, it is imperative to focus on the prerequisites for correct glucose measurement using SMBG systems ([Fig. 2]).

For the patient, lancing a fingertip to obtain a blood drop for SMBG can be a painful procedure. Despite the modern lancing devices available today, patients still feel lancing in the fingertip and repeatedly lancing the same sites can lead to considerable scarring and reduced sensitivity in the future. Younger children, who do not yet understand the necessity of these measures, may experience considerable psychological stress and disturbance of the parent-child relationship. Nonetheless, even for adult patients, the pain that is self-inflicted several times a day can be a psychological burden.

Practical implementation of the measurement

During the measurement, it is important to consider the factors that are important for a correct measurement ([Fig. 2]) see Guidelines for Blood Glucose Self-Monitoring/Leitfaden zur Blutzuckerselbstkontrolle: https://www.vdbd.de/fileadmin/portal/redaktion/Publikationen/190516_VDBD_Leitfaden_Glukose_Selbst.pdf).

Use with different patient groups

The SMBG “market” is usually only divided into patients with type 1 or type 2 diabetes and women with gestational diabetes. In reality, however, there are a number of subgroups, especially when it comes to SMBG: there are hardly any monitoring systems on the market that are suitable for patients with impaired vision or for the blind (devices with speech output or acoustic instructions for use). The same applies to elderly patients with limited manual dexterity. They need devices with simple operation and a clearly legible display.

Training/psychological aspects

The preparatory steps for SMBG, in particular obtaining a capillary blood drop, as well as correctly performing the actual measurement require sufficient theoretical and practical training. Ideally, this should be done using the SMBG system that the patient will later use. A one-time introduction is often not enough, i. e., the various steps to be taken should be repeatedly trained, discussed and closely supervised.

Performing SMBG measurements in public makes it visible that a person has diabetes, which is why measurements are often not performed in such situations (school, workplace, restaurant, etc.). This can entail significant risks as acute glucose derailments are then not detected. The patients’ understandable desire for discretion makes other glucose monitoring options (CGM, see below) attractive. However, not all patients want to permanently wear a technical device on their body or be disturbed by alarms.

Comment

The performance of SMBG monitoring systems has improved in recent decades to such an extent that considerable further improvements are no longer to be expected in the foreseeable future.

One important option for further development of SMBG systems is their interoperability, i. e., improved automatic availability of measurement results for evaluating data in programs or apps. The merging of glucose values including data from the insulin dose (by using smart pens), carbohydrates consumed (by an automated analysis of the carbohydrate content of meals) or exercise (by using data from fitness wristbands) enables an additional calculation of such data sources for calculating the optimal insulin dose.

Continuous glucose monitoring (CGM)

There are various real-time CGM (rtCGM) systems on the market, needle enzymatic sensors and an implantable glucose sensor. One system still used by patients, in which the glucose value is only available after scanning the glucose sensor (iscCGM: CGM with intermittent scanning), is only available to users as a residual stock.

Goals/indications

When using CGM systems, therapy goals can be better achieved by increasing the quality and quantity of information (continuous display of the current glucose value, trend display and alarms when pre-set limit values are reached as well as predictive alarms, systematic data analysis ([Table 3], [4], [5]). The continuous use of CGM systems can enable motivated users to increase the amount of time within the target range (time in range, TiR) and achieve their therapy goals of reducing the HbA1c value and duration and the occurrence of (severe) hypoglycaemia. In addition to assessing current glucose control, the information on glucose trend also helps in assessing the impact of therapeutic interventions on food intake, physical activity or other influencing factors. In order for patients to adequately use the quantity and quality of the information provided and to be able to translate it into therapeutic interventions, which is a complex task, they must receive theoretical and practical training in addition to technical instruction on the respective CGM system. For this purpose, there is the SPECTRUM training programme in Germany; the effectiveness of its use was proven by the CGM-TRAIN study published in 2020.

Table 3 Factors that have an influence on the continuous glucose monitoring (CGM) measurement result.

Application-related factors:

Placement of the sensor in individually unfavourable locations (e. g., too little/too much fatty tissue, mechanically stressed sites, unforeseeable factors) Sensor insertion site not approved/tested (depending on sensor system: upper arm, abdomen, thigh, buttocks) with individually varying good blood circulation, increased mobility of the sensor in subcutaneous fatty tissue Calibration error (if necessary): calibration with CGM values instead of blood glucose values, calibration during rapid rise, rapid fall or hypoglycaemia, no calibration when this would be appropriate and possible, calibration with unclean fingers Repeated calibration with incorrectly low values leads to differences between GMI (lower) and laboratory HbA1c (higher) and vice versa Pressure on the sensor site due to belt, waistband, sleeping position (falsely low values during pressure application) Mechanical instability of the patch, sensor patch partially or completely detached Sweat or water (shower, etc.) penetrates the sensor site (false low values) Inflammation of the skin at the insertion site of the sensor Technical and environmental factors: Defective sensor (e. g., transport or storage of sensors outside the recommended temperature range, error in production/related to batch). Reproducibly limited measurement accuracy with certain users when using a certain sensor system (not predictable, individual biocompatibility?) Chemical interfering substances, depending on the sensor system (see operating instructions, e. g., vitamin C, paracetamol) Too high “underpatch” in the case of patch allergy (several millimetres, off-label!), which places part of the sensor in the fatty tissue and part in the patch

Table 4 Parameters for characterising continuous glucose monitoring (CGM) data (retrospective analysis).

Consensus Advanced Technologies and Treatments for Diabetes (ATTD): all parameters should be available to assess CGM data
Time-in-range/Time-in-target-range (TiR)		70–180 mg/dl 3.9–10 mmol/l
Time-below-range (TbR)/Time-below-target-range	Level 1	54≤70 mg/l 3.0≤3.9 mmol/l
	Level 2	<54 mg/dl  < 3.0 mmol/l
Time-above-range (TaR)/Time-above-target-range	Level 1	180–250 mg/dl
		10.0–13.9 mmol/l
	Level 2	>250 mg/dl  > 13.9 mmol/l
Glycaemic variability		Coefficient of variation/standard deviation
Mean glucose value		–
Glucose management indicator (GMI)		GMI (%) = 3.31 + 0.02392 × [mean glucose in mg/dL] or GMI (mmol/mol) = 12.71 + 4.70587 × [mean glucose in mmol/L] GMI tells what a approximate A1C level is likely to be, based on the average glucose level from CGM readings for 14 or more days.
CGM visualization		Ambulatory glucose profile (AGP)
Recommendation on the amount of data that should be available for evaluation		At least 70% of CGM data from 14 days

CGM: continuous glucose monitoring; ATTD: Advanced Technologies and Treatments for Diabetes.

Table 5 Guideline values for target values of continuous glucose monitoring CGM-derived parameters in adults with type 1 or type 2 diabetes.

Consensus Advanced Technologies and Treatments for Diabetes (ATTD) 2019
Parameters	Characterisation	Guideline values for target values
Time-in-range/Time-in-target-Range (TiR)	70–180 mg/dl 3.9–10 mmol/l	>70%; >16 h 48 min
Time-below-range (TbR)/Time-below-target-range	<70 mg/dl <3.9 mmol/l	<4%; <1 h
	<54 mg/dl <3.0 mmol/l	<1%; <15 min
Time-above-range (TaR)	>180 mg/dl >10.0 mmol/l	<25%; <6 h
	>250 mg/dl >13.9 mmol/l	<5%; <1 h 12 min
Glycaemic variability	Coefficient of variation/standard deviation	≤36%

CGM: continuous glucose monitoring; ATTD: Advanced Technologies and Treatments for Diabetes.

Table 6 Information on current CGM system; the systems are in constant development.

CGM model (dated 2023)	Associated sensor	Approval age group	Life cycle per sensor	Connectivity smartphone/wearable	Connectivity insulin pump	Calibration	Initialisation phase	Recommended insertion site	Glucose display	Glucose range	Replacement for blood glucose measurements
Abbott Freestyle Libre 3	Sensor FreeStyle Libre 3	As of 4 years Pregnancy	Up to 14 days	Yes, Android and iOS App, Follower App	Yes, Ypsopump	Factory calibrated	1 h	Upper arm	Every minute	40–500 mg/dl 2.2–27.7 mmol/l	Yes, with adherence to company specifications
Dexcom G6 CGM System	Dexcom G6 Sensor	As of 2 years Pregnancy	Up to 10 days	Yes, Android, iOS, App, Smartwatch/Apple Watch	Yes, (t-slimX2, Ypsopump, Omnipod 5, Accu Check insight)	Factory calibrated; calibration optional	2 h	Abdomen, upper buttocks (children and adolescents 2–17 years)	Every 5 min	40–400 mg/dl 2.2–22.2 mmol/l	Yes, with adherence to company specifications
Dexcom G7 CGM System	Dexcom G7 Sensor	As of 2 years	Up to 10 days	Yes, Android, iOS, App, Smartwatch/Apple Watch	No	Factory calibrated; calibration optional	30 min	Abdomen, upper buttocks (children 2–6 years)	Every 5 min	40–400 mg/dl 2.2–22.2 mmol/l	Yes, with adherence to company specifications
Medtronic Guardian 4	Medtronic Guardian Sensor 4	As of 7 years	Up to 7 days	Yes, Android, iOS, app, Follower app	Yes, Smart-Guard function 780G (as of 7 years), yes, Smart ICT system (as of 7 years)	No calibration, but 1×BG input required before Smart Guard function start, calibration optional	2 h	Buttocks and back of the upper arm (children and adolescents 7–17 years) Abdomen and back of the upper arm (18 years and older)	Every 5 min	40–400 mg/dl 2.2–22.2 mmol/l	Yes, with adherence to company specifications
Medtronic Guardian 3	Medtronic Guardian Sensor 3	Without age limit	Up to 7 days	No (640 G/670 G); Yes (770 G)	Yes, 640G (no age limit), Smart-Guard 670G, 770G (as of 7 years)	2 h after insertion, 6 h after first 1×calibration, then every 12 h	2 h	Abdomen; upper buttocks; (upper arm)	Every 5 min	40–400 mg/dl 2.2–22.2 mmol/l	No
Medtrum Touch care Nano CGM	Medtrum A6 touch care CGM	As of 2 years	Up to 14 days	Yes, Android, iOS, Apple Watch	Yes, Medtrum pump system	Factory calibrated; calibration optional	2 h	Upper arm, abdomen, buttocks	Every 2 min	40–405 mg/dl (2.2–25 mmol/l)	No
Menarini GlucoMen Day CGM	GlucoMen Day CGM Sensor	From 6 years	14 days	Yes, Android, iOS	No	Every 24 hours	45 min	Abdomen	Every minute	40–400 mg/dl 2.2–22.2 mmol/l	Yes
Eversense E 3	Eversense Sensor	From 18 years	Up to 180 days	Yes, Android, iOS, App Apple Watch	No	24 h after insertion: 4 times within 6–36 h, then every 10–14 h, from day 21 once/day	24 h	Upper arm (implanted)	Every 5 min	40–400 mg/dl 2.2–22.2 mmol/l	Yes

www.dexcom.com; www.freestylelibre.de; www.medtronic.com/de-de/fachkreise/diabetes.html; www.medtronic.com/de-de/diabetes/home.html; www.medtrum.com; www.diabetes-ascensia.de; www.menarinidiagnostics.com; CGM: continuous glucose monitoring.

Indications for using CGM apply for the following patient groups ([Fig. 1]):

• Type 1 diabetes

• Type 2 diabetes with ICT

• Insulin-dependent diabetes with frequent hypoglycaemia or hypoglycaemia unawareness

• Pregnancy with pre-existing insulin-dependent diabetes

• In other individual cases

In consultation between patient and physician, an individual decision must be made as to whether CGM use is medically necessary and sensible ([Fig. 1], [3]).

Fig. 3 Practical procedure for starting real-time continuous glucose monitoring (CGM) (blue: doctor/patient; yellow: training/introduction of technology; green: costs approved or self-funded). MD: Medical Service.

CGM systems can be used either as stand-alone devices, e. g. for patients with ICT, or in combination with an insulin pump. In sensor-augmented pump therapy (SaP) or an AID system, the CGM system is in direct communication with the pump. CGM is the central factor in both SaP and AID systems. In hybrid AID systems, the basal insulin delivery is automatically adapted according to the current glucose values with the help of an algorithm. Insulin at mealtimes is administered manually by the patient. There are now several AID systems from different manufacturers available on the market. Systems that automatically deliver correction boluses in addition to basal insulin delivery (AH-AID, advanced hybrid-AID) are also available. An overview in the form of profiles of the currently common AID systems is available for download on the AGDT homepage (https://www.diabetes-technologie.de/steckbriefe-fuer-aid-systeme/).

Almost all CGM systems also allow the measured values to be transferred to a cloud. From there, the data can be forwarded to family members or the diabetes team if the patient agrees (connectivity).

In addition to CGM systems where a needle sensor is inserted under the skin, a long-term CGM system is available in which the sensor is inserted under the skin with minimal surgical intervention. Through a transmitter on the skin, which can be removed at any time, the glucose concentration in the ISF is determined and transmitted to a receiver. This is the only CGM system where vibration alarms of the transmitter are available directly on the body in addition to the usual alarms triggered by the smartphone/receiver. The sensor is removed by a certified physician after its functional period of up to 180 days.

In our opinion, when planning an intensification of diabetes therapy, the majority of patients who require a more intensive diabetes therapy should first use a CGM system and subsequently add an insulin pump. Studies demonstrate the benefit of CGM in patients who perform ICT with multiple daily injections. With regard to an improvement in HbA1c levels and a reduction in the risk of hypoglycaemia in children under 8 years of age with type 1 diabetes, a start should be made with a CGM system and with an insulin pump from diabetes diagnosis on with the option of using an AID-System. With the use of an AID system, the TiR is usually further improved than for CSII without a CGM system. This applies likewise to children and adults.

Measurement method

In the transcutaneous needle sensors of the CGM systems currently available on the German market, glucose is measured using an enzymatic method (GOD, see SMBG) in the ISF in subcutaneous fatty tissue ([Table 6]). The transcutaneous rtCGM systems have a life cycle of up to 14 days after which the glucose sensor should then be replaced according to the manufacturer's instructions. The sensors normally transmit an average value obtained every 5 min to the corresponding receiving device. As with SMBG systems, medication can result in interferences (e. g. paracetamol and vitamin C, see device operating instructions) and all factors that have an influence on the measurement result must be taken into account ([Table 2]). With the implantable long-term CGM systems, the glucose measurement is fluorescence-based which can lead to short-term measurement interruptions, especially at the beginning during bright sunlight.

Available systems

The CGM systems available up to several years ago were not directly intended to be used for a therapy decision (insulin dose adjustment); an adjustment of the insulin dose should therefore be based on the measurement result of an SMBG measurement and not on the CGM data (adjunctive usage). In practice, however, many patients have relied on the accuracy of this data and used them to make treatment decisions. Therapy decision/insulin dose adjustment is now permitted on the basis of the CGM measurement result (non-adjunctive usage) with the most frequently-used CGM systems. With the latest generation of CGM systems, there is no need for calibration. However, calibration is optional for some systems, i. e., the measurement supplied by this CGM system can be related to the blood glucose value. In some patients, the accuracy of the measurement seems to be improved by one calibration per day, especially if this is done in the first days after the sensor is inserted. It should be noted that various factors influence the quality of CGM measurements. Such patient factors include the patient's BMI, the specific body site where the glucose sensor is inserted, the ambient temperature and the mechanical, external pressure on the sensor (e. g. during sleep).

There is also always a theoretical risk, confirmed by practical experience, that certain differences in quality or measurement accuracy may occur between batches and individual sensors from one manufacturer. Therefore, it is generally recommended to perform daily comparative BG measurements, especially in the first 2 days after restarting a sensor. This is especially true when using AID systems to check them, because not only a CGM curve is recorded, but also the insulin delivery is controlled.

The performance of CGM systems is usually evaluated in clinical trials funded by the manufacturers. Head-to-head studies, in which patients wear more than one CGM system at the same time (up to 3 different systems, each with 2 devices from the same company), provide important information on the analytical performance of the CGM systems in direct comparison.

Specifications for measurement quality/standards

For the approval of CGM systems, there are no established standards for evaluating measurement accuracy such as the ISO norm for SMBG monitoring systems. If and when this could take place for CGM systems cannot be foreseen. Recently, the U.S. Food and Drug Administration (FDA) published guidelines for the performance of interoperable CGM systems to be used as part of an AID system (iCGM). So far, only few systems meet these requirements. The IFCC has established a working group to look at standards for CGM (https://www.ifcc.org/ifcc-scientific-division/sd-working-groups/wg-cgm/).

By defining the “Mean Absolute Relative Difference” (MARD), an attempt is made to describe the measurement quality of a CGM system. To determine the MARD value, the difference between individual measured blood glucose values and simultaneously-determined CGM values is calculated. This value determined in clinical studies is significantly influenced by the study protocol used and the selection of the patients examined. The MARD value should therefore only be used as a guide. Another parameter which deals with the measurement quality of a CGM system is the “Precision Absolute Relative Deviation” (PARD), calculated simultaneously for the same patient from the direct comparison (see above) of a CGM system with a second sensor from the same system.

However, due to the high inter-individual variability with regard to measurement accuracy, study data are of limited help in everyday clinical practice. What is of interest here is rather whether a particular sensor system is sufficiently accurate for a particular user. The individual, personal measurement accuracy depends on technical and application-related factors (see [Table 3]). So far, there is no established standard for assessing measurement accuracy at the patient level. An approach to estimate CGM accuracy can be found at this link (download worksheet under https://www.kirchheim-shop.de/out/media/Thurm_Gehr_Pumpenfibel_Onlineanhang_2020.pdf or QR-Code). This method has not yet been scientifically proven.

Costs/refund of expenses

Based on a positive assessment of benefit by IQWiG, the G-BA published a decision in 2016 providing for cost coverage of rtCGM if the patient submitting the application fulfils defined criteria (as is the case for therapeutic devices). The prescription for an rtCGM system can only be made by a specialist doctor such as: doctor of internal medicine, endocrinology and diabetology or a doctor of internal medicine specialised in general medicine/paediatrics/juvenile medicine with the recognition “Diabetologe DDG” (German Diabetes Society Diabetologist) or with comparable qualifications recognised by the respective regional medical association or doctors specialised in paediatrics and juvenile medicine with the paediatric endocrinology and diabetology recognition.

In reality, the implementation of the G-BA decision varies greatly in the various KV-districts, despite the now available standardized guideline of the Health Insurance Medical Service/Medizinische Dienst der Krankenversicherung (MD). The written application should be based on this guideline and it might be helpful to use the application proposal of the DDG/AGDT (available online on the DDG and AGDT homepages). In addition to this application form, the MD requests glucose protocols and, depending on the MDs, both digital and handwritten formats are accepted. The content of the protocols also varies between the different MDs. It makes sense for patients to draw up a letter describing their individual prerequisites, daily requirements and motivation for using a CGM system Besides that, the current 2023 guidelines of the German Diabetes Society should be cited, which recommend CGM for all patients with diabetes using Insulin.

In practice, the problem is that when a new CGM system comes onto the market, some manufacturers offer a type of “exchange programme”, while others do not. This can involve a justified change, e. g., to a new generation of sensor-supported pumps or to CGM systems with new functions. If the patient wants to adjust from an ICT to an AID pump or switch from another pump model to this system and uses an incompatible CGM, significant problems arise, even if the diabetologist had only prescribed a CGM for a limited period of care of, for example, 3 months. Either the health insurance company or the MD wants to prove inferiority (in the sense of the lack of improvement of the new pump therapy) with a non-compatible sensor system, or the patient is told to first use up the CGM system, even if it is not compatible with the AID pump system, because it has been automatically approved and paid for by the health insurance company for one year. Patients must therefore actively endure a lack of improvement in their metabolic situation with the pump and incompatible sensor, or even prove a deterioration, so that they can finally be granted an AID system that had been prescribed to them. A second specialist medical opinion is often necessary to explain this conflict.

The time required by the diabetes team for the application, the medical instruction on the CGM systems and the training is not reimbursed by the cost payers (health insurance companies). The EBM number in use since April 2017, and now updated – reduced – is to be understood as a medical instruction number. Individual or group training courses are regulated differently throughout Germany depending on the federal state, KV district and payers. General cost coverage for CGM training programmes is required.

Quality control (internal and external/interlaboratory tests)

There are no quality controls for CGM systems. The SMBG measurements performed regularly for calibrating the CGM systems and further SMBG measurements are the only possibility for drawing conclusions about measurement quality. Carefully performing blood glucose measurements for calibration CGM systems at times of low glucose fluctuations and correctly entering these values are prerequisites for obtaining reliable glucose measurements from CGM systems.

Even if factory-calibrated sensors are used, control measurements should be carried out in order to detect individual “bad” sensors (batches) and to avert dangers caused by this (e. g., severe hypoglycaemia after insulin administration with incorrectly high sensor values). There are no established recommendations on the frequency of control measurements. More frequent control measurements seem reasonable at the beginning of a sensor session, every 1–2 days thereafter and additionally in the situations recommended by the respective manufacturer (discrepancy between symptoms and displayed value, etc.).

Safety issues/side effects

There are a number of safety aspects to be considered when using this diagnostic option: Some examples:

• What happens when the CGM measurement results are used to make therapy decisions?

• What is the quality used to detect low glucose levels, i e. how well is hypoglycaemia detected in everyday life?

• What are the clinical consequences of miscalculations due to incorrectly performing SMBG?

• What incorrect measurements (=low glucose values) occur, e. g. when the patient lies on the sensor at night?

• Does the patient hear the alarms? Do they take place in time to be able to react properly?

• As described in the CGM system operating instructions, SMBG measurements must be carried out when implausible results are obtained!

If patients adjust their insulin therapy based on the measurement results of a CGM system, not all CGM systems have been approved for this purpose in Germany so far; however, it is practised by many patients due to the predominantly good measurement quality of the sensors. The measurement quality of CGM systems in the hypoglycaemic range is not satisfactory, therefore SMBG should be performed for symptoms indicative of hypoglycaemia (with conflicting CGM glucose values). SMBG measurement is also recommended if the CGM system indicates hypoglycaemia without symptoms of hypoglycaemia. In the case of rapid tissue glucose changes (induced e. g. by food intake or sport), there may be physiological and technical differences between the glucose concentrations in blood and ISF. These differences are not measurement errors, they stem from the fact that glucose is measured in two different compartments. The clinical experience of some diabetologists indicates that with such extreme differences, the alignment of therapy adjustments to CGM readings is safer than the alignment to SMBG readings alone.

CGM systems display the glucose trend from the near past into the close future using trend arrows ([Table 7]). It should be noted that the direction of the trend arrows can change rapidly, especially postprandially. Many users of CGM systems do not only orientate their therapy adjustment on the current glucose value, but also on the current trend arrow. Some German experts have created easy-to-use recommendations for different patient groups and published them in the form of scorecards. Together with qualified training, these scorecards can help patients react in a considered and appropriate way to fluctuations in their glucose level and the indication of their CGM. In AID systems, the sensor trend is automatically included, so that the importance of the trend arrows for the patient is reduced in AID systems.

Table 7 Tips for interpreting the indications on the display of the CGM device. It is important to include the past 2–3 hours of the trend when interpreting values. The meaning of the trend arrows varies from manufacturer to manufacturer.

	Abbott Libre 3	Dexcom G6/G7	Guardian 3/Guardian 4	Medtrum Touch Care Nano CGM	Eversense E3	Menarini GlukoMen Day CGM
→	<1 mg/dl/min <0.06 mmol/min	<1 mg/dl/min <0.06 mmol/min				<1.5 mg/dl/min <0.08 mmol/min
↗↘	1–2 mg/dl/min 0.06–0.11 mmol/min	1–2 mg/dl/min 0.06–0.11 mmol/min		Present	1–2 mg/dl/min 0.06–0.11 mmol/min	1.5–2.5 mg/dl/min 0.08–0.14 mmol/min
↑↓	>2 mg/dl/min >0.11 mmol/min	>2 mg/dl/min >0.11 mmol/min	1–2 mg/dl/min 0.06–0.11 mmol/min	Present	>2 mg/dl/min >0.11 mmol/min	2.5–3.5 mg/dl/min 0.14–0.19 mmol/min
↑↑ ↓↓		>3 mg/dl/min >0.2 mmol/min	>2 mg/dl/min >0.11 mmol/min	Present		3.5 mg/dl/min 0.19 mmol/min
↑↑↑ ↓↓↓			>3 mg/dl/min >0.2 mmol/min

Wearing glucose sensors on the skin with a plaster for several days and repeated use of the same skin site can lead to skin reactions in these areas. The reactions range from mild skin irritations to the development of contact allergies against components (especially acrylates) in the adhesives and/or the housing of the transmitters, which represent a considerable impairment and can make further use of a CGM system impossible. For these patients the implanted long-term rtCGM with daily changeable silicone plaster is a therapy option.

A questionnaire for recording skin reactions is available online at the following link: https://www.idt-ulm.de/images/Befundbogen_fr_Hautreaktionen_IfDT_englisch.pdf.

Conditions to be observed in practice

In all CGM systems, algorithms are integrated which convert the measured current flow or the fluorescence signals of the sensor into glucose values based on blood glucose calibration values, reduce the noise of the electronic measurement signal and eliminate implausible values. The algorithms of the manufacturers are different (e. g. different time delays to blood glucose, different calibration methods, differences depending on the SMBG system used for calibration); little is known about how they work. This point should be considered by the patient when changing the CGM system. The handling and concept of the CGM systems can also differ considerably. For this reason, the patient should receive proper instruction after a system change in order to understand the changes in the calibration process, the data evaluation with the new software and to react correctly.

Use with different patient groups

The G-BA decision sets out clear guidelines on the patient groups eligible for cost reimbursement of CGM systems, namely for insulin-dependent diabetes with ICT or CSII. In view of the number of people with type 2 diabetes (the scope of the costs) and the heterogeneity of this patient group, the decision on whether it makes sense for individual patients to use CGM may vary.

Additions to the list of indications for the use of CGM in special patient groups:

• For patients with specific, individual problems (type 1 or type 2)

• Temporarily for therapy review in patients taking oral antidiabetics that may induce hypoglycaemia

• During pregnancy

• In patients with pronounced secondary diseases, e. g. a painful peripheral polyneuropathy

• For training purposes as well as

• To compensate for restrictions caused by diabetes at work

Training/psychological aspects

CGM is a very powerful, but also cost-intensive diagnostic and therapeutic tool. A prerequisite for optimal use, especially with regard to the modification of therapy, is that patients and medical staff are comprehensively trained. It is not considered sufficient for patients to be solely instructed by the manufacturers in device-specific aspects. The AGDT and AGPD have developed the manufacturer-independent rtCGM training program SPECTRUM. The time required to train patients in the diabetes practices is considerable and the patients themselves must receive qualified training. The training units can be taught individually or in small homogenuous groups, depending on the patient̓s needs; they can be taught to groups or individuals in both outpatient and inpatient settings.

For patients, the permanent availability of information on the glucose trend in their own bodies can be both a blessing and a curse. On the positive side, CGM warns of acute events and helps optimise glucose control. Patients who make intensive use of the information and advice provided by the CGM systems report a significant increase in safety, freedom and quality of life; this applies in particular to children and their families. Many parents can sleep through the night for the first time in years without having to get up several times at night to carry out an SMBG measurement. Furthermore, the reduction in lancing for SMBG measurements, especially in children, is a significant psychological relief.

On the other hand, the CGM system constantly reminds the patient of diabetes. Frequent alarms (e. g. when alarm limits have not been sensibly programmed) can disturb and unsettle patients and their relatives immensely, especially if they are false positives. Some patients feel bothered by constantly wearing a technical system in everyday life and their body awareness is impaired. Other patients are not in agreement with their readings being passed on to family members or members of the diabetes team. They see it as a violation of their privacy with negative feedback and consequences.

A prerequisite for successful CGM use is comprehensive training that not only presents technical aspects but also trains data analysis and therapy adjustment. This training can only be successfully provided by qualified diabetes educators with extensive practical experience in the use of all CGM systems. In addition, the required software should also be available in the physicians office and used during consultation with the patient.

Particular attention is paid to the use of CGM as an essential component of an AID system. There, CGM autonomously controls the control loop between the current glucose value and the insulin dosage calculated using the algorithm. For patients, this means, on the one hand, learning to be aware of the CGM system, and on the other hand, trusting in its function and measurement accuracy. This aspect must be given a lot of focus in the training units.

Comment

Continuous glucose monitoring is rapidly gaining importance in the context of modern diabetes therapy due to the advantages of the permanent availability of glucose data, prevention of hypoglycaemia and reduction glucose fluctuations.

One requirement of the G-BA decision is that data security must be safeguarded when using a rtCGM system, i. e., the measured data (even if uploaded to a cloud) should not be accessible and traceable for third parties. It is therefore important to inform patients of the legal situation in this respect.

Manufacturers regularly bring new generations of their CGM systems onto the market – with improvements in measurement quality, more simplified handling, improvements in interoperability and connectivity. If such models (or a combination of insulin pump and CGM or smart pens) offer the patient a relevant therapeutic advantage, it should be possible to apply for a change via an expert assessment before the expiry of the one-year flat-rate care charge (CGM) or four-year flat-rate care charge (insulin pump). There are a number of innovative measurement principles in preclinical and clinical development that will rectify some of the drawbacks of the CGM systems available to date, as well as offer new options and be more cost-effective to manufacture.

The constant availability of glucose values in CGM systems makes it perspectively possible to supply bolus computers with significantly more data than was previously possible with SMBG values. Alternatively, the rtCGM values can be transferred to smartphone using apps. The algorithms can make recommendations for insulin doses.

Parameters derived from CGM

Goals

Today, the basis for counselling during long-term outpatient treatment for type 1 diabetes is primarily the CGM data and the therapy data stored in parallel, i. e., insulin doses, nutrition, physical activity and the like. For the evaluation of CGM data, each manufacturer offers its own software; furthermore, there are manufacturer-independent, cloud-based or locally-installed software solutions. For clinical counselling, it is crucial that data from insulin pumps, insulin pens and CGM systems can be displayed together in one software, if possible, so that insulin doses and their effects can be graphically combined.

The handling of the programmes, i. e., the active reading of data, is partly complex and requires an introduction. However, the data of insulin pumps, pens and stand-alone CGM systems can also be displayed via an app on a smartphone and transferred directly to the manufacturer̓s software. This means that the devices need to be actively read out less often.

Current software solutions usually offer a clear initial evaluation of the CGM data with the help of the “Ambulatory Glucose Profile” (AGP) and other special trend views, which shows the distribution of the values in colour as a “wave” over 24 hours. With the manufacturer-specific CGM software, CGM-derived parameters such as mean glucose, glucose management indicator (GMI), glycaemic variability (GV) or time or proportion% in, above or below target range (TiR, TaR, TbR) can be calculated. The TiR provides information about the proportion of glucose values that were in the target range during a continuous recording. This characterises the current quality of glucose control.

Recommendations for the target values of various established CGM parameters were defined in an international consensus in 2019 ([Tables 4], [5]). The American Diabetes Association has adopted these target values for the 2020 clinical practice guidelines.

One of the recommendations is to establish the evaluation with the help of the AGP ([Fig. 4]). In addition to the AGP evaluation, the glucose management indicator (GMI) represents a new, important parameter. The GMI is based on an optimised calculation formula and has replaced the eHbA1c value (originally estimated HbA1c or eHbA1c) as the HbA1c analogue.

Fig. 4 Examples of interquartile or interdecile glucose variability and possible causes of these glucose fluctuations. CU: carb unit; SEA: injection-to-food interval. *The assessment of the AGP is restricted by an “irregular” daily routine. IQR: interquartile range (interquartile range, 25th-75th percentiles), IDR: interdecile range (interdecile range, 10th-90th percentiles).

Differences between GMI and HbA1c values measured in the laboratory are possible for various technical, biological and probably also genetic reasons. The GMI is based on the glucose in the intracellular space of the fatty tissue, in which current changes in blood glucose are only reflected with a delay. The measurement of the HbA1c or calculation of the GMI takes place in two completely different compartments of the body. The GMI can be influenced by the quality of the measuring system and an incorrectly low calibration, whereas the HbA1c value can be influenced by a variety of diseases, which, among other things, affect the life span of the erythrocytes. The GMI is usually calculated over a self-defined period of 2–4 weeks, i. e., a relatively short period of time, and thus reflects recent changes in therapy or diet, whereas the HbA1c value represents a significantly longer period of 8–12 weeks (life span of the erythrocytes). This can lead to different values but can also be used to positively highlight successes of the therapy of the last 2–4 weeks due to the GMI.

Conditions to be observed in practice

Both the time above/below/in target range and glycaemic variability can provide important information on fluctuations in glucose concentration, GMI can be used as an approximation to HbA1c value. However, some points need to be considered.

The quality of the calibration (with blood glucose values or with sensor values), the measurement quality of the sensor and software settings of the respective CGM system used have an influence on the CGM-derived parameters. These can therefore vary significantly depending on the system. In principle, the use of CGM systems also provides an overview of the quality of glucose control over time. Thus, a mean glucose value over time can be calculated, which correlates with the HbA1c value. The importance of the HbA1c value remains high despite the availability of CGM data. Currently, the HbA1c value is the only relevant surrogate parameter associated with subsequent complications. New parameters obtained by appropriate evaluation of the data provided by CGM systems, such as “time-in-range” (TiR) or “time-below-range” (TbR), facilitate the assessment of the quality of glucose control ([Tables 4], [5]). For example, the TiR/TbR show fluctuations in the glucose concentration better than the HbA1c value, but the information on the parameters in the software of the different manufacturers also depends on the system. It should also be noted that there are (yet) no studies on the association with the development of diabetic complications for these parameters.

Comment

In our opinion, parameters such as TiR/TaR/TbR and the GMI are a valuable complement to the HbA1c value, but not a substitute file:///C:/Users/GFreckmann/Downloads/20190509_KLD_Stellungnahme_Time_in_Range_2019_final.pdf.

HbA1c

Goals/indications

The long-term quality of glucose control has a direct influence on the risk of developing diabetes-associated secondary diseases. The HbA1c measurement allows an assessment of the prevailing glucose control over time. The HbA1c value is mainly determined by the blood glucose values of the last 2–3 months and has been used in diabetology as a quality indicator for glucose control for many years. However, the HbA1c value does not allow an adequate statement about glucose variability. The attending physician should agree on an HbA1c therapy target with the patient, based on the patient's individual situation. An HbA1c measurement at quarterly intervals is necessary to get an overview of the quality of glucose control. If some form of self-monitoring is performed by the patient, the HbA1c value should always be assessed in combination with the results of the self-monitoring. Since considerable intra- and interindividual deviations between the measured HbA1c value and simultaneously- determined SMBG or CGM values can occur in individual patients, which are based, e. g., on diseases or other factors, the HbA1c value should never be considered alone ([Table 8]).

Table 8 Causes of incorrect HbA_1c values.

Physiological causes/influencing factors
	Falsely low	Falsely high	Opportunities
Erythrocyte formation	Increased	Slows down due to lack of available iron	Determination of an “HbF-adjusted” HbA1c value Reticulocytes+Ferritin Urea Hb electrophoresis
	Very high	Iron deficiency anaemia
	Pregnancy	Infectious anaemia
	Bleeding, blood loss	Tumour-induced anaemia
	Blood transfusion
	Erythropoietin administration		For Hb variants, determine HbA1c using an immunological method. Fructosamine
	Iron supplementation
Erythrocyte breakdown	Too soon	Too late
	Haemolytic anaemia	Splenectomy
	Chronic renal insufficiency	Aplastic anaemia
	Cirrhosis of the liver
	Folic acid deficiency?
	Hemoglobinopathies:	Hemoglobinopathies:
	HbS	HbH
	HbC	HbF (Thalassemia)
	HbD
	Spherocytosis
Laboratory technical causes/interference factors
	False high – ONLY for HPLC-HbA1c measurements through carbamylation	False high – ONLY for immunological HbA1c measurements	Possibilities for objectification:
	Terminal renal insufficiency, uraemia, creatinine>5 mg/dl	Betalactam antibiotics	Newer HPLC columns are no longer influenced by carbamylation, ask laboratory. Laboratory method other than HPLC required: Immunological technique, enzymatic technique (written note on the laboratory request form)
	Alcoholism (acetaldehyde)	Contraceptive pill
	Aspirin (from 500 mg/d over weeks)	Hydroxyethyl starch (HES) solutions
Other causes
	Falsely low	Falsely high
	Nutritional (alcohol, fat)	Pharmaceuticals: Immunosuppressants Protease inhibitors
		Genetically-induced hyperglycaetion in certain ethnic groups
		Age
		Organ transplant
		Hypertriglyceridemia
	Hereditary causes	Hereditary causes

In the case of physiological causes or influencing factors, the measurement is correct, but the HbA_1c value does not accurately reflect the metabolic state. The laboratory causes are interference factors that influence the HbA_1c value measurement Hb = haemoglobin, HPLC = high performance liquid chromatography.

Measurement method

There are a number of different methodological approaches to measuring HbA1c; in practice, a few have become established and are frequently used.

Available systems

There are various systems on the market; they can be differentiated according to measuring principles and laboratory systems, POCT (Point of Care) systems and small desktop devices that can also be used by patients.

There are HbA1c measuring systems that have been designed for use by practices and clinics, but also for use by patients at home. The size of the measuring device (comparable to a blood glucose meter) and the simple sample collection through a capillary blood sample, make it easy for patients to use. There are “professional” sets and small pack units that are primarily advertised for use in the home environment. When used, for example, in a video consultation, a HbA1c value measured by the patient in the blood can indicate the quality of glucose control as a supplement to the parameters derived from the CGM measurement. However, all HbA1c measurement systems require proper instruction in correct sample collection and sample preparation (preanalytics) as well as evaluation of the results. Small errors in sample preparation (temperature of the system) or a too small or too large blood sample in the measuring capillary falsify the results. Each HbA1c measurement system has a specific standard range that can lead to a deviating result from the measured value as obtained with the laboratory device in the outpatient clinic or practice. Such discrepancies can unsettle patients who compare different HbA1c readings – the HbA1c value calculated by the CGM system software and the GMI recently calculated by the software – and find differences. The instructions for use of the devices should include a standard range, information on precision and accuracy, interference testing of common interfering substances as well as limitations of the method, e. g., applicability for diagnostic purposes or in children or pregnant women. In principle, a HbA1c value measured at home or between outpatient appointments is associated with added value, as long as the patients find this information helpful and can use it to manage their therapy.

Specifications for measurement quality/standards

In recent decades, the measurement quality of the HbA1c value measurement has been significantly improved by a number of measures, in particular by the creation of suitable reference material. The values with the international reference method (IFCC standardisation) are given in mmol/mol Hb. Conversion into percent and vice versa is possible with the help of equations ([Table 9])

Table 9 Conversion table: HbA1c values measured according to International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) in mmol/mol or National Glycohemoglobin Standardization Program (NGSP) in%. Conversion from% to mmol/mol: HbA1c (mmol/mol)=(HbA1c (%) – 2.15)×10.929. Conversion from mmol/mol to%: HbA1c (%)=(HbA1c (mmol/mol)×0.0915+2.15.

IFCC HbA1c (mmol/mol)	NGSP% HbA1c (%)
31	5.0
37	5.5
42	6.0
48	6.5
53	7.0
58	7.5
64	8.0
69	8.5
75	9.0
80	9.5
86	10.0
91	10.5
97	11.0
102	11.5
108	12.0

Costs/refund of expenses

The costs for the HbA1c value measurements are borne by the cost payers for all patients with diabetes.

Quality control (internal and external/interlaboratory tests)

According to the specifications of the Rili-BÄK (www.bundesaerztekammer.de/rilibaek2019) for HbA1c, the operators of corresponding devices must participate in an internal and external quality control. Unit-use POCT systems are excluded from external quality control; if HbA1c is used for diabetes diagnosis, interlaboratory comparisons are required. At the end of 2019, the pass limit for external quality control (interlaboratory comparisons) was lowered from±18% to±8%. The requirements for internal quality control were reduced from 10% to 5% and to 3% after a 4-year transition period. Furthermore, commutable (exchangeable) control material (whole blood) is now used in the interlaboratory comparisons, which improves quality control considerably. Overall, these measures contribute to a significant improvement in the measurement quality of this important parameter.

Safety issues/side effects

When using different HbA1c measuring methods, differences are observed that are relevant for therapy: Various systems can display HbA1c measured values differing by 0.5% for the same blood sample. If a patient has a relatively low therapeutic target, such differences may increase the risk of hypoglycaemia. The life expectancy of erythrocytes has a significant effect on HbA1c. Illnesses which change the life expectancy of erythrocytes thereby also influence the HbA1c value ([Table 8]). For example, due to the significantly shortened erythrocyte life span, pronounced haemolytic anaemia can lead to low HbA1c values which are independent of the mean glucose values.

Practical implementation of the measurement

Information on the practical implementation and interpretation of the measurement results is provided in the Diabetes Diagnosis clinical practice guideline.

A HbA1c value (eHbA1c) can be calculated from fasting glucose values measured over a certain period of time and individual 7-point blood glucose profiles. Using CGM data, a GMI can be calculated in addition to HbA1c that reflects the predominant quality of glucose control from such data over a period of time. At the request of the American health authorities, another term is used to avoid suggesting that this parameter corresponds to the HbA1c value.

Conditions to be observed in practice

The use of POCT devices for HbA1c value measurement allows the current measured HbA1c value to be discussed directly with the patient. There is also no need to send a blood collection vial to a laboratory. However, the measurement quality of all POCT systems is not sufficient.

Use with different patient groups

The HbA1c value measurement provides the desired information on long-term glucose control in almost all diabetes types. In older patients it should be noted that the HbA1c value increases physiologically (see Diabetes Diagnosis clinical practice guideline).

Training/psychological aspects

In diabetes training, the concept of the HbA1c value should be explained to the participants so that they understand the importance of target values and work towards achieving their target values. However, thanks to the availability of CGM data, the focus can be placed on the reduction of glucose fluctuations as a medium-term therapeutic goal. If individual patients are deeply afraid of severe hypoglycaemia, they will tend to aim for rather high HbA1c values. The opposite is true for patients whose goal is to avoid diabetes-associated sequelae (“low-flyers”) because of extreme, often unrealistic fear.

Comment

The HbA1c value has proven itself as a parameter for the longer-term quality of metabolic control. The HbA1c value is established as a surrogate parameter for the incidence and progression probability of microvascular complications. This established parameter should not be abandoned without good reason simply because new CGM-derived parameters such as TiR are available. The HbA1c value continues to play an essential role in regular metabolic monitoring.

Summary and outlook

The glucose measurement and control options presented have revolutionized diabetes therapy over the past 40 years, providing patients with an unprecedented degree of flexibility and safety in dealing with their disease. This development has accelerated significantly over the last two decades, and the market launch of AID systems will represent another quantum leap in diabetes therapy.

All methods for glucose monitoring are subject to rapid change and further development. Therefore, the statements formulated here should be continuously updated through current literature reviews and observance of the manufacturers̓ homepages. There is a need for an independent institute to evaluate the performance of the measurement systems on the market, especially after their market launch. This is also due to the weaknesses of the previous CE marking system.

Unfortunately, there is no European authority which is primarily concerned with medical devices (as is the case with medicine); this is covered by the EU Commission. The German authorities (BfArM) also have relatively few practical options since medical devices are a country issue.

Acknowledgment We would like to express our heartfelt thanks to many colleagues who have helped us with their constructive comments.

German Diabetes Association: Clinical Practice Guidelines This is a translation of the DDG clinical practice guidelinepublished in Diabetol Stoffwechs 2023; 18 (Suppl 2): S114–S135DOI 10.1055/a-2075-9968

Conflict of Interest

SS is on the advisory boards of the following companies: Abbott, Dexcom, Menarini, Medtronic, Roche, Sanofi, Lilly, Glooko and received speaking fees from Berlin-Chemie, Dexcom, Lilly, Medtronic, Menarini, Novo, Roche.
DD received remuneration from Ascensia Diabetes, Insulet, Roche Diagnostics and is a member of the Advisory Boards of Ascensia Diabetes, Glooko, Lilly.
BG has received speaking and consulting fees from Ascensia, Dexcom, Diabeloop, Insulet, Lilly, Novartis, NovoNordisk, Medtronic, Roche, Vitalaire.
KL states that she has served on Advisory Boards of Abbott, Roche Diabetes Care and Biomarin within the past 3 years, and has also received speaking honoraria from Astra Zeneca, BDI, BioMarin, Chiesi, Fachkommission Bayern, Glooko, Insulet, Lilly Deutschland, Medtronic, Menarini Berlin Chemie, Merck Serono, MSD SHARP & DOHME, NovoNordisk, Roche Diabetes Care, Sanofi-Aventis.
SVS has participated in Advisory Boards of: Abbott, Dexcom, Insulet, Lilly, Medtronic and Novo Nordisk. SVS has received speaking fees from Abbott, Berlin-Chemie, Dexcom, Hexal/Sandoz, Infectopharm, Lilly, Medtronic, Merck-Serono, Novo Nordisk and Sanofi-Aventis.
AT is an independent consultant, expert in CGM systems and diabetes technology, until April 2020 he was the scientific director of Medtronic Diabetes Germany, since then he has received grants and lecture fees from the companies Evivamed, Dexcom, Abbott, Berlin-Chemie, Novo-Nordisk, Sanofi.
RZ is a member of the Advisory Boards of the following companies: Abbott, Dexcom, MySugr, NovoNordisk, Roche Diabetes Care and Vertex, and received speaking fees from Abbott, Dexcom, Glooko, Medtronic, NovoNordisk and Roche Diabetes Care as well as VitalAire.
GF is general manager and medical director of the Institute for Diabetes Technology, Research and Development Company at the University of Ulm, Ulm, Germany, which carries out clinical studies e.g. with medical devices for diabetes therapy on its own initiative and on behalf of various companies.
GF/IfDT have received research support, speakers’ honoraria or consulting fees in the last 3 years from Abbott, Ascensia, Berlin Chemie, Boydsense, Dexcom, Lilly Deutschland, Novo Nordisk, Perfood, Pharamsens, Roche, Sinocare, Terumo, Ypsomed.

Publikationsverlauf

Artikel online veröffentlicht:
19. Februar 2024