**3. Continuous glucose monitoring (CGM)**

Continuous glucose monitoring or CGM was first available for research projects in the 1970s.

Miles Laboratories in the late 1970s developed the Biostator which was large, bulky and required IV access. It had little use in everyday clinical practice, due to its size, need for constant supervision, IV access and waste of blood in order to measure glucose levels [23, 24].

In 2002, the GlucoWatch Biographer was introduced. It was shaped like a watch, similar to the Apple Watches of today. It adhered to the skin and used interstitial fluid to measure glucose levels every 10 minutes for 13 hours. [25]. See **Figure 1**.

Due to its process reverse iontophoresis, the GlucoWatch had significant drawbacks. It was painful for many individuals, had accuracy issues and was difficult particularly in warmer climates with individuals sweating. The Autosensor, which was replaced every 13 hours had caused skin changes and irritation in many patients. Eventually the GlucoWatch was discontinued in late 2007. It did, however, pave the way for the CGM systems of today.

The current CGM systems use an enzymatic modality that reacts with interstitial fluid glucose and transfers it to an electrode. The electrical current that is generated is then relayed to a reader via Bluetooth wireless or an app on a smart phone which displays the results to the individual. The data can also be downloaded to a computer. Additionally, the information can be stored to the cloud and relayed to the physician or caregiver via a secure website [26].

It must be noted that interstitial glucose measurements can lag 5–15 minutes behind blood glucose measurements particularly if there is rapid variability [27, 28]. Previously, CGM systems required calibrations twice per day which introduced a perceived limitation particularly for individuals who wished to limit "finger sticks" as an incentive to move to CGM systems.

The newer versions of CGM to include the DEXCOM G6, Guardian 3 and a flash form of CGM, the FreeStyle Libre (10-day and 14-day systems) have decreased the necessity of frequent calibrations.

In recent years, there have multiple studies with CGM involving individuals with Type 2 diabetes mellitus. The focus has been efficacy, the effect of CGM

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*Newer Modalities in the Treatment of Type 2 Diabetes Mellitus: Focus on Technology*

with regards to hypoglycemia and glucose variability [29]. A study conducted by Vigersky et al. with patients utilizing diet, lifestyle vs. other combinations of oral agent therapy with or without basal insulin noted a reduction of mean unadjusted HbA1C of 1.0% vs. 0.5% in the SMBG group at week 12 and 0.8% vs. 0.2% at week 52. This occurred without intensification of medication or an increase in hypoglycemic episodes [29]. An additional study by Fonda et al. noted even an intermittent use of CGM may be appropriate for motivating individuals or helping to avoid

The DiaMonD study (Daily Injections and Continuous Glucose Monitoring in Diabetes) study was a 6-month randomized control trial that compared the effectiveness of CGM to SMBG in individuals using MDI (multiple daily injections). This included both Type 1 and Type 2 DM patients. The results of the 6-month trial for Type 2 patients was published in 2017 and noted the following: Type 2 DM individuals after 24 weeks using CGM had an average 0.8% reduction in HbA1C levels compared with baseline. Those with higher A1C levels noted the greatest reduction with a group starting with A1C levels greater than 9.0% noting an average 1.4% reduction from baseline. Those using CGM had an increase in time spent in the target range compared with the control group (those only using SMBG). The A1C reductions occurred with minimal changes in insulin doses, little or no change

CGM has also been useful in recognizing previously undetectable episodes of hypoglycemia. Studies conducted by Zick et al.; Pazos-Couselo et al.; Klimontov and Myakina all noted a significant higher percentage of hyperglycemic episodes

The use of CGM particularly in older individuals utilizing insulin therapy has noted significantly higher incidences of nocturnal hypoglycemia compared with those utilizing only CGM. This indicates that CGM can be useful in high-risk Type 2 DM populations such as the elderly, those with special needs and individuals that have difficulty utilizing HGM such as severe arthritic conditions, vascular issues,

CGM is also a tool to assess glucose variability. This has become important in outcome measurements recently in addition to the standard A1C levels. The INITIATION study which tested an insulin initiation algorithm in Type 2 DM patients used CGM in 78 patients who were followed for 24 weeks. The results noted that insulin initiation reduced hyperglycemia but not glucose variability [37, 38]. The FLAT-SUGAR study which randomized 102 patients who were on metformin and basal/bolus insulin to either maintenance with basal/bolus therapy for changing the basal insulin to GLP-1 therapy. The drug used with this study of 26 weeks was exenatide BID. Using CGM it was noted that the GLP-1 group had lower variability of glucose as measured by the coefficient of variation. Of note with this study, A1C levels or episodes of hypoglycemia did note change significantly

These studies and others both past and presently being conducted have shown the CGM use in patients with Type 2 DM can improve A1C levels, detect risk of hypoglycemia which is not clinically apparent, particularly nocturnally and may be

There are two forms of CGM presently available for use in clinical practice: (1) Professional CGM and (2) Personal CMG. Professional CGM is placed in the physician office and does not require the patient to obtain or purchase a system. It is a blinded system in many instances, that is, the patient has no access to the results immediately and must wait for the CGM to be downloaded in the physician's office, analyzed and then informed of the results. These systems can be worn for 3, 7 or 14 days, though generally the 7- or 14-day systems are more popular

*DOI: http://dx.doi.org/10.5772/intechopen.84285*

in regimen or addition of non-insulin medications [32].

observed with the use of CGM compared with SMBG use.

between the treatment groups [39–41].

able to assess and address glucose variability.

"burnout" [30, 31].

etc. [33–36].

**Figure 1.** *GlucoWatch Biographer 2.*

#### *Newer Modalities in the Treatment of Type 2 Diabetes Mellitus: Focus on Technology DOI: http://dx.doi.org/10.5772/intechopen.84285*

with regards to hypoglycemia and glucose variability [29]. A study conducted by Vigersky et al. with patients utilizing diet, lifestyle vs. other combinations of oral agent therapy with or without basal insulin noted a reduction of mean unadjusted HbA1C of 1.0% vs. 0.5% in the SMBG group at week 12 and 0.8% vs. 0.2% at week 52. This occurred without intensification of medication or an increase in hypoglycemic episodes [29]. An additional study by Fonda et al. noted even an intermittent use of CGM may be appropriate for motivating individuals or helping to avoid "burnout" [30, 31].

The DiaMonD study (Daily Injections and Continuous Glucose Monitoring in Diabetes) study was a 6-month randomized control trial that compared the effectiveness of CGM to SMBG in individuals using MDI (multiple daily injections). This included both Type 1 and Type 2 DM patients. The results of the 6-month trial for Type 2 patients was published in 2017 and noted the following: Type 2 DM individuals after 24 weeks using CGM had an average 0.8% reduction in HbA1C levels compared with baseline. Those with higher A1C levels noted the greatest reduction with a group starting with A1C levels greater than 9.0% noting an average 1.4% reduction from baseline. Those using CGM had an increase in time spent in the target range compared with the control group (those only using SMBG). The A1C reductions occurred with minimal changes in insulin doses, little or no change in regimen or addition of non-insulin medications [32].

CGM has also been useful in recognizing previously undetectable episodes of hypoglycemia. Studies conducted by Zick et al.; Pazos-Couselo et al.; Klimontov and Myakina all noted a significant higher percentage of hyperglycemic episodes observed with the use of CGM compared with SMBG use.

The use of CGM particularly in older individuals utilizing insulin therapy has noted significantly higher incidences of nocturnal hypoglycemia compared with those utilizing only CGM. This indicates that CGM can be useful in high-risk Type 2 DM populations such as the elderly, those with special needs and individuals that have difficulty utilizing HGM such as severe arthritic conditions, vascular issues, etc. [33–36].

CGM is also a tool to assess glucose variability. This has become important in outcome measurements recently in addition to the standard A1C levels. The INITIATION study which tested an insulin initiation algorithm in Type 2 DM patients used CGM in 78 patients who were followed for 24 weeks. The results noted that insulin initiation reduced hyperglycemia but not glucose variability [37, 38]. The FLAT-SUGAR study which randomized 102 patients who were on metformin and basal/bolus insulin to either maintenance with basal/bolus therapy for changing the basal insulin to GLP-1 therapy. The drug used with this study of 26 weeks was exenatide BID. Using CGM it was noted that the GLP-1 group had lower variability of glucose as measured by the coefficient of variation. Of note with this study, A1C levels or episodes of hypoglycemia did note change significantly between the treatment groups [39–41].

These studies and others both past and presently being conducted have shown the CGM use in patients with Type 2 DM can improve A1C levels, detect risk of hypoglycemia which is not clinically apparent, particularly nocturnally and may be able to assess and address glucose variability.

There are two forms of CGM presently available for use in clinical practice: (1) Professional CGM and (2) Personal CMG. Professional CGM is placed in the physician office and does not require the patient to obtain or purchase a system. It is a blinded system in many instances, that is, the patient has no access to the results immediately and must wait for the CGM to be downloaded in the physician's office, analyzed and then informed of the results. These systems can be worn for 3, 7 or 14 days, though generally the 7- or 14-day systems are more popular

*Type 2 Diabetes - From Pathophysiology to Modern Management*

Continuous glucose monitoring or CGM was first available for research projects

In 2002, the GlucoWatch Biographer was introduced. It was shaped like a watch, similar to the Apple Watches of today. It adhered to the skin and used interstitial fluid to measure glucose levels every 10 minutes for 13 hours. [25]. See **Figure 1**. Due to its process reverse iontophoresis, the GlucoWatch had significant drawbacks. It was painful for many individuals, had accuracy issues and was difficult particularly in warmer climates with individuals sweating. The Autosensor, which was replaced every 13 hours had caused skin changes and irritation in many

patients. Eventually the GlucoWatch was discontinued in late 2007. It did, however,

It must be noted that interstitial glucose measurements can lag 5–15 minutes behind blood glucose measurements particularly if there is rapid variability [27, 28]. Previously, CGM systems required calibrations twice per day which introduced a perceived limitation particularly for individuals who wished to limit "finger sticks"

The newer versions of CGM to include the DEXCOM G6, Guardian 3 and a flash form of CGM, the FreeStyle Libre (10-day and 14-day systems) have decreased the

In recent years, there have multiple studies with CGM involving individuals with Type 2 diabetes mellitus. The focus has been efficacy, the effect of CGM

The current CGM systems use an enzymatic modality that reacts with interstitial fluid glucose and transfers it to an electrode. The electrical current that is generated is then relayed to a reader via Bluetooth wireless or an app on a smart phone which displays the results to the individual. The data can also be downloaded to a computer. Additionally, the information can be stored to the cloud and relayed to the

Miles Laboratories in the late 1970s developed the Biostator which was large, bulky and required IV access. It had little use in everyday clinical practice, due to its size, need for constant supervision, IV access and waste of blood in order to mea-

**3. Continuous glucose monitoring (CGM)**

pave the way for the CGM systems of today.

physician or caregiver via a secure website [26].

as an incentive to move to CGM systems.

necessity of frequent calibrations.

in the 1970s.

sure glucose levels [23, 24].

**102**

**Figure 1.**

*GlucoWatch Biographer 2.*

today. The systems available today in the United States for professional use are: the DEXCOM Professional system, the FreeStyle Libre Pro system, Medtronic iPro 2 system. Most of these systems do require additional calibration. Once the study is completed, the data is downloaded to either the cloud or a specific program on the computer and then can be reviewed by the physician or allied health provider in conjunction with the physician and then shared with the patient. The blinded system can be helpful in regards that the patient is not responding during the time of the study but continuing their usual habits to include diet, activity and medications. Reimbursement for use of Professional CGM has improved over the past several years particularly in the United States. Requirements as the reporting of CGM results can vary among the different health plans which can lead to limitations in its use.

Personal CGM consists of an individual obtaining a system which is unblinded and provides blood glucoses every 5+ minutes for DEXCOM and Guardian 3 systems. These systems are placed subcutaneously and have alarms with notify the patient when certain patterns or thresholds are detected. There are multiple threshold alarms, rate of change alarms, predictive alarms. Predictive alarms are useful in that it permits the individual to take preventative action rather than corrective action. However, the downside of these alarms is that there can be false positives and false negatives. This can lead to so-called "alarm fatigue" [42]. Individuals will in many instances either ignore or silence the systems due to the multitude of alarms. In some cases, they will abandon CGM altogether. The DEXCOM G5–6 system is the only CGM device at present that is approved by the FDA for a nonadjunctive indication. It can be considered a therapeutic CGM, allowing individuals and physicians to modify therapy based solely on the readings and trends.

The FreeStyle Libre system utilizes a flash monitoring system. It is placed like the other CGM systems subcutaneously but provides glucose results when the CGM is scanned. Thus, the results are intermittent depending on the frequency of scanning by the patient [43]. The newest of the FreeStyle Libre systems, the 14-day unit improves over the older 10-day system with a 1-hour warm up period compared with 12 hours. Several randomized controlled trails note that the use of flash CGM with the Libre system reduced hypoglycemia, increased the time in target range and reduced glucose variability [44, 45] Studies and personal observation have also shown higher device utilization. This may be due to the simplicity of application and ease of use. The use of this system in increasing and may prove to be an asset particularly in individuals who may not need the sophistication of the more complex CGM system but want the benefit of CGM and not have to consistently perform SMBG or finger sticks.

Additional studies in Europe have shown the cost effectiveness of CGM in the management of patients with Type 2 DM receiving intensive MDI regimens and also improvement in the detection and avoidance of hypoglycemia in individuals with Type 2 DM [46, 47].

Another technological advance in CGM has been the development and approval of the implantable CGM system by Senseonics called the Eversense System. The system consists of an implantable cylindrical sensor 3.5 mm × 18.3 mm in size. This is implanted by the physician every 90 days in the upper arm area under the skin. When the system in activated, it measures interstitial glucose levels every 5 minutes. The data is transferred to a battery powered transmitter that is worn externally over the sensor. The external transmitter also provides alerts similar to other CGM systems for impending hypo or hyperglycemia. The transmitter needs to be recharged for ~15 minutes every other day. The sensor is explanted, and a new sensor implanted every 90 days. A 180-day sensor is being developed for the future.

Several studies have shown the accuracy and acceptability of an implantable glucose sensor. The PRECISE and PRECISE II studies noted that the Eversense

**105**

*Newer Modalities in the Treatment of Type 2 Diabetes Mellitus: Focus on Technology*

system was safe and provided accurate glucose results during the 90-day sensor life [48, 49]. An additional study in the UK and Germany comprising a subgroup of individuals in the PRECISE trial who were administered quantitative psychosocial assessments that included the Diabetes Distress Scale (DDS), CGM Impact Scale and a bespoke device satisfaction questionnaire. The results of the sub study indicated that an implantable CGM was acceptable to most of the participants and the majority of users both first time to CGM or previous CGM users would continue to use an implantable CGM to manage their glucoses and DM more

As the accuracy of CGM improves, particularly in the hypoglycemia range, the acceptance should also increase. However, at this time, CGM still does not, in the eyes of the regulatory agencies substitute fully for conventional SBGM. With continued development and use, it appears that eventually CGM, with or without CSII therapy will become the "standard of care" for both Type 1 and Type 2 diabetes

Most individuals with DM, particularly Type 2 DM, who utilize insulin therapy are using insulin pen systems to deliver their daily insulin dose. Previous administration of insulin via syringe and vial has been difficult to administer and master. Additionally, accuracy of dose has been questioned. Insulin pens are one of the most

Additionally, there is the issue of documentation of insulin doses. Many patients do not record the time and dose of insulin consistently. Many will state that they took their insulin with meals, nighttime, for correction of their glucose, etc. but will not be able to provide accurate documentation. Therefore, this can be a significant barrier to glycemic control. Guidelines developed by various organizations make no mention of the need to record insulin dose administered and timing of injection

In December 2017, the FDA approved the first smart pen system in the US. This insulin pen system records the dose of insulin and time of injection and transmits the data via Bluetooth to a mobile application that is downloaded on the patient's smart phone. The mobile app has the capability of dose calculation and less than whole number units which conventional insulin pens are not able to deliver.

It can also inform the individual how much insulin is on board (IOB) similar to CSII devices. This data is stored on the individuals' smart phone and can be brought

There may an additional entry in this area. Bigfoot Biomedical is developing an insulin smart pen that will connect to the FreeStyle Libre system. It will be controlled with a mobile app and hopefully adjust long and short acting insulin doses

The benefits of a smart pen system in the treatment of individuals with DM can

1.Improvement in poor adherence to the treatment regimen and omission of

easily to the clinical visit for analysis by the physician/health care provider.

A recent review of the literature and meta-analysis noted that insulin pen devices noted improvement in patient adherence and persistence with their treatment regimen. Hypoglycemia was noted to be reduced, with a possible improvement in dose accuracy in pen devices. However, these studies were limited, and the authors of the meta-analysis recommended additional larger scale studies [52].

widely used devices worldwide in DM treatment and care [51].

whether the patient uses pen or syringe/vial.

without manual input [53].

be summarized as follows:

insulin doses.

*DOI: http://dx.doi.org/10.5772/intechopen.84285*

effectively [50].

**4. Smart pen systems**

mellitus.

*Newer Modalities in the Treatment of Type 2 Diabetes Mellitus: Focus on Technology DOI: http://dx.doi.org/10.5772/intechopen.84285*

system was safe and provided accurate glucose results during the 90-day sensor life [48, 49]. An additional study in the UK and Germany comprising a subgroup of individuals in the PRECISE trial who were administered quantitative psychosocial assessments that included the Diabetes Distress Scale (DDS), CGM Impact Scale and a bespoke device satisfaction questionnaire. The results of the sub study indicated that an implantable CGM was acceptable to most of the participants and the majority of users both first time to CGM or previous CGM users would continue to use an implantable CGM to manage their glucoses and DM more effectively [50].

As the accuracy of CGM improves, particularly in the hypoglycemia range, the acceptance should also increase. However, at this time, CGM still does not, in the eyes of the regulatory agencies substitute fully for conventional SBGM. With continued development and use, it appears that eventually CGM, with or without CSII therapy will become the "standard of care" for both Type 1 and Type 2 diabetes mellitus.
