**4. Smart pen systems**

*Type 2 Diabetes - From Pathophysiology to Modern Management*

tions in its use.

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 limita-

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

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

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with Type 2 DM [46, 47].

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

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].

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 whether the patient uses pen or syringe/vial.

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

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 without manual input [53].

The benefits of a smart pen system in the treatment of individuals with DM can be summarized as follows:

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

Having the data readily available and reminders on their phone can provide an extra incentive to be more compliant with their regimen.

2.Improvement with the risk of insulin dose errors. Access to dosing and timing of insulin can facilitate more accurate doses and limit the risk of accidental overdose or under dosing.

This being a relatively new technology, these devices will need to demonstrate improvement in clinical and QOL (Quality of Life) outcomes, cost effectiveness, ease of training and use. However, many of the technologies discussed above have underwent the same scrutiny. The issue of cybersecurity as with any connected DM devices will need to be resolved to maintain patient confidentiality and integrity of the data. Smart pens may be an alternative to individuals who do not want CSII therapy for a multitude of reasons but would like to intensify their regimen and have access to appropriate dosing and timing of insulin to improve their glucose control.
