Pediatric Annals

Special Issue Article 

A Technological Revolution: The Integration of New Treatments to Manage Type 1 Diabetes

Alfonso Galderisi, MD; Jennifer L. Sherr, MD, PhD

Abstract

Intensive insulin treatment and frequent self-monitoring of blood glucose (SMBG) have been recognized as pillars of diabetes treatment. Many patients with type 1 diabetes (T1D) struggle to achieve targeted glycemic control. Technology has vastly changed how these tenets to treatment can occur. Continuous subcutaneous insulin infusion (CSII) pumps and continuous glucose monitoring (CGM) can be used in place of their counterparts, multiple daily injections and SMBG. We present a review of CSII, CGM, and of different levels of integration among these two therapies, ranging from low glucose suspension devices to hybrid closed loop insulin delivery. Analysis of the various tools, their effect on glycemic control, and a guide to integrate them into pediatric clinical practice is presented. Although a cure for T1D remains the ultimate goal, technology holds the promise of keeping youth with T1D in targeted control and minimize the burden of this chronic medical condition. [Pediatr Ann. 2019;48(8):e311–e318.]

Abstract

Intensive insulin treatment and frequent self-monitoring of blood glucose (SMBG) have been recognized as pillars of diabetes treatment. Many patients with type 1 diabetes (T1D) struggle to achieve targeted glycemic control. Technology has vastly changed how these tenets to treatment can occur. Continuous subcutaneous insulin infusion (CSII) pumps and continuous glucose monitoring (CGM) can be used in place of their counterparts, multiple daily injections and SMBG. We present a review of CSII, CGM, and of different levels of integration among these two therapies, ranging from low glucose suspension devices to hybrid closed loop insulin delivery. Analysis of the various tools, their effect on glycemic control, and a guide to integrate them into pediatric clinical practice is presented. Although a cure for T1D remains the ultimate goal, technology holds the promise of keeping youth with T1D in targeted control and minimize the burden of this chronic medical condition. [Pediatr Ann. 2019;48(8):e311–e318.]

After the landmark discovery of insulin, integration of technology into the care of those living with type 1 diabetes (T1D) had its infancy with the introduction of pump therapy. The use of continuous subcutaneous insulin infusion (CSII) pumps to optimize glycemic control dates back to the late 1970s.1 Indeed, pump therapy paved the way for intensification of insulin therapy. After the completion of the pivotal Diabetes Control and Complications trial (DCCT),2 intensive insulin treatment and frequent self-monitoring of blood glucose monitoring (SMBG) were acknowledged as the two pillars of intensive treatment to prevent diabetes' microvascular complications.

In the quarter century since completion of the DCCT, much progress has been made in pump therapy as well as in the creation and refinement of continuous glucose monitoring (CGM) systems. The marriage of these systems through sensor-augmented pump therapy has allowed further technological advancements. Namely, sensor glucose values can now lead to suspension of basal insulin delivery, or in the case of hybrid closed loop insulin, delivery of an increase in basal insulin in response to above-target sensor glucose values. This article reviews the main features of current insulin pumps, CGMs, low glucose suspend, predictive low glucose suspend, and closed loop insulin delivery/artificial pancreas, with a specific focus on how these technologies can affect both glycemic measures as well as endpoints beyond hemoglobin A1c (HbA1c) for youth living with T1D.

Insulin Pumps

Insulin pump therapy provides a multitude of features that are not feasible with multiple daily injection (MDI) therapy. As the name implies, MDI requires that youth be given at least three injections per day, whereas pump therapy requires that the infusion set be changed every 3 days. Furthermore, this technology meets most of the pediatric age-specific needs, such as delivery of minimal insulin doses down to 0.025 units per hour, customizable basal rates, insulin on-board calculators that prevent stacking of boluses that could lead to hypoglycemia, as well as the ability to administer a bolus throughout the day for food and/or hyperglycemia, relieving the need for an injection each time.

Since 2007, a consensus statement developed by numerous professional societies, including those based in North America, Europe, and a global pediatric diabetes group, has provided indications for which pump therapy should be considered for youth living with T1D.3 A few situations in which insulin pumps should be considered, according to this guideline, include wide fluctuations in blood glucose levels regardless of HbA1c, suboptimal diabetes control, and good metabolic control but an insulin regimen that compromises a normal lifestyle.3 Most youth would fall into at least one of these categories, and although not implicitly stated, it seems pump therapy is suitable for all pediatric patients living with T1D.

More recently, the International Society for Pediatric and Adolescent Diabetes published consensus guidelines for the management of preschool children, which concluded that pump therapy should be the considered in those younger than age 7 years.4

Evidence Regarding Use of Pump Therapy

Real-life, large, retrospective registry-based analyses,5–7 as well as longitudinal clinical trials support the use of insulin pumps in youth with T1D. These studies have shown a decrease in HbA1c ranging from 0.2% to 1.1% in all age groups, along with a reduction of severe hypoglycemic events without a concomitant increase in body mass index.8 Karges et al.9 conducted an analysis in which approximately 10,000 patients on pump therapy were matched to those on MDI. Lower rates of both severe hypoglycemia and diabetic ketoacidosis (DKA) were demonstrated in the pump-treated group.9 Additionally, other studies have shown despite similar degrees of glycemic control attained, as measured by HbA1c, rates of retinopathy and peripheral nerve abnormality are lower in those treated with pumps.10

Integrating Pumps into Clinical Practice

Whereas most commercially available pumps share common features for insulin delivery (bolus calculators, multiple basal rates, insulin on-board determinations), aspects unique to each system should be considered and discussed so informed decisions can be made (eg, patch vs tubed pump, remotely bolus features, integration with sensors, automation of insulin delivery). An annual consumer guide published by Diabetes Forecast ( http://www.diabetesforecast.org) can help provide a framework for reviewing and comparing devices. If not dictated by insurance, the ability to choose the technology may help with the process of integrating it.

Advanced features of insulin pumps include temporary basal rates, allowing the user to decrease usual settings for activity or increase them at times of stress or illness. Extended boluses are useful to adapt insulin delivery to the nutritional content of a meal; high-fat meals are often absorbed more slowly.

Initial pump settings include calculation of basal rate profiles, insulin-to-carbohydrate ratios, and sensitivity factors/correction factors (Figure 1). These calculations may widely vary by age.8 Preschool-age children typically have a higher basal insulin requirement during the late evening and a subsequent need for lower early-morning basal rates. Additionally, these children also tend to require more aggressive insulin-to-carbohydrate ratios for meals with less aggressive sensitivity factors.8 Alternatively, adolescents exhibit “dawn phenomenon,” which leads to the need for higher basal rates in the early morning.

Strategies to determine initial insulin pump settings for youth with diabetes. Basal rates are depicted in blue, insulin to carbohydrate ratios in green, and correction factors or insulin sensitivity factors in orange. CSII, continuous subcutaneous insulin infusion; MDI, multiple daily injection; TDD, total daily dose; y/o, years old.

Figure 1.

Strategies to determine initial insulin pump settings for youth with diabetes. Basal rates are depicted in blue, insulin to carbohydrate ratios in green, and correction factors or insulin sensitivity factors in orange. CSII, continuous subcutaneous insulin infusion; MDI, multiple daily injection; TDD, total daily dose; y/o, years old.

Pump discontinuation has been estimated at 3% to 4% among all age groups. Wearability is the most frequent cause of discontinuation, with adolescents having the highest rate of pump attrition.11

One of the major complications seen with pump therapy is infusion set failures, whereby insulin delivery is interrupted placing the patient at risk for DKA. Failure of the infusion site due to mechanical obstruction or displacement is not uncommon in pump users, although its detection remains a challenge for current devices.12 Thus, it is critical to educate patients on this risk and advise patients that if persistent hyperglycemia is noted, then ketones should be evaluated and the infusion set changed.

Continuous Glucose Monitoring

SMBG is an integral component to achieve optimal glucose control because it is not feasible to intensify insulin regimens without first gathering data. Studies have demonstrated a correlation between the frequency of SMBG and degree of glycemic control attained (as measured by HbA1c) and reduced risk of complications.13 However, a paradigm-shift for glucose monitoring occurred when the US Food and Drug Administration (FDA) approved the first real-time CGM in 2005 as a therapy to be used in conjunction with SMBG.

Three classifications for CGM currently exist: (1) blinded/retrospective review CGM, (2) real-time CGM, and (3) intermittently scanned/viewed CGM (isCGM). Blinded CGM is used for short periods of time to inform health care providers of glucose trends and patterns to aide with therapy adjustments. Real-time CGM provide users with updated sensor glucose readings every 5 minutes. With real-time CGM, retrospective data review with a health care provider allows optimization of therapy, and real-time data and alerts can affect immediate treatment decisions. More recently, isCGM, also known as flash glucose monitoring, requires a user to scan the sensor with either a reader or a smartphone to display sensor glucose readings. Therefore, isCGM lacks the continuous stream of data, and, consequently the alerts other systems afford. However, once scanned they provide the users with sensor glucose and trend arrows along with a retrospective glucose profile upon which to base insulin dosing. Implantable subcutaneous sensors (Eversense; Senseonics, Germantown, MD) have been approved in both the United States (up to 90 days of wear) and the European Union (up to 180 days of wear). Table 1 provides a description of currently available CGMs.

Description of Currently Available Continuous Glucose Monitoring Devices

Table 1:

Description of Currently Available Continuous Glucose Monitoring Devices

Most of these devices consist of a disposable subcutaneous glucose sensor, connected to a transmitter, and a receiver, which in some cases can be a personal cellular device or an insulin pump. The sensor measures the glucose level in the interstitial fluid of subcutaneous tissue and converts it into an electrical signal that is delivered to the transmitter. Some sensors require routine SMBG to calibrate the sensors, but factory calibrated sensors been developed. Additionally, some of the sensors afford the opportunity to remotely monitor sensor glucose values, which can be especially helpful for youth with T1D.

Evidence for the Use of CGM

The Juvenile Diabetes Research Foundation (JDRF) CGM trial published in 200814 established that CGM, regardless of the mode of insulin delivery (ie, pump or MDI), can lower HbA1c by 0.5% after 26 weeks of treatment in adults older than age 25 years. Yet, the findings in pediatric participants demonstrated no change in glycemic control. However, this is likely partially due to reduced use of sensor in this age group, with a significant improvement in HbA1c noted in those who adopted the sensor for at least 6 days per week. Small observational studies in children younger than age 8 years have demonstrated successful use of this technology;15 however, a randomized controlled trial conducted with earlier-generation CGM systems failed to show a change in glycemic control after 6 months.16 Similar findings were seen in those younger than age 4 years; however, parents reported a high degree of satisfaction and there was sustained use of the device.17

CGM systems have rapidly evolved since completion of the JDRF trial. The improvements include (1) improved accuracy, (2) longer duration of wear (7–14 days), and (3) approval to use some devices in a nonadjunctive manner; thus, a user can make treatment decisions based on sensor glucose readings. Uptake of sensors has rapidly increased with data from the US T1D-Exchange, which show a 7-fold increase in CGM use in pediatric participants based on data collected in 2011 and again in 2016.18 Most striking was the growth in sensor use in children younger than age 6 years, as the 2016 data demonstrated nearly 50% of youth in this cohort were using this technology.

Integrating CGM in Clinical Practice

The choice of a CGM has to be individualized according to the characteristics of the device and the user, as well as their families. Currently available sensors have similar accuracy to a reference blood glucose analyzer, as described in Table 1.

As sensor therapy is initiated, and depending on the device chosen, patients and their families should receive targeted education on how to ensure successful incorporation and near daily use of this technology. Sensors allow for more regular adjustments of insulin dosing and potentially behavioral modifications (bolusing before eating). Guidance on how those remotely viewing sensor data will manage alerts is also essential. Confirmatory SMBG may still be advisable in the presence of rapid glucose changes or when the sensor value does not match with the user's symptoms. Finally, commonly used drugs (acetaminophen) can interfere with sensor readings and users should be warned appropriately.

The Marriage of Technologies: From Sensor Augmented Pumps to Hybrid Closed Loop

With the advent of CGM systems that could transmit the sensor glucose reading to an insulin pump, sensor augmented pump (SAP) therapy was born. Building on this framework, automation of insulin delivery has occurred in incremental steps, first with low glucose suspend systems that interrupt basal insulin delivery if a preset low sensor glucose threshold is set, then predictive low glucose suspend systems that base suspension of basal insulin delivery on a predicted low sensor glucose. The most recent development is hybrid closed loop insulin delivery, which allows for basal insulin delivery to be suspended or increased based on the sensor glucose level.

The in-loop framework described in Table 2 depicts the growing complexity of CGM and CSII devices based on five key-features: (1) presence of Integrated CGM, (2) layout for insulin delivery (including basal and bolus options), (3) output for hypoglycemia, (4) output for hyperglycemia, and (5) the patient's settings to initialize the system.

In-Loop Framework

Table 2:

In-Loop Framework

Evidence for the Use of SAP

The Sensor-Augmented Pump Therapy for A1C Reduction (STAR) 3 trial was a 1-year randomized controlled trial in which participants were randomized to either SAP or maintained on MDI therapy with SMBG.19 After 1 year, the pediatric cohort demonstrated a 0.4% reduction in HbA1c in the SAP group as compared to an increase of 0.2% in the MDI group.19 The greater effectiveness in reducing HbA1c of the STAR3 trial as compared to the JDRF CGM study for this age group might have been partially due to the benefit of initiating pump therapy, as well as the higher baseline HbA1c of 8.3% in the STAR 3 study versus JDRF CGM trial, with the baseline HbA1c being 7.6%.14,19

Evidence for the Use of Low Glucose Suspend and Predictive Low Glucose Suspend Systems

As avoidance of hypoglycemia was deemed the safest first step in automation of insulin delivery, low glucose suspend (LGS) systems, whereby basal insulin delivery is suspended when the CGM value reaches a low glucose threshold limit that is user-defined, were the first to be developed and approved. Such systems in outpatient home-based assessments have been found to reduce the percentage of time sensor values are in the hypoglycemic range (<70 mg/dL) overnight when compared to SAP.20 As concern existed that interruption of insulin delivery based on inaccurate sensor glucose readings could lead to metabolic deterioration, random overnight suspends were conducted and compared to data from usual-care evenings. On the morning after suspension, blood glucose tended to be about 50 mg/dL higher, but there was no clinically significant difference in blood beta hydroxybutyrate levels.21

LGS cannot prevent hypoglycemia. Instead, the goal of these systems is to reduce the duration and severity of hypoglycemia experienced. Recognizing a low cannot be prevented once it has occurred, thus predictive low glucose suspend (PLGS) systems seek to interrupt insulin delivery prior to the hypoglycemic threshold with a substantial reduction in time spent at less than 70 mg/dL, although there may be a rise in time spent in the hyperglycemic range.22,23 Two PLGS systems are currently commercially available (t:slim X2 with Basal IQ Technology [Tandem, San Diego, CA] and the Minimed 640G and 670G systems [Medtronic, Northridge, CA]).

Integrating LGS and PLGS in Clinical Practice

With LGS systems, patients should be counseled to allow this feature to work overnight. During the day, oral carbohydrates should be consumed. Ideally, rather than using an LGS, patients should be encouraged to use the PLGS feature. Yet, consideration should be given to the amount of carbohydrates to consume if hypoglycemia occurs while on a PLGS system, as frequently the amount of carbohydrates needs to be reduced to prevent rebound hyperglycemia.

Evidence for the Use of Hybrid Closed Loop Insulin Delivery

Closed loop systems integrate an insulin pump, CGM, and a control algorithm to automatically adjust insulin delivery. Most systems are hybrid closed loop (HCL) systems, requiring the user to manually bolus for meals with the algorithm automatically adjusting the basal rate based on CGM data. The control algorithm represents the core of the closed loop system, with three control approaches adopted: proportional integrative derivative,24 model predictive control,25 and fuzzy logic.26

After the initial controlled in-clinic,24,27 and camp-based studies,28 free-living outpatient trials have largely demonstrated that HCL can improve time-in-target glucose range, defined as 70 to 180 mg/dL, by 10% to 20% with a reduction of time spent in the hypoglycemic range when the comparator group was insulin pump or SAP. This holds true in children and adolescents29–31 regardless of baseline glycemic control.32

The first HCL system was approved by the FDA in 2016, with commercial launch in the US the following year. In 2018, the age of approval was lowered to 7 years and the system received CE (conformité Européenne) approval in the European Union. The 3-month pivotal trial supporting the approval of the device demonstrated its safety in the outpatient setting.33 Although not designed with an efficacy endpoint, the study demonstrated a lowering of HbA1c by 0.5% in adult participants and 0.6% in adolescents.34 Similarly in children age 7 to 13 years, use of the system led to a 0.4% reduction in HbA1c and an increase in time in range by 9%.35

HCL in Clinical Practice

Integrating HCL into clinical practice remains a challenge for both users and clinicians. Knowledge of the device and setting realistic expectations are critical for its use, as the first generation of HCL still requires frequent user input. The first commercially available system requires calibration of the glucose sensor, and users may be exited to usual pump settings if certain predefined scenarios occur. Additionally, as these first-generation systems will be hybrid, users will need to bolus for meals. Exercise still poses a challenge, and mechanisms to automatically detect activity are being explored so the onus of complying with a cornerstone of care, physical activity, can be placed on technology. Finally, infusion set failures are not circumvented, making it essential that patients remember to go back to the basics if persistent hyperglycemia occurs—namely, checking for ketones and changing the insulin infusion set. Thus, users cannot consider first-generation closed loops as “set and forget” diabetes devices.

The CARE (calculate, adjust, revert, educate) approach has been suggested to provide a framework for health care providers to understand how various HCLs systems function and how to assist their patients with use of this technology. This approach has four fundamental questions regarding automated insulin delivery and how it pertains to the patient and the device: (1) how does the system calculate insulin delivery, (2) how can I adjust insulin dose, (3) when does the system revert to the open loop mode and why, and (4) where can the user/provider find education resources.36

The Cognitive Component: Understanding the Impact of Technology

Youth using insulin pumps and their families report an improvement of their health-related quality of life;37 however, the burden of daily use of technology is not trivial. With sensor therapy, patients are faced with potentially frequent alarms as well as the wearability of devices, which can affect one's body image.38 This can undermine success of this technology. Technology does not yet hold the promise of a diabetes-free daily life, and setting realistic expectations for the users and their families is necessary to afford success.8

Conclusions

Technological advancements in the field of diabetes are changing the way this chronic medical condition is managed. Similar to devices used on a daily basis, the rate of innovation and development of more refined features is growing rapidly. As health care providers, it is essential to afford patients the opportunity to use these treatments. Measures beyond glycemic control, including the assessment of time in target range defined as 70 to 180 mg/dL, measures of hypoglycemia, glycemic variability, and quality of life, have been identified as critical components in assessing success in managing this lifelong condition. Technology may be the key to multifactorial success.

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Description of Currently Available Continuous Glucose Monitoring Devices

Device
Dexcom G6 (San Diego, CA) Eversense Senseonics (Germantown, MD) Abbott FreeStyle Libre (Lake Bluff, IL) Medtronic Guardian 3 (Dublin, Ireland)
Site of insertion Subcutaneous Implantable subcutaneous Subcutaneous Subcutaneous
Sensor type Blinded and real-time Real-time Blinded and intermittently scanned CGM Real-time
Sensor wear (days) 10 90a 14 7
Calibration (SMBG) Not requiredb 2 times per day Not requiredb 3–4 times per day
Customizable alerts Yes Yes No Yes
Approved for age (years)+ in the US ≥2 ≥18 ≥18 ≥7c
Connectivity with smartphone Yes Yes Yes Noc
Remote monitoring No No No Noc
MARD 9% 8.5% 9.4% 8.7%d

In-Loop Framework

Device

CSII SAP LGS pLGS HCLa

Integrated CGM No Yes Yes Yes Yes

Layout for insulin delivery
  Basal rate delivery setting Manual Manual Manual Manual Automated
  Manual meal bolus Yes Yes Yes Yes Yes
  Complex boluses (extended, splitted) Yes Yes Yes Yes No

Output for hypoglycemia None CGM alert Basal suspension at low-threshold valueb Basal suspension before low-threshold valueb Automated basal adaption to glucose target

Output for hyperglycemia None CGM alert CGM alert CGM alert Automated basal adaption to glucose target

Patient's individual settings to initialize the system
  Basal rate Yes Yes Yes Yes Yes
  Insulin-to-carbs ratio Yes Yes Yes Yes Yes
  Sensitivity factor Yes Yes Yes Yes No
  Time of active insulin Yes Yes Yes Yes Yes
  Target range Yes Yes Yes Yes Noc
  Target value No No No No Yesc
Authors

Alfonso Galderisi, MD, is a Postdoctoral Fellow in Pediatric Endocrinology. Jennifer L. Sherr, MD, PhD, is an Associate Professor in Pediatrics, Pediatric Endocrinology. Both authors are affiliated with the Yale School of Medicine.

Grant: This work was supported by the Juvenile Diabetes Research Foundation (5-ECR-2014-112-A-N), the 2016 International Society for Pediatric and Adolescent Diabetes Research Fellowship Program, and the 2017 Robert Leet Patterson and Clara Guthrie Patterson Trust Mentored Research Award.

Disclosure: Jennifer L. Sherr serves as a consultant to Medtronic Diabetes, Sanofi, and Lexicon; is on advisory boards for Bigfoot Biomedical, Eli Lilly, and Insulet; and has received research support from Medtronic Diabetes and Insulet. The remaining author has no relevant financial relationships to disclose.

Address correspondence to Jennifer L. Sherr, MD, PhD, Pediatric Endocrinology, Yale Pediatric Diabetes Center, Yale School of Medicine, One Long Wharf Drive, Suite 503, New Haven, CT 06510; email: jennifer.sherr@yale.edu.

10.3928/19382359-20190725-03

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