11/4/24, 6:55 PM https://emedicine.medscape.

com/article/2500145-print

emedicine.medscape.com

Continuous Glucose
Monitors/Hybrid Closed-Loop
Systems
Updated: May 02, 2024
Author: Satish K Garg, MD, MBBS, DM;

Overview
Since the 1990s, significant improvement has been seen in the development and implementation of insulin pumps,
continuous glucose monitors (CGMs), and hybrid closed-loop (HCL) systems.[1] The different technologies, used
independently or in combination, have improved glucose control, allowing patients to reduce their time above and below
appropriate glucose ranges.[2, 3, 4] These advances have also facilitated telehealth and virtual care worldwide, especially
during the coronavirus disease 2019 (COVID-19) pandemic.[5, 6, 7, 8, 9, 10, 11, 12, 13] However, while the adoption of
such technologies has improved in developed economies, their widespread use in emerging economies is still limited due to
barriers such as cost, knowledge gaps, and implementation challenges.[14, 15]

Indeed, although approximately 150-200 million people worldwide require insulin for optimal diabetes management, most
using multiple daily injections,[16, 17] a pre-2020 estimate indicated that less than 1% of these patients employ continuous
subcutaneous insulin infusion (CSII).[16, 18, 19]

Prevalence and cost of diabetes

Diabetes prevalence has increased worldwide, with more than 500 million people now living with the disease,[20] including
35-40 million in the United States.[21] This prevalence is higher in minority and socioeconomically disadvantaged
populations,[22, 23, 24, 25] but it is known that these groups do not receive the optimum diabetes care and are not offered
the same diabetes technologies.[26, 27, 28, 29] By 2017, the annual total cost of diabetes in the United States had grown
to $327 billion.[30]

Despite the development of new diabetes technologies and therapeutics,[31, 32, 33] the life expectancy of persons with
type 1 diabetes is 10-12 years below that of the general population.[34, 35, 36, 37]

Urine monitoring and self monitoring of blood glucose

Patients with diabetes previously monitored their glucose levels through urine analysis,[38] but during the 1980s, self
monitoring of blood glucose (SMBG) became available, allowing patients to test their glucose level via a finger stick.[38]
Blood was collected on a test strip and analyzed by an SMBG device, with SMBG coming to be considered the standard of
care in diabetes, especially for patients on insulin therapy.[39]

Continuous Glucose Monitors

CGMs use sensors to frequently measure interstitial glucose levels, typically providing alarms when glucose levels are too
high or too low or are rapidly rising or falling.[40] Data from the sensors, which are usually inserted subcutaneously or
implanted in the subcutaneous space,[41, 42] are displayed on a receiver, smartphone, or smartwatch.

CGM accuracy has increased significantly since the end of the 20th century.[43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,
55, 56] Indeed, most CGMs can now measure glucose values every 1-5 minutes,[57] and there have been improvements in
the precision of CGM data (with lowering of “the random noise component overlapped to the true glycemic signal”).[58]
CGM use has, in fact, seen a significant rise since 2010 due to advances in sensor size, accuracy, features, algorithms, and
connectability with insulin pumps and "smart" insulin pens.[59] (Launched in 2020, the first smart insulin pen with CGM
integration, Medtronic Diabetes’ InPen with Real-Time Guardian Connect CGM Data, allowed glucose readings and insulin
dose information to be viewed in the same app.[60] ) By 2022, there were more than 7 million CGM users worldwide.[61]

Current CGM manufacturers include Medtronic Diabetes (Northridge, CA), Dexcom Inc. (San Diego, CA), Abbott Diabetes
Care (Alameda, CA), and Senseonics Inc. (Germantown, MD).
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CGM use has been shown to increase time in range (TIR; the amount of time blood glucose levels for a person with diabetes
stay within a recommended target range), improve glucose control (A1c), and decrease episodes of diabetic ketoacidosis
and severe hypoglycemia. It can also help in the early detection of type 1 and type 2 diabetes.[62, 63, 64, 65, 66, 67]

A prospective, observational study by Charleer et al provided evidence that the use of real-time CGMs (rtCGMs) improves
glycemic control in persons with type 1 diabetes in whom such control has been insufficient. The study involved individuals
who had been using CSII therapy and then entered an rtCGM reimbursement program. The investigators found that overall
baseline HbA1c declined from 7.7% to, after participants had been in the program for 12 months, 7.4%, with the reduction
being greater in patients who had begun CGM use due to insufficient and variable glycemic control than in those who had
switched to CGMs owing to hypoglycemia or an ongoing or planned pregnancy. Moreover, while the rate at which patients
were admitted to the emergency room or hospital as a result of severe hypoglycemia and/or ketoacidosis was 16% in the
year prior to the start of rtCGM reimbursement, that figure dropped to 4% in the year after entry into the program.[68]

The first professional CGM, a Medtronic device in which glucose data were downloaded for review after 3 days, was
approved by the FDA in 1999.[69] In 2001, the GlucoWatch biographer (Cygnus Inc, Redwood City, CA) was approved. An
rtCGM, it displayed glucose data every 20 minutes for 12 hours by utilizing reverse iontophoresis, a process through which
the secretion of subcutaneous fluid could be stimulated, with the fluid's glucose being measured via an electrode.[43, 44, 70,
38]

The first transcutaneous CGM sensors were approved by the FDA to be worn for 3 days. In 2007, however, with FDA
approval of the Dexcom SEVEN, wear time was increased to 7 days.[71, 72] Transcutaneous CGM sensors can now often
be worn for 7-14 days.[72, 73]

In the past, CGMs required SMBG calibrations, but newer devices serve as standalone sources of clinical decisions.[43, 44,
45, 46, 47, 48, 49, 50, 51, 52, 55, 56] Indeed, in December 2016, the Dexcom G5 Mobile CGM system became the first
CGM to receive FDA approval for "non-adjunctive" use, which meant that the device could be used in place of, rather than
as an adjunct to, finger-stick blood glucose monitoring when decisions about insulin administration or the treatment of
hypoglycemia were being made.[74]

Approved by the FDA in 2018, Dexcom's G6 included compatibility with different insulin pumps, as well as blood glucose
monitors and other electronic diabetes management devices, becoming the first CGM to be approved for such
interoperability.[75, 76] An interoperable CGM (iCGM) designation, as outlined by the FDA, requires a lower mean absolute
relative difference (MARD), with accuracy being great in devices having reduced MARD values. In addition, paracetamol
and/or vitamin C, which can falsely increase glucose readings, must not interfere with the iCGM's measurements.[77]

CGM manufacturers are working on developing CGMs that can take continuous ketone and/or lactate measurements
through the same device as a means of reducing the likelihood of diabetic ketoacidosis.[78]

Flash glucose monitors

In 2014, a 14-day factory-calibrated CGM, called the FreeStyle Libre, was approved in Europe.[79] The FreeStyle Libre
represented the first “flash” glucose monitoring technology. Instead of transmitting data automatically from a wearable sensor
to a receiver or smartphone, the FreeStyle Libre allowed information to be accessed when the patient scanned a dedicated
receiver or smartphone over the sensor. As such, it was classified as an intermittently scanned CGM rather than an rtCGM.
[40, 80, 81]

The Libre 2 includes hypoglycemic and hyperglycemic alerts,[82, 83] and the Libre 3 is an rtCGM in which the data are
displayed every minute on a smartphone only.[84] The Libre 3 is an interoperable CGM. In 2023, modified versions of the
Libre 2 and 3 were FDA-approved for use with automated insulin delivery (AID) systems (discussed below).[85]

Implantable sensors

While transcutaneous CGM sensors are inserted by the patients themselves, a minor surgical procedure is required to insert
and remove an implantable sensor, which is placed subcutaneously in the upper arm.[73]

In the early 2000s, Dexcom investigated an implantable sensor that was the size of an AA battery. However, the sensor had
high MARD values due to foreign body reactions.[46] The studies were discontinued early, and it was never filed for FDA
approval. In 2018, the Eversense CGM, the first CGM with an implantable sensor, was approved for 90-day use by the FDA.
[86, 87] In 2022, the FDA approved the Eversense E3 CGM implantable sensor for 180-day use.[88] In 2024, the FDA
approved it as the first implantable CGM to be used in an AID.[89]

CGMs in type 2 diabetes

Although the use of CGMs has primarily been aimed at persons with type 1 diabetes, the devices have come to increasingly
be employed in type 2 diabetes.[90] For example, the CGM device sugarBEAT (Nemaura Medical; Loughborough, UK) was
developed specifically for individuals with type 2 diabetes, being produced for such patients who are not at high risk for
hypoglycemia; it can also be utilized in persons with prediabetes. The sugarBEAT CGM uses an adhesive patch and sensor,
drawing glucose molecules from the interstitial fluid just beneath the skin’s surface for measurement. A Bluetooth connection
is employed to transmit data every 5 minutes to a smartphone app. The device is worn for 14 hours at a time during the day
and for just 2-4 days monthly. Although sugarBEAT is noninvasive, a once-daily fingerstick is still needed for calibration.

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In May 2019, it received a CE (Conformité Européenne) Mark in Europe for use as a class IIb medical device. Although still
awaiting FDA approval in the United States, permission has in the meantime been granted for this CGM to be marketed as a
“wellness” device, with sugarBEAT in this capacity producing retroactive reports for the physician and patient rather than
real-time values.[91]

Insulin Pumps and Artificial Pancreases

Insulin pumps

In normal, healthy individuals, glucose levels are tightly regulated via continuous delivery of insulin, resulting from the ability
of beta cells in the pancreas to sense glucose values. CSII through insulin pumps attempts to mimic this physiology,[92] with
intensive insulin therapy improving glycemic control and significantly reducing microvascular and macrovascular
complications of insulin-dependent diabetes.[93]

Insulin pumps typically include the pump itself, which is about the size of a small cell phone and contains an insulin reservoir;
a small catheter inserted into the patient’s subcutaneous tissue; and tubing that delivers insulin from the pump to the
catheter. The pump can be worn in various locations, such as under the clothing or on a belt. Tubeless pumps, also known
as patch pumps, are available as well; with these, a small pump/reservoir is attached to the skin with adhesive and
connected directly to the catheter, with no tubing in between. Insulin delivery via a patch pump is programmed through a
handheld device.[94, 95]

Currently, there are three main manufacturers of insulin pumps in the United States: Medtronic Diabetes, Tandem Diabetes
Care (San Diego, CA), and Insulet Corporation (Acton, MA).

The first insulin pump was developed by Kadish in 1963, as part of a large, portable closed-loop system (as discussed
below). Owing to its size, however, the system was not practical for daily use and garnered little attention.[96] In 1974, Miles
Laboratories (Elkhart, IN) developed the Biostator, the first commercial inpatient insulin pump (also in a closed-loop system),
[97, 98] while in 1976 Kamon created the first portable autosyringe insulin pump.[96] Like Kadish's device, however, these
pumps were bulky and complex, making them infeasible for outpatient use.

In 1983, the MiniMed 502, from MiniMed Inc., was introduced.[99, 100] (The company was later acquired by Medtronic.)
Many versions of this product have since been produced, with the pumps improving glucose trend tracking and thus helping
users administer insulin corrections and understand what contributed to fluctuations in insulin values.[101]

Insulet released the first tubeless pump, the OmniPod Insulin Management System, in 2011.[102, 99] Tandem released the
t:slim Insulin Delivery System, the first touch-screen insulin pump available in the United States, in 2012.[103]

Over time, insulin pumps have evolved to receive wireless transmission of glucose values from a CGM and to have
programmable delivery patterns and remote control capabilities.

Hybrid closed-loop systems

With insulin delivery devices and CGMs having come a long way, it became obvious that they could be integrated into what
are now commonly known as hybrid closed-loop (HCL) systems, or so-called artificial pancreases, using an algorithm to
automatically start or stop insulin delivery. Unliked a fully closed-loop system, an HCL still requires patients to determine the
number of carbohydrates in their food and input that data into the system, manually requesting the insulin dose needed for
meals.[104]

In 2006, the MiniMed Paradigm REAL-Time system 515 displayed glucose values on the insulin pump.[105] MiniMed
Paradigm Veo featured “low-glucose suspend” (LGS), which stopped insulin delivery if the user reached a preset low (40-110
mg/dL).[106] It was released internationally in 2009 but was not approved in the United States. In 2013, however,
Medtronic's MiniMed 530G received FDA approval. Featuring “threshold suspend” (TS), it suspended insulin delivery when
the sensor's glucose value was between 60-90 mg/dL.[107] Use of TS reduced nocturnal hypoglycemic events by 37.5%
(ASPIRE [Automation to Simulate Pancreatic Insulin REsponse] In-Home study).[108] The 640G, which was launched in
2015 but was not approved in the United States, included "predicted LGS" (PLGS).[109] The PLGS system predicted
hypoglycemia within 20 mg/dL of the preset range and stopped insulin delivery 30 minutes before the threshold.[110]

The first true HCL system was the Medtronic MiniMed 670G system, approved in the United States in 2016.[111, 112, 113]
This system also included a PLGS function. In addition, it featured AID for hyperglycemia[114] and adjusted the basal
insulin delivery based on a proportional integral derivative (PID) algorithm.[115] In a single-arm registration study, the 670G
system was shown to significantly reduce hypoglycemia in patients with type 1 diabetes.[112, 116] However, the system
required frequent calibrations (as a safety mechanism), especially when there were periods of minimum and maximum
insulin delivery. Although initially the 670G was well accepted by patients with type 1 diabetes, due to the repeated need for
calibrations and multiple alarms, many patients discontinued the system.[117]

The 780G system, commonly referred to as an advanced HCL (AHCL) system, has gained favor with patients because it
does not require frequent calibrations and is able to automatically bolus insulin every 5 minutes in the event of unanticipated
hyperglycemia.[118] It has been available in Europe since 2020 and was approved in the United States in April 2023.[119,

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120, 121, 122] The early registration studies on 780G showed significant improvement in TIR, with a reduction in
hypoglycemia, especially nocturnally;[123] many real-world studies have confirmed the registration study data.[124, 125]

Tandem’s t:slim X2 device, approved by the FDA in 2019, was the first so-called alternate controller-enabled (ACE) infusion
pump, which meant that it was designed to be interoperable with any compatible CGM, blood glucose monitor, or automated
insulin dosing system. As a result, in contrast to the MiniMed 670G HCL, in which the insulin pump is compatible only with a
Medtronic CGM using the company’s own Guardian Sensor 3, the t:slim X2 is compatible with the Dexcom G6.[126]
The t:slim X2 pump utilizes a model predictive control (MPC) algorithm, which calculates insulin delivery by reducing "the
difference between model-predicted glucose concentrations and target glucose over a pre-specified prediction time horizon."
[127, 128, 115]

The t:slim X2 has an automatic glucose suspend feature that stops insulin delivery if the sensor glucose value is less than 70
mg/dL.{ref110) Additionally, it includes a PLGS feature that interrupts delivery if glucose values are expected to fall below 80
mg/dL in 30 minutes.[129] The Control-IQ version of this pump corrects predicted hyperglycemia (>180 mg/dL) by
automatically delivering a correction bolus every hour and adjusts basal insulin delivery to maintain glucose values between
112-160 mg/dL.[130]

In 2022, Insulet's OmniPod 5 was approved by the FDA, becoming the first HCL system to feature a tubeless insulin pump.
[131, 132] This system employs an MPC algorithm similar to that of the t:slim X2. In a single-arm study, use of the OmniPod
5 was shown to produce an increase in TIR in addition to a reduction in hypoglycemia.[133, 134]

The HCL systems sold in the United States by all three of the above companies are associated with increased TIR, with
reduction in hypoglycemia.[135, 136, 137] In addition, HCL systems allow higher glucose thresholds for patients during
exercise.[111, 112, 119, 138] None of the systems have been approved for use in pregnant individuals with diabetes.[139]
However, off-label use has shown significant improvement in glycemia and maternal and fetal outcomes in pregnant patients
with type 1 diabetes.[140, 141]

Next steps

Efforts are underway to make a true artificial pancreas, which, using a combination of insulin and glucagon, would mimic
normal beta-cell function.[142] Another aim, in order to better control post-prandial glucose levels, is to develop an artificial
pancreas employing pramlintide with insulin.[143, 144, 145, 146, 147]

In 2023, researchers from the University of Cambridge reported on the successful trial of a fully closed-loop artificial
pancreas for patients with type 2 diabetes. The device used an off-the-shelf glucose monitor and insulin pump, which were
combined with an app, CamAPS HX, designed by the investigators to predict insulin requirements. In this way, the artificial
pancreas functioned independently, without needing input from the patient. Employing a glucose target range of 3.9-10.0
mmol/L, the trial demonstrated that patients using the closed-loop device remained in the target range 66.3% of the time,
compared with 32.3% of the time for patients on standard therapy.[148, 149]

Contributor Information and Disclosures

Author

Satish K Garg, MD, MBBS, DM Professor, Departments of Medicine and Pediatrics, Barbara Davis Center for Childhood
Diabetes, Director of Adult Diabetes Program, Garg Endowed Clinical and Research Chairs, University of Colorado Denver
School of Medicine; Editor-in-Chief, Diabetes Technology and Therapeutics

Satish K Garg, MD, MBBS, DM is a member of the following medical societies: American Association of Clinical
Endocrinology, American Diabetes Association, Association of Physicians of India, Diabetic Association of India, Endocrine
Society, European Association for the Study of Diabetes, Geriatric Society of India, Indian Society for Atherosclerosis
Research, International Diabetes Federation, Pediatric Endocrine Society, Research Society for the Study of Diabetes in
India

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Eli Lilly and Company, Novo-
nordisk, Medtronic, Dexcom, Lifescan, and Bayer <br/>Received research grant from: Eli Lilly, Dexcom, Dario, JDRF, T1D
Exchange, Jaeb Center, Medtronic, .

Coauthor(s)

Erika Rodriguez, MS, BA Clinical Research Assistant, Barbara Davis Center for Childhood Diabetes, University of Colorado
Denver School of Medicine

Disclosure: Nothing to disclose.

Abdulhalim Muidh Almurashi, MD Diabetes and Family Medicine Consultant, Fellow in Diabetes Technology, Barbara
Davis Center for Childhood Diabetes, University of Colorado Denver School of Medicine

Abdulhalim Muidh Almurashi, MD is a member of the following medical societies: American Diabetes Association, Saudi

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Scientific Diabetes Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-
in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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