Continuous glucose monitor

Continuous glucose monitor
A continuous glucose monitor (CGM) is a device used for monitoring blood glucose on a continual basis by insulin-requiring people with diabetes, e.g. people with type I, type II diabetes or other types of diabetes (e.g. gestational diabetes). A continuous glucose monitor consists of three parts: a small electrode placed under the skin, a transmitter sending readings at regular intervals (ranging from every 1 to 15 min), and a separate receiver. Currently approved CGMs use an enzymatic technology which reacts with glucose molecules in the interstitial fluid generating an electric current. This electric current (proportional to the glucose concentration) is then relayed from a transmitter attached to the sensor out to a reader which displays the data to the patient.
Traditional fingerprick testing of blood glucose levels measures the level at a single point in time. CGM use allows trends in blood glucose to be displayed over time. Some CGM devices have to be periodically calibrated by users with traditional blood glucose measurements, while some do not require user calibration.
CGM is an increasingly adopted technology which has shown to have benefits for people with diabetes. Some studies have demonstrated reduced time spent in hypoglycemia or a lower glycated hemoglobin, both favorable outcomes. A Cochrane systematic review found that there is limited and conflicting evidence of the effectiveness of continuous glucose monitoring systems in children, adults or patients with poorly controlled diabetes. However, the use of continuous glucose monitors appears to lower hemoglobin A1c levels, more than just monitoring through capillary blood testing, particularly when used by individuals with poorly controlled diabetes together with an integrated insulin pump. However, there are important limitations: CGM systems are not sufficiently accurate for detecting hypoglycemia, a common side-effect of diabetes treatment. This is especially problematic as some devices offer alarm functions to warn of hypoglycemic episodes and people might rely on those alarms. Still, on the Cochrane systematic review mentioned above, the use of continuous glucose monitors did not increase the risk of hypoglycaemia or ketoacidosis. Some manufacturers warn users of relying only on CGM-measurements and the National Institute for Health and Care Excellence recommends to validate hypoglycaemic values via fingerprick testing of blood glucose level. Another limitation is that glucose levels are taken from the interstitial fluid rather than the blood. As it takes time for glucose to travel from the bloodstream into the interstitial fluid, there is an inherent lag behind the current blood glucose level and the level measured by the CGM. This lag time varies based on the person and the device, and is generally 5–20 minutes.
Flash glucose monitoring
The original Freestyle Libre monitor introduced by Abbott Diabetes Care in 2015 was described as doing "flash glucose monitoring," with a disposable 14-day sensor probe under the skin (as with other CGM sensors), but factory-calibrated without requiring calibration against a finger-stick glucose test. The sensor measures the glucose level of interstitial fluids (as a proxy for blood sugar levels) continuously; up to eight hours of these readings, averaged over each 15-minute period, are stored in the sensor unit, unlike most other CGM systems, which use a wireless link (typically Bluetooth) to an external device for each reading. Data stored in the sensor are transmitted on demand to a "reader" held within a centimeter or two of the sensor unit, employing near-field communication (NFC) technology. As only eight hours worth of data can be stored, downloads must not be spaced more than eight hours apart.
Differences in US insurance coverage favoring "flash glucose monitoring" over "continuous glucose monitoring" were an advantage to early adoption of Abbott's less expensive system. In the UK, flash glucose monitors and sensors are available to many patients without charge on the National Health Service (NHS).
The later Freestyle Libre 2 version of Abbott's device uses different, incompatible, sensors. It can be programmed to transmit a low blood sugar (hypoglycemia) or high sugar warning via Bluetooth to a nearby device and, as of 2023, transmits glucose readings via bluetooth on a 60-second basis effectively making a CGM and not a flash glucose monitor. The following Freestyle Libre 3 is smaller, and transmits its readings via Bluetooth, as other meters do; it is not described as flash monitoring.
History
United States
The first CGM system was approved by the FDA in 1999. Continued development has extended the length of time sensors can be worn, options for receiving and reading data, and settings for alerting users of high and low glucose levels.
The first iteration of the Medtronic MiniMed took glucose readings every ten seconds with average readings reported every five minutes. Sensors could be worn for up to 72 hours.
A second system, developed by Dexcom, was approved in 2006. The sensor was approved for use for up to 72 hours, and the receiver needed to be within five feet for transmission of data.
In 2008, the third model was approved, Abbott Laboratories' Freestyle Navigator. Sensors could be worn for up to five days.
In 2012, Dexcom released a new device that allowed for the sensor to be worn for seven days and had a transmission distance of 20 feet. Dexcom later introduced an app allowing data from the sensor to be transmitted to an iPhone. This system was approved for paediatric use in 2015.
In September 2017, the FDA approved the first CGM that does not require calibration with fingerstick measurement, the FreeStyle Libre. The Libre is considered a "flash monitoring" system (FGM), and thus not a true ("real-time") CGM system. This device could be worn for up to ten days, but required 12 hours to start readings. and was followed by an updated device that could be worn for up to 14 days, and needed only one hour to start a new sensor. The FreeStyle Libre 2 was approved in Europe in October 2018, and enabled configuration of alerts when glucose is out of range.
In June 2018, the FDA approved the Eversense CGM system (manufactured by Senseonics Inc) for use in people 18 years of age and older with diabetes. This is the first FDA-approved CGM to include a fully implantable sensor to detect glucose, which can be worn for up to 90 days. The Eversense XL, a 180-day version of the system, was approved in Europe in October 2017.
China
China develops and produces CGM systems. The first CGM system to be approved for the European Union is manufactured by Medtrum Technologies. The sensor's intended use is up to 14 days and measures glucose levels every 2 minutes via a smartphone application. Medtrum was founded in 2008 and is based in Shanghai, China.
At the end of 2017, Medtrum introduced the TouchCare A6 CGM (later A7 or Slim in some countries) which measures glucose levels in the interstitial fluid up to 14 days. The TouchCare system comes with mobile applications, including a remote view application. The TouchCare system has glucose alerts and requires calibration every 24 hours.
At the end of 2021 the Medtrum Nano was announced, a very slim device not requiring calibration, approved for up to 14 days use, with customisable glucose alerts.
Medtrum makes both CGM and insulin pumps, both controlled by a single smartphone application which enables the user to monitor glucose levels and trigger insulin delivery in a closed-loop system.
United Kingdom
UK NICE guidelines introduced for the NHS in March 2022 in England and Wales advise that all Type 1 diabetic patients should be offered either flash glucose monitoring or CGM. People with Type 2 diabetes should be offered flash glucose monitoring or CGM if they use insulin twice daily or more, are otherwise advised to finger-prick eight times a day, have recurrent or severe hypoglycaemia, have impaired hypoglycaemia awareness, or cannot monitor their own blood sugar levels but they or a carer could use a scanning device. Details differ in Scotland and Northern Ireland.
Device characteristics
Continuous vs flash monitoring: Dexcom, Eversense and Libre2 & 3 use continuous monitoring where information on the glucose levels are continuously updated. Continuous monitoring allows to set automatic alarms that are triggered when the glucose level goes out of pre-configured thresholds. In contrast, with flash monitoring such as the Freestyle Libre1, the glucose level is read automatically by the sensor; however, data is only transmitted to the user on user request. The glucose information store on the sensor contains all the data since the previous read (up to 8 hours). FreeStyle Libre 2 allows configuration of alarms when glucose reaches a pre-determined level.
Implantable sensors: Since the electronics and battery require a relatively large package, most CGM sensors are worn over the skin with the actual sensing probe penetrating the skin. However the Eversense sensor is an actual implant, and receives its power wirelessly from a so-called transmitter worn above the skin. The "transmitter" receives data from the sensor every 5 minutes and forwards that data to a nearby device wirelessly. However unlike the Freestyle Libre, the implanted device is too small to have its own battery and memory, so that no glucose readings are generated during periods in which the transmitter is not being worn. The transmitter must be removed at least once a day for recharging (10 minutes) and replacement of the adhesive.
Closed-loop system
The CGM is a key element in the development of a "closed-loop" system for the treatment of type I diabetes. A closed-loop system monitors blood glucose by CGM and sends data to an insulin pump for calculated delivery of insulin without user intervention. A number of insulin pumps currently offer an "auto mode" however this is not yet a fully closed loop system. There are several implementations, including the artificial pancreas system and the open source OpenAPS.
Emerging CGM technologies
The continuous glucose monitoring space remains subject to extensive research and development in building lower cost, more accurate and more easy-to-use sensing solutions, some of which aim to be noninvasive. A noninvasive CGM has been defined as a medical device that can measure glucose levels in the body without puncturing the skin, drawing blood or causing any pain.
As of August 2023, besides Dexcom and Abbott Diabetes, no other manufacturer has attained a significant market share worldwide. There have been regulatory approvals of noninvasive sensing systems in Europe, though market adoption has been low, not affecting the Abbott-Dexcom dominance.
Emerging invasive CGM technologies
Multiple invasive CGM solutions have been under development since the early 2000s.
Senseonics has commercialized its 180-day Eversense XL sensing systems in both the U.S. and European markets. In June 2023, it announced what it deemed favorable safety and accuracy data for its 365-day sensor, suggesting it may be commercializable in the future.
A solution built by U.S. firm GlySens, aimed to remove the need for an external reader by creating a sensor that could be implanted under the skin, that directly transmitted glucose values to an external app. As of August 2023, this undertaking has stalled and the system has not been approved anywhere and the company is defunct.
Another invasive CGM technology under development by Profusa Inc, based in Emeryville, California, builds on sensing research projects previously undertaken by the company under DARPA grants. This technology is composed of a hydrogel microsensor that is placed under the skin subcutaneously in a non-surgical procedure. In a 2020 literature review several biomedical engineers supported Profusa’s claims that the non-surgical insertion procedure differentiates it favorably from Senseonics’ Eversense system, as the latter requires a surgical procedure to insert and remove the sensor. The Profusa sensor allegedly also does not need to be removed because it overcomes the foreign body response. A reader is placed on the skin on top of where the sensor is, with the sensor transmitting a light signal to it. The sensor is claimed to last for three to six months. The is information then passed on to a smartphone where it can be tracked through an app. As of August 2023, this sensor has not attained regulatory approval in any jurisdiction, though a similar Profusa system measuring oxygen levels under the skin, has CE certification in Europe. Profusa has filed to go public via SPAC transaction.
A similar approach was under development by another California-based company called Metronom Health. This company has not released news releases, nor has any news covered any progress in terms of its research and development.
Emerging noninvasive CGM technologies
The ease of use many CGM users expect would be provided by a safe and accurate noninvasive device has led to significant innovation and research.
Noninvasive approaches can be divided into interstitial fluid-based, radio frequency-based or breath-based. Interstitial fluid-analyzing sensors either use a device to analyze fluid on the skin or under the skin by sending infrared lasers to detect glucose levels in fluid. Radio frequency devices go through the skin and may derive glucose level information from blood directly.
Apple has reportedly been working on a noninvasive CGM that it seeks to integrate into its Apple Watch. In March 2023 it was reported to have established proof-of-concept of a noninvasive CGM. Another company working on noninvasive CGM is Masimo, which sued Apple for patent infringement in this area in 2020. Masimo has also filed new patents through its subsidiary Cercacor (pending as of September 2023) covering a joint continuous glucose monitoring and pump-closed loop delivery system.
Samsung announced that it would be incorporating glucose monitoring with its smartwatch with a targeted release year of 2025. As of October 2023 the last update was in December 2022. It is not clear whether the watch will integrate readings from an external CGM such as Dexcom's or Abbott's, or work standalone. The company in 2020 published literature regarding a non-invasive method it had developed with MIT scientists to engage in continuous glucose monitoring using spectroscopy. The company has filed patents related to this technology.
SugarBeat, built by Nemaura Medical, is a wireless non-invasive blood glucose monitoring system using a disposable skin patch. The patch connects to a rechargeable transmitter which detects blood sugar and transfers the data to a mobile app every five minutes. The patch can be used for 24 hours. Electronic currents are used to draw interstitial fluid to the surface to analyse the glucose level. SugarBeat has achieved regulatory approval in Saudi Arabia and Europe, though market penetration rates remain very low. The company declared US$503,906 in revenue for the fiscal year ending March 2022, which compares to Dexcom's more than $3 billion. it had submitted a US FDA premarket approval application for sugarBEAT.
Another noninvasive system is built by US company Movano Health. It uses a small ring placed on the arm. Movano said in 2021 that it was building the smallest ever custom radio frequency (RF)-enabled sensor designed for simultaneous blood pressure and glucose monitoring. Movano is listed as MOVE on NASDAQ. By August 2023 Movano had shifted to building sensor rings for other parameters, such as heart rate, blood oxygen levels, respiration rate, skin temperature variability, and menstrual symptom tracking.
DiaMonTech AG is a Berlin, Germany-based privately-held company working on DTech, a CGM that uses infrared laser technology to scan the tissue fluid in the skin and detect glucose molecules. Short pulses of infrared light are sent to the skin, which are absorbed by the glucose molecules. This generates heat waves that are detected using its patented IRE-PTD method. The company claims a high selectivity of its method, but no evidence has been published.
BOYDsense, based in Toulouse, France, is developing a sensor that measures glucose in the breath through the detection of volatile organic compounds (VOCs), a large group of carbon-based molecules that are gaseous at room temperature. The system is in its preclinical development stage and has not received regulatory approval.
The BioXensor developed by British company BioRX uses patented radio frequency technology, alongside a multiple sensor (also capturing blood oxygen levels, ECG, respiration rate, heart rate and body temperature) approach. The company claims this enables the measurement of blood glucose levels every minute reliably, accurately, and non-invasively. BioXensor had not received regulatory approval .
Israeli company HAGAR completed a study of its GWave non-invasive CGM, reporting high accuracy. This sensor uses radiofrequency waves to measure glucose levels in the blood. The device had not received regulatory approval anywhere as of August 2023. One of the criticisms of radiofrequency technology as a way of measuring glucose is that studies in 2019 found that glucose can only be detected in the far infrared (nanometer wavelengths), rather than radiofrequencies even in the centimeter and millimeter wavelength range, putting into question the viability of radio frequencies for measuring glucose.
Glucomodicum is based in Helsinki, Finland. Their attempted solution uses interstitial fluid to non-invasively measure glucose levels continuously. It does not have regulatory approval.
KnowLabs is a U.S company building a CGM called the Bio-RFID sensor, which works by sending radio waves through the skin to measure molecular signatures in the blood, which Know Labs' machine learning algorithms use to compute the user's blood sugar levels. The company reported that it had built a prototype, but had not attained regulatory approval as of August 2023.
Spiden is a Swiss startup building a multi-biomarker and drug level monitoring noninvasive smartwatch wearable with continuous glucose monitoring capability as its first application. It has so far not attained regulatory approval as of October 2023.
References
Diabetes-related supplies and medical equipment
Medical devices