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“Newer Continuous Glucose Monitoring Systems”

Satish K. Garg, MD

Professor of Medicine and Pediatrics, Director of adult Diabetes program,

University of Colorado Denver and Barbara Davis Center for Diabetes, Aurora, Colorado.

Over the past decade there have been many advances in diabetes technologies, such as Continuous Glucose Monitoring devices/systems (CGMs), insulin-delivery devices, and hybrid closed-loop systems. There have been significant advances in CGMs in the past decade. In fact, ten years ago very few people use to believe in the use of CGMs, even though they had been available for the past two decades. Many providers used to question who, why, and when will patients ever use CGMs similar to the questions asked about Self-Monitoring of Blood Glucose (SMBG) about four decades ago. At the time of this writing, more than five million people world-wide are using a CGM for their diabetes management, especially those who require insulin (all patients with Type 1 diabetes (T1D) and about 20% of patients with Type 2 diabetes (T2D)). Total sales of all CGMs now exceeds more than $7 billion and the use of SMBG is going down every day.

Most of the CGMs have improved their accuracy significantly in the past two decades. I still remember doing studies on the GlucoWatch and earlier versions of Dexcom STS where mean absolute relative difference (MARD) used to be in the range of 15-26%. Now most of the CGMs (Guardian by Medtronic, G6 by Dexcom, and Libre 2 by Abbott) have single-digit MARD. In addition, the majority of the new CGMs do not require calibrations and the newer CGMs last for 10-14 days. An implantable CGM by Senseonics (Eversense®) is approved in the USA for 3 months and a different version is approved in Europe for 6 months. FDA has still not approved the 6-month version of Eversense® implantable sensor in the USA, which also has single-digit accuracy.

The newer CGMs that are likely to be launched in the next 3-6 months; hopefully around the ATTD Conference, include 10.5-day Dexcom G7 (60% smaller than the existing G6), 7-day Medtronic Guardian 4, 14-day Libre 3, and 6-month Eversense®. Most of the newer CGM data can be viewed on Android or iOS/iPhone smart devices, and in many instances they have several features like predictive alarms and alerts, easy insertion, automatic initialization (in some instances down to 27 mins, Dexcom G7) with single-digit MARDs. It has also been noticed that arm insertion site might have better accuracy than abdomen or other sites like the buttock for kids. Lag time between YSI and different sensors have been reported differently, sometimes it’s down to 2-3 mins; however, in many instances, it’s still 15-20 mins.

Diabetes effects communities of color disproportionately higher. For example, the highest prevalence of diabetes in the USA is amongst Native Americans (14.7%), which is nearly two times higher than Caucasians. African Americans and Hispanics also have higher prevalence of diabetes in the USA. It’s also known that LatinX, African Americans, and Native Americans are much less likely to be offered new technologies like continuous subcutaneous insulin infusion (CSII/insulin pumps) and CGMs. Use of technology, especially CGMs, is expected to remove many of the social barriers and disparities in care for people with diabetes. A large database during the COVID-19 pandemic recently reported better Time-in-Range (TIR) in patients with diabetes irrespective of their ethnic background. However, the baseline TIR was significantly lower for minorities as compared to Caucasians.

I believe the future will bring a larger increase in the use of CGMs for people with insulin-requiring diabetes (estimated at more than 100 million people globally) and those with T2D on non-insulin therapies (estimated at more than 400 million people globally). I also envision an increase in the number of pre-diabetes patients (estimated at more than 200 million people globally) using CGMs so that early medical intervention for diabetes management can be entertained. The intermittent or continuous use of CGM would depend upon the clinical needs. Needless to say, healthy individuals without diabetes (who can afford CGMs) might even use these technologies for self-evaluation of their glucose profiles after meals.

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Living with type 1 diabetes (T1D) is challenging as it requires intensive monitoring of glucose levels, nutritional intake and physical activity, and correct titration of insulin in order to obtain near-normal glucose levels. The Endocrine Society has proposed real-time continuous glucose monitoring (RT-CGM) as the gold standard for people with T1D. RT-CGM devices display interstitial glucose levels around the clock and are designed to set off alarms to warn people when glucose levels are trending too high or too low. The evolution in pump and CGM technology has led to the development of hybrid closed loop (HCL) systems where basal insulin delivery is automatically guided by sensor glucose values using an algorithm. CGM and HCL systems have demonstrated improvements in HbA1c, time spent in hypoglycaemia, hospitalisations for severe hypoglycaemia or ketoacidosis, and quality of life. However, there are still some shortcomings with currently available CGM devices.

Firstly, currently available sensors rely entirely on continuous glucose measurements and do not provide an alert for high ketone levels or impending diabetic ketoacidosis (DKA). Monitoring ketones is also advised for sick-day management, but in reality many at-risk patients do not have ketone test strips at home. Production of ketone bodies may occur as a result of insulin deficiency (e.g. in case of pump failure or inadequate bolus dosing), sickness, insufficient intake of carbohydrates (very low calorie diet), or sodium-glucose co-transporter-2 inhibitors (SGLT2-i) therapy. Continuous ketone monitoring (CKM) may facilitate earlier detection of ketones, thereby possibly reducing hospitalisations for DKA in high-risk patients.

The first-in-human results obtained in 12 volunteers of a CKM device were published in 2021 by Alva et al. The electrochemical sensor used wired enzyme to measure β-hydroxybutyrate (BHB), the major pathologic analyte. This sensor delivered a linear response over the 0-8 mM range with good accuracy and stability, both in vitro and in vivo, for 14 days. With a single retrospective calibration the mean absolute difference (MAD) for BHB concentrations <1.5 mM was 0.129 mM and 91.7% of the sensor results were within ±0.3 mM of the reference. For BHB ≥1.5mM the mean absolute relative difference (MARD) was 14.4%.

Teymouran et al. reported data of a new real-time CKM microneedle platform based on the electrochemical monitoring of BHB alongside with glucose. This sensor detects BHB based on the NAD-dependent dehydrogenase enzyme and a selective low-potential fouling-free anodic detection of NADH using an ionic liquid-based carbon paste transducer electrode. In vitro data showed that the sensor had a high sensitivity (with low detection limit, 50 µM), high selectivity in the presence of potential interferences, along with good stability. The BHB microneedle sensor has been coupled with an oxidase-based glucose microneedle sensor on the same array platform, leading to an attractive sensor array towards the simultaneous real-time continuous monitoring of both glucose and ketones. The ability to detect lactacte has also been demonstrated based on lactate oxidase catalyzed lactate oxidation to pyruvate.

A third sensor that has been developed by Indigo Diabetes nv is an implantable continuous multimetabolite sensor monitoring glucose, BHB, and lactate using near-infrared (NIR) spectroscopy technology with an expected lifetime of 2 years. In a first-in-man study, exploratory data on accuracy were promising (95.6 % of all data points for glucose ranging between 40-400 mg/dl were located in zone A, a MAD of 10.5 mg/dl for values between 40 and 70 mg/dl and a MARD of 10% for values between 70-180 mg/dl and of 4% for values >180 mg/dl were observed). Administration of paracetamol, acetylsalicylic acid, ibuprofen, sorbitol, caffeine, fructose, aspartame and vitamin C did not significantly influence the accuracy of glucose measurements. Also for BHB good accuracy was observed. Continuous measurement of ketones was compared to blood strip measurements over a physiological range of 0-4 mM; the sensor showed a MAD of 0.19 mM. The lactate concentrations measured over a range of 0-20 mM showed an MAD of 0.53 mM in relation to Biosen EKF reference measurements in blood.

A second area of concern relates to the design of current sensors, patient’s experiences and costs. The short sensor lifespan, the likelihood of accidental sensor dislocation, the occurrence of skin reactions, and privacy reasons (keep their diabetes hidden), limit the implementation of these sensors.

The Indigo Diabetes nv sensor is a miniaturized near-infrared spectrometer on a silicon photonics chip that measures optical transmittance in the interstitial fluid at up to 24 wavelengths between 1680 and 2400 nm. The sensor is covered by a biocompatible silicone envelope. It is implanted subcutaneously in the abdominal region and has an expected lifespan of 2 years or more.

In summary, there is a compelling need for a patient tailored device that is implantable, has a long lifespan and continuously monitors multiple biomarkers thereby helping to prevent episodes of hypoglycaemia or ketoacidosis under all circumstances (exercise, illness, SGLT2i therapy, very low carb diet), and possibly increasing quality of life.