Accuracy of a 14-Day Factory-Calibrated Continuous Glucose Monitoring System With Advanced Algorithm in Pediatric and Adult Population With Diabetes.

BACKGROUND: In this study, we evaluated the analytical performance of the second-generation factory-calibrated FreeStyle Libre Flash Glucose Monitoring (FreeStyle Libre 2) System compared to plasma venous blood glucose reference, Yellow Springs Instrument 2300 (YSI). METHODS: The study enrolled participants aged four and above with type 1 or type 2 diabetes at seven sites in the United States. Adult participants (18+ years) participated in three in-clinic sessions and pediatric participants (4-17 years) participated in up to two in-clinic sessions stratified to provide data for days 1, 2, 3, 7, 8, 9, 12, 13, or 14 of sensor wear. Participants aged 11+ underwent supervised glycemic manipulation during in-clinic sessions to achieve glucose levels across the measurement range of the System. Performance evaluation included accuracy measures such as the proportion of continuous glucose monitoring (CGM) values that were within ±20% or ±20 mg/dL of reference glucose values, and bias measures such as the mean absolute relative difference (MARD) between CGM and reference values. RESULTS: Data from the 144 adults and 129 pediatric participants were analyzed. Percent of sensor results within ±20%/20 mg/dL of YSI reference were 93.2% and 92.1%, and MARD was 9.2% and 9.7% for the adults and pediatric participants, respectively. The System performed well in the hypoglycemic range, with 94.3% of the results for the adult population and 96.1% of the data for pediatric population being within 15 mg/dL of the YSI reference. The time lag was 2.4 ± 4.6 minutes for adults and 2.1 ± 5.0 minutes for pediatrics. CONCLUSIONS: The System demonstrated improved analytical accuracy performance across the dynamic range during the 14-day sensor wear period as compared to the previous-generation device.NCT#: NCT03607448 and NCT03820050.

Use of a diabetes-specific nutritional shake to replace a daily breakfast and afternoon snack improves glycemic responses assessed by continuous glucose monitoring in people with type 2 diabetes: a randomized clinical pilot study.

INTRODUCTION: This pilot study evaluated the impact of a diabetes-specific nutritional shake (DSNS) used twice daily by people with type 2 diabetes (T2D) on glycemic response assessed by continuous glucose monitoring (CGM). RESEARCH DESIGN AND METHODS: Adults (n=81) with T2D managed by oral medications were studied in a randomized, open-label, three-group parallel study design. The study was conducted in two phases over 14 days: Baseline (days 1-6), during which study participants consumed their habitual self-selected diets (SSD), followed by the Intervention (days 7-14), during which participants were randomized as follows: (1) SSD group received no study product (n=32); (2) DSNS breakfast/afternoon snack (Bkfst/AS) group consumed one DSNS as a breakfast meal replacement and a second to replace their mid-afternoon snack (n=24); (3) DSNS breakfast/prebed snack (Bkfst/PBS) group consumed one DSNS as a breakfast meal replacement and added a second as a prebed snack (n=25). Glucose was assessed by CGM throughout the study. Additionally, participants were asked about snacking behaviors, cravings, and other questions related to the use of DSNS as meal replacements and snacks. RESULTS: All groups reduced their postprandial glycemic response (positive area under the curve (pAUC, mg/min*dL-1)) and adjusted peak value (mg/dL) when compared with the baseline phase. Participants consuming DSNS in place of their usual breakfast showed greater reductions in pAUC compared with the SSD group (p=0.008) for the DSNS Bkfst/AS group with a trend (p=0.069) for the DSNS Bkfst/PBS group. Adjusted peak value showed greater reductions in both DSNS groups as compared with the SSD group (p=0.002 for DSNS Bkfst/AS and p=0.010 for DSNS Bkfst/PBS). Nocturnal glucose variability was significantly decreased during the intervention phase compared with baseline phase in the DSNS Bkfst/AS group (p=0.020), with no significant differences between groups. After intervention, the DSNS Bkfst/AS group had a significantly lower percentage of participants (17%) reporting cravings for starchy meals/sides compared with before the study (33%) (p=0.046). This group also reported a significant increase in confidence in choosing foods to control their diabetes (from 58.3% to 91.7%, preintervention vs postintervention, respectively, p=0.005). CONCLUSIONS: Use of DSNS to replace breakfast and as an afternoon snack improves both glycemic control and behavioral factors related to dietary management of diabetes. TRAIL REGISTRATION NUMBER: NCT04230889.

Feasibility of Factory Calibration for Subcutaneous Glucose Sensors in Subjects With Diabetes.

BACKGROUND: Continuous glucose monitoring using subcutaneously inserted sensors currently requires blood glucose tests for sensor calibration. Alternatively, sensors precalibrated during the manufacturing process may eliminate the need for fingerstick calibrations. In this study we evaluated the feasibility of sensor factory calibration in subjects with diabetes. METHODS: A total of 33 subjects with diabetes were asked to wear 4 sensors in parallel, 2 on the arm and 2 on the abdomen. Sensors from a lot with low in vitro sensitivity coefficient of variation were used in the study. Based on frequent capillary blood glucose measurements, the average glucose sensitivity of each sensor was determined over a 5-day wear time. The in vivo sensitivities were analyzed for inter- and intrasubject variation. Mean absolute relative difference (MARD) calculation and consensus error grid analysis (EGA) were performed using a single calibration factor for all sensors, to simulate factory calibration and compared against conventional finger-stick calibration. RESULTS: The sensitivity coefficient of variation between sensors increased from 2.9% in vitro to 6.0% in vivo. No difference in sensor response between subjects (P = .069) as well as between insertion sites (arm and abdomen) was detected (P = .104). Applying one calibration factor to all sensors in the study resulted in an MARD of 13.4%, and 83.5% of the values fell in consensus EGA zone A. Multiple fingerstick calibration resulted in an MARD of 12.7% and 84.1% in zone A. CONCLUSIONS: Feasibility of factory calibration was demonstrated in subjects with diabetes using sensors based on "wired enzyme" technology, resulting in accuracy metrics similar to sensors calibrated with capillary blood glucose.

Continuous glucose monitoring in the subcutaneous tissue over a 14-day sensor wear period.

BACKGROUND: Glucose monitoring systems using subcutaneously inserted sensors are currently labeled for up to 7 days of wear. In this study, we evaluated the feasibility of a 14-day wear duration using a modified version of the sensor found in the Freestyle Navigator™ continuous glucose monitoring system. METHODS: Sixty-two subjects with diabetes were enrolled in the study. One sensor per subject was inserted on the arm for a wear time of 14 days. Two different calibration algorithms were applied retrospectively, one that uses periodic sensor recalibrations and one without recalibrations. Sensor in vivo stability was determined by least square regression analysis using capillary blood glucose. Mean absolute relative difference (MARD) and mean relative difference were calculated. Consensus error grid analysis was performed by day and over the 14-day wear period to evaluate accuracy of both systems. The sensor insertion sites were inspected after sensor removal for skin reactions. RESULTS: Sensor data from 55 subjects were used for the analysis. The accuracy metrics for the system with recalibration were calculated to MARD = 13.9% and 84.0% in zone A (error grid analysis). The system without recalibration performed significantly better, resulting in MARD of 12.2% and 88.0% in zone A (p < .0001). The maximum change of in vivo sensor sensitivity over the 14-day wear period was 2% per day. Two subjects reported pain during the first 5 days of sensor wear, and 1 subject reported itching at the sensor site. No further skin reactions were noticed. CONCLUSIONS: The study shows that a 14-day sensor wear period is achievable. Moreover, sensors using "wired enzyme" technology showed excellent in vivo stability, with no significant sensitivity loss over the 14-day wear period.

Clinical implications and economic impact of accuracy differences among commercially available blood glucose monitoring systems.

BACKGROUND: Despite accuracy standards, there are performance differences among commercially available blood glucose monitoring (BGM) systems. The objective of this analysis was to assess the potential clinical and economic impact of accuracy differences of various BGM systems using a modeling approach. METHODS: We simulated additional risk of hypoglycemia due to blood glucose (BG) measurement errors of five different BGM systems based on results of a real-world accuracy study, while retaining other sources of glycemic variability. Using data from published literature, we estimated an annual additional number of required medical interventions as a result of hypoglycemia. We based our calculations on patients with type 1 diabetes mellitus (T1DM) and T2DM requiring multiple daily injections (MDIs) of insulin in a U.S. health care system. We estimated additional costs attributable to treatment of severe hypoglycemic episodes resulting from BG measurement errors. RESULTS: Results from our model predict an annual difference of approximately 296,000 severe hypoglycemic episodes from BG measurement errors for T1DM (105,000 for T2DM MDI) patients for the estimated U.S. population of 958,800 T1DM and 1,353,600 T2DM MDI patients, using the least accurate BGM system versus patients using the most accurate system in a U.S. health care system. This resulted in additional direct costs of approximately $339 million for T1DM and approximately $121 million for T2DM MDI patients per year. CONCLUSION: Our analysis shows that error patterns over the operating range of BGM meter may lead to relevant clinical and economic outcome differences that may not be reflected in a common accuracy metric or standard. Further research is necessary to validate the findings of this model-based approach.

Overnight closed-loop insulin delivery with model predictive control: assessment of hypoglycemia and hyperglycemia risk using simulation studies.

BACKGROUND: Hypoglycemia and hyperglycemia during closed-loop insulin delivery based on subcutaneous (SC) glucose sensing may arise due to (1) overdosing and underdosing of insulin by control algorithm and (2) difference between plasma glucose (PG) and sensor glucose, which may be transient (kinetics origin and sensor artifacts) or persistent (calibration error [CE]). Using in silico testing, we assessed hypoglycemia and hyperglycemia incidence during over-night closed loop. Additionally, a comparison was made against incidence observed experimentally during open-loop single-night in-clinic studies in young people with type 1 diabetes mellitus (T1DM) treated by continuous SC insulin infusion. METHODS: Simulation environment comprising 18 virtual subjects with T1DM was used to simulate overnight closed-loop study with a model predictive control (MPC) algorithm. A 15 h experiment started at 17:00 and ended at 08:00 the next day. Closed loop commenced at 21:00 and continued for 11 h. At 18:00, protocol included meal (50 g carbohydrates) accompanied by prandial insulin. The MPC algorithm advised on insulin infusion every 15 min. Sensor glucose was obtained by combining model-calculated noise-free interstitial glucose with experimentally derived transient and persistent sensor artifacts associated with FreeStyle Navigator (FSN). Transient artifacts were obtained from FSN sensor pairs worn by 58 subjects with T1DM over 194 nighttime periods. Persistent difference due to FSN CE was quantified from 585 FSN sensor insertions, yielding 1421 calibration sessions from 248 subjects with diabetes. RESULTS: Episodes of severe (PG < or = 36 mg/dl) and significant (PG < or = 45 mg/dl) hypoglycemia and significant hyperglycemia (PG > or = 300 mg/dl) were extracted from 18,000 simulated closed-loop nights. Severe hypoglycemia was not observed when FSN CE was less than 45%. Hypoglycemia and hyperglycemia incidence during open loop was assessed from 21 overnight studies in 17 young subjects with T1DM (8 males; 13.5 +/- 3.6 years of age; body mass index 21.0 +/- 4.0 kg/m2; duration diabetes 6.4 +/- 4.1 years; hemoglobin A1c 8.5% +/- 1.8%; mean +/- standard deviation) participating in the Artificial Pancreas Project at Cambridge. Severe and significant hypoglycemia during simulated closed loop occurred 0.75 and 17.11 times per 100 person years compared to 1739 and 3479 times per 100 person years during experimental open loop, respectively. Significant hyperglycemia during closed loop and open loop occurred 75 and 15,654 times per 100 person years, respectively. CONCLUSIONS: The incidence of severe and significant hypoglycemia reduced 2300- and 200-fold, respectively, during stimulated overnight closed loop with MPC compared to that observed during open-loop overnight clinical studies in young subjects with T1DM. Hyperglycemia was 200 times less likely. Overnight closed loop with the FSN and the MPC algorithm is expected to reduce substantially the risk of hypoglycemia and hyperglycemia.