John J. Mastrototaro

The MiniMed continuous glucose monitoring system.

S-13 DIABETES is a major source of morbidity, mortality, and economic expense. All patients with type 1 diabetes and an estimated 3–4 million patients in the United States with type 2 diabetes must take insulin to control their glucose levels. The majority of these patients selfmonitor their blood glucose one or more times each day, using fingerstick blood sampling and analysis with a portable glucose meter device. Approximately 200,000 type 1 diabetes patients in the United States practice intensive insulin therapy, requiring four or more blood glucose measurements each day coupled with either multiple daily injections of insulin or an insulin pump. The Diabetes Control and Complications Trial (DCCT) clearly demonstrated the importance of frequent self-monitoring of blood glucose (SMBG) in attaining tight glycemic control.1 Patients undergoing intensive therapy had a 39–76% reduced occurrence of long-term complications as compared to patients treated with conventional therapy. The primary drawback of intensive therapy was a threefold increase in the occurrence of severe hypoglycemia, despite performing four or more SMBG tests per day. Consequently, methods to improve the ability to achieve intensive control without hypoglycemia are being explored. There is a tremendous need to develop and commercialize a truly simple, accurate method of measuring glucose that can provide a basis for more accurate and directed disease selfmanagement. Generally, it is not practical to perform SMBG frequently enough throughout the day to accurately identify every blood glucose excursion. MiniMed® has taken a first step in advancing the practice of glucose self-monitoring by developing a short-term, continuous glucose sensor. The sensor is inserted subcutaneously and is capable of reliable operation for up to 3 days, followed by replacement with a new sensor at a different location, if necessary. The assay method is based on electrochemical detection of glucose through its reaction with glucose oxidase. Data are collected once every 5 min by a pager-sized monitor device and can be periodically downloaded into a computer for analysis and interpretation. In future product iterations, the sensor will function as a hypoglycemia and hyperglycemia alarm, by notifying the user when blood glucose levels reach preselected thresholds (such as 60 mg/dL and 200 mg/dL), and will provide real-time glucose readouts. The alarm feature will be especially important in patients with hypoglycemic unawareness, which is believed to occur in anywhere from 25% to 50% of patients with type 1 diabetes,2 especially those who have neuropathy or those without complications who are following intensive glycemic control regimens.3 Fanelli et al.4 have shown that meticulous control to prevent low glucose excursions can result in a significant recovery of hypoglycemic awareness.

Performance Evaluation of the MiniMed® Continuous Glucose Monitoring System During Patient Home Use

BACKGROUND The recent availability of a continuous glucose monitor offers the opportunity to match the demands of intensive diabetes management with a period of equally intensive blood glucose monitoring. The present study evaluates the performance of the MiniMed continuous glucose monitoring system (CGMS) in patients with diabetes during home use. METHODS Performance data and demographic information were obtained from 135 patients who were (mean +/- SD) 40.5+/-14.5 years old, had an average duration of diabetes of 18.0+/-9.8 years, 50% were female, 90% were Caucasian, and 87% of whom had been diagnosed with type 1 diabetes. Patients were selected by their physician, trained on the use of the CGMS and wore the device at home for 3 days or more. The performance of the CGMS was evaluated against blood glucose measurements obtained using each patients home blood glucose meter. Evaluation statistics included correlation, linear regression, mean difference and percent absolute difference scores, and Clarke error grid analysis. RESULTS The CGMS values were compared to 2477 SMBG tests (r = 0.91, slope = 0.93, intercept = 14.5 mg/dL, mean absolute difference = 18.0%+/-19.8%). Clarke error grid analysis showed 96.2% of the data pairs falling within the clinically acceptable regions (zones A and B). CONCLUSIONS These results demonstrate the agreement of the CGMS to blood glucose meter values, under conditions of home use, in patients selected by their physicians as candidates for continuous monitoring. The detailed glucose information provided by the CGMS should make successful management of diabetes more easily achieved.

Sensor-Augmented Insulin Pump Therapy: Results of the First Randomized Treat-to-Target Study

BACKGROUND The objective of the study was to evaluate the clinical effectiveness and safety of a device that combines an insulin pump with real-time continuous glucose monitoring (CGM), compared to using an insulin pump with standard blood glucose monitoring systems. METHODS This 6-month, randomized, multicenter, treat-to-target study enrolled 146 subjects treated with continuous subcutaneous insulin infusion between the ages of 12 and 72 years with type 1 diabetes and initial A1C levels of >or=7.5%. Subjects were randomized to pump therapy with real-time CGM (sensor group [SG]) or to pump therapy and self-monitoring of blood glucose only (control group [CG]). Clinical effectiveness and safety were evaluated. RESULTS A1C levels decreased (P<0.001) from baseline (8.44+/-0.70%) in both groups (SG, -0.71+/-0.71%; CG, -0.56+/-0.072%); however, between-group differences did not achieve significance. SG subjects showed no change in mean hypoglycemia area under the curve (AUC), whereas CG subjects showed an increase (P=0.001) in hypoglycemia AUC during the blinded periods of the study. The between-group difference in hypoglycemia AUC was significant (P<0.0002). Greater than 60% sensor utilization was associated with A1C reduction (P=0.0456). Fourteen severe hypoglycemic events occurred (11 in the SG group and three in the CG group, P=0.04). CONCLUSIONS A1C reduction was no different between the two groups. Subjects in the CG group had increased hypoglycemia AUC and number of events during blinded CGM use; however, there was no increase in hypoglycemia AUC or number of events in the SG group. Subjects with greater sensor utilization showed a greater improvement in A1C levels.

Determination of Plasma Glucose During Rapid Glucose Excursions with a Subcutaneous Glucose Sensor

Continuous glucose monitoring has the potential to improve glucose management and reduce the risk of hypoglycemia in individuals with diabetes. Accurate sensors may also allow the development of a closed-loop insulin delivery system. The purpose of this work was to determine the delay time associated with a subcutaneous glucose sensor during rapidly changing glucose excursions. Subcutaneous glucose sensors (Medtronic MiniMed, Inc., Northridge, CA) were inserted in five healthy men. After a 2-h stabilization period, a 3-h hyperglycemic (approximately 11 mM) clamp was performed followed by a 90-min period in which plasma glucose was allowed to decline to as low as 2.8 mM. Sensors were calibrated using two points (basal and hyperglycemia), and the calibrated sensor glucose measurements were compared with those from a reference analyzer (Beckman Instruments, Fullerton, CA). Response time was estimated from a first-order kinetic model. Plasma glucose levels, determined with the subcutaneous sensor, were highly correlated with those obtained with the reference glucose analyzer (r(2) = 0.91, p < 0.001; mean absolute difference of approximately 8%). The half-time for the sensor response was estimated to be 4.0 +/- 1.0 min. The subcutaneous glucose sensor has the potential to facilitate the detection of hypoglycemia and improve overall glycemic control when used in a real-time monitor. The rapid response should be sufficient to allow a fully automated closed-loop insulin delivery system to be developed based on the subcutaneous sensing site.

Efficacy and reliability of the continuous glucose monitoring system.

S-19 TIGHT CONTROL OF GLUCOSE has been shown to reduce both microvascular and macrovascular complications of diabetes mellitus,1–3 yet euglycemia is achieved only by a minority of patients.4 Intensive control of blood glucose cannot be achieved without vigilant attention to blood glucose levels.5Consequently, the goal of achieving normoglycemia has stimulated the search for optimal methods of monitoring changes in glucose levels in response to food, exercise, insulin, and antidiabetes medications. When it was first introduced, the technique of self-monitored blood glucose (SMBG) testing of capillary blood via fingerstick represented a major advance in methods of monitoring and improving glycemic control. Now that intensive therapy has become the standard of care for both type 1 and type 2 diabetes, SMBG has been established as a cornerstone of patient management. Current American Diabetes Association (ADA) guidelines recommend SMBG testing at least three to four times each day in patients with type 1 diabetes and at least once a day in patients with type 2 diabetes who cannot be managed with diet and exercise alone.6 Unfortunately, there are many impediments to adequate SMBG practice, including patient education and motivation, as well as improper technique.7,8 But even highly motivated patients who carefully perform frequent fingerstick measurements may miss substantial fluctuations in glucose levels, particularly episodes of nocturnal hypoglycemia. Furthermore, the blood glucose meters that are available today do not consistently achieve either the ADA or the Food and Drug Administration (FDA) goals for meter accuracy.9,10 The recent development of a method for continuously and automatically measuring glucose levels offers a dramatic improvement in the ability to monitor blood glucose—and, thus, intensively manage diabetes. The MiniMed® Continuous Glucose Monitoring System (CGMS, MiniMed Inc., Northridge, CA) is the first commercially available continuous glucose monitor. In this chapter, we summarize the results of a multicenter clinical evaluation of the CGMS, the results of a pilot study demonstrating the efficacy of the CGMS in diabetes management, and the results of a large postmarketing surveillance study confirming the performance of the CGMS during its initial commercial use.

Use of the Continuous Glucose Monitoring System to Guide Therapy in Patients With Insulin-Treated Diabetes: A Randomized Controlled Trial

OBJECTIVE To show improved glycemic control in patients with insulin-treated diabetes after adjustments to the diabetes management plan based on either continuous glucose monitoring using the Continuous Glucose Monitoring System (CGMS) or frequent self-monitoring of blood glucose (SMBG) using a home blood glucose meter. PATIENTS AND METHODS From January to September 2000, patients aged 19 to 76 years with insulin-treated diabetes were assigned to insulin therapy adjustments based on either CGMS or SMBG values. At the end of the study, patients in both groups used the CGMS for 3 days; these values were used to calculate measures of hypoglycemia. Repeated-measures analysis of variance with post hoc comparisons were used to test differences in hemoglobin A1c levels and hypoglycemia between the 2 study groups. RESULTS A total of 128 patients were enrolled in the study. Nineteen discontinued study participation, leaving 51 in the CGMS group and 58 in the SMBG group. No significant differences were noted in demographics or baseline characteristics between the 2 groups. There were no significant differences in hemoglobin A1c levels between the CGMS group and the SMBG group at baseline (9.1% +/- 1.1% vs 9.0% +/- 1.0%, P = .70), and both groups showed statistically significant (P < .001) and similar (P = .95) improvement in hemoglobin A1c levels after 12 weeks of study. However, the CGMS group had a significantly shorter duration of hypoglycemia (sensor glucose, < or = 60 mg/dL) at week 12 of the study (49.4 +/- 40.8 vs 81.0 +/- 61.1 minutes per event, P = .009). CONCLUSION Use of the CGMS to guide therapy adjustments in patients with insulin-treated diabetes reduces the duration of hypoglycemia compared with therapy adjustments guided by SMBG values alone.

Delays in minimally invasive continuous glucose monitoring devices: a review of current technology.

Through the use of enzymatic sensors—inserted subcutaneously in the abdomen or ex vivo by means of microdialysis fluid extraction—real-time minimally invasive continuous glucose monitoring (CGM) devices estimate blood glucose by measuring a patients interstitial fluid (ISF) glucose concentration. Signals acquired from the interstitial space are subsequently calibrated with capillary blood glucose samples, a method that has raised certain questions regarding the effects of physiological time lags and of the duration of processing delays built into these devices. The time delay between a blood glucose reading and the value displayed by a continuous glucose monitor consists of the sum of the time lag between ISF and plasma glucose, in addition to the inherent electrochemical sensor delay due to the reaction process and any front-end signal-processing delays required to produce smooth traces. Presented is a review of commercially available, minimally invasive continuous glucose monitors with manufacturer-reported device delays. The data acquisition process for the Medtronic MiniMed (Northridge, CA) continuous glucose monitoring system—CGMS® Gold—and the Guardian® RT monitor is described with associated delays incurred for each processing step. Filter responses for each algorithm are examined using in vitro hypoglycemic and hyperglycemic clamps, as well as with an analysis of fast glucose excursions from a typical meal response. Results demonstrate that the digital filters used by each algorithm do not cause adverse effects to fast physiologic glucose excursions, although nonphysiologic signal characteristics can produce greater delays.

The Accuracy and Efficacy of Real-Time Continuous Glucose Monitoring Sensor in Patients with Type 1 Diabetes

BACKGROUND The accuracy and efficacy of the Medtronic Diabetes (Northridge, CA) Real-Time (RT)-Continuous Glucose Monitoring (CGM) sensor were analyzed in 72 subjects with type 1 diabetes. METHODS This was a retrospective analysis of 60,050 temporally paired data points (sensor and glucose meter values) obtained during the course of an outpatient ambulatory study evaluating the efficacy of a sensor-augmented pump system in adults and adolescents. Subjects uploaded sensor values and self-monitoring blood glucose data to the CareLink Clinical Application (Medtronic Diabetes) via the Internet, every 2 weeks during the course of the study. RESULTS The overall percentage of sensor readings within +/-20% or +/-30% agreement of reference glucose readings was 75.6% and 86.8%, respectively. The highest rate of agreement occurred in the 240-400 mg/dL range, where 79.9% of sensor readings were within +/-20% of meter values and 91.5% of sensor readings were within 30% of meter values. The mean absolute relative difference for all subjects was 15.8%, and the median absolute relative difference was 10.9%. The bias was -2.13 mg/dL. Paired glucose measurements from the RT-CGM and meter demonstrated that 95.9% of paired points in the overall subject population fell in zones A and B of the Clarke Error Grid. Consensus Error Grid Analysis established that 99.2% of paired data points were in zones A and B. CONCLUSIONS This study reports the accuracy of a continuous glucose sensor with a large number of paired data points (60,050). RT-CGM is safe and well tolerated and provides readings that are in close agreement with glucose meter values.

Accuracy of a New Real-Time Continuous Glucose Monitoring Algorithm

Background: Through minimally invasive sensor-based continuous glucose monitoring (CGM), individuals can manage their blood glucose (BG) levels more aggressively, thereby improving their hemoglobin A1c level, while reducing the risk of hypoglycemia. Tighter glycemic control through CGM, however, requires an accurate glucose sensor and calibration algorithm with increased performance at lower BG levels. Methods: Sensor and BG measurements for 72 adult and adolescent subjects were obtained during the course of a 26-week multicenter study evaluating the efficacy of the Paradigm® REAL-Time (PRT) sensor-augmented pump system (Medtronic Diabetes, Northridge, CA) in an outpatient setting. Subjects in the study arm performed at least four daily finger stick measurements. A retrospective analysis of the data set was performed to evaluate a new calibration algorithm utilized in the Paradigm® Veo™ insulin pump (Medtronic Diabetes) and to compare these results to performance metrics calculated for the PRT. Results: A total of N = 7193 PRT sensor downloads for 3 days of use, as well as 90,472 temporally and nonuniformly paired data points (sensor and meter values), were evaluated, with 5841 hypoglycemic and 15,851 hyperglycemic events detected through finger stick measurements. The Veo calibration algorithm decreased the overall mean absolute relative difference by greater than 0.25 to 15.89%, with hypoglycemia sensitivity increased from 54.9% in the PRT to 82.3% in the Veo (90.5% with predictive alerts); however, hyperglycemia sensitivity was decreased only marginally from 86% in the PRT to 81.7% in the Veo. Conclusions: The Veo calibration algorithm, with sensor error reduced significantly in the 40- to 120-mg/dl range, improves hypoglycemia detection, while retaining accuracy at high glucose levels.

Accuracy of the Enlite 6-day glucose sensor with guardian and Veo calibration algorithms.

OBJECTIVE This study investigates the accuracy of a newly developed, next-generation subcutaneous glucose sensor, evaluated for 6-day use. RESEARCH DESIGN AND METHODS Seventy-nine subjects (53 men, 26 women) with type 1 diabetes and 18 subjects (14 men, four women) with type 2 diabetes completed a three-center, prospective, sensor accuracy study. The mean age for the group was 42.2±15.0 years (mean±SD), ranging from 18 to 71 years, with a mean glycosylated hemoglobin level of 7.6±1.5%, ranging from 5.5% to 14%. Subjects wore Enlite™ sensors (Medtronic Diabetes, Northridge, CA) in the abdominal and buttocks region for two separate 7-day periods and calibrated with a home-use blood glucose meter. Subjects participated in an in-clinic testing day where frequent sampled plasma glucose samples were acquired every 15 min for 10 h. Sensor data was retrospectively processed with Guardian(®) REAL-Time (Medtronic) and Paradigm(®) Veo™ (Medtronic) calibration routines, and accuracy metrics were calculated for each algorithm and sensor location. Physiological time lag for each measurement site was calculated. RESULTS Based on 6,404 plasma-sensor glucose paired points, the Enlite sensor with Veo calibration algorithm produced a mean absolute relative difference of 13.86% with 97.3% of points within the A+B zones of the Clarke error grid. Threshold-only alarms detected 90.1% of hypoglycemia and 90% of hyperglycemia. Mean time lag measured at the abdominal region was 7.94±6.48 min compared with 11.70±6.71 min (P<0.0001) at the buttocks area. CONCLUSIONS The Enlite sensor accurately measures glucose when compared with gold standard laboratory measurements over its 6-day use. Sensors placed in the buttocks region exhibited greater time lags than sensors placed in the abdomen.