Down Alert Function of the GlucoWatch® G2TM Biographer (GW2B) During Insulin-induced

Hypoglycemia in Children

Eva Tsalikian1, Craig Kollman2, Rosanna Fiallo-Scharer3, Roy Beck2, Bruce Buckingham4, Nelly Mauras5, Stuart Weinzimer6, William Tamborlane6, Katrina Ruedy2, Dongyuan Xing2 and the

Diabetes Research In Children Network (DirecNet) Study Group.

1Department of Pediatrics, University of Iowa, Carver College of Medicine, Iowa City, IA; 2Jaeb Center for Health Research, Tampa, FL; 3Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, CO; 4Division of Pediatric Endocrinology and Diabetes,

Stanford University, Stanford, CA; 5Nemours Children’s Clinic, Jacksonville, FL; 6Department of Pediatrics, Yale University School of Medicine, New Haven, CT.

AbstractDown Alert Function of the GlucoWatch® G2TM Biographer (GW2B) During Insulin-induced Hypoglycemia in Children

The GW2B alarm system for the detection of hypoglycemia has limitations regarding sensitivity and high false alarm rates. We previously reported that the GW2B hypoglycemia alarm would have to be set at 100mg/dL to detect 84% of serum glucose levels <60 mg/dL but at a false alarm rate of 80%. The GW2B also continuously monitors the rate of fall in sensor glucose levels and has a “down-alert” alarm that predicts impending hypoglycemia. In the down-alert algorithm, the slope between two GW2B glucose values at least 10 minutes apart is used to predict the glucose value 20 minutes later. As part of an inpatient protocol to evaluate the accuracy of the GW2B, an insulin-induced hypoglycemia test was performed on 50 children who were wearing 74 GW2Bs. Following IV insulin administration, venous blood was obtained every 5 minutes for up to 90 minutes, for measurement of reference glucose (RG) in a central laboratory. For analysis, the RG values were paired with the GW2B glucose values. This provided an opportunity to evaluate the “down alert” performance of the GW2B. Analysis of these data is in progress. Our preliminary assessment suggests that the down-alert alarm may be considerably more effective in predicting hypoglycemia than the hypoglycemia alarm. Since the GW2B glucose value has a lag time of about 20 minutes, the down alert is actually predicting whether the current glucose level of the individual is hypoglycemic rather than the glucose level 20 minutes earlier as is the case with the hypoglycemia alarm. Therefore, the GW2B down alert alarm may have greater utility than the hypoglycemic alarm.

• The study was conducted by the Diabetes Research in Children Network (DirecNet) at five academic centers in the United States.

• The Diabetes Research in Children Network (DirecNet) is a NIH-funded collaborative study group that consists of five clinical centers, a coordinating center, a central laboratory, and representatives from NICHD and NIDDK.

• The major objective of DirecNet is to critically evaluate the clinical usefulness of current and future glucose sensor devices in youth with T1DM.

• Continuous glucose sensors have been developed to provide frequent glucose determinations throughout the day and night in individuals with diabetes.

Introduction• In pediatric patients with type 1 diabetes mellitus (T1DM)

hypoglycemia is a major management challenge particularly at night.

• In very young children with T1DM, there are heightened concerns that hypoglycemia will cause permanent neurologic sequelae.

• As part of a study to evaluate the accuracy of the GlucoWatch® G2TM Biographer compared with venous blood glucose (BG) measurements in children with T1DM, hypoglycemia was induced with intravenous (IV) insulin.

• This provided the opportunity to study the GlucoWatch® G2TM Biographer hypoglycemia alarm and down alert function for reliability (sensitivity) and false positive alarm rates.

Objective

To evaluate the performance of the hypoglycemia alarm and “down alert” function of the second generation GlucoWatch Automatic Glucose Biographer, the GlucoWatch® G2TM Biographer ("GW2B“, Cygnus, Inc.) in children with T1DM.

Data from the DirecNet Inpatient Accuracy Study were used to evaluate the sensitivity and false alarm rates during insulin induced hypoglycemia and overnight.

Methods• The sensitivity and false alarm rates during insulin induced hypoglycemia and

overnight hypoglycemia were examined• Children were admitted to the CRC of each center• An indwelling intravenous catheter was inserted into an arm vein for plasma

glucose determinations by a central laboratory. • In each subject, blood samples were obtained every 60 minutes during the day

(7:00 AM to 9:00 PM) and every 30 minutes during the night (9:30 PM to 6:30 AM).

• One or two GW2Bs were placed on each child accordingto recommended procedures.

N= 89

Gender Female N (%) 44 (49)

Age mean ± SD (years) 9.9 ± 4.1

Race/Ethnicity N (%)

White 77 (87)

Hispanic or Latino 7 (8)

African-American 2 (2)

Other 3 (3)

Duration of Diabetes mean ± SD (years) 4.6 ± 3.2

Insulin Route N (%)

Pump 39 (44)

Injections 50 (56)

HbA1c mean ± SD 7.8% ± 1.2%

BMI percentile mean ± SD 67% ± 23%

Demographic and clinical characteristics of study subjects

Statistical Methods

1) The GW2B was considered to have given a hypoglycemia alarm for a glucose reading ≤ 60 mg/dL.

2) A down alert extrapolates the current glucose trend 20 minutes into the future. A linear slope was calculated based on the difference in glucose values from the current and previous readings and a down alert is issued if that slope predicts a reading ≤ 60 mg/dL.

3) Separate analyses were performed for the insulin-induced hypoglycemia test and overnight.

Each GW2B glucose reading was retrospectively evaluated at ahypothetical setting of 60 mg/dL regardless of the actual settingfor the hypoglycemia alarm and down alert function.

Total

Reference Glucose Nadir < 60 mg/dLa

Reference Glucose Nadir

> 60 mg/dL Number of Subjects 46 34 12 Number of GWBs 66 50 16 Hypoglycemia Alarmb during test 13 12 (24%) 1 within ± 30 min. of hypoglycemiac 12 12 (24%) N/A within ± 20 min. of hypoglycemiac 7 7 (14%) N/A within ± 10 min. of hypoglycemiac 2 2 (4%) N/A Down Alertb during test 53 44 (88%) 9 within ± 30 min. of hypoglycemiac 44 44 (88%) N/A within ± 20 min. of hypoglycemiac 41 41 (82%) N/A within ± 10 min. of hypoglycemiac 23 23 (46%) N/A

* - 0.05-0.10 units/kg body weight of regular insulin (mean = 3.6 ± 2.0) was given by intravenous bolus injection to children >7 years of age; blood samples were obtained q. 5 minutes for up to 90 minutes following insulin bolus recovery of blood glucose following hypoglycemia. a – Percentage denotes sensitivity (# alarms divided by # true hypoglycemic cases). b – At an alarm setting of 60 mg/dL. Only consider the first alarm during the test. c – Defined as first time reference glucose is < 60 mg/dL.

GW2B Alarm during Insulin-Induced Hypoglycemia Test*

Reference Glucose Gold Standard Defined Episodes

BG < 60 mg/dL BG < 70 mg/dL

GW2Bs worn during an episode N=13 N=35 Hypoglycemia Alarm (alarm setting of 60 mg/dL) during episode 1 (8%) 11 (31%) from 30 min before to end of episode 1 (8%) 12 (34%) ± 30 min either side of episodec 3 (23%) 12 (34%) Down Alert

(alarm setting of 60 mg/dL) during episode 6 (46%) 25 (71%) from 30 min before to end of episode 10 (77%) 28 (80%) ± 30 min either side of episodec 10 (77%) 29 (83%) Hypoglycemia Alarm or Down Alert (alarm setting of 60 mg/dL)

during episode 6 (46%) 25 (71%) from 30 min before to end of episode 10 (77%) 28 (80%) ± 30 min either side of episodec 10 (77%) 29 (83%)

*Number of subjects with a hypoglycemia episode < 60 mg/dL=9; < 70 mg/dL =20

Sensitivity of GW2B Alarms during Overnight (11PM-6AM) Episodes of Hypoglycemia*

False Alarm Rates for GW2B Overnight (11PM–6AM)

a – Linearly extrapolated value between half-hourly measurements. b – At an alarm setting of 60 mg/dL. c – Determined separately for each GW2B.

Reference Glucosea > 60 mg/dL

Reference Glucosea >70 mg/dL

N

At time of

alarm

For 30 min. after

within ± 30 min.

At time of

alarm

For 30 min. after

within ± 30 min.

Hypoglycemia Alarmb First alarm onlyc 25 84% 76% 60% 48% 32% 16% First or 2nd alarmc 43 88% 79% 60% 49% 35% 14% All alarms 90 92% 88% 68% 59% 49% 17% Down Alertb First alarm onlyc 68 96% 87% 78% 81% 68% 65% First or 2nd alarmc 112 93% 84% 76% 79% 63% 59% All alarms 212 94% 85% 76% 73% 57% 50% Hypoglycemia Alarm or Down Alertb

First alarm onlyc 69 93% 84% 77% 78% 65% 62% First or 2nd alarmc 115 90% 82% 74% 76% 60% 57% All alarms 257 93% 86% 74% 71% 57% 44%

In Summary

• Only 24% of truly hypoglycemic incidents during the hypoglycemia test and 8% of incidents overnight were detected by the hypoglycemia alarm.

• Corresponding sensitivity rates of the down alert were 88% and 77%, respectively.

• Adding the hypoglycemia alarm to the down alert did not improve sensitivity.

• However, 65% of first overnight down alerts were false positives (reference glucose > 70mg/dL within ±30 min.) compared to only 16% for the hypoglycemia alarm.

In Conclusion

• The down alert can add sensitivity and earlier warnings of hypoglycemia by attempting to anticipate the current trend rather than waiting for a sensor reading below the set hypoglycemia alarm level.

• This increased sensitivity comes at the cost of a significantly elevated false alarm rate.

• Barbara Davis Center– H. Peter Chase– Rosanna Fiallo-Scharer– Jennifer Fisher– Barbara Tallant

• University of Iowa– Eva Tsalikian– Michael Tansey– Linda Larson– Julie Coffey– Amy Sheehan

• Nemours Children’s Clinic– Tim Wysocki– Nelly Mauras– Keisha Bird– Kelly Lofton

• Stanford University

– Bruce Buckingham

– Darrell Wilson

– Jennifer Block

– Paula Clinton

• Yale University

– William Tamborlane

– Stuart Weinzimer

– Elizabeth Boland

– Kristen Sikes

– Amy Steffen

• Jaeb Center for Health Research– Roy Beck– Katrina Ruedy– Craig Kollman– Dongyuan Xing– Cynthia Silvester