Internet-based pilot study comparing low fat with high fat evening snacks in children and adolescents with Type 1 Diabetes using continuous glucose monitoring. Darrell M. Wilson 1, Kimberly Caswell 1, H. Peter Chase 2, Michael Tansey 3, Larry A. Fox 4, Stuart Weinzimer 5, Dongyuan Xing 6, Roy Beck 6, Craig Kollman 6, William Tamborlane 5, Katrina Ruedy 6 and the Diabetes Research in Children Network (DirecNet) Study Group. 1 Stanford, CA; 2 Denver, CO; 3 Iowa City, IA; 4 Jacksonville, FL; 5 New Haven, CT; 6 Tampa, FL

Introduction: Bedtime snacks are frequently employed in the treatment of children with type 1 diabetes to prevent nocturnal hypoglycemia, and the inclusion of protein and/or fat is commonly recommended. Methods: Ten subjects with T1DM (age 6-18y, HbA1c 6.9 ± 0.5%) enrolled in a pilot trial evaluating the Navigator glucose sensor completed a study comparing the effect of bedtime snack fat content on nocturnal hypoglycemia. On ≥12 separate nights, each subject received either a low-fat (30 gm carbohydrate, 3 gm protein, 1 gm fat; 138 kCal) or high-fat (30 gm CHO, 2 gm protein, 20 gm fat; 320 kCal) snack in random order. Subjects checked their glucose and via a website, were assigned to a high or low fat snack. Subjects used their usual evening snack algorithm to determine the size (in 15 gram carbohydrate increments). Data were from nights with at least 5h (average of 8.1±1.3h) of sensor data after the snack. Results: Average BG (mg/dl) on 128 valid study nights before snack were similar in both groups (163 ± 55, high fat; 164±53, low fat). The proportion of nights with hypoglycemia (sensor glucose ≤70) was similar in both groups (23% high fat vs 21% low fat). Likewise, the proportion of nights with hyperglycemia (sensor glucose ≥200) was similar in both groups (68% high fat vs 61% low fat). Conclusion: Even very well controlled children and adolescents with T1DM have a very high frequency of high and low glucose levels. However, the altering the amount of fat in the bedtime snack had no impact on frequency of hyperglycemia or hypoglycemia. This study also highlights the feasibility of web based research in patients’ home environment. Abstract

Background Hypoglycemia is a frequent and potentially serious complication of intensive insulin therapy, particularly in children with type 1 diabetes Almost half of severe hypoglycemia episodes occur overnight, while children are not being actively supervised or monitored Common practice suggests the ingestion of a fat-containing bedtime snack may reduce the risk of nocturnal hypoglycemia, presumably via delaying carbohydrate absorption

Rationale The purpose of this outpatient study was to determine whether, among children with type 1 diabetes (T1DM) utilizing insulin pump, a pre-bedtime snack with a relatively high fat content provides greater protection from nocturnal hypoglycemia than a snack containing the same amount of carbohydrate and protein, but a lower fat content.

Methods - Subjects Ten subjects 6-<18 years old with T1DM for over a year and using an insulin infusion pump Mean hemoglobin A 1C - 6.9% Enrolled in a pilot trial evaluating the Abbott Navigator ® Continuous Glucose Monitoring System On ≥12 nights, subjects were randomized to a carbohydrate snack or a carbohydrate plus fat snack

Sensor Delivery Unit ReceiverTransmitter Sensor Abbott FreeStyle Navigator Sensor

Snacks LOW FAT 30 gm CHO 2.5 gm protein 1.3 gm fat 138 kCal HIGH FAT 30 gm CHO 2 gm protein 20 gm fat 320 kCal

Web-based Snack Assignment and Data Collection Subjects logged on the study website and –entered the pre-snack glucose level –entered the level of activity during that day –used usual practices for determining the amount of carbohydrate (in 15-gram increments) –entered the amount of insulin to be taken to cover the snack A minimization algorithm was used to determine the order of the snack types based on –the pre-snack meter glucose level –the self-reported amount of activity during that day

Web-based Snack Assignment and Data Collection

Outcome Measures The primary outcome was hypoglycemia –at least one glucose value ≤70 mg/dL on either the Navigator or the FreeStyle meter Hyperglycemia was defined as at least one glucose value ≥200 mg/dL and at least 50 mg/dL above pre-snack glucose on either the Navigator or the FreeStyle meter. At least 12 nights with at least 5 hours of sensor data were collected

Results High fatLow fat Nights (#)6266 Pre-snack Meter Glucose (M±SD)163 ± ± 53 Pre-snack Sensor Glucose (M±SD)162 ± ± 54 Mean Sensor Glucose Overnight * (M±SD) 171 ± ± 45 Hypoglycemia #(%)12 (19%)13 (20%) Hyperglycemia #(%)22 (35%)20 (30%) *p-value=0.02

Time to Hyperglycemia for the high-fat and low-fat Nights. Hyperglycemia was defined as the first glucose value ≥200 mg/dL and at least 50 mg/dL above pre-snack Navigator glucose. *p-value from permutation test to account for correlated data from the same subject

Time to Hypoglycemia for the high-fat and low-fat Nights. Hypoglycemia was defined as the first glucose value ≤70 mg/dL. *p-value from permutation test to account for correlated data from the same subject

The Mean Sensor glucose value at each hour in each group after bedtime snack. BG at baseline (hour zero) is the average sensor reading over the 30 minutes prior to the snack. BG at each hour after snack is the average of sensor readings within ± 15 minutes of the hour *p-value<0.01 at 5 hours after snack High Fat Low Fat *

Results There were no meaningful differences between the high and low fat snacks on the frequency of hyperglycemia or hypoglycemia. –Mean overnight glucoses were higher in the high fat snack There was no meaningful difference in the timing of hyper- or hypoglycemia This study highlights the feasibility of web- based research in patients’ home environment.

Discussion The addition of fat to a bedtime snack does not improve overnight glycemic control and may cause hyperglycemia This study demonstrates the utility of web-based randomization and data collection systems in examining clinically important outpatient problems in patients with chronic diseases.