Clinical Care/Education/Nutrition/Psychosocial Research ORIGINALDiabetes ARTICLE Care Publish Ahead of Print, published online February 19, 2011 Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes 1 2 TADEJ BATTELINO, MD, PHD REVITAL NIMRI, MD especially useful in patients with hypogly- 2 3 MOSHE PHILLIP, MD PER OSKARSSON, MD, PHD 1 3 cemia unawareness and/or frequent epi- NATASA BRATINA, MD, PHD JAN BOLINDER, MD, PHD sodes of hypoglycemia (18). However, the hypoglycemia preventive effect of con- tinuous glucose monitoring has not been — OBJECTIVE To assess the impact of continuous glucose monitoring on hypoglycemia in established. Therefore, we designed a ran- people with type 1 diabetes. domized, controlled, multicenter clinical RESEARCH DESIGN AND METHODS—In this randomized, controlled, multicenter trial to evaluate the effect of continuous study, 120 children and adults on intensive therapy for type 1 diabetes and a screening level of glucose monitoring on hypoglycemia in glycated HbA1c ,7.5% were randomly assigned to a control group performing conventional children and adults with type 1 diabetes. home monitoring with a blood glucose meter and wearing a masked continuous glucose monitor every second week for five days or to a group with real-time continuous glucose monitoring. The primary outcome was the time spent in hypoglycemia (interstitial glucose concentration ,63 RESEARCH DESIGN AND mg/dL) over a period of 26 weeks. Analysis was by intention to treat for all randomized patients. METHODS RESULTS—The time per day spent in hypoglycemia was significantly shorter in the contin- uous monitoring group than in the control group (mean 6 SD 0.48 6 0.57 and 0.97 6 1.55 Patients Patients aged between 10 and 65 years h/day, respectively; ratio of means 0.49; 95% CI 0.26–0.76; P = 0.03). HbA1c at 26 weeks was lower in the continuous monitoring group than in the control group (difference 20.27%; 95% with type 1 diabetes diagnosed for more CI 20.47 to 20.07; P = 0.008). Time spent in 70 to 180 mg/dL normoglycemia was significantly than 1 year, with reasonable metabolic longer in the continuous glucose monitoring group compared with the control group (mean control assessing carbohydrate intake and P hours per day, 17.6 vs. 16.0, =0.009). self-adjusting insulin, and a HbA1c level , — 7.5%, using intensive insulin treatment CONCLUSIONS Continuous glucose monitoring was associated with reduced time spent with either an insulin pump or multiple in hypoglycemia and a concomitant decrease in HbA1c in children and adults with type 1 di- abetes. daily injections, and not using a real-time continuous glucose monitoring device for at least 4 weeks were eligible for the study. All eligible patients identified from the local diabetes registries were invited to he benefits of intensive treatment of reduced adherence to therapeutic deci- participate and screened consecutively type 1 diabetes, established almost sions (10). Finally, hypoglycemia may T fi based on the order of their positive reply. 20 years ago (1), are dif cult to ach- be associated with permanent damage The study protocol was designed by ieve, despite the increased use of insulin to the central nervous system (CNS) the researchers and approved by the in- analogs and insulin pumps, with only a (11) and may permanently influence cog- stitutional or national medical ethics minority of patients maintaining their gly- nitive functions in children (12) but not committees from all three centers, and cated HbA within the target range (2). in adults (13). 1c the conduct of the study was consistent Intensive insulin treatment and lower Recently, devices for real-time con- with the Good Clinical Practice provi- HbA increase exposure to hypoglyce- tinuous glucose monitoring have been 1c sions of the Declaration of Helsinki with mia (3,4). The risk of hypoglycemia is introduced to aid self-management of all amendments and local regulatory re- even higher in children and adolescents glycemic control and have been shown quirements. A written informed consent (5,6) and increases with the duration of to improve HbA levels in people with 1c was obtained from all participants and pa- diabetes (7). Frequent hypoglycemia is type 1 diabetes (14–17). In clinical practice rents of minors (under 18 years of age, associated with hypoglycemia unaware- recommendations, it has also been sugges- who signed an assent) before enrollment. ness (8,9), which may in turn lead to ted that continuous glucose monitoring is At screening patients provided a ccccccccccccccccccccccccccccccccccccccccccccccccc blood sample for measurement of HbA1c From the 1Department of Pediatric Endocrinology, Diabetes and Metabolism, UMC-University Children’s and entered a 4-week run-in period dur- Hospital, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; the 2The Jesse Z and Sara Lea ing which self-monitoring of blood glu- Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider cose (SMBG) was conducted according Children’s Medical Center, Petah Tikva and Sackler Faculty of Medicine, Tel-Aviv University, Israel; and the ’ 3 to patients standard glycemic manage- Department of Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, ment regimen. A FreeStyle blood glucose Sweden. Corresponding author: Tadej Battelino, [email protected]. meter (Abbott Diabetes Care, Alameda, Received 20 October 2010 and accepted 13 January 2011. CA) was provided to familiarize patients DOI: 10.2337/dc10-1989. Clinical trial reg. no. NCT00843609, clinicaltrials.gov. with FreeStyle test strips and collect base- This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10. line SMBG frequency and glucose levels. 2337/dc10-1989/-/DC1. © 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly Diaries were distributed for recording cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ events of hypoglycemia and associated licenses/by-nc-nd/3.0/ for details. food intake, insulin doses, and exercise. care.diabetesjournals.org DIABETES CARE 1 Copyright American Diabetes Association, Inc., 2011 Continuous glucose monitored in type 1 diabetes All patients meeting the eligibility criteria, events, and serious adverse events regard- including all data collected for patients including HbA1c result from the screening less of cause, were reviewed and reported. that discontinued prematurely. An excur- visit, were invited to attend the randomi- Diabetes self-management was ad- sion was defined as all consecutive re- zation visit. justed by patients based on the blood cordings outside the boundary covering glucose measurements in the control at least 10 min. The duration of an group and blood glucose measurements excursion was defined as the elapsed Study design and continuous glucose data in the con- time from first excursion to the first Following the 1-month run-in period, tinuous glucose monitoring group. Sam- reading indicating return inside the ex- patients were randomized to participate ples for HbA1c were collected at days 1, cursion boundary. Continuous glucose in a 6-month intervention period. Pa- 60, and 180. All samples for HbA1c were monitoring data in both groups were used tients were assigned to home monitoring sent to a central laboratory (LKF, Kiel, to estimate the amount of time per day the with a FreeStyle blood glucose meter Germany; measurement by Bio-Rad Vari- glucose level was hypoglycemic (,63 and a masked continuous glucose moni- ant II Turbo analyzer, Bio-Rad Laborato- mg/dL, ,70 mg/dL, or ,55 mg/dL), hyper- tor to be worn for 5 days every second ries, Hercules, CA). glycemic (.180 mg/dL or .250 mg/dL), week (control group) or to a group with and in the target range (70 to 180 mg/dL real-time continuous glucose monitoring, Statistical analysis or 90 to 180 mg/dL) for each patient. The wearing individual sensors for 5 days The primary outcome was time spent in number of hypoglycemic excursions (,55 continuously for 26 weeks (continuous hypoglycemia (,63 mg/dL) during the and ,63 mg/dL) per day and separately monitoring group). Patients and investi- 26-week study period. A sample size of during the night period of 0000–0600 h gators were masked for the continuous 120 patients was planned to have a power was also calculated. The risk associated glucose monitoring data in the control of 80% to detect a difference in the time with glucose concentration outside the group. Patients were allocated to either spent in hypoglycemia between study recommended range was assessed by cal- group by permuted block randomization groups, assuming a population difference culating low blood glucose indexes (LBGI) stratified according to age (10 to 17 years of 42%, a SD of 1.12, an a-level of 0.05, andhighbloodglucoseindexes(HBGI) pediatric, 18 to 65 years adult) and study and a loss to follow-up of no more than 17%. (20). Comparisons between study groups center. The randomization sequence was All analyses were performed accord- were performed with the use of the Mann- computer generated, and allocations were ing to the intent-to-treat (ITT) principle, Whitney U test. Confidence intervals for concealed using envelopes. Both groups were provided with the FreeStyle Navi- gator (Abbott Diabetes Care), a continu- Table 1—Baseline characteristics of the patients ous glucose monitoring system that measures glucose in interstitial fluid. All patients were trained to insert and Control Continuous calibrate subcutaneous sensors and to Group Monitoring Group operate the continuous monitoring de- N 58 62 vice. Patients in the continuous monitor- Female sex, number (%) 19 (33) 26 (42) ing group were instructed in the use of Age (years)* 26.0 6 14.6 25.7 6 14.1 real-time glucose readings; however, no Pediatric, number (%) 26 (45) 27 (44) written guidelines were given on adjust- BMI (kg/m2)* 22.0 6 3.8 22.4 6 3.8 ment of diabetes management based on Duration of diabetes (years)* 11.4 6 11.4 11.6 6 11.3 the real-time readings.