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To evaluate long-term effects of continuous glucose monitoring (CGM) in intensively treated adults with type 1 diabetes.
We studied 83 of 86 individuals ≥25 years of age with type 1 diabetes who used CGM as part of a 6-month randomized clinical trial in a subsequent 6-month extension study.
After 12 months, median CGM use was 6.8 days per week. Mean change in A1C level from baseline to 12 months was −0.4 ± 0.6% (P < 0.001) in subjects with baseline A1C ≥7.0%. A1C remained stable at 6.4% in those with baseline A1C <7.0%. The incidence rate of severe hypoglycemia was 21.8 and 7.1 events per 100 person-years in the first and last 6 months, respectively. Time per day with glucose levels in the range of 71–180 mg/dl increased significantly (P = 0.02) from baseline to 12 months.
In intensively treated adults with type 1 diabetes, CGM use and benefit can be sustained for 12 months.
In a 6-month randomized trial of intensively treated individuals with type 1 diabetes and baseline A1C ≥7.0%, adults ≥25 years of age benefited from use of continuous glucose monitoring (CGM) compared with adults using conventional blood glucose monitoring (1). In a contemporaneous parallel study of individuals with type 1 diabetes who had A1C levels <7.0%, those in the CGM group had a reduction in biochemical hypoglycemia compared with those in the control group while maintaining A1C levels in the target range (2). This report describes the 12-month follow-up of adult subjects in the two randomized trials' CGM groups.
The protocol has been described in detail (1–3). We analyzed 12-month follow-up data for 83 of the 86 adults (≥25 years of age) who were initially randomized to the CGM group in either the ≥7.0% (n = 49) or <7.0% (n = 34) baseline A1C cohorts; 2 subjects discontinued study participation during the first 6 months and one after completion of the 9-month visit. An insulin pump was used by 75 (90%) subjects and multiple daily injections (MDIs) of insulin by 8 (10%). Subjects were provided with either a DexCom SEVEN (DexCom, San Diego, CA), MiniMed Paradigm REAL-Time System (Medtronic MiniMed, Northridge, CA), or FreeStyle Navigator (Abbott Diabetes Care, Alameda, CA). Follow-up visits during the extension study occurred at 9 and 12 months postrandomization. A1C was measured at the University of Minnesota using the Tosoh A1C 2.2 Plus Glycohemoglobin Analyzer method (4). Severe hypoglycemia was defined as an event that required assistance from another person to administer resuscitative actions (5).
The amount of CGM use was determined from CGM downloads. Statistical testing was performed with a paired t test for measures with an approximate normal distribution and with a signed-rank test for other measures. Changes in glucose variability were evaluated in least squares regression models based on van der Waerden rank normal scores.
Median CGM use was 7.0 days/week (interquartile range 6.3–7.0) at 6 months and 6.8 days/week (interquartile range 5.8–7.0) at 12 months (see online appendix supplemental Table S1, available at http://care.diabetesjournals.org/cgi/content/full/dc09-0846/DC1). Use at 12 months did not vary with baseline A1C level (Spearman r = −0.10; P = 0.38).
Among subjects with baseline A1C ≥7.0%, mean change in A1C from baseline to 12 months was −0.4 ± 0.6% (P < 0.001), similar to the change from baseline to 6 months. The reduction in A1C occurred mainly in the first 8 weeks and then remained relatively stable through the next 44 weeks (supplemental Fig. S1). Among subjects with baseline A1C <7.0%, A1C remained within the target range over the entire 12 months of the study (6.4, 6.3, and 6.4% at baseline, 6 months, and 12 months, respectively; P = 0.42 for change from baseline to 12 months).
A severe hypoglycemic event was experienced by 8 (10%) of the 83 subjects (9 events) during the first 6 months and 3 subjects (4%; 3 events) in the second 6 months. The rate of severe hypoglycemic events fell from 21.8 events per 100 person-years during the first 6 months to 7.1 events per 100 person-years (95% CI 0–16.7) during the second 6 months (P = 0.18). The rate was not associated with baseline A1C (Spearman r = −0.004; P = 0.97). In subjects with baseline A1C ≥7%, the incidence fell from 20.5 events per 100 person-years in the first 6 months to 12.1 events per 100 person-years in the second 6 months, whereas in the A1C <7% cohort, the incidence fell from 23.6 events per 100 person-years to no events during the second 6 months (supplemental Fig. S2).
The median amount of time per day with glucose in the range of 71–180 mg/dl increased significantly (P = 0.02) from baseline to 12 months, reflecting a decrease in both hypoglycemia and hyperglycemia. Similar trends were seen both in subjects with baseline A1C ≥7.0% and in those with baseline A1C <7.0% (Table 1). The increase in time in range was seen during both daytime and nighttime (supplemental Table S2). Variability assessed with the SD of glucose values (P = 0.02) and mean amplitude of glycemic excursions (P = 0.03) was reduced with CGM use from baseline to 12 months. Body weight, daily insulin dose, and frequency of daily blood glucose meter tests did not change meaningfully during the study.
In this 6-month extension to a randomized clinical trial, we found that most adults ≥25 years of age continued to use CGM on a daily or near-daily basis and had sustained benefits of improved glucose control noted by A1C levels and the amount of time sensor glucose values were in the target range. These benefits persisted despite less-intensive follow up, designed to approximate usual clinical practice, than that during the 6-month randomized phase of the study.
An additional important observation was the remarkably low rate of severe hypoglycemic events during the extension phase of the study. The rate of severe hypoglycemia in our CGM subjects with a mean A1C of 6.8% during the 6-month extension phase was markedly lower than the rate of severe hypoglycemia in the Diabetes Control and Complications Trial (DCCT) intensive treatment group, which had mean A1C of 7.1% (7 vs. 62 events per 100 person-years) (6). The total absence of severe hypoglycemia during the second 6 months of the study in the subjects who had a baseline A1C <7.0% is particularly striking, especially because these subjects were able to maintain a mean A1C of 6.4%.
It is possible that the decline in severe hypoglycemic events during the second 6 months of the study resulted from learning from prior experience, including appropriate setting of the low alarms, glucose targets, and titration of basal and bolus insulin doses. It is also intriguing to speculate that the reduction in exposure to biochemical hypoglycemia over the 12 months of the study may have protected subjects from severe hypoglycemic events by enhancing their counterregulatory hormone defense mechanisms against hypoglycemia (7).
Our findings demonstrate that the benefits of CGM can be sustained for at least 12 months in motivated adults with type 1 diabetes practicing intensive diabetes management. In such individuals, CGM provides the ability to achieve target A1C levels much more safely than previously reported.
B.B. received consulting fees, honoraria, travel reimbursement, and research funds from Abbott Diabetes Care and Medtronic MiniMed as well as grant support from DexCom. I.H. received consulting fees and travel reimbursement from Abbott Diabetes Care and grant support from Medtronic MiniMed. L.L. received consulting fees from Lifescan, consulting fees and a speaker honorarium from Abbott Diabetes Care, consulting fees and research funding from Medtronic MiniMed, and consulting and speaker fees from Roche. W.V.T. received consulting fees from Abbott Diabetes Care and Lifescan as well as consulting fees, a speaker honorarium, and research funding from Medtronic MiniMed. S.W. received research support, a speaker honorarium, and travel reimbursement from Medtronic MiniMed as well as a speaker honorarium from Animas Corp/Lifescan. H.W. received consulting fees from Abbott Diabetes Care and research funding from Medtronic MiniMed. No other potential conflicts of interest relevant to this article were reported.
The study was designed and conducted by the investigators listed in the online appendix, who collectively wrote the manuscript and vouch for the data. The investigators had complete autonomy to analyze and report the trial results. There were no agreements concerning confidentiality of the data between the Juvenile Diabetes Research Foundation and the authors or their institutions. The Jaeb Center for Health Research had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Parts of this study were presented in abstract form at the 69th Scientific Sessions of the American Diabetes Association, New Orleans, Louisiana, 5–9 June 2009.
The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group recognizes the efforts of the subjects and their families and thanks them for their participation.
The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group writing committee members are as follows: lead authors Bruce Bode, MD, Roy W. Beck, MD, PhD, and Dongyuan Xing, MPH; and additional authors Lisa Gilliam, MD, PhD, Irl Hirsch, MD, Craig Kollman, PhD, Lori Laffel, MD, MPH, Katrina J. Ruedy, MSPH, William V. Tamborlane, MD, Stuart Weinzimer, MD, and Howard Wolpert, MD.
Clinical trial reg. no. NCT00406133, clinicaltrials.gov.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.