The study design and methods have been described previously (15
). Patients with type 1 diabetes (n
= 175) participated in this randomized study comparing insulin glargine and NPH/Lente insulin, each used with premeal insulin lispro in an MDI regimen. A subset of patients (glargine, n
= 74; NPH/Lente, n
= 75) volunteered to use the CGMS (Medtronic/MiniMed, Northridge, CA), which measures interstitial glucose concentrations every 5 min for 3 days via a glucose oxidase–based method, to compare variability in interstitial glucose levels across the two regimens. CGMS accuracy has been demonstrated to be similar from day to day (16
). The median relative absolute difference between sensor and reference plasma glucose values in children with type 1 diabetes has been 11% during outpatient use (17
). In this study, patients and the health care team were blinded to CGMS results, which were not used for diabetes management but only for the assessment of glycemic variability.
Eligibility criteria and baseline characteristics
Patients aged 9–17 years with type 1 diabetes (for ≥1 year), at Tanner stage ≥2 puberty, with A1C level 7.0–9.5%, and at least two insulin injections per day or continuous subcutaneous insulin infusion were enrolled. Excluded were patients with diabetic ketoacidosis in the past 3 months or two or more episodes of severe hypoglycemia (i.e., an event requiring the assistance of another person and accompanied by either a blood glucose level of <36 mg/dl [<2.0 mmol/l] or prompt recovery after oral carbohydrate intake, intravenous glucose, or glucagon administration) in the past 12 months. Patients had to be willing to perform self-monitoring of blood glucose (SMBG) at least four times daily. The CGMS subgroup had to be willing to use the MiniMed CGMS for up to 3 consecutive days on three occasions.
Patients were randomized to receive either basal insulin glargine once daily before breakfast or intermediate-acting insulin (NPH or Lente) twice daily; starting doses were 40–50% of the total daily insulin dose. Both groups received insulin lispro before each meal based on carbohydrate intake, with individualized correction doses based on the degree to which blood glucose levels deviated from the target glucose values.
Continuous glucose monitoring
Interstitial glucose was measured during three periods (week 0, week 12, and week 24) for 3 consecutive days each. Patients were to enter at least four SMBG values daily to calibrate the CGMS and to record important events (e.g., insulin boluses, snacks, and exercise).
Measures of glycemic control and glycemic variability
Glycemic control was assessed by A1C at baseline, 12 weeks, and 24 weeks and by the time CGMS glucose values were <70, <50, ≤40, ≥250, and ≥350 mg/dl (<3.89, <2.78, ≤2.22, ≥13.88, and ≥19.45 mmol/l) (refer to ). A1C was measured using ion-exchange high-performance liquid chromatography with the Bio-Rad Variant II Turbo analyzer (Bio-Rad, Hercules, CA). The system was certified by the National Glycohemoglobin Standardization Program with values traceable to the Diabetes Control and Complications Trial reference method; the reported normal range is 4.27–6.07%, with coefficients of variation of 1.94 and 2.58% at A1C values of 6.25 and 12.5%, respectively.
Adjusted mean change from baseline in time spent above or below specified sensor glucose levels in CGMS subset
Measures of glucose variability from the CGMS were 1
) SD of the mean of the sensor values, 2
) mean amplitude of glycemic excursion (MAGE) (18
), and 3
value, which is expressed by the formula below (19
Minutes spent at glucose levels <70, <50, ≤40, ≥250, and ≥350 mg/dl (<3.89, <2.78, ≤2.22, ≥13.88, and ≥19.45 mmol/l) were calculated.
For CGMS data to be analyzable, each patient had to have a sufficient duration (i.e., 24 h of sensor data for each day) of CGMS data and a date for CGMS data collection at the appropriate time in the study. Some patients in the insulin glargine (n = 29) and the NPH/Lente (n = 30) groups were excluded from the analysis because of discrepancies between CGMS and SMBG values recorded by the same patient, unfamiliarity with the mechanics of the CGMS, or technical problems during CGMS measurement. Forty-five patients in each group had analyzable data at baseline and at any end point, and 33 patients in the glargine group and 36 in the NPH/Lente group had data at baseline and week 24.