The problems inherent in using a blood glucose measurement to document overnight hypoglycemia are avoided by using CGM to assess hypoglycemia. Current CGM devices record a glucose measurement every 1 to 5 minutes, depending on the device. For certain outpatient studies designed to reduce hypoglycemia, particularly overnight studies, CGM may be the only good outcome. A drawback to using current generation CGM as an outcome measure is that its accuracy is less than blood glucose measurements. However, with available data to estimate the variability of CGM, this inaccuracy can be accounted for in the study design by increasing sample size as will be discussed later.
In a nocturnal hypoglycemia prevention trial, CGM-measured outcomes could include the occurrence of a single glucose level below a threshold such as 60 or 70 mg/dl, consecutive glucose values below a threshold, or such measures as area under the curve or low blood glucose index. From prior analyses of the JDRF CGM RCT data set (unpublished), all four of these outcome measures are highly correlated. When a single glucose level is the outcome, there are several considerations in selecting the level to use for this purpose. The outcome level (1) should be at or below the level at which a counter-regulatory response to hypoglycemia occurs, (2) should be rare in people without diabetes, (3) should occur with sufficient frequency overnight in people with diabetes with respect to determination of the sample size for the study, and (4) should be at or above the glucose level at which the CGM hypoglycemia alarm is set. Setting the threshold to be 60 mg/dl, 70 mg/dl, or a level in between could satisfy all four criteria.
As summarized by the American Diabetes Association Workgroup on Hypoglycemia,11
the counter-regulatory response to decreasing blood glucose is triggered at a blood glucose level of 65–70 mg/dl, and frequent episodes of lower glucose levels, including asymptomatic nocturnal hypoglycemia, lead to defective counter regulation and hypoglycemia unawareness. We (and others) have found that 1.5% of glucose readings in people who do not have diabetes are between 60 and 70 mg/dl (≈4 readings or 20 min each day) while values ≥60 mg/dl make up only 0.2% of CGM glucose readings in people who do not have diabetes.12
To achieve sufficient statistical power, sample size and study duration will be highly dependent on the frequency of hypoglycemia in the control arm (i.e., hypoglycemia prediction algorithm not active). Data from the JDRF CGM RCT were used to estimate the frequency of CGM-determined nocturnal hypoglycemia that might be expected in the control arm of a nocturnal hypoglycemia prevention trial (
Continuous glucose monitoring data were evaluated from 10:00 pm to 6:00 am during the first 6 months of the study in 231 subjects in the CGM treatment group (age 8–72 years, baseline HbA1c 4.7–10.6%). Analysis was restricted to 25,473 nights with at least 6 h of CGM data, ranging from 3 to 182 per subject. Results for frequency of hypoglycemia at different glucose thresholds are summarized in
. It can be seen that, as expected, the hypoglycemia rate is greater at a threshold of 70 mg/dl than at 60 mg/dl, which is greater than the rate at 50 mg/dl. It also can be seen in the table that rates are similar for an outcome of a single value below the threshold and for an outcome requiring two consecutive values below the threshold. From a sample size perspective, the hypoglycemia rate for a threshold of 50 mg/dl is too low for a trial to be feasible. A level of either 60 or 70 mg/dl could be feasible, although the sample size requirement will be lower for a threshold of 70 mg/dl because of the higher hypoglycemia rate.
Frequency of Nocturnal Hypoglycemia in the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Randomized Control Triala
provides sample sizes and number of study nights for a range of treatment effects in order to have statistical power of 90% with a type 1 error rate of 5%. As can be seen, the sample size will be lower with a threshold of 70 mg/dl than of 60 mg/dl for a relative 50% reduction in the frequency of nocturnal hypoglycemia. It can also be seen in the table that another factor favoring 70 mg/dl as the threshold is that CGM accuracy is better at 70 mg/dl than at 60 mg/dl as will be discussed in the next section.
Sample Sizea and Study Duration Estimates for Binary Hypoglycemia Outcomes in a Nocturnal Hypoglycemia Prevention Trialb