We found the rate of occurrence of SH during the study to be most strongly associated with a history of SH in the 6 months prior to entry into the study. In addition, the rate was higher in females than males. Both of these findings are consistent with prior findings in the DCCT (3
). As in our study, multivariate analyses conducted on the DCCT data did not identify a predictive model with high sensitivity (3
). The incidence rate of SH in this study (17.9 events per 100 person-years) was similar to that of the conventional therapy group in the DCCT (18.7 events per 100 person-years), but significantly lower than the rate in the intensive treatment group (61.2 events per 100 person-years) in the DCCT (Supplementary Fig. 1
). A similar SH rate was found in the Sensor-Augmented Pump Therapy for A1c Reduction (STAR) 3 trial (~13 events per 100 person-years in both the CGM group and control group) (14
). Our results need to be viewed in the context of the study participants who were well-versed in self-management, were receiving intensive insulin management with either an insulin pump or multiple daily injections of insulin, and were performing frequent home blood glucose monitoring.
We also found that CGM-measured hypoglycemia occurred more often on days prior to SH than on other days. However, although the statistical association was strong, the predictive value of biochemical hypoglycemia for subsequent SH was very low. This is because on any given day, SH is a rare event (<1% probability). This probability increases eightfold when more than 30% of CGM values the day prior are in the hypoglycemic range, but there is still less than a 5% chance of SH on the following day. Thus, if a CGM were programmed to sound a warning whenever 30% of values over a 24-h period were ≤70 mg/dL, more than 95% of alarms would be false. The four CGM measures of hypoglycemia studied here (% ≤70 mg/dL, AUC, LBGI, and ≤54 mg/dL for at least 30 consecutive min) are all highly correlated, and results were similar regardless which was used.
One possibility to in part explain the low predictive value could be that subjects modified their diabetes management based on the presence of CGM-measured hypoglycemia, and this reduced their risk of an SH event on the next day. Evidence against this explanation, however, is that during the randomized trial phase of the study, the SH rate in the CGM group was similar to that in the control group (8
). Another possible factor contributing to the low PPV is measurement error from CGM. Studies of CGM accuracy have shown that the median error during hypoglycemia ranges from 13 to 24 mg/dL (15
) so that some episodes of true biochemical hypoglycemia are missed by CGM, and some CGM readings in the hypoglycemic range occur when the true glucose concentration is >70 mg/dL.
Kovatchev et al. (17
) studied 96 adults with insulin-dependent diabetes and found that history of SH and LBGI calculated from 1 month of home glucose meter data accounted for 40% of the variance of SH episodes over the following 6 months. In another study of 85 adults with type 1 diabetes, Kovatchev et al. (18
) reported that LBGI values from home glucose meter data were significantly higher in the 24 h prior to and immediately following an SH episode compared with other days in the same subjects. Cox et al. (19
) reported that LBGI was predictive of SH with a sensitivity rate of 58–60% among 100 adults with type 1 diabetes, but did not report the false-positive rate. Our results with CGM data were similar to these studies in that hypoglycemic indices were significantly higher on the day prior to an SH event and that over 50% of SH events could be predicted from these measures depending on the threshold used. However, our data also show a very large false alarm rate (≥95%) when these indices are used to predict SH events. The SH rates in these previous studies, ranging from 192 to 803 events per 100 person-years (17
), were much larger than that observed in the current study (17.9 events per 100 person-years) and in the DCCT.
In conclusion, the ability to predict the likelihood that SH will occur in the near future remains elusive. The strongest predictor is the occurrence of prior SH. Although biochemical hypoglycemia substantially increases the risk of the occurrence of SH on the next day, SH only occurs in about 1 in 20 days after preceding biochemical hypoglycemia, and thus this is a poor predictor.