Insulin pump therapy with automated insulin suspension: toward freedom from nocturnal hypoglycemia.

Patients with diabetes and physicians are aware of the distress and on rare occasions mortality caused by severe hypoglycemia, in particular by nocturnal hypoglycemia. Up to 75% of severe hypoglycemia episodes in children occur at night,1 and concern about hypoglycemia is a major barrier to achieving target glycemic levels, often leading to maladaptive behaviors, such as underdosing insulin or taking extra carbohydrates, that increase blood glucose levels, again most pronounced at night.2 When continuous glucose monitoring first became available, there was hope that real-time information about glucose levels and trends with alarms to warn patients about impending hypoglycemia would significantly reduce hypoglycemic episodes. It was therefore disappointing that initial trials, including large trials such as Juvenile Diabetes Research Foundation Continuous Glucose Monitoring (JDRF-CGM)3 and Sensor-Augmented Pump Therapy for A1c Reduction 3 (STAR-3),4 failed to show a reduction in hypoglycemia. Despite use of continuous glucose monitoring, there was a high incidence of prolonged nocturnal hypoglycemia.5 The Sensing With Insulin Pump Therapy to Control HbA1c (SWITCH) study6 did demonstrate a 51% reduction in time with sensor glucose levels lower than 63 mg/dL when patients were using continuous glucose monitoring compared with those who did not, but there were no severe hypoglycemia events in the study in either group of this crossover study. Several factors may help explain the apparent lack of efficacy of continuous glucose monitoring for reducing hypoglycemia. First,thehypoglycemiarateamongpatientsenteredintothetrials was very low, and some trials excluded patients with problematic hypoglycemia. Second, even though alarms alert the patient about impending hypoglycemia, this alert was not beneficial at night, because patients were observed to sleep through 74% of the alarms.7 Third, the delay between interstitial and capillary glucose, and overall [in]accuracy of the systems, particularly at night, was also likely a contributing factor.8 These data suggest that continuous glucose monitoring with alarms alone is not sufficient to prevent severe nocturnal hypoglycemia. In 2009, a pump that automatically suspends basal insulin delivery for up to 2 hours when sensor glucose level falls below a preset threshold (referred to as “low glucose suspend”) became available in Europe. In early nonrandomized “before and after” studies, this device was shown to reduce the duration of nocturnal hypoglycemia.9,10 The study by Ly et al11 reported in this issue of JAMA is the first randomized controlled trial to show a reduction in severe hypoglycemiawiththeuseofaninsulinpumpwiththethresholdsuspend feature. The investigators recruited 95 patients, all with impaired awareness of hypoglycemia, with mean Gold scores of 6.4 (on a Likert scale of 1 to 7 on which 7 indicates complete absence of symptoms of hypoglycemia). During the 6-month runin phase, there were 6 severe hypoglycemia events in the pumponly group and 5 events in the sensor-augmented group. At the end of 6 months, there were 6 events in the pump-only group and no events in the group with the sensor-augmented pump with the threshold suspension feature. There was also reduction in sensor-detected time with glucose levels lower than 60 mg/dL and 70 mg/dL. Although an earlier study by Ly et al12 had shown improvement in epinephrine responses to experimental hypoglycemia in 11 children after 4 weeks of continuous glucose monitoring, these findings were not replicated in the study by Ly et al, which found no change in the counterregulatory hormone responses to hypoglycemia. Several issues should be considered in interpreting these findings. Although all patients had impaired awareness of hypoglycemia, the incidence of severe hypoglycemia in each group in the preceding 6 months was low. Rates of mild hypoglycemia were much higher at baseline in the threshold-suspension group, related to 2 outliers in the youngest age group. When these outliers were removed from the analysis, the reduction in moderate hypoglycemia was no longer significant, although the reduction in severe hypoglycemia remained statistically significant. In addition, patients in this study were young (mean age, <20 years),withrelativelyshortdurationofdiabetesincludinganumber of younger children in whom recall of severe hypoglycemia may have been dependent on parents. These demographic features are very different from the majority of patients with impaired awareness of hypoglycemia, who typically are older than 40 years and have more than 25 years of diabetes duration.13 It is possible that patients with longer duration of diabetes, who may have associated problems such as lipohypertrophy, antiinsulin antibodies and more entrenched health beliefs that may predispose to severe hypoglycemia may not be able to demonstrate similar reductions in severe hypoglycemia events. The efficacy of the threshold-suspension device also should be considered in the context of pharmacokinetics of currently available insulin. It takes at least 30 minutes after suspension of basal insulin delivery before plasma insulin levels will decline enough to allow blood glucose to increase, suggesting that althoughsuspensionofbasal insulinalonewilloftennotbeenough to prevent hypoglycemia from occurring, it will usually be sufficient to reduce the duration and depth of hypoglycemia. If hypoglycemia is caused by an excess of bolus insulin, suspending Related article page 1240 Opinion