In the present analysis of a series of studies using closed-loop insulin delivery for overnight glucose control in young people and adults with T1DM, we have demonstrated efficacy and safety superior to that achieved by conven-tional insulin pump therapy (). Compared with CSII, closed-loop increased the time spent in target glucose range (3.91–8.0 mmol/liter) and reduced the time spent in hypoglycemia, with no difference in average overnight insulin infusion. This evaluation of pooled studies showed improvements during closed loop for all outcome measures. Glycemic control achieved with closed loop in adults tended to be better than that achieved in young people, although this difference was less pronounced after midnight. During CSII therapy, however, superior glucose control was demonstrated in adults throughout the night.
Figure 6 Distribution of plasma glucose after midnight in young and adults during closed-loop (top panel) and during conventional pump (bottom panel) therapy. Vertical dashed lines denote the threshold of significant hypoglycemia (3.0 mmol/liter) and the target (more ...)
A key feature of the closed-loop system, demonstrated by our data, is its applicability in various patient populations. Insulin needs vary considerably between individuals—contributing factors include age, diabetes duration, and body weight as well as lifestyle factors such as exercise, dietary intake, and alcohol use. Our algorithm initializes individual insulin sensitivity based on body weight, total daily insulin dose, and usual basal infusion rates. It performed well in young children who tend to require lower total daily insulin per body weight, adolescents for whom the physiological demands of puberty necessitate much higher doses,24
and adults with longer disease duration. Our algorithm also dealt effectively with exercise, alcohol consumption, and late start of closed loop.
In addition to physiological changes, behavioral factors may contribute to the poorer glycemic control seen in children and adolescents.25
Reasons include infrequent self-testing of blood glucose, missed insulin boluses, and less structured eating patterns.26
An important factor is the perceived fear of hypoglycemia held by both patients and caregivers, particularly during the overnight period, which may lead to excess carbohydrate consumption and/or less insulin administered with resulting hyperglycemia.5
Overnight closed-loop glucose control may be of particular benefit in this setting.27
Lifestyle differences between children and adults have a major impact on insulin demands, with the former tending to be more physically active. Exercise is associated with a significant and protracted risk of hypoglycemia in T1DM.28
The closed-loop algorithm was able to cope with this risk and avoid significant nocturnal hypoglycemia following moderate-intensity evening exercise in APCam03. Managing fluctuations in glycemic control attributable to usual daily activities will be an essential requirement prior to employment of closed loop during daytime hours. Preliminary results of studies using our closed-loop system during the daytime as well as overnight in adolescents indicate improved efficacy compared with conventional therapy,29
but further studies are warranted to establish daytime benefits of closed-loop insulin delivery.
As well as assessing the feasibility of our closed-loop system across a range of ages, our studies also evaluated its performance following common scenarios such as large evening meals and alcohol consumption. Postprandial glucose control remains a major challenge for patients with T1DM. Although glucose concentrations increased after the large evening meals in APCam01 (87 g carbohydrate) and to a lesser extent in Angela02 (100 g carbohydrate), overall glycemic control was maintained during closed loop with reduced occurrence of delayed hypoglycemia, as a result of the algorithm minimizing basal insulin infusion following the prandial insulin bolus.
Alcohol consumption is associated with a significant threat of delayed hypoglycemia,30
further complicated by its effects on cognition and blunting of the counter-regulatory response.31
Although we did not see the anticipated increased frequency of hypoglycemia during either treatment in Angela02, closed-loop performance was unaffected by moderate evening alcohol intake (9.6 ml/kg). We also assessed the impact of a later start of closed loop (22:00) on overnight glycemic control, which may not be an uncommon occurrence in adults following an evening out, showing preserved efficacy.
The closed-loop system used in our studies required manual CGM entry and alteration of pump settings every 15 min by the research nurse, which is associated with a risk of human error as well as an inherent delay in changing the pump. This approach is not feasible in clinical practice and requires development of an automated system with wireless data transmission. We have tested a prototype automated closed-loop system in eight children overnight, demonstrating safe and efficacious control.32
The limitations associated with interpreting pooled data from studies with variations between protocols should be taken into account. Equally, the combined analysis of a larger number of subjects provides stronger evidence of the improvement in glucose control during closed loop. When designing the studies, the differences in meal size and timing were chosen as being representative of likely common scenarios in the two age groups.
There have been several closed-loop studies33–38
reported, none of which was randomized, and only one study had a control group for comparison. All our studies employed a randomized crossover design, thus minimizing any effect of interindividual variability on insulin sensitivity. They were designed to match real life as closely as possible in preparation for home testing of the closed loop. We used commercially available CGM and pump devices. Our algorithm considered only real-time interstitial glucose measurements based on output from a single sensor worn by participants, compared with other closed-loop studies34,38
that used venous glucose or more than one sensor for CGM output. Importantly, the algorithm advice was always followed unlike other closed-loop studies where researchers have sometimes deviated from the algorithm, limiting the interpretation of data.35
In addition to the patient groups presented here, pregnant women with T1DM have unique insulin requirements, and maintenance of tight glycemic targets is essential to avoiding maternal and fetal adverse outcomes.39
Insulin needs vary considerably with each trimester, including a progressive increase in the ratio of bolus to basal insulin doses. A feasibility study of overnight closed-loop in 10 subjects during early and late pregnancy demonstrated near-optimal glycemic control.40