Impact of Hybrid Closed Loop Therapy on Hypoglycemia Awareness in Individuals with Type 1 Diabetes and Impaired Hypoglycemia Awareness

Abstract

Objective:

This study evaluated the efficacy of using a hybrid closed loop (HCL) system in restoring hypoglycemia awareness in individuals with impaired awareness of hypoglycemia (IAH).

Research Design and Methods:

Participants with IAH (Gold score ≥4) were recruited into a randomized crossover pilot study. They participated in two 8-week periods using a HCL system (Medtronic 670G™) (intervention) and standard insulin pump therapy (control). Hyperinsulinemic hypoglycemic clamp studies were undertaken at baseline and at the end of each study period for the evaluation of the counter-regulatory hormonal and symptomatic responses to hypoglycemia.

Results:

Seventeen participants (mean age [standard deviation] 35.8 years [11.2 years]) were included in the study. Peak epinephrine levels (median, interquartile range [IQR]) in response to hypoglycemia were similar postintervention and control periods; 234.7 pmol/L (109.2; 938.9) versus 188.3 pmol/L (133.7; 402.9), P = 0.233. However, both peak adrenergic and neuroglycopenic symptom scores were higher after intervention; 5.0 (4.5; 9.0) versus 4.0 (4.0; 5.5), P = 0.009, and 8.5 (6.0; 15.0) versus 6.5 (6.0; 7.0) P = 0.014, respectively. Self-reported hypoglycemia awareness improved: median (IQR) Gold score was 4.0 (3.0; 5.5) versus 5.5 (4.5; 6.0); intervention versus control, P = 0.033. Time spent <3.9 and <3.0 mmol/L was lower in the intervention group than in control, P = 0.002. Other patient-reported outcomes (hypoglycemia fear and diabetes treatment satisfaction) did not change.

Conclusions:

A short-term use of a HCL system failed to demonstrate an improvement in counter-regulatory hormonal responses. However, higher hypoglycemia symptom scores during controlled hypoglycemia, better self-reported hypoglycemia awareness, and less time spent in hypoglycemia suggest the potential benefits of a HCL system in people with IAH.

Trial Registration:

anzctr.org.au Identifier: ACTRN12616000909426.

Introduction

Hypoglycemia begets hypoglycemia¹ and recurrent episodes of mild hypoglycemia contribute to the development of defective counter-regulatory hormone responses to subsequent reductions in blood glucose levels.¹ This results in impaired awareness of hypoglycemia (IAH) and increases the risk of subsequent severe hypoglycemia.² IAH is a syndrome in which the ability to detect the onset of hypoglycemia is diminished or absent³ and patients are unable to initiate self-treatment. Clinically, IAH manifests as loss of some of the symptoms of hypoglycemia over a period of time, potentially prolonging the time spent in hypoglycemia. Around 20%–25% of adolescents and adults with type 1 diabetes (T1D) have IAH.^4,5

The adrenergic responses that contribute to the warning symptoms during hypoglycemia⁶ are impaired in people with T1D with IAH.⁷ This loss of symptoms and counter-regulatory hormone failure places them at a sixfold increased risk of severe hypoglycemia.⁸ Recovery of these responses can be achieved by complete and meticulous avoidance of hypoglycemia for 4–6 weeks.^7,9 This level of meticulous avoidance of hypoglycemia is difficult in clinical practice and hard to sustain. Emphasis on holistic management, education, medications, and diabetes technology has been trialed as tools to reduce hypoglycemia and improve IAH with varying degrees of success.^10

–15 Furthermore, the improvement of self-reported hypoglycemia awareness is controversial, some studies show an improvement and others do not.^16

–19

Technological devices used in the management of T1D have the potential to restore hypoglycemia awareness in individuals with IAH by reducing hypoglycemia. Low glucose threshold suspend and predictive low glucose suspend systems both reduce the frequency of hypoglycemic events and episodes of severe hypoglycemia in people at risk for hypoglycemia.^19,20

Hybrid closed loop (HCL) insulin delivery systems that integrate continuous glucose monitoring (CGM), an insulin pump, and an algorithm that determines insulin delivery based on CGM data have been shown to reduce the glycemic excursion associated with conventional therapy.^21
–23 A number of studies have demonstrated safety and efficacy, improvement in time in range, and less time spent in hypoglycemia across all age groups.^21
–23

As hypoglycemia may be reduced with the HCL system by ∼3% in adults and ∼1.5% in adolescents,²³ it is an important management modality that needs to be further investigated in individuals with IAH. A 4-week study investigating the effectiveness of a HCL system in adults at high risk for hypoglycemia found a reduction of risk and frequency of hypoglycemia.²⁴ However, the use of HCL technology has not been investigated in restoration of hypoglycemia awareness in individuals with T1D and IAH.

Hence, the aim of this pilot study was to investigate the use of a HCL system in restoring hypoglycemia awareness, and to produce estimates to inform the design and power calculation for further research. An 8-week study period was chosen as counter-regulatory hormone responses are expected to improve in 4–6 weeks of hypoglycemia avoidance.⁷ Hormonal and symptom responses to experimentally induced hypoglycemia were assessed in a hyperinsulinemic hypoglycemic clamp study.

Research Design and Methods

Study participants

Adolescents aged >12 years and adults up to the age of 55 years, diagnosed with T1D for >1 year and C-peptide negative, were recruited. To be eligible, participants were required to demonstrate IAH, defined as a Gold score ≥4.⁸ Participants were on either standard or sensor-augmented insulin pump therapy. Exclusion criteria included the commencement of CGM in the 3 months before the study, use of oral antidiabetic medications or steroids during the previous 3 months, and medical conditions (adrenal, growth or multiple pituitary hormone deficiency, pregnancy, chronic kidney disease, and cardiovascular disease) that precluded participation in a hyperinsulinemic hypoglycemic clamp study.

The study protocol was approved by the Institutional Review Board (Child and Adolescent Health Service Human Research Ethics Committee) (20160SIEP), and the study was carried out at Princess Margaret Hospital/Perth Children's Hospital in Western Australia. Informed consent was obtained from the adolescent and adult participants, and from parents if the participant was <18 years of age.

Design

The pilot study employed a randomized crossover design with participants spending 8 weeks in each of the two study arms: using their own pump therapy and CGM if they were already using CGM (control) or the MiniMed^® 670G (Medtronic, Northridge, CA) system (intervention). Before randomization and after finishing each study arm, participants underwent a hyperinsulinemic hypoglycemic clamp study and completed questionnaires related to their diabetes management.

There was no formal wash-out period between the two study arms. However, previous literature suggests that meticulous avoidance of hypoglycemia for 4 weeks can restore hypoglycemia awareness by improving counter-regulatory hormonal response in a hyperinsulinemic hypoglycemic clamp study.^7,14 Therefore, a total study period of 8 weeks was assumed to be sufficient to prevent a carry-over effect in either direction.

Study protocol

At the first visit, eligibility criteria were confirmed, and participants were consented to the study. Baseline demographic (age, gender, height, weight, and blood pressure) and clinical diabetes data (duration of diabetes, details of insulin pump therapy, history of severe hypoglycemia, C-peptide, and glycated hemoglobin [HbA1c]) were recorded. In addition, participants completed questionnaires related to their current diabetes management (see outcome measures hereunder). Participants were fitted with a blinded CGM system (Guardian™ 3 Sensor) to assess baseline hypoglycemia exposure and glycemic variability. After 7 days, the blinded sensor was changed at the research facility. The CGM system used in this study had a mean absolute relative difference of 10.3% across the entire sensor-wear period.²⁵

After 2 weeks of blinded CGM data collection, participants underwent a hyperinsulinemic hypoglycemic clamp study and were randomized to either control or intervention. Randomization to the sequence of intervention and control was computer generated and used a counterbalanced design. Randomization was stratified by two age groups (below and above 35 years) and occurrence of severe hypoglycemia (yes/no) during the past 12 months.

Before starting the intervention period, participants were trained in pump and sensor use, followed by a 2-week familiarization phase. Participants in both the control and intervention arms received weekly phone calls. To ensure availability of CGM data, participants in the control group had blinded CGM for the last 2 weeks of the study period.

Hyperinsulinemic hypoglycemic clamp study

The hyperinsulinemic hypoglycemic clamp study was undertaken at baseline and at the end of the 8-week control and intervention study periods.

The participant presented at the research unit, after an overnight fast, for the clamp study in the morning. Hypoglycemia in the 24 h preceding the clamp study was avoided, and for participants who had a blood glucose level <3.5 mmol/L the night before the clamp study or on arrival at the research unit, the study was rescheduled. The clamp procedure involved cannulation of the antecubital veins of both arms: one for insulin and glucose infusion, and the other for regular sampling of venous bloods for monitoring of blood glucose levels.

Insulin lispro (Humalog, Eli Lilly, NSW, Australia), 1:1 diluted in 0.9% saline, was infused at a constant rate of 80 mU/(m²·min) and blood glucose targets were achieved by adjusting the rate of infusion of 20% glucose solution in water. The clamp protocol was modified from the clamp protocol described by Amiel et al. in 1988.²⁶ Before induction of hypoglycemia, blood glucose was maintained between 5 and 6 mmol/L for 60 min followed by gradual reduction for 30 min to a nadir of 2.8 mmol/L. The blood glucose level of 2.8 mmol/L was maintained for 40 min before euglycemia was restored.

For the duration of the clamp procedure, blood glucose levels were measured using the glucose oxidase technique with a bedside YSI analyzer (YSI 2300; Yellow Springs Instruments, Yellow Springs, OH). Venous blood was collected during the euglycemic and hypoglycemic phase to determine epinephrine, norepinephrine, plasma insulin, cortisol, and growth hormone concentrations. Glucagon response was not measured because of the known early loss of glucagon secretion after T1D diagnosis,²⁷ and previous studies showing absent or nonsignificant rise in glucagon response in people with IAH.^7,15,26 At the same time as the venous blood sampling, participants completed a hypoglycemia symptom questionnaire²⁸ that assessed adrenergic and neuroglycopenic symptoms on a 7-point Likert scale.

Outcome measures

Several outcome measures were explored. The primary outcome of the study was the plasma epinephrine response to experimentally induced hypoglycemia during the hyperinsulinemic hypoglycemic clamp study.

Secondary outcomes included other hormones measured during the clamp study (norepinephrine, growth hormone, cortisol, and insulin) and symptoms of hypoglycemia. These were assessed with a questionnaire in which the participants rated their symptoms on a scale of 1 (no symptoms) to 7 (extreme) concomitantly with venous blood samples for counter-regulatory hormonal response. The scores of the symptoms were added to give a total adrenergic and neuroglycopenic symptoms score at each timepoint.²⁸ Adrenergic symptom questions included the items shaking, sweating, heart pounding, and feeling anxious/tense. Neuroglycopenic items included difficulty concentrating, trouble thinking, blurred vision, feeling irritable/annoyed, feeling light-headed, and feeling confused.

Outcomes related to the participant's diabetes management were determined by two hypoglycemia awareness questionnaires (Gold and Clarke),^8,29 the Hypoglycemia Fear Survey (HFS)³⁰ and the Diabetes Treatment Satisfaction Questionnaire (DTSQ).³¹

Glycemic outcomes included percentage time spent in different CGM ranges (time in range between 3.9and 10.0 mmol/L, <3.9 mmol/L, <3.0 mmol/L, >10.0 mmol/L, >13.9 mmol/L), mean CGM glucose level (mmol/L), coefficient of variation (CV) during the last 2 weeks of the intervention and control period,³² and HbA1c after each 8-week period.

Hormone assays

Plasma epinephrine and norepinephrine levels were assayed using high-performance liquid chromatography (HPLC) (Waters e2695 Separations Module, coupled to a Waters 2465 ECD Detector, Waters Corporation, Milford, MA, USA). A chemiluminescent immunoassay (Abbott Architect i2000, Abbott Diagnostics, Abbott Park, IL, USA) for insulin and cortisol and a chemiluminescent immunometric assay (Immulite 2000 XPi Immunoassay System, Siemens Healthcare Diagnostics, Tarrytown, NY, USA) for growth hormone (GH) levels were used.

Statistical analysis

Median (interquartile range [IQR]) or mean (standard deviation [SD]) is presented for demographic characteristics and outcomes unless otherwise specified.

A two-stage approach to analysis of the primary outcome was taken. A preliminary test for carry-over effects was conducted before assessing treatment effect. To test for a treatment effect, a linear mixed model including a random effect for participant and fixed effects for period and treatment was conducted. Visual inspection of model residuals showed a positive skew and heteroskedasticity that was improved by log transformation. Model results based on the transformed outcome measure are presented.

Secondary outcomes were analyzed using linear mixed models where possible. Where model residuals displayed significant departure from normality or heteroskedasticity that was not able to be addressed through transformation, a Wilcoxon signed rank test was carried out to assess the effect of treatment. Data were analyzed using STATA for Windows (Version 16.0; StataCorp LP, Texas, USA) and alpha was set at 0.05 for all tests.

Results

Figure 1 shows the consort flow diagram of the study. Twenty-three individuals attended the first visit and consented to the study. Three participants withdrew before the first clamp study and randomization (two for personal reasons and one due to skin reactions with sensor wear). Two participants withdrew during the first clamp study (one due to cannulation problems and one due to hypoglycemia symptoms experienced during the clamp despite a Gold score ≥4), and one shortly after randomization to the HCL arm (inability to adapt to the HCL glycemic target). Two participants withdrew after the second clamp study: one after the intervention and the other after the control period. Fifteen participants completed both study periods.

FIG. 1.

Consort diagram of participants in the study.

Mean (SD) age was 35.8 (11.2) years, mean diabetes duration was 24.2 (11.3) years, and mean HbA1c was 7.8% (1.2) (61.8 mmol/mol (13.0)). Further demographic and diabetes baseline data are given in Supplementary Table S1. Five (33%) participants were already using CGM: three of the five (60%) with predictive low glucose suspend. One clamp study was rescheduled due to the occurrence of hypoglycemia <3.5 mmol/L on arrival to the research unit.

Counter-regulatory hormonal and symptom score responses

Counter-regulatory hormonal responses and symptom score during euglycemia and to hypoglycemia (peak response and area under the curve) during the hyperinsulinemic hypoglycemic clamp after control and intervention period are displayed in Table 1.

Table 1.

Hormonal and Symptom Score Response During Euglycemia and to Hypoglycemia During the Hyperinsulinemic, Hypoglycemic Clamp After Control and Intervention Period

	Control (n = 16)			Intervention (n = 16)			P
Outcome	Baseline euglycemic phase	Peak hypoglycemic phase	AUC	Baseline euglycemic phase	Peak hypoglycemic phase	AUC	P
Hormonal response
Epinephrine, pmol/L	<103.7 (<103.7; 152.4)	188.3 (133.7; 402.9)	92.7 (74.2; 160.8)	<103.7 (<103.7; 123.1)	234.7 (109.2; 938.9)	86.5 (70.1; 314.3)	0.171^†
Norepinephrine, pmol/L	2067.7 (1421.6; 2748.5)^*	2232.0 (1673.4; 3643)^*	1377.0 (964.5;1930.9)	2160.6 (1331.3; 2928.2)	2734.4 (2011; 3765.9)^*	1534.0 (1186.4; 2221.8)	0.875^‡
Cortisol, nmol/L	206.5 (156.5)	192.5 (178.0; 292.5)	121.5 (108.1; 171.7)	213 (183.5; 234.0)	215.3 (191.0; 300.5)	134.6 (119.4; 172.6)	0.256^§
Growth hormone, μg/L	2.1 (0.9; 9.3)	5.9 (0.9; 9.2)	7.7 (3.0; 20.5)	3.1 (0.7;10.9)	6.1 (1.1; 9.1)	11.7 (4.7;30.2)	0.460^§
Insulin, pmol/L	972.7 (722.5; 998.8)	—	591.7 (481.25; 672.9)	911.9 (749.0; 1005.2)	—	557.6 (489.6; 621.5)	0.156^§
Symptom score response
Total, peak	10.0 (10.0; 10.0)	11.0 (10.0; 12.0)	7.0 (6.7; 7.5)	10.0 (10.0; 10.0)	15.5 (10.5; 24.5)	8.5 (6.9; 12.4)	0.011^§
Adrenergic, peak	4.0 (4.0; 4.0)	4.0 (4.0; 5.5)	2.7 (2.7; 3.2)	4.0 (4.0; 4.0)	5 (4.5; 9)	3.0 (2.8; 4.2)	0.009^§
Neuroglycopenic, peak	6.0 (6.0; 6.0)	6.5 (6.0; 7.0)	4.1 (4.0; 4.3)	6.0 (6.0; 6.0)	8.5 (6.0; 15)	5.1 (4.0; 7.9)	0.014^§

Raw median and IQR presented. P-values are based on comparison of peak response between control and intervention using a Wilcoxon signed-rank tests apart from ^† where the P-value is based on the mixed models adjusting for period and sequence using the log-transformed epinephrine values. ^*Data missing from 1 participant, ^‡paired data available for analysis from 14 participants, ^§paired data available for analysis from 15 participants.

AUC, area under the curve; IQR, interquartile range.

Using the method proposed by Grizzle,³³ there was no evidence for a carryover effect for peak epinephrine responses (P = 0.09). Peak epinephrine responses were not different during the hypoglycemic phase of the clamp between the control and intervention period, median (IQR) 188.3 pmol/L (133.7; 402.9) versus 234.7 pmol/L (109.2; 938.9), with a mixed model not indicating a statistically significant effect of study arm on log-transformed epinephrine, P = 0.171. Likewise, there was no difference in the norepinephrine, cortisol, and growth hormone response between the intervention and control periods.

Mean hypoglycemic stimulus during the 40 min of the hypoglycemic phase of the hyperinsulinemic hypoglycemic clamp was comparable between control and intervention period, median (IQR) was 2.72 mmol/L (2.56; 2.77) versus 2.61 mmol/L (2.51; 2.74), P = 0.363.

Symptom responses differed significantly, median (IQR) peak adrenergic score after control was 4 (4; 5.5) versus 5 (4.5; 9) after intervention, P = 0.009; median (IQR) peak neuroglycopenic score after control was 6.5 (6; 7) versus 8.5 (6; 15) after intervention, P = 0.014.

Glycemic outcomes

Glycemic outcomes (CGM) during run-in, after control, and after intervention period are given in Table 2. Median time spent in CGM glucose ranges (<3.0, <3.9, 3.9–10, >10, >13.9 mmol/L) during run-in before the first study arm was not different between intervention and control. Percentage time spent <3.9 and 3.0 mmo/L was significantly lower when using the HCL system compared with the control period: median percentage (IQR) time spent <3.9 mmol/L was 5.2% (3.0; 9.0) after control versus 1.7% (0.9; 2.5) after intervention, P = 0.002, and time spent <3.0 mmol/L was 2.0% (0.4; 3.9) versus 0.3% (0.1; 0.6), respectively, P = 0.002. The median time in target range was higher after using the HCL system, 57.5% (46.1; 68.7) after control versus 71.1% (65.3; 74.7) after intervention, with a mixed model indicating a statistically significant effect of study arm, P = 0.001.

Table 2.

Continuous Glucose Monitoring Results: Percentage Time in Glycemic Ranges During Run-In Before Randomization, After Control and Intervention Period

Outcome	Run-in	Control	Intervention	P
CGM: percentage time in glycemic ranges	n = 17	n = 16
<3.0 mmol/L, %	0.9 (0.5; 1.5)	1.9 (0.4; 3.9)	0.3 (0.1; 0.6)	0.002^*
<3.9 mmol/L, %	4.3 (3.6; 6.5)	5.2 (3.0; 9.0)	1.7 (0.9; 2.5)	0.002^*
3.9–10 mmol/L, %	62.5 (55.3; 69.3)	57.5 (46.1; 68.7)	71.1 (65.3; 74.7)	0.001^†
>10.0 mmol/L, %	31.1 (24.2; 43.3)	34.0 (24.3; 51.4)	28.8 (24.0; 34.9)	0.078^*
>13.9 mmol/L, %	9.4 (4.7; 12.5)	11.6 (6.5; 22.6)	5.7 (3.5; 9.2)	0.004^*
Mean CGM glucose level, mmol/L	8.6 (8.0; 9.7)	9.0 (8.0; 10.4)	8.8 (8.4; 9.1)	0.421^*
SD CGM glucose level, mmol/L	3.4 (3.1; 4.1)	3.8 (3.1; 4.4)	2.9 (2.6; 3.3)	<0.001^*
Coefficient of variation	0.40 (0.37; 0.44)	0.41 (0.38; 0.46)	0.34 (0.31; 0.38)	<0.001^*
Time CGM active, %	86.8 (80.9; 90.7)	80.5 (78.3; 88.3)	93.9 (88.0; 97.9)	<0.001^*

Raw median and IQR presented.

P-values comparing control and intervention are based on Wilcoxon signed-rank tests apart from ^† that is based on mixed models adjusting for period and sequence. ^*Paired data available for analysis from 15 participants.

CGM, continuous glucose monitoring, SD, standard deviation.

Median (IQR) CGM glucose level was comparable after control and intervention period, P = 0.421, median CV was significantly lower while using the HCL system, 0.41 (0.38; 0.46) after control versus 0.34 (0.31; 0.38) after intervention. Mean (SD) percentage time spent in auto mode was 89% (9.8).

Mean HbA1c (SD) after each 8-week period was comparable after control and intervention, 7.4% (±0.8) and 7.3% (±0.7), respectively, P = 0.141.

Self-reported diabetes management outcomes

Self-reported diabetes management outcomes after intervention and control period are given in Table 3.

Table 3.

Self-Reported Diabetes Management Outcomes After Control and Intervention Period

Outcome	Control	Intervention	P
Questionnaire scores	n = 16	n = 16
Gold	5.5 (4.5; 6.0)	4 (3.0; 5.5)	0.033^‡
Clarke	4.0 (4.0; 6.0)^*	4 (4; 5.5)^†	0.872^§
HFS total score	61.5 (47.5; 77)	46.5 (36.5;71)	0.428^‡
Worry subscore	46.5 (34.5; 55.5)	35.5 (29.5; 49.5)	0.222^‡
DTSQ_status	28.0 (25.0;33.0)	29.5 (24.0;33.0)	0.783^‡
Perceived hyperglycemia	4.0 (3.0;4.0)	3.0 (3.0;4.0)	0.329^‡
Perceived hypoglycemia	3.0 (2.0;4.0)	2.0 (1.0;3.0)	0.004^‡

Raw median and IQR presented. P-values are based on comparison between control and intervention on Wilcoxon signed-rank tests.

Data missing from 2 participants (invalid score), ^†data missing from 1 participant (invalid score), ^‡paired data available for analysis from 15 participants, ^§paired data available for analysis from 13 participants.

DTSQ, Diabetes Treatment Satisfaction Questionnaire; HFS, Hypoglycemia Fear Survey.

The Gold score reported by the participants after intervention was lower compared with control, median (IQR) 5 (4.5; 6) after control versus 4 (3; 5.5) after intervention, P = 0.033; however, there was no difference in the Clarke score, P = 0.872.

Total HFS score and the worry subscore did not change. Diabetes treatment satisfaction (DTSQ) was comparable after control and intervention, P = 0.783; however, the perceived frequency of hypoglycemia was significantly lower after intervention compared with control, P = 0.004.

Conclusions

In this pilot study, short-term use of HCL insulin delivery system failed to demonstrate an improvement in counter-regulatory hormonal responses to hypoglycemia. However, it resulted in improved adrenergic and neuroglycopenic symptoms during hypoglycemia. The study also showed that although participants continued to have self-reported impaired hypoglycemia awareness, there was an improvement from baseline. Participants spent a median of 4 min per day <3 mmol/L with HCL compared with a median of 29 min per day during the control period. Less time spent in hypoglycemia and more time spent in target range after the use of a HCL system corroborate findings of previously published closed loop studies,^21,25,34 and also in people at increased risk for hypoglycemia.²⁴

In this study, when people with IAH used HCL, they spent less time in hypoglycemia with more time in target glucose range and less time in the very high glucose range. This is significant as in earlier studies, restoration of hypoglycemia was achieved by meticulous avoidance of hypoglycemia at the expense of higher overall blood glucose levels as reflected by higher HbA1c values.^7,9,14 However, the reduction in time spent in hypoglycemia was not associated with improvement in counter-regulatory hormones during controlled hypoglycemia in our study.

This study indicated better perception of hypoglycemia symptoms after the use of a HCL system. Previous studies in people with IAH showed that the hypoglycemia symptom and hormonal response can be restored by the use of diabetes technology such as CGM and/or insulin pumps.^14,15 However, the use of a HCL insulin pump over 8 weeks did not result in improved catecholamine response.

This may be explained by two reasons: first, the short duration of the use of the HCL insulin system in the study design. Fritsche et al. found an improvement of beta-adrenergic sensitivity after 2 months of hypoglycemia avoidance and an improvement of symptomatic but not hormonal responses after 4 months,³⁵ whereas Leelarathna et al. showed an improvement in both symptomatic and hormonal response after 6 months of hypoglycemia avoidance.¹⁵ A second reason for the lack of finding a restored catecholamine response may be the small number of participants in this study that may have precluded detecting a significant change. However, findings from this study enabled us to generate estimates of potential outcome measures and assess the feasibility of the study design to inform a larger trial.

This study also demonstrates a small improvement in self-reported hypoglycemia awareness and the frequency of perceived hypoglycemia after the use of a HCL insulin system. Although some studies assessing the use of diabetes technology in people with IAH showed an improvement in self-reported awareness of hypoglycemia for up to 24 months,^18,36 others did not.^16,17,37 Although our study participants continued to have IAH according to the Gold score, there was an improvement from baseline. Furthermore, results of self-reported hypoglycemia awareness should always be interpreted with caution. A reduction may be attributed to “technological awareness” and not true restoration of physiological awareness.^37,38

The failure to demonstrate an improvement in other self-reported outcomes such as fear of hypoglycemia evaluated with the HFS total and worry score is in line with findings from a longer term real-life study.³⁹

This study is the first study to assess the impact of a HCL insulin delivery system on restoration of hypoglycemia awareness in people with T1D and IAH. A strength of this study is that it addresses the important question of the effect of a HCL insulin delivery system on hypoglycemia awareness in a randomized trial. This is particularly important in this vulnerable cohort with IAH, since an improvement in hypoglycemia awareness may improve not only glycemic control but also acute complications such as severe hypoglycemia.

This pilot study has several limitations. First, it was an open-label study and participants could not be blinded to the insulin pump system they were using. Therefore, a reporting bias of self-reported hypoglycemia awareness scores and the other patient-reported outcomes may have occurred. Hence, results of the hypoglycemia awareness score and hypoglycemia symptom scores should be interpreted with caution.

Another limitation is the short duration of the intervention and the relatively small sample size of this study and, therefore, the lack of power to detect small differences in the outcome measures. Furthermore, there was a considerable drop-out rate for various reasons, although most drop-outs occurred before randomization, before or during the first clamp study. Lastly, the additional support provided by the health care professionals may have contributed to the improvements seen.

These limitations reduce the generalizability of the results. A long-term study with a higher number of participants using a parallel study design will address this further and evaluate whether the trends toward improvements in hypoglycemia awareness shown in this pilot study persist and whether longer use of a HCL system results in improved counter-regulatory hormonal response.

To conclude, the use of an automated insulin delivery system has the potential to contribute to the restoration of subjective hypoglycemia awareness through reduction of hypoglycemia exposure, without deterioration of glycemic control.

Footnotes

Authors' Contributions

M.A.B. was responsible for the study design, data collection, data analysis, and article preparation. M.B.A. contributed to the study design, data collection, and reviewed and edited the article. J.D., N.P., and J.O. contributed to data collection and reviewed and edited the article. M.D.B. contributed to the study design and reviewed and edited the article. G.S. was responsible for data analysis and reviewed and edited the article. T.W.J. and E.A.D. contributed to the study design and data analysis. T.W.J. is the guarantor of this study and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by the JDRF Australian Type 1 Diabetes Clinical Research Network (4-SRA-2016-350-M-B), a special initiative of the Australian Research Council (ARC), and National Health and Medical Research Council (NHMRC) (ID APP1078190) and the Perth Children's Hospital Foundation (PCH) (9729). M.A.B. was funded by a research fellowship of the Swiss National Science Foundation (SNSF) (P2BSP3_161893); Walter and Margarete Lichtenstein Foundation of the University of Basel, Switzerland; and supported by a Research Training Program Fellowship from the University of Western Australia. M.B.A. was supported by JDRF mentored clinical research fellowship. Medtronic^® provided the study equipment (HCL insulin pumps and sensors) through an unrestricted grant.

Supplementary Material

Supplementary Table S1

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