The results of this study build on evidence from a feasibility study evaluating fully closed-loop therapy in people with type 2 diabetes and end-stage renal failure on dialysis Here, we demonstrate that this technology can benefit the wider population with type 2 diabetes requiring insulin and can be safely implemented in the home setting.

As a considerable proportion of people with type 2 diabetes struggle to achieve the recommended glycemic targets with currently available therapies, including insulin therapy 14 , fully closed-loop systems offer a new approach to improve glycemic outcomes to reduce the risk of long-term complications.

We postulate that this might be due to the higher personal glucose targets applied for the more vulnerable population requiring dialysis, who have a greater risk of hypoglycemia. The majority of participants in the present study used the default glucose target of 5.

Analysis of glucose metrics in fortnightly intervals in the present study shows that closed-loop insulin delivery results in an almost immediate improvement in glycemic control compared with standard insulin therapy proportion of time in target range, In this study, very few participants used a glucose sensor as part of their usual care.

Therefore, some of the glycemic benefits observed during the closed-loop therapy period may be attributable to use of a continuous glucose monitor alone. A major contributor to the clinical inertia in the escalation of insulin therapy among healthcare professionals, and a feared side effect of insulin among people with type 2 diabetes, is the risk of hypoglycemia 15 , We have shown that fully closed-loop insulin delivery does not increase the risk of hypoglycemia despite improved glycemic control and there were no episodes of severe hypoglycemia during closed-loop therapy.

The study cohort spent very little time in hypoglycemia during both intervention periods. The degree of comorbidity burden in our study population is reflected in the number of nonstudy-related SAEs reported during the study. These were hospital admissions for treatment of comorbidities diabetic foot disease or infection.

One severe adverse event was related to study procedures and occurred during the closed-loop therapy period an abscess at the pump cannula site requiring hospital admission for incision and drainage with no long-term sequelae. Closed-loop therapy was continued provided that the participant was able to manage the system themselves and the treating healthcare professionals were satisfied that this was clinically appropriate.

Training and maintenance of study devices by participants was acceptable. One participant withdrew because of difficulty managing the devices, whereas all other participants were able to manage the devices independently and reported a high degree of satisfaction while using the closed-loop system.

Feedback from users highlighted the elimination of the need for injections or finger-prick testing, and increased confidence in managing blood glucose as key benefits Supplementary Table 8. There was a trend toward higher levels of hypoglycemia-related anxiety during closed-loop therapy, which may reflect increased awareness and monitoring of glucose levels associated with sensor glucose use.

Questionnaire feedback on drawbacks of the closed-loop system mainly consisted of practical annoyances with wearing of devices, connectivity issues between devices and a perceived increase in hypoglycemia episodes. Increased exposure to diabetes technologies in people with type 2 diabetes insulin pumps and glucose sensors may mitigate some of these negatives if the glycemic benefits are perceived to be worthwhile.

Future-generation closed-loop systems with improved connectivity, longer infusion set wear time and larger insulin reservoirs may also resolve these issues. The strengths of this study include its randomized crossover design and the inclusion of a wider population with type 2 diabetes self-managing the devices in an outpatient setting, increasing the scope for uptake of this technology.

The use of a fully closed-loop system obviates the need for ongoing healthcare professional input with optimization and support following initial training on the devices.

The limitations of the study are that study participants were recruited from a single center and one general practice, and the group was not ethnically diverse, with only one participant not of white ethnicity. Although the present study demonstrated glycemic benefits over the 8-week intervention period, the results should not be generalized beyond this period.

We also did not collect data on the use of boost and ease-off functionality during the closed-loop therapy period. There were a relatively large number of protocol deviations Supplementary Table 9 ; however, the majority of these 25 out of 30 were outside of protocol visits with no effect on data analysis.

In conclusion, this study suggests that fully closed-loop insulin delivery is a safe and efficacious approach to manage type 2 diabetes in adults.

Larger randomized controlled trials with diverse populations and longer follow-up are required to ensure generalizability across a wider target population and to determine whether it is a cost-effective approach that provides sustained benefits for people with type 2 diabetes requiring insulin therapy.

The study used an open-label, single-center, randomized, two-period crossover design, contrasting fully closed-loop glucose control using faster-acting insulin aspart Fiasp, Novo Nordisk closed-loop and standard multiple daily insulin injection therapy control during two 8-week periods of unrestricted living.

The intervention periods were separated by a 2-week to 4-week washout period during which participants used their pre-study treatment. Assignment of participants to the two groups with a different order of interventions was random.

Ethical and regulatory approvals were obtained from the London-Stanmore Ethics Committee and the Medicines and Healthcare Products Regulatory Agency. The study protocol is provided in the Supplementary Information.

The safety aspects of the trial were overseen by an independent data and safety monitoring board. The study is registered with ClinicalTrials. Participants had to be literate in English, willing to perform regular finger-prick blood glucose monitoring and willing to wear study devices and follow study-specific instructions.

Exclusion criteria were type 1 diabetes, pregnancy or breastfeeding, severe visual or hearing impairment, allergy to insulin or the adhesive of plasters or serious skin disease affecting device placement, lack of reliable telephone facility for contact, alcohol abuse, Illicit or prescription drug abuse, any physical or psychological disease, or use of medication s likely to interfere with the conduct of the trial or interpretation of the results.

Written informed consent was obtained from all study participants before any study-related activities. Participants received £30 for each 8-week study period completed, and all reasonable traveling expenses were reimbursed.

Participants were randomized in a ratio to an 8-week period of fully closed-loop glucose control with faster-acting insulin aspart Fiasp followed by an 8-week period of standard insulin therapy, or vice versa. Randomization was performed using a web-based, permuted blocks-of-four randomization method to assign study participants to one of the two treatment sequences.

Participants and investigators were not masked to the intervention used during each period because of the nature of the interventions. Study visits and procedures are shown in Supplementary Tables 10 and Participant demographics and medical history, body weight and height, HbA1c and total daily insulin dose were recorded at enrollment.

The sex of participants was self-reported. The closed-loop app CamAPS HX, CamDiab involves the Cambridge adaptive model predictive control algorithm HX software v. Over time, the algorithm adapts to observed glucose patterns, enabling it to tailor insulin delivery more accurately to minimize glucose excursions.

The default target glucose used by the closed-loop algorithm is 5. Before the closed-loop therapy period commenced, participants underwent a 1-h to 2-h training session with the study team on the use of the insulin pump, continuous glucose monitoring and closed-loop system. The usual insulin therapy of participants was discontinued, but all other medications were continued as directed by their clinical team without interference from the study team.

The insulin pump delivered faster-acting insulin aspart continuously as directed by the algorithm, without prandial boluses or carbohydrate announcement. The study did not interfere with the usual activities or dietary intake of participants.

Other diabetes therapies were continued throughout the closed-loop therapy period. Participants were given h access to a study helpline in the event of any study-related issues.

At the end of the closed-loop therapy period, devices were removed and the usual insulin therapy of participants was restarted.

During the 8-week control therapy period, a glucose sensor Dexcom G6 was worn by participants throughout the standard insulin therapy period. Sensor glucose on the sensor glucose receiver was masked to the participant and investigators until the end of the study.

Other diabetes therapies were continued throughout the control therapy period. Fingerstick blood glucose monitoring was performed by participants as per their usual practice.

Participants were unrestricted in their usual activities and dietary intake. Participants remained under the care of their local clinical team for glycemic management. At the end of the standard insulin therapy period, the glucose sensor was removed and the usual insulin therapy of participants was continued.

Questionnaires were completed by participants at the end of each study period. At the end of the closed-loop therapy period, participants completed a closed-loop experience questionnaire to feed back on the closed-loop system, provide suggestions for improvement and indicate whether they would recommend the system to friends or family.

The primary endpoint was the proportion of time the sensor glucose measurement was in the target glucose range of 3.

Key endpoints included the proportion of time with sensor glucose above Secondary efficacy endpoints included the proportion of time with sensor glucose below 3. and the coefficient of variation of sensor glucose, and the total daily insulin dose.

Utility evaluation included percentage time of sensor glucose availability, and percentage time of closed-loop operation. Psychosocial assessments were measured using questionnaires collected at the end of each study period.

Exploratory endpoints included analysis of a subset of sensor glucose metrics time in target range, mean glucose, s. There was no prespecified analysis disaggregated by sex. As previous studies using closed-loop systems in an inpatient setting and in outpatients requiring dialysis may not provide reliable information about the s.

of the primary endpoint in this particular population, no formal power calculation was applied. The sample size corresponds to the sample size of previous feasibility closed-loop randomized trials 10 , 12 , The statistical analysis plan was agreed by the investigators in advance.

All analyses were carried out on an intention-to-treat basis. Comparisons were made between values obtained during the 8-week randomized interventions. A two-sample t -test on paired differences was used to compare normally distributed variables For highly skewed residuals for key and secondary endpoints, a transformation windsorization was used.

A gatekeeping strategy was used, in which the primary endpoint was tested first and, if passing the significance testing, other key endpoints were tested in order. If a nonsignificant result was encountered, formal statistical hypothesis testing was terminated, and analysis of any key endpoints below the one in question any that were lower in the hierarchy was considered exploratory.

for normally distributed values or median IQR for non-normally distributed values. Endpoints were calculated using GStat software v. Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

The data that support the findings of this study are available from the corresponding author for the purposes of advancing the management and treatment of diabetes.

All data shared will be de-identified. The study protocol and statistical analysis plan are available in the Supplementary Information. Chatterjee, S. Type 2 diabetes. Lancet , — Article CAS Google Scholar. International Diabetes Federation.

International Diabetes Federation Diabetes Atlas , 9th edn Skyler, J. et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association.

Diabetes Care 32 , — Article Google Scholar. Nauck, M. Treatment of type 2 diabetes: challenges, hopes, and anticipated successes. Lancet Diabetes Endocrinol. Cahn, A. New forms of insulin and insulin therapies for the treatment of type 2 diabetes.

Heller, S. Hypoglycemia in patient with type 2 diabetes treated with insulin: it can happen. BMJ Open Diabetes Res. Care 8 , e Boughton, C. New closed-loop insulin systems. Diabetologia 64 , — Leelarathna, L.

Hybrid closed-loop therapy: where are we in ? Diabetes Obes. Forlenza, G. Current status and emerging options for automated insulin delivery systems. Diabetes Technol. Thabit, H. Closed-loop insulin delivery in inpatients with type 2 diabetes: a randomised, parallel-group trial.

Bally, L. Closed-loop insulin delivery for glycemic control in noncritical care. Fully closed-loop insulin delivery in inpatients receiving nutritional support: a two-centre, open-label, randomised controlled trial.

Fully automated closed-loop glucose control compared with standard insulin therapy in adults with type 2 diabetes requiring dialysis: an open-label, randomized crossover trial.

Khunti, K. Achievement of guideline targets for blood pressure, lipid, and glycaemic control in type 2 diabetes: a meta-analysis.

Diabetes Res. The International Hypoglycaemia Study Group. Hypoglycaemia, cardiovascular disease, and mortality in diabetes: epidemiology, pathogenesis, and management. Khunti, S. Therapeutic inertia in type 2 diabetes: prevalence, causes, consequences and methods to overcome inertia.

Polonsky, W. Investigating hypoglycemic confidence in type 1 and type 2 diabetes. Cox, D. Fear of hypoglycemia: quantification, validation, and utilization.

Diabetes Care 10 , — Assessment of diabetes-related distress. Diabetes Care 18 , — Design and Analysis of Cross-Over Trials , 3rd edn CRC Press, Book Google Scholar. Download references. Dexcom supplied discounted continuous glucose monitoring devices and sensors for the study; company representatives had no role in the study conduct.

This study was supported by the National Institute for Health and Care Research Cambridge Biomedical Research Centre. The University of Cambridge has received salary support for M.

from the National Health Service in the East of England through the Clinical Academic Reserve. The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. We are grateful to all of the study participants for their contribution, time and support.

The views expressed are those of the authors and not necessarily those of the National Institute for Health and Care Research, the Department of Health and Social Care or other funders. Aideen B. Daly, Charlotte K.

Boughton, Munachiso Nwokolo, Malgorzata E. Wilinska, Alina Cezar, Mark L. Cambridge University Hospitals NHS Foundation Trust, Wolfson Diabetes and Endocrine Clinic, Cambridge, UK. Charlotte K. You can also search for this author in PubMed Google Scholar.

and R. co-designed the study. and S. NCT, clinicaltrials. Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest. filter your search All Content All Journals Diabetes Care.

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Article Navigation. Original Article August 24 Fully Closed-Loop Glucose Control Compared With Insulin Pump Therapy With Continuous Glucose Monitoring in Adults With Type 1 Diabetes and Suboptimal Glycemic Control: A Single-Center, Randomized, Crossover Study Charlotte K.

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