Efficacy and safety of closed-loop control system for type one diabetes in adolescents a meta analysis

This meta-analysis compares the efficacy and safety of Closed-Loop Control (CLC) to Sensor-Augmented Insulin Pump (SAP) for adolescent patients with Type 1 Diabetes Mellitus (T1DM). Eleven randomized-controlled trials were included with a total of 570 patients, from a total of 869 articles found adhering to PRISMA guidelines. The efficacy of the therapies were evaluated from the day, night and during physical activities monitoring of the of the mean blood glucose (BG), Time In Range (TIR), and Standard Deviation (SD) of the glucose variability. The safety measure of the therapies, was assessed from the day and night recording of the hypoglycemic and hyperglycemic events occurred. Pooled results of comparison of mean BG values for day, night and physical activities, − 4.33 [− 6.70, − 1.96] (P = 0.0003), − 16.61 [− 31.68, − 1.54] (P = 0.03) and − 8.27 [− 19.52, 2.99] (P = 0.15). The monitoring for day, night and physical activities for TIR − 13.18 [− 19.18, − 7.17] (P < 0.0001), − 15.36 [− 26.81, − 3.92] (P = 0.009) and − 7.39 [− 17.65, 2.87] (P = 0.16). The day and night results of SD of glucose variability was − 0.40 [− 0.79, − 0.00] (P = 0.05) and − 0.86 [− 2.67, 0.95] (P = 0.35). These values shows the superiority of CLC system in terms of efficacy. The safety evaluation, of the day, night and physical activities observations of average blood glucose goal hypoglycemic events − 0.54 [− 1.86, 0.79] (P = 0.43), 0.04 [− 0.20, 0.27] (P = 0.77) and 0.00 [− 0.25, 0.25] (P = 1.00) and hyperglycemic events − 0.04 [− 0.20, 0.27] (P = 0.77), − 7.11 [− 12.77, − 1.45] (P = 0.01) and − 0.00 [− 0.10, 0.10] (P = 0.97), highlights the commendable safety factor of CLC. The CLC systems can be considered as an ideal preference in the management of adolescents with type 1 diabetes to be used during a 24 h basis.

intake control, strict medical control and continuous monitoring makes it difficult for young youth to control their T1DM situations.
The management of T1DM has been revolutionized by the recent advances in technology, like the insulin pumps and continuous glucose monitoring sensors 12 .The Sensor-Augmented Insulin Pump (SAP), which mimics the insulin production by the pancreas via continuous subcutaneous insulin injection (CSII), is a conventional treatment 13 .This traditional approach of SAP therapy does not functionally prevent the chances of occurrence of hypoglycemia.This was a hindrance to the guarantee that the mean blood glucose value will meet therapeutic expectations after using the SAP therapy 14 .The most current development is the integration of the insulin pumps and continuous glucose monitoring sensors, to modify and administer insulin based on the values detected by the sensor 15 .This paved way for the artificial pancreas or called as the closed-loop system for diabetes management.The Closed-Loop Control System (CLC) insulin delivery systems is characterized by real-time glucose-responsive insulin administration and combines glucose-sensing and insulin-delivery components 16 .
Though these advances in diabetes technology are widely used in clinical practice 17 , clinical evidence for the practice of use of CLC insulin delivery as an alternative to SAP therapy has not yet done or available 18 .Studies on inpatient and outpatient adolescent patients with T1DM have been done on closed-loop systems with improved glycemic outcomes and reduction in hypoglycemia in children, especially in the overnight period.CLC has been associated with fewer adverse effects than other insulin therapies in the treatment of adolescents with T1DM [19][20][21][22][23][24][25][26] .Though the effectiveness SAP insulin delivery was stated to be effective in maintaining the daytime glycemic outcomes, it needs to be compared with contemporary interventions [27][28][29] .There is a serious gap in the availability of evidence to support clinical decisions for the right insulin therapy for adolescent T1DM.It is very crucial to identify if Closed-loop insulin delivery can be a potential replacement for SAP insulin therapy of adolescent T1DM management by comparing the glycemic outcomes and hypoglycemic events to measure the adverse effects of the therapies.This meta-analysis is therefore aimed to compare the efficacy and safety of CLC to SAP for adolescents with type 1 diabetes (T1DM) by evaluating the glycemic outcomes and hypoglycemic events of the two therapies.
The participants, intervention, comparisons, outcomes, and type of studies (PICO) of the current review were as follows: Participants (P): Patients younger than 19 years, Intervention (I): Closed-Loop Control (CLC) in T1DM adolescent patients.Comparisons (C): Sensor-augmented insulin pump (SAP) in T1DM adolescent patients.Outcomes (O): Efficacy of the intervention assessed by average blood glucose value measured by continuous glucose measurement, time in range (TIR), and standard deviation (SD) of glucose variability.Safety was evaluated according to reported hypoglycemic events.Hence this review raises the research question "Does Closed-Loop Control System have a better efficacy and safety compared to Sensor-Augmented Insulin Pump for managing type one diabetes in adolescents?"

Methodology
This study adheres to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 30 and complies all the steps advised in Cochrane handbook of systematic reviews.This study has been registered with Prospero with ID CRD42022333310.

Search strategy.
A through bibliographic search of electronic databases of PubMed, MEDLINE, EMBASE, and the Cochrane Library was undertaken in this study.Boolean operators were used for the keywords designed, for searching and identifying the relevant literature.Table 1 is explanatory of the combination of keywords used in this study for the assimilation of articles to review.Grey literature was obtained by searching Web of Science, ProQuest Dissertations and clinicaltrials.gov.The reference sections of retrieved original articles and reviews were scanned for studies that might have been missed in the primary searches.Studies were filtered with regard to study design, methodological features, the reported glycemic outcomes, and the adverse effects evaluated under each study.
The participants, intervention, comparisons, and outcomes (PICO) of the current meta-analysis were as follows.

Data extraction.
Relevant full text articles were assimilated after review of the titles and abstracts.The eligibility criteria including the inclusion and exclusion criteria for this study are described in Table 2. Figure 1 illustrates the PRISMA flow diagram for the studies selected in the search process and eligibility appraisal.Review manager 5.4.1 (Revman, Cochrane Collaboration, and Oxford, UK) was used to manage, analyze, and synthesize the included study data.The institutional research board and ethics committee ruled out that approval was not required for this study being a review study.
Data extraction of the related was done using a custom made data-extraction form in excel.All relevant information on the included studies was extracted into an electronic database, including participant and intervention characteristics, relevant glycemic outcomes and hypoglycemic events to evaluate the adverse effects of treatments, type of insulin delivery technology used and industrial funding or influence on the study.www.nature.com/scientificreports/Quality assessment.The risk of bias method from the Cochrane Collaboration was used 33 to appraise the quality of the included studies.The studies were graded as low, high, or unclear risk of bias for each of the following items using this method.The domains included in this grading of risk of bias were the random sequence generation and allocation concealment, (both items relate to selection bias), masking of participants and personnel (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other biases.Data analysis.Statistical analysis and the assessment of heterogeneity was done for each reported outcomes in the included studies.All the aggregated outcome measurements has been unified in units to meaningfully analyze the data.The weighted mean difference (WMD) with 95 % confidence interval (CI) was calculated for all the continuous outcomes.The I 2 statistic and χ 2 test was used to evaluate the heterogeneity of the analysis results.If I 2 > 50% or p < 0.1 for the χ 2 test, the random-effects model was adopted; otherwise, the fixed-effects model was used 35 .P value less than 0.05 was considered statistically significant.All statistical analyses were performed by RevMan software (version 5.0, Oxford, United Kingdom).When the level of heterogeneity was less than 50%, a fixed-effect model was used 36 .The meta-analysis was performed with Review manager 5.4.1 (Rev-Man, Cochrane Collaboration, Oxford, UK).

Informed consent.
For this type of study, formal consent is not required.
Patient and public involvement.This study being a meta-analysis systematic literature review, the patients selected were recruited by the researchers of the included studies.All the patient and families related aspects involved in design and implementation of the interventions were priori addressed by the authors of the selected studies.

Results
Study search and data extraction.An initial search gave 869 articles from the keyword combinations.
The included trials were published between 2015 and 2022.After strict screening and quality assessment 11 [37][38][39][40][41][42][43][44][45][46][47] Randomized Controlled Trials (RCT) were selected for the review which were relevant to the search terms and criteria.A total of 570 adolescent patients were included in this study from the selected studies.This included 298 patients who took CLC insulin therapy and 272 patients who had SAP as their insulin therapy.Only 10 [37][38][39][40][41][42][43][44]46,47 articles were included in the meta-analysis after reviewing and accounting for heterogeneity. (Fig.).Table 3 provides the summary of the data extracted from the attributes of the included studies.

Characteristics and quality of trials.
In relation to the masking of participants and personnel, almost all of the trials were rated at ''low risk of bias'' (9 of 11 trials, 81.81%); as for attrition bias and reporting bias, almost all the trials were rated at ''low risk of bias, '' because they reported the complete outcome data (10 out of 11 trials, 90.90%).There were no studies at ''high risk of bias'' with any issues relating to random sequence generation, allocation concealment and masking of outcome assessment (11 out of 11 trials, 100%).Figure 2 shows the risk of bias summary based on review quality appraisal judgements about each risk of bias item for each included study.
Efficacy: glycemic outcomes during day, night and during strenuous physical activities.The results from the included studies were pooled by unifying the measurement units to mg/dL.Hence all the pooled comparison results in this meta-analysis are in mg/dL.Test for overall effect: Z = 4.30 (P < 0.0001)] Excluding 4 studies 40,43,44,46 to due to statistical heterogeneity only four studies [37][38][39]46      Figure 5a and b shows the Forest plot of this stated results. Figre 5a and b are explaining these results.Two studies 39,50 reported the variability as the coefficient of variation and it was converted to standard deviation and pooled.It can be noted that no studies directly reported the standard deviation of glucose variability during physical activities.
Hyperglycemic events: day, night and during strenuous physical activities.Hyperglycemic events were monitored to assess the AEs of both the insulin delivery systems under comparison.Six studies [37][38][39][40][41]43

Discussion
A significant morbidity and mortality have been associated with T1DM among adolescents due to its poor prognosis.Before, SAP therapy was a crucial advancement in diabetes treatment but, currently the development of CLC insulin delivery systems has been dramatically gaining clinical importance.Till now, there has been no comprehensive meta-analyses comparing the day and night time efficacy and safety features between traditional SAP therapy and the currently used CLC insulin delivery for pediatric and adolescents with type 1 diabetes.This study is the first meta-analysis to examine the day and night time efficacy and safety monitoring comparison of CLC insulin delivery systems versus SAP therapy in the treatment of adolescents with T1DM.The results from this study shows the supreme authority of the CLC insulin delivery systems in maintaining all the glycemic outcomes than SAP therapy for day and night values of mean BG, TIR, and SD of glucose variability.This study considered the monitoring results during daily routine activities along with strenuous physical activities like skiing and camp activities.Thus, this study, clearly updates and upholds well-defined evidence of the CLC insulin delivery's efficacy to be clinically used for young patients with T1DM.The safety comparison results from this studies identifies that, CLC insulin delivery was associated with fewer AEs, especially hypoglycemic and hyperglycemic-related events during day and night, than SAP which deems CLC to be an ideal treatment of choice for adolescents with type 1 diabetes.

Limitations
The limitation of this study is that only 11 RCTs were included, and the number of included patients were limited.One 45 among the included studies though it participated adolescent patients, failed to separate the adolescent result reports from the adults.Many studies and RCTs are concentrated around the insulin therapy of adults and pediatric T1DM based studies are not given enough attention.Although in this study, CLC insulin delivery was seen to have decreased risk of AEs, hypoglycemia is still the dominant AE.There is an imminent need of extensive high-quality RCTs to ensure the reliability of this conclusion.The included studies were mostly conducted in Europe and United States, which may cause a regional bias in identifying with race related outcomes.There was significant heterogeneity when all the included studies were pooled, which could decrease the reliability of the results.The included studies used different equipments, which possibly increased the heterogeneity of the results.This led to the exclusion of studies with conflicting results from the majority of included studies and had more confidence results.For this reason, random-effects meta-analysis was utilized to incorporate heterogeneity among studies.Finally, all the 11 [37][38][39][40][41][42][43][44][45][46][47] included studies had the industrial support on their research which can have potential influence results reported by them, favoring the equipment or technology used in the experiment.

Figure 2
is descriptive of the risk of bias tool used in this study.Outcome evaluation.Efficacy: glycemic outcomes-day, night and during strenuous physical activities.The primary endpoints were the day, night and during strenuous physical activities monitoring of the mean (1) Blood Glucose (BG) level from continuous glucose monitoring, (2) Time In range (TIR) for the percentage of time spent in normoglycemia, 70-180 mg/dL34 , and (3) Standard Deviation (SD) of glucose variability.

Figure 2 .
Figure 2. Risk of bias summary about the methodological quality of studies included using the Cochrane risk of bias tool.Symbols show low risk of bias (+), and high risk of bias (−).

Figure 3 .
Figure 3. (a) Forest plot of comparison: Mean BG-Day.(b) Forest plot of comparison: Mean BG-Night.(c) Forest plot of comparison: Mean BG-Physical activity.

Figure 4 .
Figure 4. (a) Forest plot of comparison: Time in Range TIR-Day.(b) Forest plot of comparison: Time in Range TIR-Night.(c) Forest plot of comparison: Time in Range TIR-Physical activity.

Figure 5 .
Figure 5. (a) Forest plot of comparison: SD of glucose variability-Day.5(b) Forest plot of comparison: SD of glucose variability-Night.
CLC insulin delivery exhibits significantly better day and night efficacy and safety than SAP therapy in adolescents with type 1 diabetes.Closed-loop safely and significantly improves glycemic control, maintains time in range, reduces hypoglycemia and hyperglycemia in adolescent populations with T1DM.Tedious and continuous technical improvement of closed-loop systems is required to further improve safety and efficacy, likely through the development of open-frame, personalized, cloud-based ecosystems.

Table 1 .
Keyword strategy used in the database search.Efficacy of the intervention assessed by average blood glucose value measured by continuous glucose measurement, time in range (TIR), and standard deviation (SD) of glucose variability.Safety was evaluated according to reported hypoglycemic events.

Table 2 .
Eligibility criteria for study selection in this study.
Studies which included at least 3 of the glycemic outcomes: % time in range (TIR) 70-180 mg/dL, mean glucose, mg/dL, coefficient of variation and hypoglycemic events Reviews, letters, editorials, survey reports, abstracts only availableStudies participating T1DM adolescent patients Studies with descriptive results and outcomes not numerically reportedFull text availability Non-English articles

Table 3 .
The summary of the attributes included studies.