Effetto dei sistemi automatizzati di somministrazione di insulina sugli esiti riferiti dalla persona nelle persone con diabete: una revisione sistematica e meta-analisi.

Introduction

Automated insulin delivery (AID) systems have changed the landscape of management of type 1 diabetes.1 Hereby, an algorithm calculates the dose of insulin to be administered based on data from a continuous glucose monitoring (CGM) sensor. AID systems have consistently shown that they significantly improve glycaemic control.2,3 In randomised controlled trials, AID systems generally increase time in range (% 70–180 mg/dl [3.9–10 mmoL/l]) by 10% compared to, for example, sensor-augmented pump therapy.2,3 There is also convincing evidence that AID systems can reduce the exposure to hypoglycaemic values.2,4

Besides these glycaemic effects, there is the expectation that AID systems at least partly simplify diabetes management and alleviate some of the burden of diabetes self-management.5, 6, 7 Thus, the effects of AID systems on psychosocial aspects are important to consider in order to fully comprehend the effects of AID therapy on diabetes management.5,8 Recent reviews highlighted the importance of person-reported outcomes (PROs) in evaluating new technological interventions for diabetes and established key domains of PROs such as diabetes distress, sleep quality, fear of hypoglycaemia, and quality of life.9, 10, 11, 12 A narrative review by Speight et al. showed the complexity of analysing effects of AID therapy on PROs. The review showed the multitude of existing PRO measures that are being used in evaluation studies. They did not find conclusive evidence for the effectiveness of AID systems regarding improved psychosocial well-being but highlighted the heterogeneity in the effects on different PROs, for example diabetes-specific vs. generic PROs.8 A recent systematic review and meta-analysis demonstrated beneficial effects of AID systems on fear of hypoglycaemia.13 However, this meta-analysis did not analyse effects of AID systems on other important PROs such as diabetes distress, sleep quality, treatment satisfaction, and quality of life. Thus, there is a need for a comprehensive systematic review and meta-analysis on the effects of AID therapy on different dimensions of PROs. By analysing randomised controlled trials and observational trials, we conducted a systematic review and meta-analysis on the effects of AID system on a variety of PRO measures.

Methods

This systematic review and meta-analysis follows the guidelines for Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The protocol was registered in PROSPERO in August 2022 (PROSPERO CRD42022352502). Four electronic databases (PubMed, PsycINFO, Cochrane, and GoogleScholar) were searched until August 7th, 2024. A combination of MeSH Terms and/or keywords such as “Pancreas, Artificial”, “Patient Outcome Assessment”, “automated insulin delivery”, “hybrid closed loop”, “patient reported outcomes”, “quality of life”, “distress”, “fear of hypoglycaemia”, “well-being” combined with Boolean operators “AND” “OR” were used. The full search strategy is reported in Supplementary Table S1. Studies that were published in English or German and either observational studies, case control studies, controlled trials, or randomised controlled trials, were included. For narrative synthesis, also qualitative studies were included. No restriction on population was applied, so that studies could include children, adolescents, adults, or pregnant women with type 1 diabetes or adults with type 2 diabetes. The intervention had to be an AID system consisting of an insulin pump, continuous glucose monitoring system (CGM), and an algorithm that controls insulin delivery based on CGM data. The control group, if included, could either be multiple daily injection (MDI) of insulin, stand-alone insulin pump therapy, or sensor augmented insulin pump therapy but without a control algorithm or with low glucose suspend function only. Studies were included if they reported results of at least one PRO assessed via a validated questionnaire. No restrictions were made on the type of PRO, and all PRO were considered for the systematic review. Studies only reporting glycaemic outcomes were not included.

The systematic review was conducted using the Covidence tool. The literature search and abstract screening was performed by two independent reviewers (T.R. and C.G.). Full-text screening and risk of bias assessment was performed by three independent researchers (T.R., C.G., and D.E.). If necessary, consensus was reached by discussing the respective paper with a fourth reviewer (N.H.). Data extraction was independently performed by T.R. and C.G., and validated by D.E.

Prior to data extraction, an extraction mask was created in Covidence. Duplicate data was resolved by D.E. in the validation process of data extraction. All data for every reported PRO measure was extracted. For randomised controlled trials, baseline and follow-up mean scores and standard deviation (SD) for the intervention and control group were extracted; for observational trials, pre and post scores (mean and SD) were extracted. Median and interquartile range were transformed into mean and SD following the estimation provided by Wan et al.14 Key PRO included diabetes distress, fear of hypoglycaemia, hypoglycaemia unawareness, quality of life, sleep quality, treatment satisfaction, and the INSPIRE measure. Three questionnaires assessing diabetes distress were considered: Problem Areas in Diabetes (PAID) scale,15 Diabetes Distress Scale (DDS),16 and the DDS for type 1 diabetes (T1-DDS).17 Since they all address diabetes distress, they were combined in the meta-analyses and one meta-analysis was calculated for all diabetes distress measures. For fear of hypoglycaemia, the Hypoglycaemia Fear Survey (HFS-II) with its two subscales for worries (HFS-W) and behaviour (HFS-B) was considered.18 Two assessment tools for hypoglycaemia unawareness were considered, the Clarke questionnaire19 and the Gold score.20 Also here, these two questionnaires were combined in meta-analyses, also to increase the number of studies included in the meta-analyses on hypoglycaemia unawareness. Quality of life measures included the WHO-5 well-being index,21 and the PEDsQL™ for paediatric health-related quality of life.22 The Pittsburgh Sleep Quality Index (PSQI) was considered for the assessment of sleep quality.23 For treatment satisfaction, the Diabetes Treatment Satisfaction Questionnaire (DTSQ)24 was considered. The INSPIRE measure was considered as an AID-specific assessment tool of user experiences.25 Data for other PRO were also extracted; however meta-analyses were only conducted when three or more studies could be synthesised. For studies reporting on PROs, glycaemic parameters were extracted when reported: HbA1c, % of glucose values <54 mg/dl (3.0 mmol/L), <70 mg/dl (3.9 mmol/L), between 70 and 180 mg/dl (3.9–10 mmol/L), >180 mg/dl (10 mmol/L) and >250 mg/dl (13.9 mmol/L) as well as coefficient of variation (CV). The following information were also extracted from included articles: funding (industry vs. public vs. both), study design (randomised controlled trial vs. observational study vs. qualitative study), cross-over design (yes vs. no), inclusion and exclusion criteria, number of participants, setting, age, sex, type of diabetes, primary outcome, and type of AID system.

Risk of bias of randomised controlled trials was assessed using the revised Cochrane risk-of-bias tool for randomised trials (RoB 2.0) or, when appropriate, the risk-of-bias tool for randomised crossover trials.26 Cochrane's Risk Of Bias In Non-Randomized Studies–of Interventions (ROBINS-I) tool was used for observational trials.27 The robvis tool was used to create risk-of-bias plots.28

Statistical analyses were conducted using R (version 4.3.2) with the meta package (version 6.5–0) and metafor package (version 4.4–0). In general, meta-analyses were calculated separately for randomised controlled trials and observational trials. Standardised mean differences (SMD) using Hedges g with 95% confidence intervals (CIs) were calculated. In case of sufficient studies (>4 studies), random-effects meta-analyses were conducted using the Knapp-Hartung method29 and the Paule-Mandel method30, 31, 32 for estimating heterogeneity. In case of few studies (<5 studies), heterogeneity cannot be reliably estimated from random effects models,33 and thus, the common effects (CE) model is used following the recommendations of Bender et al.34 and the German Institute for Quality and Efficiency in Health Care (IQWiG).35 Heterogeneity was assessed using I2 and τ2. The values of τ2, which indicate the extent to which the effect sizes vary across the included studies beyond what would be expected by chance, between 0.1 and 0.5 were considered acceptable, values between 0.5 and 1.0 fairly high, and values above 1.0 extreme.35 Prediction intervals for a treatment effect in a single new study were provided. Visual inspection of the symmetry in funnel plots and Egger's test were performed to assess publication bias, both in RCTs and non-RCTs.

Subgroup analyses were conducted to analyse the effects of AID in different populations (paediatric/adolescent vs. adults vs. parents), if a sufficient number of studies was available. A leave-one-out sensitivity analysis was conducted for every meta-analysis, separately. To evaluate the impact of different generations of AID system and to take the evolution of AID therapy into account, meta-regression analyses with publication year and generation of device (Hybrid Closed Loop vs. Advanced Hybrid Closed Loop) as predictors were conducted.

There was no funding for this systematic review.

Results

A total of 606 studies were retrieved from the systematic search. After import in Covidence, 42 duplicates were eliminated automatically, and screening started. Title and abstract screening resulted in an exclusion of 472 studies, leading to 92 full texts to be assessed. After full text screening, 62 studies were included in this review including 9253 participants (Fig. 1). Out of the 62 included studies, 27 were RCTs,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62 25 were observational pre-post trials,6,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86 six were qualitative studies,87, 88, 89, 90, 91, 92 and the remaining four were other trials (e.g. prevalence trial or a cross-sectional web-survey).93, 94, 95, 96 The RCT by Beato-Vibora et al. compared two AID systems without a non-AID control group, and thus, the two AID study arms were extracted as separate pre-post studies.64 In case of Ng et al. from 2022,66 only the newer data from 2024 were used.77Fig. 1PRISMA flow chart of analysed studies.

The included studies are summarised in Table 1. Overall, a variety of 45 different quantitative questionnaires was used (Table 2, Supplementary Table S2). Number of participants ranged from 13 to 2778 with an average of 126.8 (SD = 377.4), the average age of the participants ranged from 3.3 to 67.0 with an overall average age of 25.0 (SD = 15.8). The gender ratio was balanced, overall, 57.4% of all participants were female (56.9% in the intervention groups and 54.7% in the control groups of RCTs). The average diabetes duration ranged from 1.9 to 38.0 years with an overall average of 12.7 years (SD = 9.5). Regarding the funding of the studies, 16.1% did not receive any funding, 17.7% a funding by industry, 41.9% a funding by a public funding (e. g. JDRF, NIH, NICE) and 24.2% by both—industry and public funding. The majority of studies consisted of people with type 1 diabetes, except one observational trial on people with type 2 diabetes65 and one web-based survey (98.9% type 1 diabetes).93Table 1Characteristics and narrative summary of included studies.Lead author (year)RCTStudy designSample (mean age)Manufacturer and model of examined AIDType of control intervention (only RCTs)Diabetes duration in years (overall)PROsPrimary results (significant)Funding sourcesAbraham et al. (2021)42yesParallel group, multicentric, randomized135 children and adolescents, 37 parents (15.3 years)Medtronic 670GAll but AID7.7DTSQ Child &Adult, GoldScore, HFS-II (worry), PAID,PedsQL, STAIChild & Adult•Improvement in PedsQL and DTSQ•No change in PAID and HFS-IIPublicAdams et al. (2018)74noClinical, multicentric, pre-post15 adolescents, 14 adults (23 years)Medtronic 670G14.0––DDS, DTQ,HFS-II•Improvement in DDS and DTQ•No change in HFS-IIPublicAkiyama et al. (2024)81noProspective, single-center observational22 adults (48.2 years)Medtronic 770G15.0DTSQ, PAID, DTR-QOL•No change in DTSQ, PAID, DTR-QOLNo fundingBarnard et al. (2017)52yesCrossover,multicentric,open-label,randomised32 adults (38.6 years), 26 children and adolescents (12 years)OtherCGM; Insulin pump21.1DTQ, semi structured interviews•DTQ slightly positive, interviews implicate more satisfaction•Topics: ease of use, alarms and calibrationsIndustry and publicBarnard et al. (2015)51yesCrossover, multicentric, open-label, randomised22 adults (43 years)OtherCGM; Insulin pump29.0DTQ, semi structured interviews•No changes in DTQ•Benefits: improved glycaemic control, less worries•Topics: technical issues, alarms, size and weight of the devicesPublicBarnard et al. (2014)45yesCrossover, mixed methods,monocentric,randomised,15 adolescents (15.6 years), 13 parentsOtherCGM7.2DTQ, HFS-II, semi structured interviews•Slight improvements of HFS-II in adolescents, slight worsening in parents•Interviews: better sleep quality, less worries in parents•Topics: alarms, calibration, uncomfortable to wearPublicBeato-Víbora et al. (2023)64yesMulticentric, head-to-head, randomised151 adults (39.9 years)Medtronic 780G & t:slim Control-IQHead-to-head comparison21.6Clarke ScoreDDS, DQoL,GMEQ, HFS-II,INSPIRE, PSQI•Improvements in all PROs (except GMEQ & INSPIRE)NoneBeato-Víbora et al. (2021)73noLongitudinal, prospective52 adults (43 years)Medtronic 780G27.0Clarke ScoreDDS, DQoL,DTSQ, GoldScore, GMEQ,HFS-II, PSQI•Improvements in Clarke score, DQoL, GMEQ, HFS-II and PSQI•No changes in DTSQ and DDSNoneBeato-Víbora et al. (2020)71noLongitudinal, multicentric, prospective36 adults, 22 children and adolescents (overall: 38 years)Medtronic 670G15.0Clarke Score,DDS, DQoL,DTSQ, GoldScore, HFS-II,PSQI•Improvements in all PROsNoneBenhalima et al. (2024)61yesParallel-group, randomised95 pregnant women (30.5 years)Medtronic 780GMDI; Insulin pumpIntervention: 17.0 years; Control: 30.3 years)HFS-II, Gold Score, PAID-5, SF-36, CES-D, DTSQ•Improvements in DTSQ and GOLD Score•No changes in other PROsIndustry and publicBisio et al. (2022)68noSingle arm, two treatment phases15 adults (68.7 years)t:slim–Control-IQ35.2CES-D, DDS,HFS-II, PSQI•Improvement of DDS•No changes in other PROsIndustry and publicBisio et al. (2021)70noSingle arm, two treatment phases13 children (9.1 years), 13 adultst:slim–Control-IQ5.6CDI-2, CES-D,CSHQ-A,HFS-II, PAID,PSQI,Technology questionnaire for parents•Improvement in CES-D, HFS-II, PAID and PSQI in parentsIndustry and publicBoscari et al. (2022)67noField study, monocentric, retrospective31 adults (38 years)t:slim–Control-IQ19.0DTSQc,DTSQs, HFS-II,PSQI•Improvements in DTSQ and HFS-IINoneBraune et al. (2021)93noWeb-based cross-sectional897 adults, children and adolescents (35.6 yers)Open-source AID21.4Questionnaire with 14 fixed-choice questions•main motivation for usage of an open source AID-system are better glycaemic outcomes and a reduction of short- as well as long-term complications and an increase in the life expectancyPublicBurckhardt et al. (2021)54yesCrossover, randomised17 adults and adolescents (35.8 years)Medtronic 670GAll but AID24.2Clarke Score,DTSQ, GoldScore, HFS-II•Improvements in Gold scorePublicChoudhary et al. (2022)37yesControlled, multi-national, multicentric, prospective, randomised82 adults (40.6 years)Medtronic 670G (version 4.0)CGM; Multiple daily insulin injections (Pen)Intervention: 18.8; Control:18.1DQoL, DTSQ,HFS-IIImprovements in DTSQ and HFSIndustryCobry et al. (2020)75noField study37 children and adolescents (13.9 years), 37 parentsMedtronic 670G6.5GMSS, HFS-II,PAID-PR,PAID-T, PSQI•Improvements in GMSS in children and adolescents•No improvements in HFS-II•No improvements in parents' responsesPublicCobry et al. (2021)56yesMulticentric, cross-over, randomized101 children (11.2 years), 101 parentst:slim–Control-IQCGM; Insulin pump5.2C-HFS,INSPIRE, P-HFS,PAID,PedsQL, PSQI•No differences between the groupsIndustry and publicCobry et al. (2022)94noSecondary analysis of RCT (Cobry et al., 2021; only poor parental sleepers)49 parentst:slim–Control-IQ5.2Change in PROs only for poor sleepers (PSQI >5)•Improvements in all PROs of the parents•Improvements in C-HFSIndustry and publicCobry et al. (2024)80noProspective, observational33 adolescents (11.1 years), 39 parentst:slim–Control-IQ2.5PSQI, PROMIS sleep disturbance, PAID, PedsQL, HFS, DTQ, INSPIRE•Improvements in parental PSQI•Adolescents: Improvements in worry subscale of HFS•Parents: Improvements in overall HFS and worry subscaleNoneDeBeaufort et al. (2022)46yesMulti-national, randomised, crossover74 adults (parents of 74 children, 5 years)CamAPSCGM; Insulin pumpNot reportedESS, HFS-II,WHO-5•Improvements in HFS-II in parents•Improvements in WHO-5PublicDuBose et al. (2021)72noField study, multicentric9 children, 11 adolescents, 60 adults (31.8 years), 20 parentsMedtronic 670G16.2HFS-II,INSPIREImprovements in HFS-II total score and behaviour subscale only for parentsPublicEdd et al. (2023)60yesMulticentric, prospective, parallel-group, randomised82 adults (40.6 years)Medtronic 780GCGM; Multiple daily insulin injections (Pen)Intervention: 18.4; Control:17.8DQoL, DTSQc,DTSQs, HFS-IIImprovements in all PROsIndustryEkhlaspour et al. (2019)76noFeasibility study13 adults (27.9 years)Other13.9T1-DDS, DTSQ,GMSS, HCS,WHO-5, focus groups•No improvements in PROsPublicFarrington et al. (2018)90yesCross-over, randomised16 pregnant women (between 18 and 45 years)Early version of CamAPSMultiple daily insulin injections (Pen); Insulin pumpSemi structured interviews•Benefits: inner peace, wonder about new technologies, improved glucose controle•Issues: technical issues, size of the systems, maintenance and logisticsPublicFarrington et al. (2017)58yesCross-over, randomized16 pregnant women (34.1 years)Early version of CamAPSMultiple daily insulin injections (Pen); Insulin pump23.6DTQ, HFS-II, semi structured interviews•No improvements in PROs•Benefits: better glycaemic control, improved sleep quality•Issues: thinking more about diabetes, fear of hypoglycaemias remainedPublicForlenza et al. (2019)36yesMulticentric, parallel-group, randomised24 children (9.6 years)t:slim–Control-IQCGM; Insulin pumpIntervention: 4.7; Control:4.4TAM•TAM answers mostly positive, satisfied with the systemIndustryGianini et al. (2022)96noMixed-methods, longitudinal24 children and adolescents (14.5 years)Medtronic 780G7.2C-HFS, PAID,WHO-5, focus groups•Improvements in all PROs•Focus groups: improved sleep quality in children and parents, improved quality of life and well-being, facilitated diabetes managementPublicGraham et al. (2024)85noReal-world, observational, prospective2778 children, adolescents and adults (29.0 years)t:slim–Control-IQNot reportedDIDS, DIDP•Improvements in DIDS and DIDPIndustryHood et al. (2021)57yesCrossover, multi-national, multicentric, randomized113 adolescents and young adults (19 years)Medtronic 780GMedtronic 670G12.0DDS, GMSS,HCS,TechnologyAttitudes•Improvements in GMSSPublicHood et al. (2022)39yesParallel-group, randomised98 children and adolescents (12.7 years), 98 adults (parents)CamAPSInsulin pumpIntervention: 6.3; Control: 6.6–CESD,GMSS, HCS,HFS-worry, P-DDS,PAID-T,PedsQL,TechnologyAttitudes, focus groups•No improvements in all PROs•Benefits: improved glycaemic control, more freedom and independence for children/adolescents•Issues: unhandiness of the system, connectivity problemsPublicHood et al. (2024)62yesParallel-group, randomised102 children (4.2 years) with parentst:slim–Control-IQCGM + MDI/CSII/open loop AIDIntervention: 1.84; Control: 1.96HFS-II, PedsQL, PSQI, HCS•Improvements in HFS-II, HCS, PedsQL, and PSQIPublicIturralde et al. (2017)91noQualitative, retrospective15 adolescents (16.6 years), 17 adults (28.2 years)Medtronic 670GAdolescents: 8.2; Adults: 18.3Focus groups•Benefits: better glycaemic control (also overnight), more flexible options for activity•Issues: unexpected new challenges, difficulties in wearing, problems in processing hyperglycaemiaPublicJalilova et al. (2024)79noSingle-center cohort study41 children and adolescents (12.5 years)Medtronic 780G5.5PedsQL, SDQ, HFS-C, R-CADS•No improvements in all PROsNoneKimbell et al. (2022)89noQualitative33 parents of 30 children (4.9 years)CamAPS2.7Interviews•Clinical benefits due to the AID, reduced diabetes distress•Parents: Better sleep quality, reduced worries, increased self-confidence•Children: better sleep quality, well-being, concentration, reduced distressIndustry and publicKropff et al. (2017)55yesCross-over, mixed-methods, randomised32 adults (47 years)OtherSAP28.6AP AcceptanceQuestionnaire,DTSQc,DTSQs, HFS-II, semi-structured interviews•No changes in HFS-II and DTSQ•Benefits: trust in the devices, though controlling device's functions•Issues: sleep disorders due to alarmsPublicKudva et al. (2021)41yesMulti-centre, randomised105 adults (25–71 years), 63 adolescents and young adults (14–24 years)t:slim–Control-IQCGM; Insulin pumpIntervention: 17.0; Control:15.0–Clarke Score,DDS, HAS,HCS, HFS-II,INSPIRE, SUS,TAS, TES•Improvements in HFS-II (adults only)•No changes in the other PROsIndustry and publicLakshman et al. (2024)92noQualitative11 adults (41.5 years)CamAPS19.9Interviews•Reduced mental load, reduced burden, improved mood•A break from diabetes•Reports on increased snackingIndustry and publicLee et al. (2023)38yesMulti-centric, parallel-group, randomised124 pregnant women (31.1 years)CamAPSCGM + MDIIntervention: 18.0; Control:16.0DDS, EQ-5D,HFS-II (worry),INSPIRE, PSQI, interviews•No improvements in all PROsIndustry and publicLevy et al. (2023)65noSingle-arm, prospective30 adultst:slim–Control-IQDIDP, DIDS,SUS, PROMISSleepDisturbance•No improvements in PROsIndustryMarks et al. (2024)84noSingle-arm, prospective, pilot13 minoritised youth (14.8 years)t:slim–Control-IQ8.1T1DAL, PAID, INSPIRE, DMQ•Improvements in T1DAL, PAID, and DMQIndustryMcAuley et al. (2020)40yesParallel- groups, randomised120 adults (44.2 years)Medtronic 670GInsulin pump; Multiple daily insulin injections (Pen)Intervention: 24.0; Control: 24.1DIDP, DTSQ,PAID, PRMQ,PSQI, W-BQ28•Improvements in DIDP and W-BQ28Industry and publicMcAuley et al. (2022)43yesCrossover, randomized, two-stage30 adults (67 years)Medtronic 670GSAP38.0Clarke Score,DIDP, GDS,Gold Score,HFS-II, PAID-5,PSQI•No changes in PROsIndustry and publicMichaels et al. (2024)78noProspective, single-arm, dual-centre17 adults and teens (18.8 years)Medtronic 780G9.7HFS-II, DTSQ, INSPIRE, PSQI, PedsQL•Improvements in PedsQL and DTSQPublicMusolino et al. (2019)53yesCrossover, multi-national, multicentric, randomised24 children (5 years), 20 parentsFlorenceM closed loopInsulin pump3.1Closed-loopExperienceQuestionnaire•Benefits: reduced burdens in the diabetes management, improved sleep quality, less worries regarding children•Issues: size of the device, battery capacity, connectivity problemsPublicNg et al. (2022)66noReal-world, observational, prospective39 children and adolescents (11.8 years)t:slim–Control-IQ; CamAPS3.8HFS-II, P-HFS•Improvements in all PROsPublicNg et al. (2024)77noReal-world, observational, prospective221 children and young people (12.3 years)t:slim–Control-IQ; CamAPS, Medtronic 780G6.6HFS-II, PROMIS sleep disturbance•Improvements in all PROsPublicPatel et al. (2022)95noPrevalence trial, retrospective comparison184 adults (46 years)Open-source AIDFSL + CSII25.0DDS-2, GoldScore•No between-group differences in retrospective comparisonsNonePetrovski et al. (2022)63noSingle-arm, monocentric, prospective34 children and adolescents (12.5 years)Medtronic 780G4.3DTSQ•Improvements in DTSQPublicPinsker et al. (2021)6noRetrospective, mixed-methods1435 adolescents and adults (45.5 years)t:slim - Control-IQ25.4DIDS, TAS, WHO-5, open questions regarding trust and satisfaction•Improvements in DIDS•Reduction in WHO-5IndustryPolonsky et al. (2022)69noSingle-arm, prospective, multicentric115 adults (39.3 years)Omnipod 519.0DTSQc, HCS, IDSS, PSQI, SUS, T1-DDS, WHO-5•Improvements in DTSQ, HCS, SUS and T1-DDSIndustryPulkkinen et al. (2022)86noSingle-arm, prospective, retrospective registry controls35 children (4.3 years) and their parentsMedtronic 780G2.3PAID-PR•Improvements in PAIDIndustryReznik et al. (2024)83noMulticentric, longitudinal, real-life55 adolescents (15.1 years), 202 adults (42.4 years)t:slim–Control-IQAdolescents: 7.0; Adults: 24.1PAID, ADDQOL, PSS, GAD 7, FSS, HFS-II, PSQI, PHQ-9•Adolescents: Improvements in HFS-II•Adults: Improvements in PAID, ADDQOL, PSS, GAD 7, HFS-IIIndustrySharifi et al. (2016)50yesCrossover, prospective, randomized12 adolescents (15.2 years), 16 adults (42.1 years)OtherCGM; Insulin pump with low glucose suspendAdolescents: 6.6; Adults: 26.9Cogstate,DTSQc,PSQI•Improvements in DTSQ•Worsening in PSQI in adultsPublicVan Bon et al. (2010)87noQualitative22 adults (42 years)Hypothetical AP27.0Interviews•Attitudes towards AID therapy mostly positive: better sleep quality, glycaemic control, life quality, less burdens•Issues: necessity to wear 2 subcutaneous devices at the same time and accuracy of the systemsPublicVan Bon et al. (2024)82noMulticentric, prospective, single-arm, intervention trial78 adults (47.7 years)Bihormonal fully closed-loop26.7WHO-5, PAID, PSQI, INSPIRE, Gold Score•Improvements in WHO-5, PAID, PSQIIndustryVon dem Berge et al. (2022)48yesCrossover, monocentric, randomised, two-stage38 children (8.7 years)Medtronic 670GInsulin pump with predictive low glucose suspend4.3DISABKIDS, HFS-II•No changes in the PROsIndustry and publicWang et al. (2021)88noQualitative21 adults (50.0 years)Medtronic 670G27.5Semi structured interviews•Benefits: reduction of hypoglycaemia, improvement of HbA1c and nocturnal glycaemic control•Issues: frequency of alarms, missing options for individual input, sensor issues and bad processing of hyperglycaemiaNoneWeissberg-Benchell et al. (2016)44yesCrossover, randomised19 children (9.8 years)OtherInsulin pumpNot reportedHFS-II,PAID-C•Improvements in HFS-IINoneWeissberg-Benchell et al. (2017)59yesCrossover, multicentric, randomised39 adults (33.3 years)Dual-hormone AIDCGM + insulin pump16.9DTSQc,DTSQs,T1-DDS, WHO-5•Improvements in all PROsPublicWheeler et al. (2022)47yesCrossover, multicentric, randomised16 children (7–12 years), 14 adolescents (13–17 years), 29 adults (18–65 years) (23.5 years)Medtronic 670GInsulin pump with predictive low glucose suspend13.2DTQ, DTSQc,DTSQs, HCS,HFS-II, PSQI,WHO-5•Improvements in DTSQ in adolescents and adults•Improvements in DTQ in all participants•Improvements in PSQI in participants >16 yearsIndustry and publicZiegler et al. (2015)49yesMulti-national, multicentric, crossover, randomised20 children (12.3 years), 20 adolescents (15.6 years), 19 adults (31.2 years)OtherSAP11.6AP Satisfaction,C-HFS, HFS-II,TAM-Q•Improvements in the HFS-II worry subscale•Improvements in TAM-Q•Overall high satisfaction with the AID-systemIndustry and publicAbbreviations: Technologies/devices: AID, Automated Insulin Delivery; CGM, Continous Glucose Monitoring; CSII, Continous Subcutaneous Insulin Infusion; MDI, Multiple Daily Injections; SAP, Sensor-Augmented Pump, Person-Reported Outcomes; ADDQoL, Audit of Diabetes-Dependent Quality Of Life; AP Acceptance, Artificial Pancreas Acceptance; CDI-2, Childrens‘ Depression Inventory 2nd Edition; CES-D, Center for Epidemiologic Studies Depression Scale; C-HFS, Children Hypoglycemia Fear Survey; CogState, Cognitive functioning task; CSHQ-A, Children's Sleep Habit Questionnaire—Abbreviated; DDS, Diabetes Distress Scale; DIDP, Diabetes Attitudes, Wishes and Needs Impact of Diabetes Profile; DIDS, Diabetes Impact and Devices Satisfaction; DISABKIDS, diabetes treatment satisfaction and burden; DMQ, Diabetes Management Questionnaire; DQoL, Diabetes Quality of Life; DTQ, Diabetes Technology Questionnaire; DTSQ, Diabetes Treatment Satisfaction Questionnaire; DTSQc, Diabetes Treatment Satisfaction Questionnaire—Change; DTSQs, Diabetes Treatment Satisfaction Questionnaire—State; DTR-QOL, Diabetes-Therapy-Related Quality Of Life; EQ-5D, European Quality of Life 5 Dimensions; ESS, Epworth Sleepiness Scale; FSS, Fatigue Severity Scale; GAD-7, Generalised Anxiety Disorder 7-item; GDS, Geriatic Depression Scale; GMEQ, Glucose Monitoring Experience Questionnaire; GMSS, Glucose Monitoring Satisfaction Survey; HAS, Hyperglycemia Avoidance Scale; HCS, Hypoglycemia Confidence Scale; HFS-II, Hypoglycemia Fear Survey 2nd Edition; IDSS, Insulin Delivery Satisfaction; INSPIRE, Insulin Delivery Systems: Perceptions, Ideas, Reflections, and Expectations; PAID, Problem Areas in Diabetes; PAID-C, Problem Areas in Diabetes—Child; PAID-PR, Problem Areas in Diabetes–Parent Report; PAID-T, Problem Areas in Diabetes—Teen; P-DDS, Parent Diabetes Distress Scale; PedsQL, Pedriatic Quality of Life Inventory; P-HFS, Parent Hypoglycemia Fear Survey; PHQ-9, Patient Health Questionnaire–Depression; PRMQ, Prospective and Retrospective Memory Questionnaire; PSQI, Pittsburgh Sleep Quality Index; R-CADS, Revised Child Anxiety and Depression Scale; SDQ, Strength and Difficulties Questionnaire; SF-36, 36-Item Short Form Health Survey; STAI, State-Trait-Anxiety Inventory; SUS, System Usability Scale; T1-DAL, Type 1 Diabetes And Life; T1-DDS, Type 1 Diabetes Distress Scale; TAM-Q, Technology Acceptance Model Questionnaire; TAS, Technology Acceptance Survey; TES, Technology Expectation Survey; W-BQ28, Well-Being Questionnaire—diabetes-specified of the W-BQ; WHO-5, World Health Organization-5 Well-Being Scale.Table 2Results of the meta-analyses for person-reported outcomes in randomised controlled trials and observational, pre-post studies.Studies and participantsEffect sizeHeterogeneityStudies (N)ObservationsSMD95% CIp-valueI2τ2χ2 (p)Randomised controlled trials Diabetes distressb131248−0.159−0.309; −0.0100.0322a23.0%0.014215.58 (0.21) Fear of hypoglycaemiab141085−0.339−0.566; −0.1110.0005a42.6%0.086022.66 (0.046) Worry subscaleb161376−0.236−0.355; −0.117<0.0001a0.0%0.05.61 (0.99) Behaviour subscaleb12983−0.250−0.435; −0.064<0.0001a32.1%0.026616.20 (0.13) Impaired awareness of hypoglycaemiab4434−0.231−0.424; −0.0370.01930.0%0.00.71 (0.87) Quality of lifec33440.3470.134; 0.5600.00140.0%0.01.11 (0.57) Paediatric quality of lifec55290.2490.050; 0.4480.0081a0.0%0.02.33 (0.68) Sleep qualityb8577−0.109−0.498; 0.2800.4247a68.4%0.139622.18 (<0.01) Treatment satisfactionc86420.184−0.164; 0.5320.2838a67.2%0.116221.34 (<0.01) INSPIREc32640.199−0.057; 0.4560.1266a52.5%0.05554.21 (0.12)Observational, pre-post studies Diabetes distressb211009−0.217−0.403; −0.0310.0133a68.5%0.102863.42 (<0.01) Fear of hypoglycaemiab161029−0.445−0.540; −0.349<0.0001a0.0%0.09.43 (0.85) Worry subscaleb17862−0.423−0.527; −0.320<0.0001a0.0%0.012.09 (0.74) Behaviour subscaleb12622−0.376−0.584; −0.168<0.0001a31.2%0.046315.99 (0.14) Impaired awareness of hypoglycaemiab5338−0.212−0.419; −0.0040.0066a0.0%0.03.73 (0.44) Quality of lifec41641−0.049−0.118; 0.0190.158487.1%0.143023.19 (<0.01) Sleep qualityb15841−0.158−0.255; −0.0610.0016a0.0%0.012.01 (0.61) Treatment satisfactionc62140.668−0.044; 1.3810.060779.6%0.385524.50 (<0.01) INSPIREc10443−0.028−0.236; 0.1790.8189a42.9%0.030415.77 (0.07)SMD, standardised mean difference; 95% CI, 95% confidence interval; I2, measure of heterogeneity; τ2, measure of heterogeneity; χ2, test statistic for heterogeneity.ap-value from hierarchical meta-analysis with study as random, level-2 factor.bNegative SMDs indicate improvement.cPositive SMDs indicate improvement.

Characteristics and narrative summary of included studies.

DTQ slightly positive, interviews implicate more satisfaction

Topics: ease of use, alarms and calibrations

Benefits: improved glycaemic control, less worries

Topics: technical issues, alarms, size and weight of the devices

Slight improvements of HFS-II in adolescents, slight worsening in parents

Interviews: better sleep quality, less worries in parents

Topics: alarms, calibration, uncomfortable to wear

Improvements in all PROs (except GMEQ & INSPIRE)

Improvements in Clarke score, DQoL, GMEQ, HFS-II and PSQI

Improvement in CES-D, HFS-II, PAID and PSQI in parents

main motivation for usage of an open source AID-system are better glycaemic outcomes and a reduction of short- as well as long-term complications and an increase in the life expectancy

Improvements in GMSS in children and adolescents

Adolescents: Improvements in worry subscale of HFS

Parents: Improvements in overall HFS and worry subscale

Benefits: inner peace, wonder about new technologies, improved glucose controle

Issues: technical issues, size of the systems, maintenance and logistics

Benefits: better glycaemic control, improved sleep quality

Issues: thinking more about diabetes, fear of hypoglycaemias remained

TAM answers mostly positive, satisfied with the system

Focus groups: improved sleep quality in children and parents, improved quality of life and well-being, facilitated diabetes management

Benefits: improved glycaemic control, more freedom and independence for children/adolescents

Issues: unhandiness of the system, connectivity problems

Improvements in HFS-II, HCS, PedsQL, and PSQI

Benefits: better glycaemic control (also overnight), more flexible options for activity

Issues: unexpected new challenges, difficulties in wearing, problems in processing hyperglycaemia

Clinical benefits due to the AID, reduced diabetes distress

Parents: Better sleep quality, reduced worries, increased self-confidence

Children: better sleep quality, well-being, concentration, reduced distress

Benefits: trust in the devices, though controlling device's functions

Reduced mental load, reduced burden, improved mood

Benefits: reduced burdens in the diabetes management, improved sleep quality, less worries regarding children

Issues: size of the device, battery capacity, connectivity problems

No between-group differences in retrospective comparisons

Improvements in DTSQ, HCS, SUS and T1-DDS

Adults: Improvements in PAID, ADDQOL, PSS, GAD 7, HFS-II

Attitudes towards AID therapy mostly positive: better sleep quality, glycaemic control, life quality, less burdens

Issues: necessity to wear 2 subcutaneous devices at the same time and accuracy of the systems

Benefits: reduction of hypoglycaemia, improvement of HbA1c and nocturnal glycaemic control

Issues: frequency of alarms, missing options for individual input, sensor issues and bad processing of hyperglycaemia

Improvements in DTSQ in adolescents and adults

Improvements in PSQI in participants >16 years

Improvements in the HFS-II worry subscale

Overall high satisfaction with the AID-system

Abbreviations: Technologies/devices: AID, Automated Insulin Delivery; CGM, Continous Glucose Monitoring; CSII, Continous Subcutaneous Insulin Infusion; MDI, Multiple Daily Injections; SAP, Sensor-Augmented Pump, Person-Reported Outcomes; ADDQoL, Audit of Diabetes-Dependent Quality Of Life; AP Acceptance, Artificial Pancreas Acceptance; CDI-2, Childrens‘ Depression Inventory 2nd Edition; CES-D, Center for Epidemiologic Studies Depression Scale; C-HFS, Children Hypoglycemia Fear Survey; CogState, Cognitive functioning task; CSHQ-A, Children's Sleep Habit Questionnaire—Abbreviated; DDS, Diabetes Distress Scale; DIDP, Diabetes Attitudes, Wishes and Needs Impact of Diabetes Profile; DIDS, Diabetes Impact and Devices Satisfaction; DISABKIDS, diabetes treatment satisfaction and burden; DMQ, Diabetes Management Questionnaire; DQoL, Diabetes Quality of Life; DTQ, Diabetes Technology Questionnaire; DTSQ, Diabetes Treatment Satisfaction Questionnaire; DTSQc, Diabetes Treatment Satisfaction Questionnaire—Change; DTSQs, Diabetes Treatment Satisfaction Questionnaire—State; DTR-QOL, Diabetes-Therapy-Related Quality Of Life; EQ-5D, European Quality of Life 5 Dimensions; ESS, Epworth Sleepiness Scale; FSS, Fatigue Severity Scale; GAD-7, Generalised Anxiety Disorder 7-item; GDS, Geriatic Depression Scale; GMEQ, Glucose Monitoring Experience Questionnaire; GMSS, Glucose Monitoring Satisfaction Survey; HAS, Hyperglycemia Avoidance Scale; HCS, Hypoglycemia Confidence Scale; HFS-II, Hypoglycemia Fear Survey 2nd Edition; IDSS, Insulin Delivery Satisfaction; INSPIRE, Insulin Delivery Systems: Perceptions, Ideas, Reflections, and Expectations; PAID, Problem Areas in Diabetes; PAID-C, Problem Areas in Diabetes—Child; PAID-PR, Problem Areas in Diabetes–Parent Report; PAID-T, Problem Areas in Diabetes—Teen; P-DDS, Parent Diabetes Distress Scale; PedsQL, Pedriatic Quality of Life Inventory; P-HFS, Parent Hypoglycemia Fear Survey; PHQ-9, Patient Health Questionnaire–Depression; PRMQ, Prospective and Retrospective Memory Questionnaire; PSQI, Pittsburgh Sleep Quality Index; R-CADS, Revised Child Anxiety and Depression Scale; SDQ, Strength and Difficulties Questionnaire; SF-36, 36-Item Short Form Health Survey; STAI, State-Trait-Anxiety Inventory; SUS, System Usability Scale; T1-DAL, Type 1 Diabetes And Life; T1-DDS, Type 1 Diabetes Distress Scale; TAM-Q, Technology Acceptance Model Questionnaire; TAS, Technology Acceptance Survey; TES, Technology Expectation Survey; W-BQ28, Well-Being Questionnaire—diabetes-specified of the W-BQ; WHO-5, World Health Organization-5 Well-Being Scale.

Results of the meta-analyses for person-reported outcomes in randomised controlled trials and observational, pre-post studies.

SMD, standardised mean difference; 95% CI, 95% confidence interval; I2, measure of heterogeneity; τ2, measure of heterogeneity; χ2, test statistic for heterogeneity.

p-value from hierarchical meta-analysis with study as random, level-2 factor.

Results of the overall meta-analyses of the several PROs in RCTs can be found in the top part of Table 2. Meta analysis of 13 RCTs with 1248 participants examining diabetes distress38, 39, 40, 41, 42, 43, 44,56,57,59,61 found that the usage of an AID system resulted in a significant reduction of diabetes distress (SMD = −0.159; 95% CI [−0.309; −0.010], I2 = 23.0%, p = 0.0322; Fig. 2). There was no substantial heterogeneity (χ2 = 15.58, p = 0.21). Subgroup analyses for adults, adolescents, parents, and studies examining mixed groups demonstrate higher effect sizes for the adult (SMD = −0.206; 95% CI [−0.429; 0.017]) and parent (SMD = −0.511; 95% CI [−0.881; −0.140]) population compared to the paediatric/adolescent (SMD = −0.024; 95% CI [−0.236; 0.189]) population (Supplementary Figures S1 and S2).Fig. 2Forest plot regarding diabetes distress in randomised controlled trials (RCTs).

Forest plot regarding diabetes distress in randomised controlled trials (RCTs).

Also, the fear of hypoglycaemia, assessed by the HFS-II in up to 16 RCTs with 983–1376 participants,37, 38, 39,41, 42, 43, 44,46,47,54, 55, 56,58,61,62 was found to be reduced in people using an AID system (SMD = −0.339; 95% CI [−0.566; −0.112], I2 = 42.6%, p = 0.0005; Fig. 3). Subgroup analyses for overall fear of hypoglycaemia found the highest effect sizes in the paediatric/adolescent (SMD = −0.464; 95% CI [−0.696; −0.231]) and parent population (SMD = −0.299; 95% CI [−0.579; −0.018]), with lower but still significant effects in the adult (SMD = −0.238; 95% CI [−0.442; −0.035]) population (Supplementary Figures S3 and S4). Furthermore, also the worry subscale of the HFS-II (HFS-W: SMD = −0.236; 95% CI [−0.355; −0.117], I2 = 0.0%, p < 0.0001) and the behaviour subscale (HFS-B: SMD = −0.250; 95% CI [−0.435; −0.064], I2 = 32.1%, p < 0.0001) were significantly lower in people using an AID system compared to the control groups (Table 2, Supplementary Figures S5–S8). Subgroup analyses showed higher effect sizes for the worry subscale in children/adolescents (Supplementary Figure S6) and higher effect sizes for the behaviour subscale in adults (Supplementary Figure S8).Fig. 3Forest plot regarding fear of hypogylcaemia in randomised controlled trials (RCTs).

Forest plot regarding fear of hypogylcaemia in randomised controlled trials (RCTs).

The effect of AID systems on impaired awareness of hypoglycaemia (IAH) was analysed in four RCTs41,42,54,61 and showed a significant improvement (SMD [CE] = −0.231, 95% CI [−0.424; −0.037], I2 = 0.0%, p = 0.0193, Table 2, Supplementary Figure S9). People using an AID system reported higher quality of life at follow-up than people in the control group (Table 2). This effect could be found in studies assessing quality of life in adults (SMD [CE] = 0.347; 95% CI [0.134; 0.560], I2 = 0.0%, p = 0.0014; Fig. 4 and Supplementary Figure S10)46,47,59 as well as paediatric quality of life (SMD = 0.249; 95% CI [0.050; 0.448], I2 = 0.0%, p = 0.0081; Fig. 5 and Supplementary Figure S11).39,42,56,62 Regarding sleep quality,38,40,43,47,50,56,62 treatment satisfaction40,42,47,54,55,59,61 and the INSPIRE questionnaire,41 no significant benefit for AID systems compared to the control group could be found in the meta-analyses (Table 2, Supplementary Figures S12–S16). Some evidence for improved sleep quality due to AID use was seen in parents (SMD = −0.549, 95% CI [−0.870; −0.229]; Supplementary Figure S13).Fig. 4Forest plot regarding quality of life in randomised controlled trials (RCTs).Fig. 5Forest plot regarding pediatric quality of life in randomised controlled trials (RCTs).

Forest plot regarding quality of life in randomised controlled trials (RCTs).

Forest plot regarding pediatric quality of life in randomised controlled trials (RCTs).

Of the included RCTs that also reported glycaemic effects besides PROs, meta-analyses showed significant improvements of HbA1c (SMD = −0.420, p = 0.0012), time in range (SMD = 1.061, p = <0.0001), % >180 mg/dl (SMD = −0.832, p = 0.0023) and % <54 mg/dl (SMD = −0.329, p = 0.0319) (Supplementary Table S3, Supplementary Figures S17–S22).

Results of the overall meta-analyses of the several PROs in observational, pre-post studies can be found in the lower part of Table 2. In observational trials, diabetes distress was significantly reduced from baseline to follow-up after AID use (SMD = −0.217; 95% CI [−0.403; −0.031], I2 = 68.5%, p = 0.0133; Supplementary Figure S23).64,68, 69, 70, 71,73, 74, 75, 76,80, 81, 82, 83, 84,86 Subgroup analysis revealed a significant effect in studies including adult population (Supplementary Figure S24). Overall fear of hypoglycaemia (HFS-II: SMD = −0.445; 95% CI [−0.540; −0.349], I2 = 0.0%, p < 0.0001; Supplementary Figure S25) as well as two subscales worry (HFS-W: SMD = −0.423; 95% CI [−0.527; −0.320], I2 = 0.0%, p < 0.0001; Supplementary Figure S27) and behaviour (HFS-B: SMD = −0.376; 95% CI [−0.584; −0.168], I2 = 31.2%, p < 0.0001; Supplementary Figure S29) were significantly reduced at follow-up.64,66, 67, 68,70, 71, 72, 73, 74, 75,77,78,80,83 Results were consistent across the subgroups (Supplementary Figures S26, S28, S30). In observational trials, IAH64,71,73,82 was found to be improved after using an AID system (SMD = −0.212; 95% CI [−0.419; −0.004], I2 = 0.0%, p = 0.0066; Supplementary Figure S31). There was no significant change in quality of life6,69,76,82 from baseline to follow-up (SMD [CE] = −0.049; 95% CI [−0.118; 0.019], I2 = 87.1%, p = 0.1584; Supplementary Figure S32). Sleep quality64,67, 68, 69, 70,73,75,78,80,82,83 improved from baseline to follow-up after using an AID-system (SMD = −0.158; 95% CI [−0.255; −0.061], I2 = 0.0%, p = 0.0016; Supplementary Figure S33), with the highest effect in the population of parents (Supplementary Figure S34). No significant effects were found for treatment satisfaction63,67,71,73,78,81 (Supplementary Figure S35)and the INSPIRE measures64,72,78,80,82,84 (Supplementary Figures S36, S37).

Of the included observational trials that also reported glycaemic effects besides PROs, meta-analyses showed a significant improvement of HbA1c (SMD = −0.747, p < 0.0001), time in range (SMD = 1.157, p = 0.0004), % > 180 mg/dl (SMD = −0.942, p = 0.0025) and % > 250 mg/dl (SMD = −0.743, p = 0.0023) (Supplementary Table S3, Supplementary Figures S38–43).

Qualitative research revealed high expectations but also consistently positive effects of AID therapy of people's life.87, 88, 89, 90, 91, 92 Furthermore, in a cross-sectional web-based survey, Braune et al. found that a majority of people with diabetes (71.6%) and parents of children with diabetes (80.0%) reported a better sleep quality.93 Also, Kimbell et al. could confirm these findings, as well as less diabetes related distress, less worries of parents of children with diabetes and more normality for them as well as for siblings of the children with diabetes.89 Cobry et al. identified parents post-hoc as poor-sleepers and found significant improvements in sleep quality and fear of hypoglycaemia in this subpopulation.94 On the other hand, also aspects like more cognitive and emotional effort due to the AID therapy in people with diabetes with good glycaemic control (HbA1c <7.5%) could be found.88 Using two items of the DDS and one self-designed item on quality of life, Patel et al. showed evidence for reduced diabetes distress and an extremely positive impact on quality of life with high recommendation of AID therapy.95 Lastly, Lakshman et al. identified the theme “a break from diabetes” because of AID, and participants reported less mental load, but also increased snacking.92

An overview of results for questionnaires for which no meta-analysis (N <3) could be conducted is provided in Supplementary Table S2. An indication for a beneficial effect of AID therapy on diabetes-specific quality of life (DQoL) can be found. Otherwise, results were rather mixed.

In general, inspection of Funnel plots did not reveal any signs of substantial publication bias in most PROs (Supplementary Figures S44–S62). Egger's tests were negative for all PROs (data not shown) for which an Egger's test could be conducted (k >10).

Sensitivity analyses revealed that some studies showed a meaningful impact when leaving them out of the analyses (Supplementary Figures S63–S81). In RCTs assessing diabetes distress, mainly two studies56,59 had some impact on the SMD when leaving them out. For fear of hypoglycaemia, mainly one study showed an impact on the SMD.44 Regarding quality of life only three studies for adults and five for paediatrics/adolescents were found, therefore, sensitivity analyses emphasized this limitation.

Results of the meta-regression analyses revealed that in RCTs, neither publication year nor generation of device had a significant impact on SMDs. Only in pre-post studies was there a significant association between newer studies and greater benefits for the HFS-II worry subscale (p = 0.0012), quality of life (p < 0.0001), and the INSPIRE measures (p = 0.0406) (Supplementary Table S4). In pre-post studies there was also a significant association between generation of the device and greater benefits for the HFS-II worry subscale (p = 0.0175) and the INSPIRE measures (p = 0.0036) (Supplementary Table S5).

Risk of bias assessments for RCTs (Supplementary Figures S82–S85) and observational trials (Supplementary Figures S86–S87) showed in general a low to moderate risk of bias. Only four of 27 RCTs (14.8%) showed a high risk of bias. The main source of bias in RCTs came from the lack of blinding of participants. In observational studies, only one out of 25 studies (4%) showed a serious risk of bias. The main source of bias in observational trials were concerns about confounding factors and bias due to selection of participants.

Discussion

This systematic review and meta-analysis demonstrate the significant benefit of AID systems on different aspects of PROs, both in RCTs and observational studies. In particular, the usage of AID systems in RCTs led to a reduction in diabetes distress and fear of hypoglycaemia as well as to improved quality of life in adults and children/adolescents and hypoglycaemia awareness. Effect sizes were strongest for quality of life, followed by fear of hypoglycaemia, paediatric quality of life, impaired awareness of hypoglycaemia, and diabetes distress. In pre-post studies, significant improvements in diabetes distress, fear of hypoglycaemia, impaired awareness of hypoglycaemia, and sleep qualitywere observed. Effect sizes were strongest for fear of hypoglycaemia, followed by diabetes distress, impaired awareness of hypoglycaemia, and sleep quality.

Most convincing evidence for the beneficial impact of AID systems were found for fear of hypoglycaemia with its two components, worries about hypoglycaemia and avoidance behaviour. This corroborates the recent review by Talbo et al.13 In our analysis, the effect sizes indicated a reduction in fear of hypoglycaemia of almost half a standard deviation indicating a moderate effect. Interestingly, worries and avoidance behaviour seem to benefit similarly, indicating a psychological as well as behavioural effect of AID systems. As issues with hypoglycaemia can be one of the main sources of diabetes distress,17 this may explain the beneficial effect of AID on overall diabetes distress found in RCTs and observational trials. Reduced fear of hypoglycaemia and reduced diabetes distress may also play a part in the improvements in quality of life, found in RCTs.5 In contrast, however, observational studies indicate a slight worsening of quality of life after AID use. However, this effect was rather small (SMD <0.05) and further studies are needed. Interestingly, beneficial effects on sleep quality were not found in RCTs but only in observational studies. This heterogeneity of the effect on sleep quality may be due to the inclusion of all different AID systems. Some AID systems, especially the earlier ones, required multiple calibration and thus, may have had more alarms potentially disturbing sleep and treatment satisfaction.50,97 However, evidence of the meta-analysis of RCTs and observational trials indicate a beneficial effect on parents sleep quality. In contrast to previous CGM studies,98, 99, 100, 101 a beneficial effect of AID on impaired awareness of hypoglycaemia was found in meta-analysis in RCTs and observational studies, possibly due to the avoidance of hypoglycaemic values.102 However, the assessment of impaired awareness of hypoglycaemia may be confounded by CGM-related glucose alarms and warnings.

In general, effect sizes of PROs were low-to-moderate, particularly when compared to the effect sizes found for glycaemic outcomes in this review and the one by Jiao et al.2 This may be due to the fact that PROs are usually considered as secondary outcomes in AID studies and, thus, studies are often not sufficiently powered to detect a significant effect on PROs.98 This may also partly explain the finding that for diabetes distress, for example, most of the individual studies included did not yield a significant SMD. Only by combining the studies, the meta-analysis revealed a significant effect of AID on diabetes distress. Also, leave-on-out sensitivity analyses indicated that some effects are mainly driven by single studies. Thus, more sufficiently powered studies with PROs as primary outcome are needed to increase the stability of beneficial effects of AID on psychosocial variables. Also, more mechanistic studies are needed to understand the underlying mechanisms how an AID system affects different PROs.

On the other hand, it's important to emphasise that an AID system is primarily a technology whose main purpose is to improve glycaemic control, and does not constitute a psychosocial intervention. Thus, improvements in certain PRO domains (e.g. depression) are not likely.8,10 Therefore, the multitude of effects found in this meta-analysis on diabetes-specific and generic PROs must be highlighted. In addition, the beneficial effects of AID on diabetes distress, fear of hypoglycaemia, and impaired awareness of hypoglycaemia were corroborated by both meta-analysis of RCTs and observational trials.

The following limitations of the meta-analysis must be considered. First, a central limitation is the enormous number of different questionnaires used to assess PROs in the included studies. Thus, we focused on the most central PROs for which meta-analysis could be conducted. The variety in PROs used is not only a result of the pluralism of psychosocial aspects in diabetes but is also the result of the lack of a core outcome set for PROs and PROMs in diabetes.10 As Speight et al. already underlined, this multitude of PROMs leads to a large complexity in analysing the effects of AID therapy on PROs.8 This meant that most PROs lacked sufficient numbers of trials to do meta-analyses or only a limited number of studies (<4) could be synthesized for e.g. quality of life and impaired awareness of hypoglycaemia. Also, the relevance of PROs in the examined studies seemed to be secondary, since PRO data sometimes was not reported completely or only in the supplementary material. We therefore emphasize the necessity of a core outcome set of PROMs and a standardised reporting allowing meta-analytical approaches. Recently, a consensus statement on PRO domains in diabetes research was published12 and efforts to offer a Tool Box for the selection of PROMs were made.9,10 Furthermore, a list of the most commonly used PROs in medical device studies can be found in de Wit et al.103 Thus, for future trials, we would argue to use these Tool Boxes for the selection of PROMs. The prediction intervals provided in the forest plots of this meta-analysis can be seen as guidance for effect and sample size considerations for each PROM. Second, it must be noted that glycaemic outcomes were not the main aim of the literature search and were only extracted for those studies that reported PROs. Therefore, the meta-analyses of glycaemic outcomes did not include all relevant studies on AID. Third, sensitivity analyses indicate the relative importance of single studies on overall SMDs and shows that the effects should be interpreted with caution. Lastly, the inclusion of different generations of AID systems may have introduced a degree of bias with respect to the observed effects on PROs.

Overall, heterogeneity within PROs was rather low with the highest τ2 value still below 0.4 and therefore well within an acceptable level.35 Also, methodological quality of the included studies did not seem to introduce a risk of bias. Taken together, robustness of the effects can be assumed. Regarding quality of life and impaired awareness of hypoglycaemia, further RCTs are needed as the common effects (CE) model and the random effects model yielded different results. Furthermore, there was no evidence that publication year or the generation of the device had a substantial impact on meta-analytic findings, also indicating the robustness of effects. While AID systems certainly evolve over time (e.g. older versions were only activated at night50), the impact of different generations of AID systems was rather low. There was some evidence from observational trials that indicate that newer AID generations may improve quality of life,82 fear of hypoglycaemia, and the INSPIRE measure more strongly. However, with the next generation of AID systems, which promise to enable fully closed-loop therapy,82 this needs to be further investigated.

In summary, this systematic review and meta-analysis demonstrate that the use of an AID system is associated with an improved psychosocial well-being compared to non-AID therapy. Evidence for reduced distress, fear of hypoglycaemia, as well as improved well-being can be seen from RCTs and observational studies. These quantitative findings also mirror the findings from qualitative research in which people with diabetes frequently report less burden and improved well-being when using an AID system. However, more research is needed with a core outcome set of PROMs to strengthen the evidence and demonstrate the added value of AID therapy. Furthermore, efficacy and safety of AID therapy in elderly people needs to be further investigated. Taken together, however, the results justify the widening of access to AID therapy as an added valued of AID therapy was demonstrated. This should be taken into account by health technology assessment bodies.

Contributors

T.R., N.H., C.G., and D.E. designed the study. T.R. and C.G. performed the literature search and abstract screening. T.R., C.G., and D.E. performed full-text screening, risk of bias assessment, and data extraction. N.H. supervised the consensus process and helped with the interpretation and discussion of the results. T.R. and D.E. analysed the data and wrote the first draft of the manuscript. N.H., C.G., B.K. and T.H. helped with the discussion of the results and revised the manuscript. All authors read and approved the final version of the manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. T.R., N.H., and D.E. have accessed and verified the underlying data.

Data sharing statement

All data of the included studies in this systematic review are available in the referenced articles as listed in the References or by contacting their respective corresponding authors.

Declaration of interests

T.R. reports honoraria for lectures from Berlin-Chemie AG.

N.H. reports Advisory Board member fees from Abbott Diabetes Care and Insulet as well as honoraria for lectures from Berlin Chemie AG, Becton Dickenson, Sanofi Germany, Roche Diabetes Care, and Dexcom Germany.

B.K. reports Advisory Board member fees from Abbott Diabetes Care, Embecta, Roche Diabetes Care, Novo Nordisk, Berlin Chemie AG, and Dexcom Germany as well as honoraria for lectures from Sanofi Germany, Novo Nordisk, Abbott Diabetes Care, Roche Diabetes Care, Berlin Chemie AG, Embecta, Dexcom, and Feen. In addition, he reports support for travel and fees for scientific meetings from Sanofi, Roche Diabetes Care and Berlin Chemie AG as well as unpaid obligations as workshop leader and member of working groups of the German Diabetes Association.

T.H. reports consulting fees from Eli Lilly, NovoNordisk, Sanofi, Boehringer Ingelheim, and Abbott Diabetes Care as well as honoraria for lectures from Abbott Diabetes Care, Sanofi, and Eli Lilly.

D.E. reports Advisory Board member fees from Dexcom Germany and Roche Diabetes Care as well as honoraria for lectures from Berlin Chemie AG, Sanofi-Aventis, Dexcom Germany, Boehringer Ingelheim, and Roche Diabetes Care.