Hybrid closed-loop systems for managing blood glucose levels in type 1 diabetes: a systematic review and economic modelling

Abstract

Background Hybrid closed-loop systems are a new class of technology to manage type 1 diabetes mellitus. The system includes a combination of real-time continuous glucose monitoring from a continuous glucose monitoring device and a control algorithm to direct insulin delivery through an insulin pump. Evidence suggests that such technologies have the potential to improve the lives of people with type 1 diabetes mellitus and their families. Aim The aim of this appraisal was to assess the clinical effectiveness and cost-effectiveness of hybrid closed-loop systems for managing glucose in people who have type 1 diabetes mellitus and are having difficulty managing their condition despite prior use of at least one of the following technologies: continuous subcutaneous insulin infusion, real-time continuous glucose monitoring or flash glucose monitoring (intermittently scanned continuous glucose monitoring). Methods A systematic review of clinical effectiveness and cost-effectiveness evidence following predefined inclusion criteria informed by the aim of this review. An independent economic assessment using iQVIA CDM to model cost-effectiveness. Results The clinical evidence identified 12 randomised controlled trials that compared hybrid closed loop with continuous subcutaneous insulin infusion + continuous glucose monitoring. Hybrid closed-loop arm of randomised controlled trials achieved improvement in glycated haemoglobin per cent [hybrid closed loop decreased glycated haemoglobin per cent by 0.28 (95% confidence interval −0.34 to −0.21), increased per cent of time in range (between 3.9 and 10.0 mmol/l) with a MD of 8.6 (95% confidence interval 7.03 to 10.22), and significantly decreased time in range (per cent above 10.0 mmol/l) with a MD of −7.2 (95% confidence interval −8.89 to −5.51), but did not significantly affect per cent of time below range (< 3.9 mmol/l)]. Comparator arms showed improvements, but these were smaller than in the hybrid closed-loop arm. Outcomes were superior in the hybrid closed-loop arm compared with the comparator arm. The cost-effectiveness search identified six studies that were included in the systematic review. Studies reported subjective cost-effectiveness that was influenced by the willingness-to-pay thresholds. Economic evaluation showed that the published model validation papers suggest that an earlier version of the iQVIA CDM tended to overestimate the incidences of the complications of diabetes, this being particularly important for severe visual loss and end-stage renal disease. Overall survival’s medium-term modelling appeared good, but there was uncertainty about its longer-term modelling. Costs provided by the National Health Service Supply Chain suggest that hybrid closed loop is around an annual average of £1500 more expensive than continuous subcutaneous insulin infusion + continuous glucose monitoring, this being a pooled comparator of 90% continuous subcutaneous insulin infusion + intermittently scanned continuous glucose monitoring and 10% continuous subcutaneous insulin infusion + real-time continuous glucose monitoring due to clinical effectiveness estimates not being differentiated by continuous glucose monitoring type. This net cost may increase by around a further £500 for some systems. The Evidence Assessment Group base case applies the estimate of −0.29% glycated haemoglobin for hybrid closed loop relative to continuous subcutaneous insulin infusion + continuous glucose monitoring. There was no direct evidence of an effect on symptomatic or severe hypoglycaemia events, and therefore the Evidence Assessment Group does not include these in its base case. The change in glycated haemoglobin results in a gain in undiscounted life expectancy of 0.458 years and a gain of 0.160 quality-adjusted life-years. Net lifetime treatment costs are £31,185, with reduced complications leading to a net total cost of £28,628. The cost-effectiveness estimate is £179,000 per quality-adjusted life-year. Conclusions Randomised controlled trials of hybrid closed-loop interventions in comparison with continuous subcutaneous insulin infusion + continuous glucose monitoring achieved a statistically significant improvement in glycated haemoglobin per cent in time in range between 3.9 and 10 mmol/l, and in hyperglycaemic levels. Study registration This study is registered as PROSPERO CRD42021248512. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR133547) and is published in full in Health Technology Assessment; Vol. 28, No. 80. See the NIHR Funding and Awards website for further award information. Plain language summary Type 1 diabetes mellitus is a lifelong condition whereby an individual’s pancreas significantly reduces or stops producing the hormone insulin that manages blood glucose levels. The individual must self-administer insulin and monitor their blood glucose levels. Hybrid closed-loop systems provide a control algorithm that reviews data and the impact of its past actions. Hybrid closed loop can reduce the burden on the patient by taking responsibility for handling the number of data and providing insulin when needed. The aim of this project is to review the clinical and financial benefits of hybrid closed-loop systems for managing glucose in people who have type 1 diabetes mellitus and are having trouble managing their condition. We looked at published studies following precise scientific approaches. We searched several online resources to find these studies. The National Institute for Health and Care Research provided additional studies that had not been published. The studies we found included the following information: people – with type 1 diabetes mellitus (any age group and including pregnant women) technology – people using a hybrid closed-loop system comparison – people using flash or intermittent glucose monitoring + pump therapy results – type 1 diabetes mellitus-related outcomes, such as glucose management, quality of life, heart disease, and complications related to the use of hybrid closed loop. Our online search found 12 randomised controlled trials that compared hybrid closed loop with continuous glucose monitoring + pump therapy. People in the hybrid closed-loop group had better glucose management (their glucose levels dropped by 0.28%). People in the hybrid closed-loop group had better glucose levels in the recommended range (between 3.9 and 10.0 mmol/l). People in the hybrid closed-loop group experienced less hyperglycaemic levels (above 10.0 mmol/l). The financial costs of hybrid closed loop suggest that it is more expensive (£1500) than continuous glucose monitoring + pump therapy. Studies that looked at hybrid closed loop in people with type 1 diabetes mellitus seem to suggest that it is better for diabetes management in terms of glucose levels, better time in range between 3.9 and 10 mmol/l, and less hyperglycaemic levels. Scientific summary This summary contains reference to confidential information provided as part of the National Institute for Health and Care Excellence (NICE) appraisal process. This information has been removed from the summary and the results discussions and conclusions of the summary do not include the confidential information. These sections are clearly marked in the summary. Background Type 1 diabetes mellitus (T1DM) was formerly known as insulin-dependent diabetes. It is the result of an autoimmune process that leads to the destruction of the insulin-producing beta cells in the pancreas. Treatment with insulin is aimed at replicating the function of the pancreas to manage hyperglycaemia and avoid hypoglycaemia. The NICE glucose control target for type 1 diabetes is 48 mmol/mol (formerly 6.5%) but few people with type 1 diabetes achieve that. Interventions to manage diabetes include education, continuous glucose monitoring (including a sensor, transmitter and display device) and insulin therapy [multiple daily injections or continuous subcutaneous insulin infusion (CSII)]. CSII is an external pump that delivers insulin continuously from a refillable storage reservoir by means of a subcutaneously placed cannula. Sensor-augmented pump therapy systems combine continuous glucose monitor (CGM) with CSII. The systems are designed to measure interstitial glucose levels (every few minutes) and allow immediate real‑time adjustment of insulin therapy. The systems may produce alerts if the glucose levels become too high or too low. Sensor-augmented pumps can operate in standard (manual) and advanced (automatic) modes. In the manual open loop mode, the CGM and glucose pump do not communicate with each other, and insulin doses are programmed by the user, who makes manual adjustments. Hybrid closed-loop (HCL) systems are a new class of technology that use a combination of real-time glucose monitoring from a CGM device and a control algorithm to direct insulin delivery through an insulin pump. Evidence suggests that such technologies have the potential to improve the lives of people with type 1 diabetes and their families. The aim of this work was to evaluate the clinical effectiveness and cost-effectiveness of HCL systems in managing type 1 diabetes. Objectives The overall objectives of this project are to examine the clinical effectiveness and cost-effectiveness of HCL systems for managing glucose levels in people who have type 1 diabetes. What is the clinical effectiveness of HCL systems in managing glucose in people who have type 1 diabetes and are having difficulty managing their condition despite prior use of at least one of the following technologies: CSII, real-time continuous glucose monitoring (rtCGM), flash glucose monitoring [intermittently scanned continuous glucose monitoring (isCGM)]? What is the cost-effectiveness of HCL for managing glucose in people who have type 1 diabetes and are having difficulty managing their condition despite prior use of at least one of the following technologies: CSII, rt-CGM, isCGM? Methods Systematic review methods followed the principles outlined in the Cochrane Handbook. A comprehensive search was developed iteratively and undertaken in a range of relevant bibliographic databases and other source. Date limits were used to identify records added to the databases since the searches for Diagnostic Guidance 2021 (run in 2014). Two reviewers screened titles and abstracts and assessed the eligibility of studies. Studies that satisfied the following criteria were included. Populations People (of any age) who have type 1 diabetes and are having difficulty managing their condition despite prior use of at least one of the following technologies: CSII, rtCGM, is CGM. Intervention Hybrid closed loop. Comparator Real-time continuous glucose monitoring with CSII (non-integrated). Intermittently scanned continuous glucose monitoring with CSII. Outcomes Intermediate Per cent time in target range (percentage of time a person spends with blood glucose level in the target range of 3.9–10 mmol/l). Per cent time below and above target range. Change in glycated haemoglobin (HbA1c). Rate of glycaemic variability. Fear of hypoglycaemia. Rate of severe hypoglycaemic events (events recorded/unit time). Rate of severe hyperglycaemic events (events recorded/unit time). Episodes of diabetic ketoacidosis (events recorded/unit time). Rate of ambulance call-outs (events recorded/unit time). Rate of hospital outpatient visits (events recorded/unit time). Measures of weight gain. Clinical Retinopathy. Neuropathy. Cognitive impairment. End-stage renal disease. Cardiovascular disease. Mortality. Outcomes in women who are pregnant/have recently given birth Premature birth. Miscarriage related to fetal abnormality. Increased proportion of babies delivered by caesarean section. Macrosomia (excessive birthweight). Respiratory distress syndrome in the newborn. Device-related Adverse events related to the use of devices. Patient-reported Heath-related quality of life. Psychological well-being. Impact on patient. Anxiety about experiencing hypoglycaemia. Acceptability of testing and method of insulin administration. Carer-reported Impact on carer (fear of hypoglycaemia, time spent managing the condition, time spent off work, ability to participate in daily life, time spent at clinics, impact on sleep). Study design Hybrid closed-loop systems studies included randomised controlled trials (RCTs) with a parallel-group or crossover design in which HCL or advanced HCL (AHCL) intervention was compared with a relevant comparator; observational studies (single-arm studies) of various designs: audit, retrospective and prospective cohort; and studies reporting outcomes after HCL or AHCL treatment. Healthcare setting Self-use supervised by primary or secondary care. Publication type Peer-reviewed papers. Language English. Prioritisation for full-text assessment We applied a two-step approach to identifying and assessing the relevant evidence in terms of study design, study length and sample size. The most rigorous and relevant studies (mainly RCTs) were prioritised for data extraction and quality assessment. Observational studies were recorded and reported narratively. Two reviewers extracted data independently using a piloted data extraction form. Disagreements was resolved through consensus, with the inclusion of a third reviewer when required. The risk of bias of randomised trials was assessed. We synthesised the evidence statistically. The network meta-analysis was conducted under a frequentist approach using a random-effects model. Results Clinical systematic review The clinical evidence identified 12 RCTs that compared HCL with CSII + CGM or sensor-augmented pump therapy. Studies were heterogeneous in terms of population, age groups, gender, RCT design, numbers of participants and variable adjustment methods. Studies did not consistently describe comparators. Overall, the HCL arm of RCTs achieved improvement in HbA1c% {HCL decreased HbA1c% by 0.28 [95% confidence interval (CI) −0.34 to −0.21], increased % time in range (TIR) (between 3.9 and 10.0 mmol/l) with a mean difference of 8.6 (95% CI 7.03 to 10.22), significantly decreased TIR (% above 10.0 mmol/l), with a mean difference of −7.2 (95% CI −8.89 to −5.51), but did not significantly affect % time below range (< 3.9 mmol/l)}. Comparator arms also showed improvements, but these were smaller than those observed in the HCL arm. Available evidence from the RCTs suggests that these gains in glycaemic management reported with HCL were not accompanied by a greater risk of hypoglycaemia; however, the power to detect small event sizes was limited because of the small study groups and the relatively short treatment duration. External submissions National Health Service England submitted two observational audit studies: the first audit was conducted in adults and the second was conducted in children and young people. The audit included adult participants who had worse glycaemic management in terms of HbA1c and hyperglycaemia at baseline than in published observational studies. The studies were non-randomised with no control group and had a before-and-after design. This limits the scientific value of the evidence as there is a greater risk of bias due to lack of randomisation, lack of a true control and selection bias. The improvement in HbA1c % and % time in range (between 3.9 and 10 mmol/L) were much greater in the NHS adult study in comparison to published evidence. The baseline level of the audit was considerably above than in all included observational studies, therefore there was a greater scope for improvement. In the NHS audit of children and young people baseline HbA1c was lower (~7.8%) and benefit was more modest (-0.61%) than in adults. For % time in range < 3.9 mmol/L the NHS audit adult study reported a change of -0.5% and an associated P value of <0.001. The CYP Pilot also reported a statistically significant improvement. Economics Systematic review of cost-effectiveness The literature search identified six studies, which were included. Five of the studies were economic evaluations of HCL systems, whereas one was a budget impact analysis. The structure of the models used in the cost-effectiveness studies was judged to be of good quality. The studies’ authors clearly stated their research question, the viewpoint of their analyses and their modelling objectives. Studies that used the iQVIA model described the model as one with a complex semi-Markov model structure with interdependent sub-models, so more thorough, easier access to its reported features would be of benefit to the intended audience. All cost-effectiveness studies noted that HCL was cost-effective over the lifetime versus comparator interventions. Company submission The Evidence Assessment Group (EAG) received economic submissions from Medtronic, Dexcom and CamDiab. The Tandem submission referenced the economics of the Dexcom submission. The Medtronic treatment costs applied the anticipated April 2023 commercial-in-confidence prices rather than the current list prices. Using the iQVIA CORE Diabetes Model (CDM), it estimated that compared with the 640G system with rtCGM the 780G HCL system improved HbA1c by 0.8%, which resulted in a saving of £5816, patient gains of 0.21 QALYs and dominance of HCL. For the comparison with CSII + isCGM, the same HbA1c improvement was applied alongside an annual reduction of 0.9 severe hypoglycaemia events. This resulted in a net cost of £13,057, a patient gain of 0.70 QALYs and cost-effectiveness of £18,672 per QALY. (Confidential information has been removed.) Independent economic assessment Owing to the complexity of modelling type 1 diabetes, the EAG does not build a de novo model. In common with the NICE’s guideline NG17 and its diagnostics guidance DG21 and most of the company submissions, the EAG uses the iQVIA CDM to model cost-effectiveness. The published model validation papers suggest that an earlier version of the iQVIA CDM tended to overestimate the incidences of the complications of diabetes. Medium-term modelling of overall survival appeared good, but there was uncertainty about its longer-term modelling. It is not known whether these issues persist in the current iQVIA CDM. The EAG assesses the cost-effectiveness of HCL and CSII + CGM. Direct treatment costs are supplied by the NHS supply chain using current list prices. The EAG provides a confidential patient access scheme appendix that applies the confidential possible future prices. Current prices suggest that HCL is around an annual average of £1500 more expensive than CSII + CGM, although this may increase by around a further £500 for some systems. CSII + CGM is cheaper than HCL in large part due to 90% or more of adult patients using isCGM sensors rather than rtCMG sensors. Patient baseline characteristics in the EAG base case are drawn from the National Diabetes Audit subgroup of type 1 diabetes patients on pumps. The EAG base case applies the EAG RCT network meta-analysis estimate of −0.29% HbA1c for HCL relative to CSII + CGM. Because there is no direct evidence of an effect on symptomatic or severe hypoglycaemia events, the EAG does not include these in its base case. The change in HbA1c results in a gain in undiscounted life expectancy of 0.458 years and a gain of 0.160 QALYs. Net lifetime treatment costs are £31,185, with reduced complications leading to a net total cost of £28,628. The cost-effectiveness estimate is £179,000 per QALY. The EAG provides scenario analyses that estimate symptomatic and severe hypoglycaemia events based on the differences in the time < 3.0 mmol/l for HCL and CSII + CGM. These improve the cost-effectiveness of HCL to £163,000 per QALY if it is valued using the EAG preferred source, to £121,000 if it is valued using the same source as NG17 and to £109,000 if it is valued using other credible sources. If the NHS adult pilot change between baseline and 6 months of −1.5% HbA1c is assumed to be the net effect of HCL compared with CSII + CGM, the undiscounted gain in life expectancy more than doubles to 1.004 years, and the patient gain increases to 3.103 QALYs. Net lifetime treatment costs increase to £35,912 due to the greater life expectancy, but considerable cost savings from reduced eye complications of £16,442 and reduced renal complications of £6731 lead to a net total cost of £12,447 and a cost-effectiveness of £12,398 per QALY. Reducing the modelled complication costs by their possible overestimation worsens the cost-effectiveness to £21,583 per QALY. This does not take into account any quality-of-life effects and survival effects from the possible overestimation of complication rates. The key model inputs are: the net effect on HbA1c the duration of the net effect on HbA1c the model time horizon treatment costs. The EAG has some concerns about using the iQVIA T1DM to model a paediatric population. Exploratory modelling of a paediatric population broadly mirrors that of the adult population, although the NHS paediatric pilot reported a smaller −0.70 HbA1c change between baseline and 6 months, with a corresponding worsening in the cost-effectiveness estimate for this scenario. The EAG does not formally consider the cost-effectiveness of HCL compared with CSII + CGM for pregnant women due to a lack of evidence. It only notes the relationship between HbA1c and birth defects. Conclusions Randomised controlled trials of HCL interventions in comparison with CSII + CGM achieved a statistically significant improvement in HbA1c%, in TIR between 3.9 and 10 mmol/l, and in hyperglycaemic levels. The outcome estimates reported for observational studies were quantitatively broadly in line with those from the RCTs. There is a research need for well-designed studies because the studies were heterogeneous. Future research should clearly describe comparators because these are not clear in the current literature. Study registration This study is registered as PROSPERO CRD42021248512. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR133547) and is published in full in Health Technology Assessment; Vol. 28, No. 80. See the NIHR Funding and Awards website for further award information.