Hybrid closed-loop systems for managing blood glucose levels in type 1 diabetes: a systematic review and economic modelling
Authors: Asgharzadeh Asra , Patel Mubarak , Connock Martin , Damery Sara , Ghosh Iman , Jordan Mary , Freeman Karoline , Brown Anna , Court Rachel , Baldwin Sharin , Ogunlayi Fatai , Stinton Chris , Cummins Ewen , Al-Khudairy Lena 
Published: December 2024

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.