Fully closed-loop insulin delivery—are we nearly there yet?
Authors: Charlotte K Boughton
Journal: The Lancet Digital Health (2021)

Hybrid closed-loop insulin delivery systems are transforming the management of type 1 diabetes for children and adults. However, the currently available systems still require the user to count carbohydrates and manually initiate the required bolus of insulin to be delivered before meal consumption. Carbohydrate counting is challenging and frequently inaccurate; it requires a level of numeracy and literacy which might be a barrier for some, and represents a substantial burden for the user, often impairing quality of life. The development of insulin-only fully closed-loop systems, which obviate the need for manual entry of meal-time boluses, have been limited by the relatively slow absorption and action of insulin following subcutaneous delivery. New faster acting insulin analogues, including Fiasp (Novo Nordisk, Denmark) and Lyumjev (Eli Lilly, USA) have shown only small benefits over standard insulin analogues when applied in closed-loop systems,1Boughton CK Hartnell S Thabit H et al.Hybrid closed-loop glucose control with faster insulin aspart compared with standard insulin aspart in adults with type 1 diabetes: a double-blind, multicentre, multinational, randomized, crossover study.Diabetes Obes Metab. 2021; 23: 1389-1396Crossref PubMed Scopus (9) Google Scholar, 2Bode BW Carlson AL Liu R et al.233-OR: Ultra-Rapid Lispro (URLi) demonstrates similar time-in-target range to Humalog with the Medtronic MiniMed 670G hybrid closed-loop system.Diabetes. 2020; 69: 233Crossref Google Scholar and the potential for an insulin-only fully closed-loop system without the need to bolus remains elusive. Alternative approaches to achieve a fully closed-loop system include dual hormone systems, which incorporate a second hormone such as glucagon3El-Khatib FH Balliro C Hillard MA et al.Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover trial.Lancet. 2017; 389: 369-380Summary Full Text Full Text PDF PubMed Scopus (134) Google Scholar or pramlintide,4Haidar A Tsoukas MA Bernier-Twardy S et al.A novel dual-hormone insulin-and-pramlintide artificial pancreas for type 1 diabetes: a randomized controlled crossover trial.Diabetes Care. 2020; 43: 597-606Crossref PubMed Scopus (45) Google Scholar or the use of adjunctive therapies including sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists alongside an insulin-only closed-loop system.5Haidar A Yale JF Lovblom LE et al.Reducing the need for carbohydrate counting in type 1 diabetes using closed-loop automated insulin delivery (artificial pancreas) and empagliflozin: a randomized, controlled, non-inferiority, crossover pilot trial.Diabetes Obes Metab. 2021; 23: 1272-1281Crossref PubMed Scopus (6) Google Scholar, 6Renukuntla VS Ramchandani N Trast J Cantwell M Heptulla RA Role of glucagon-like peptide-1 analogue versus amylin as an adjuvant therapy in type 1 diabetes in a closed loop setting with ePID algorithm.J Diabetes Sci Technol. 2014; 8: 1011-1017Crossref PubMed Scopus (40) Google Scholar These approaches are all undergoing evaluation in clinical trials. In The Lancet Digital Health, Ahmad Haidar and colleagues7Tsoukas MA Majdpour D Yale JF et al.A fully artificial pancreas versus a hybrid artificial pancreas for type 1 diabetes: a single-centre, open-label, randomised controlled, crossover, non-inferiority trial.Lancet Digit Health. 2021; (published online Sept 24.)https://doi.org/10.1016/S2589-7500(21)00139-4Summary Full Text Full Text PDF PubMed Google Scholar compare a Fiasp alone hybrid closed-loop system with a novel Fiasp plus pramlintide fully closed-loop system in 24 adults with type 1 diabetes in a supervised setting as a proof of concept study. Pramlintide, an analogue of amylin, delays gastric emptying, suppresses glucagon secretion, and increases satiety. When used as an adjunct to an insulin-only closed-loop system, pramlintide improved postprandial glucose excursions.4Haidar A Tsoukas MA Bernier-Twardy S et al.A novel dual-hormone insulin-and-pramlintide artificial pancreas for type 1 diabetes: a randomized controlled crossover trial.Diabetes Care. 2020; 43: 597-606Crossref PubMed Scopus (45) Google Scholar The dual hormone system uses a fixed 10 μg:U pramlintide to insulin ratio and incorporates an automated meal detection algorithm. Although the Fiasp plus pramlintide fully closed-loop system did not demonstrate non-inferiority when compared to the Fiasp-alone hybrid closed-loop system, the performance of the fully closed-loop system was impressive. The overall proportion of time spent in the target glucose range (3·9–10·0 mmol/L) was 74·3% (IQR 61·5–82·8), albeit over a short time period of 24 h. In a less supervised setting, one might expect carbohydrate counting to be less reliable and thus the performance of the comparator hybrid closed-loop system to be less than the 78·1% (66·3–87·5) observed in this trial, an issue which would not affect the Fiasp plus pramlintide closed-loop system. The difference in overall time in target glucose range between the two systems was attributable to an increase in the 2 h post-prandial glucose excursions with the fully closed-loop system. Hypoglycaemia burden was higher than might be expected in such a short study under close supervision. Eight (33%) participants had an episode of hypoglycaemia with the Fiasp plus pramlintide fully closed-loop system, however 14 (58%) participants had hypoglycaemia with the Fiasp alone hybrid closed-loop system. The predominant side-effects of pramlintide are gastrointestinal, and include nausea and abdominal bloating. Two participants withdrew during the run-in period due to gastrointestinal side-effects, and almost a third of participants (29%) had gastrointestinal side-effects with pramlintide (over half of which were reported as moderate to severe), despite the run-in period of dose escalation. A key question is whether the quality-of-life benefits associated with not performing carbohydrate counting and manual bolusing outweigh the side-effects of pramlintide. The potential beneficial effects of pramlintide on body weight and reduced insulin requirements are important given the increasing prevalence of obesity in people with type 1 diabetes.8Conway B Miller RG Costacou T et al.Temporal patterns in overweight and obesity in Type 1 diabetes.Diabet Med. 2010; 27: 398-404Crossref PubMed Scopus (205) Google Scholar For those who can tolerate it, the addition of pramlintide offers a valuable opportunity to reduce insulin doses and body weight, which is likely to positively impact on cardiovascular health.9Ratner RE Dickey R Fineman M et al.Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial.Diabet Med. 2004; 21: 1204-1212Crossref PubMed Scopus (227) Google Scholar Translation into clinical practice is limited at present because a pramlintide and insulin co-formulation to prevent needing two separate pumps is not yet commercially available, which might pose substantial device burden. Furthermore, pramlintide is not currently licenced for use outside of the USA, which might also limit its application. Outpatient studies with this novel fully closed-loop system are needed to confirm the efficacy and safety over a longer duration in a real-world setting, to determine tolerability of pramlintide across a larger sample size, and to explore potential weight benefits. However, this study represents an important advancement towards a fully closed-loop system to truly reduce the burden of management of type 1 diabetes. I declare no competing interests. A fully artificial pancreas versus a hybrid artificial pancreas for type 1 diabetes: a single-centre, open-label, randomised controlled, crossover, non-inferiority trialThe Fiasp plus pramlintide fully closed-loop system was not non-inferior to the Fiasp-alone hybrid closed-loop system for the overall percentage of time in the glucose target range. However, participants still spent a high percentage of time within the target range with the fully-closed loop system. Outpatient studies comparing the fully closed-loop hybrid systems with patient-estimated, rather than precise, carbohydrate counting are warranted. Full-Text PDF Open Access