The dual hormone (insulin and glucagon) ‘‘artificial pancreas’’: Promises and challenges
Achieving tight glycaemic control without severe hypoglycaemia still is a major challenge in insulin-treated diabetes. While curative cell based and immunological therapies could theoretically provide the ideal solution for patients with diabetes, there are still many issues to be solved. Closed-loop technologies may provide a more promising alternative for the near future, although various challenges will still need to be overcome to safely avoid hypoglycaemia and still achieve good blood glucose levels in a closed-loop setting.
From a controlling perspective, a major challenge is the use of exogenous subcutaneously (s.c.) applied insulin with a rather slow onset and long duration of action, which is unable to react fast enough to the wide and highly variable range in insulin requirements under different physiological conditions. To put a physiological break on the insulin action when blood glucose tends to go low, bihormonal artificial pancreas (AP) systems are being developed which, in addition to insulin, use human pancreas hormone glucagon to counteract the effect of insulin. Glucagon leads to a rapid conversion of hepatic glycogen (the stored form of glucose) into glucose which is then released into the bloodstream. A number of academic working groups have demonstrated short-term efficacy and safety of automated insulin and glucagon delivery among people with type 1 diabetes mellitus [[i]] [[ii]] [[iii]] [[iv]]. Glucagon’s effects on reducing caloric intake and increasing energy expenditure could even be beneficial within the context of the growing prevalence of patients with diabetes who are overweight or obese [[v]].
The need for a stable glucagon formulation
However, bihormonal AP systems also face some challenges, in particular with regard to the chemical/physical stability of glucagon. Up to now, commercially available glucagon formulations used as rescue medication for severe hypoglycaemia need to be reconstituted and have to be used immediately after reconstitution [[vi]] [[vii]]. Native glucagon is a highly unstable peptide prone to spontaneous polymerization and formation of amyloid-like fibrils after reconstitution [[viii]]. Recently, stability data over 24 hours have been provided which however still means that daily glucagon renewal is required [[ix]].
To solve the stability issues, much of the recent glucagon research has focused on developing a stable liquid glucagon formulation that will maintain in-use stability and compatibility medium- or long-term [[x]] [[xi]] [[xii]] [[xiii]]. First data of early phase clinical trials have been provided by both Zealand Pharma A/S and Xeris Pharmaceuticals demonstrating safety and efficacy of their formulations in clinical trials [[xiv]]. Profil has been involved in the research on Zealand’s glucagon analogue and presented promising data at American Diabetes Association 77th Scientific Sessions (ADA) and 53rd European Association for the Study of Diabetes (EASD) [[xv]].
A “technological cure” for diabetes
While these first short-term trials with new glucagon formulations do give rise for hope, comprehensive long-term AP studies are still needed to support long-term efficacy and safety of chronic glucagon (analogue) administration and to fully characterize potential benefits . Nevertheless, a recently published systematic review indicated that dual-hormone AP systems were associated with a greater improvement in time in target range compared with single-hormone systems and showed lower heterogeneity in their studies [[xvi]]. Thus, improvements in the stability of glucagon formulations might be important to make the dream of a “technical cure” of diabetes with dual-hormone closed loop delivery systems become true.
[i] Russell SJ, El-Khatib FH Sinha M, et al. Outpatient Glycemic Control with a Bionic Pancreas in Type 1 Diabetes. New England Journal of Medicine. 2014: 1-13.doi: 10.1056/NEJMoa1314474.
[ii] Haidar A, Legault L, Matteau-Pelletier L et al. Outpatient overnight glucose control with dual-hormone artificial pancreas, single-hormone artificial pancreas, or conventional insulin pump therapy in children and adolescents with type 1 diabetes: an open-label, randomised controlled trial. The Lancet Diabetes & Endocrinol 2015;3:595-604.
[iii] Haidar A, Legault L, Messier V et al. Comparison of dual-hormone artificial pancreas, single-hormone artificial pancreas, and conventional insulin pump therapy for glycaemic control in patients with type 1 diabetes: an open-label randomised controlled crossover trial. The Lancet Diabetes & Endocrinol 2015;3:17-26
[iv] Blauw H, van Bon AC, Koops R, et al.: Performance and safety of an integrated bihormonal artificial pancreas for fully automated glucose control at home. Diabetes Obes Metab 2016;18:671–677.
[v] Taleb N, Haidar A, Messier V et al. Glucagon in the artificial pancreas systems; potential benefits and safety profile of future chronic use. Diabetes Obesity and Metabolism 2016; doi: 10.1111/dom.12789.
[vi] SPC GlucaGen HypoKit 1 mg, Novo Nordisk [article online], Available from https://www.medicines.org.uk/emc/medicine/4258/SPC/GlucaGen+Hypokit+1+mg/ Accessed 24 Oct 2017.
[vii] Glucagon for Injection, Lilly USA [article online], Available from http://www.lillyglucagon.com/assets/pdf/glucagon_brochure.pdf Accessed 24 Oct 2017.
[viii] Pedersen JS. The nature of amyloid-like glucagon fibrils. J Diabetes Sci Technol 2010;4:1357-1367.
[ix] Taleb N, Coriat A, Khazzak Ch et al. Stability of Commercially Available Glucagon Formulation of Dual-Hormone Artificial Pancreas Clinical Use. Diabetes Technology & Therapeutics. 2017;19, 10:589-594.
[x] Jackson MA, Caputo N, Castle JR, et al.: Stable liquid glucagon formulations for rescue treatment and bi-hormonal closed-loop pancreas. Curr Diab Rep 2012;12:705–710.
[xi] Bakhtiani PA, Caputo N, Castle JR, et al.: A novel, stable, aqueous glucagon formulation using ferulic acid as an excipient. J Diabetes Sci Technol 2015;9:17–23.
[xii] Pohl R, Li M, Krasner A, De Souza E. Development of Stable Liquid Glucagon Formulations for Use in Artificial Pancreas. J Diabetes Sci and Technol. 2015;Vol 9:(1)8–16.
[xiii] Newswanger B, Ammons S, Phadnis N et al.: Development of a highly stable, nonaqueous glucagon formulation for delivery via infusion pump systems. J Diabetes Sci Technol 2015;9:24-33
[xiv] Castle JR, Youssef JE, Branigan D et al. Comparative Pharmacokinetic / Pharmacodynamic Study of Liquid Stable Glucagon Versus Lyophilized Glucagon in Type 1 Diabetes Subjects. J Diabetes Sci Technol. 2016;10(5):1101-7.
[xv] Heise T, Væver Bysted B, Mouritzen U et al. Dasiglucagon, a novel soluble glucagon analog, successfully restores blood glucose levels after hypoglycemia in people with type 1 diabetes mellitus (T1DM). Abstract number #2017-A-3502 and poster presentation number 389-P at ADA, 2017 and Abstract and poster presentation number #738 at EASD, 2017.
[xvi] Weisman A, Bai J-W, Cardinez M et al. Effect of artificial pancreas systems on glycaemic control in patients with type 1 diabetes: a systematic review and meta-analysis of outpatient randomised controlled trials. Lancet Diabetes and Endocrinology. 2017;Vol 5(7):p501–512.