Discussion
UC, obesity, nausea, hypoglycaemia
OBESITY, TYPE 1 DIABETES, ADVERSE EVENT, HYPERGLYCAEMIA, HYPOGLYCAEMIA
This investigational drug and device trial demonstrated that low-dose s.c. dasiglucagon was a safe, effective and feasible alternative to usual carbohydrate consumption for treatment and prevention of non-severe hypoglycaemia during free-living conditions. Utilisation of dasiglucagon for hypoglycaemia management resulted in faster hypoglycaemia recovery; higher hypoglycaemia treatment and prevention success; markedly reduced carbohydrate intake; high treatment satisfaction; and modest, non-significant improvements in percentage of time in, below and above range. The side effects profile of dasiglucagon was in line with those previously reported for low-dose glucagon, with mild and transient nausea being the most frequent adverse event.Use of low-dose glucagon to manage hypoglycaemia has a number of potential merits. As hypoglycaemia adversely impacts mental health and well-being [In this study, the occurrence of rebound hyperglycaemia following successful hypoglycaemia treatment was not lower in the DASI period compared with UC. At the same time, restoration of euglycaemia within 30 min after initial treatment, although more effective than in the UC period, was not met in all cases in the DASI period. The findings prompt a discussion of utilising a flexible dosing regimen of dasiglucagon. In the current trial, the instructed dose of 80 μg was effective and well-suited for many participants and hypoglycaemic episodes. However, in some cases, data suggest that either a higher or lower dose would have been favourable. As is also evident from hypoglycaemia management in clinical practice, inter- and intraindividual differences in carbohydrate requirements exist depending on initial glucose concentration, preceding physical activity, insulin on board and other variables. Therefore, a flexible dosing regimen for dasiglucagon, allowing individuals to tailor the dose for each use case, could potentially further optimise the glycaemic control by ensuring sufficient efficacy while minimising the risk of subsequent hyperglycaemia.Due to the growing prevalence of obesity in individuals with type 1 diabetes and the fact that hypoglycaemia-associated carbohydrate consumption may play an important role, there has been increasing focus on developing treatment strategies focusing not only on glycaemic control, but also on weight management [The present trial provides a number of new insights. It is the first study to evaluate the use of pen-administered low-dose dasiglucagon for management of non-severe hypoglycaemia in outpatient settings. Previously, Haymond and colleagues conducted an exploratory outpatient study investigating the use of syringe-administered glucagon (Gvoke, Xeris Pharmaceuticals, Chicago, IL, USA) for management of non-severe hypoglycaemia [The study has some limitations. As all participants used insulin pumps (selected to ensure precise insulin administration data) and stand-alone CGMs, were moderately physically active and had regular episodes of non-severe hypoglycaemia, additional studies are required to generalise the findings to the broader population with type 1 diabetes, especially to individuals using other treatment modalities. Another limitation is the study duration. Although the two 2 week intervention periods were sufficient to generate important and clinically meaningful findings, endpoint evaluation in longer trials is required. Additionally, a longer trial duration would have allowed participants to better familiarise themselves with the utilisation and treatment response of dasiglucagon which could potentially improve glycaemic control further. The current sample size was selected for feasibility and was not powered to demonstrate a significant difference in the primary outcome. However, the present trial was able to demonstrate statistically significant differences in a range of outcomes that have substantial clinical implications. Nevertheless, larger studies are required to generate more robust data.Looking ahead, more questions need to be addressed. Larger studies of longer duration are required to assess the long-term efficacy and safety, changes in body weight and a more extensive set of PROs. In addition, utilisation of a flexible dosing regimen and inclusion of individuals using other treatment modalities, including both advanced hybrid closed-loop users and multiple daily injection users, are required to address and reflect the full potential of using low-dose dasiglucagon to manage hypoglycaemia.In conclusion, this study demonstrated that use of pen-administered low-dose dasiglucagon, a novel, ready-to-use glucagon analogue, to treat and prevent non-severe hypoglycaemia during free-living conditions was safe, fast and efficacious while significantly reducing the total daily carbohydrate intake and yielding high treatment satisfaction. The findings support the continued study of utilising low-dose glucagon as a non-caloric alternative to carbohydrates for management of hypoglycaemia in individuals with type 1 diabetes.