Discussion
hypoglycaemia, insulin-naive, intercurrent illness, generalised, diabetes
HYPOGLYCAEMIA, TYPE 1 DIABETES, DISEASE, HIGH INSULIN, TYPE 2 DIABETES, DIABETES
In the current study, the main findings related to hypoglycaemia frequency and glucodynamics were that the risk of hypoglycaemia was comparable for icodec vs glargine U100 following double and triple doses, the duration of decline in PG towards clinically significant hypoglycaemia (PGPhase 2 clinical trials up to 26 weeks in insulin-naive or previously insulin-treated individuals with type 2 diabetes have shown low rates of level 2 and level 3 hypoglycaemia for once-weekly icodec that are comparable to once-daily glargine U100 [Avoiding hypoglycaemia is obviously a focus point for individuals with diabetes [The present findings may not only apply to situations where an unintentionally high insulin dose is administered, e.g. due to miscalculation of the insulin dose or forgetting that a dose has been taken and hence taking two weekly doses close to each other. Rather, they may also be generalised to situations where the usually administered insulin dose is too high to match the insulin needs, due to reduced insulin requirement. This could occur during and after exercise, during intercurrent illness, or during hospitalisation that often implies fasting prior to medical testing or operative procedures [The considerably extended half-life of icodec is mainly due to strong, reversible binding to albumin, whereby an essentially inactive depot of icodec is formed throughout the circulation and the interstitial compartment, from which icodec is slowly and continuously released [Previously, the symptomatic and endocrine responses to hypoglycaemia have been studied for insulin detemir, insulin degludec and glargine U100 in healthy individuals and in individuals with type 1 diabetes [Increased secretion of adrenaline from the adrenal medulla during hypoglycaemia development plays a role in early counterregulation by increasing endogenous glucose production and reducing insulin-stimulated glucose uptake [In individuals with type 2 diabetes who are recently diagnosed, and in those where the disease has not yet progressed to the level where the glucagon secretory capacity becomes absent, glucagon is known to be the most important counterregulatory hormone [There is no apparent explanation why adrenaline and cortisol responses were greater with icodec vs glargine U100 after triple dose. A potential reason might be impaired physiological response to hypoglycaemia caused by antecedent hypoglycaemia due to the shorter period of 7 days between the two hypoglycaemia inductions during glargine U100 treatment in contrast to the 3 weeks between hypoglycaemia inductions during icodec treatment. However, the effect of antecedent hypoglycaemia has been shown to last less than 2 days [A strength of the trial was the enrolment of individuals with type 2 diabetes, the population which could potentially benefit the most from once-weekly basal insulin. At the same time, it must be recognised that the current results do not necessarily apply to individuals with type 1 diabetes. To mimic a clinically relevant situation, hypoglycaemia induction was carried out following a high dose given on top of the individually titrated normal dose at steady state and using the intended dosing frequency of once per week for icodec. Furthermore, s.c. administration was used in contrast to many previous studies using an i.v. hyperinsulinaemic–hypoglycaemic glucose clamp to study hypoglycaemia under controlled conditions [The subgroup approach used to investigate the physiological response to hypoglycaemia, whereby participants were only included in the analysis if they actually experienced hypoglycaemia during the hypoglycaemic induction experiment, could potentially have led to selection bias. However, baseline characteristics in the subgroup were similar to those in the full group of participants, thus reducing the likelihood of such bias. Furthermore, not all participants contributed to hypoglycaemia induction results for both icodec and glargine U100, which might have also had an impact on the conclusions. However, in a sensitivity analysis of the counterregulatory hormone responses that only included individuals who experienced hypoglycaemia for both insulin products, numerical results comparable to the main statistical analyses were obtained. It cannot be excluded that the substantial number of statistical comparisons performed in the trial with no multiplicity adjustment may have led to type 1 error(s). On the contrary, the lack of treatment differences in cognitive function tests, despite greater responses in adrenaline and cortisol, with icodec vs glargine U100 after triple dose could have been due to the relatively small sample size combined with the inherently large variation in the cognitive function measures.In conclusion, it is reassuring that double and triple doses of once-weekly icodec do not lead to an increased risk of hypoglycaemia compared with once-daily glargine U100, and that the time to develop hypoglycaemia and recover from hypoglycaemia are comparable for icodec and glargine U100. The study also suggests that hypoglycaemia induced by icodec is accompanied by symptomatic and counterregulatory responses, at least as robust as those seen for glargine U100, to support restoration of euglycaemia. Thus, the current study provides further reassurance about the safety of once-weekly icodec.