This is the first study to examine how the ultra-long-acting basal insulin IDeg (estimated duration of action >42 h) affects the hypoglycaemic response during development of, and recovery from, hypoglycaemia in patients with type 1 diabetes. The results indicate that there are no marked differences in hypoglycaemic response or hypoglycaemic awareness induced by IDeg compared with the long-acting basal insulin IGlar. Similar effects on hypoglycaemic symptom and cognitive function scores during hypoglycaemia induction, PG nadir and recovery from hypoglycaemia were observed with both insulins. One interesting observation was a modest effect in enhancing some of the counter-regulatory hormone responses around the glucose nadir with IDeg, and a lower glucose infusion rate during recovery with IDeg compared with IGlar; however, this had no obvious effect on the HSS or cognitive function.
The main strengths of this trial relative to other hypoglycaemic experimental designs include the extensive measurement of symptomatic, cognitive and counter-regulatory hormonal responses and the double-blind crossover design, which eliminates potential investigator and patient bias as well as inter-patient variability. Given that IDeg has a duration of action >42 h, we considered it important to characterise how recovery from hypoglycaemia induced by IDeg develops with respect to the increase in PG and the persistence of symptoms and effects on cognitive function in advance of the introduction of IDeg into clinical practice. Finally, we included people with type 1 diabetes, rather than healthy patients, to ensure the pharmacodynamic response was not confounded by endogenous insulin production [20
]. In addition, intrapatient variability is likely to be lower in type 1 diabetes because of the lack of substantial endogenous insulin production. Though we recognise that a degree of hypoglycaemia unawareness is inevitable in a study population with an average diabetes duration of 21 years and is a study limitation, our main goal was to assess the counter-regulation in a clinically relevant type 1 diabetes population. Results, particularly from HSS, indicate sufficient hypoglycaemia awareness in all participating patients. Patients with severe hypoglycaemia unawareness were excluded from the study altogether.
We used a stepwise hypoglycaemic clamp technique using s.c. delivery in an attempt to achieve highly standardised study conditions to compare physiological and counter-regulatory responses with IDeg and IGlar. Although experimental hypoglycaemic studies involving other basal insulins have generally used a model incorporating i.v. delivery [23
], we considered s.c. administration more appropriate. This approach is more clinically relevant, particularly as the mode of protraction for both IDeg and IGlar is activated by s.c. administration. We attempted to standardise trial conditions by administering IDeg and IGlar at midnight, approximately 7 h prior to inducing hypoglycaemia. A dose three times higher than the patient’s regular insulin dose was administered on day 5 to try to achieve an appropriately low glucose target. The design was based on pharmacokinetic and pharmacodynamic modelling of existing data for both insulins. Thus, we set out to control for differing glycaemia, and to achieve comparability despite the use of two insulins with different action profiles. The delay in initiating hypoglycaemia (by maintaining patients in a euglycaemic clamp) until 7–9 h after administration of trial insulin was designed to control for differences in depth and duration of hypoglycaemia, and to control for the fall in glucose towards the hypoglycaemic plateau. However, variable glucose infusion rates during the clamp procedure tended to be lower with IDeg than IGlar, particularly at baseline (7–9 h post dosing) and during the recovery phase. Therefore, we cannot draw any firm conclusions regarding the relation between the observed differences in counter-regulatory hormone responses and in particular the rate of glucose recovery.
While the intensity of the hypoglycaemic response is multifactorial, important determinants are probably prior glycaemic experience, absolute PG level and the rate of PG decline. The comparable self-measured PG profiles and number of hypoglycaemic episodes suggest that glucose control was similar for IDeg and IGlar during the 5 days leading up to the hypoglycaemic clamp experiment. Moreover, in this trial, mean PG was similar with IDeg and IGlar throughout the hypoglycaemic clamp procedure. The rate of decline during hypoglycaemic induction was identical for both insulins once PG fell below 4.5 mmol/l, suggesting that the hypoglycaemic stimulus was comparable during clamp procedures. This is an important criterion for comparing the response between the two insulins.
We observed moderate differences in counter-regulatory hormone responses (as measured by the rate of increase, AUC and hormone level at PG nadir) during the development of hypoglycaemia for three of the five counter-regulatory hormones (adrenaline, growth hormone and cortisol) when induced with IDeg compared with IGlar; however, the underlying mechanism for the observed differences could not be identified in this study. As glucagon responses to hypoglycaemia are attenuated by both type 1 diabetes and hyperinsulinaemia [21
], it is not surprising that no differences in glucagon response were observed. Elevated cortisol levels have been associated with autonomic failure [26
] but more recent studies could not confirm this finding [27
]. Enhanced counter-regulatory hormone response might contribute to a reduced risk of hypoglycaemia, an important limiting factor in achieving good glycaemic control with intensified insulin therapy.
Although basal insulins such as IGlar are associated with a reduction in severe and nocturnal hypoglycaemia compared with neutral protamine Hagedorn insulin [29
], this appears to be due to improvements in insulin kinetics rather than to differences in glucose counter-regulation. Comparable physiological responses to induced hypoglycaemia have been shown for IGlar and human insulin in a stepped hypoglycaemic clamp [24
] and clinical trials have shown comparable glycaemic control with IDeg and IGlar when treated to target [31
]. Moreover, results from the large-scale confirmatory clinical trials provide promising evidence of a lower risk of hypoglycaemia with IDeg compared with IGlar, particularly at night [7
In conclusion, this trial provides reassuring data regarding the response to hypoglycaemia association with IDeg. IDeg and IGlar elicit comparable symptomatic and cognitive responses to induced hypoglycaemia, and recovery from hypoglycaemia remains similar. Furthermore, our trial suggests that IDeg may elicit a more pronounced endocrine response to hypoglycaemia than IGlar, albeit modest. Whether this translates into a clinically relevant difference cannot be answered by our trial. Adequately powered randomised multicentre studies in clinical settings are needed to establish the relevance of the effects of this new insulin on hypoglycaemia awareness, glucose counter-regulation and particularly rates of severe hypoglycaemia among individuals with type 1 diabetes.