Insulin degludec is not associated with a delayed or diminished response to hypoglycaemia compared with insulin glargine in type 1 diabetes: a double-blind randomised crossover study

Abstract

Aims/hypothesis: Insulin degludec (Des(B30)LysB29(γ-Glu Nε-hexadecandioyl) human insulin; IDeg) is a new basal insulin with an ultra-long flat action profile. The acute physiological responses to hypoglycaemia with IDeg and insulin glargine (A21Gly,B31Arg,B32Arg human insulin; IGlar) were compared.

Methods: Twenty-eight adult type 1 diabetic patients with normal hypoglycaemia awareness (age = 41 ± 12 years, HbA1c = 7.8 ± 0.6% [62.8 ± 7 mmol/mol]) were randomised to once-daily IDeg or IGlar for 5 days in a two-period crossover design. Participants and research staff were blinded to group assignment. Patients were assigned the lowest available randomisation number from a set of blinded randomisation codes provided by the trial sponsor. Hypoglycaemia was induced by administering three times the usual daily insulin dose at midnight on day 5. Plasma glucose (PG) was stabilised by glucose clamp (5.5 mmol/l) for 7-9 h post dosing. Next morning, PG was allowed to decrease stepwise from 5.5 to 3.5 mmol/l (maintained for 30 min) to 2.5 mmol/l (for 15 min). PG was then increased to 3.9 mmol/l (for 120 min), before being returned to baseline. Hypoglycaemic symptom score (HSS), hypoglycaemic awareness, cognitive function, counter-regulatory hormones and vital signs were assessed during each glucose plateau. The primary analysis was to compare IDeg vs IGlar with respect to HSS at nadir PG concentration (2.5 mmol/l).

Results: The full analysis set for treatment comparisons comprised data from all 28 exposed patients. Rates of PG decline and PG at nadir were similar for IDeg and IGlar. No treatment differences in HSS (estimated difference: 0.17 [95% CI -1.71, 2.05]; p > 0.05), cognitive function or awareness were observed at any time. Growth hormone and cortisol responses during hypoglycaemia were greater with IDeg than IGlar (AUC treatment ratio [IDeg/IGlar]: 2.44 [1.30, 4.60], p < 0.01; and 1.23 [1.01, 1.50]; p < 0.05), and adrenaline (epinephrine) responses trended higher (1.40 [0.96, 2.04], p = 0.07). The rates of recovery from hypoglycaemia were similar.

Conclusions/interpretation: IDeg and IGlar elicit comparable symptomatic and cognitive responses to induced hypoglycaemia. IDeg may elicit a moderately greater endocrine response, but times to PG recovery were similar for the two insulins.

Trial registration: ClinicalTrials.gov NCT01002768.

Funding: Novo Nordisk.

Figures

Fig. 1

Stepwise glucose clamp procedure. Run in: participants were clamped at a PG level of 5.5 mmol/l (100 mg/dl) 2 h before dosing until 7–9 h after dosing. Hypoglycaemia induction: variable i.v. glucose was terminated and PG was allowed to decrease to 3.5 mmol/l (63 mg/dl), maintained for 30 min, and thereafter to a target nadir of 2.5 mmol/l (45 mg/dl), maintained for 15 min. Recovery: at end of nadir PG, a fixed i.v. glucose infusion (5.5 mg kg−1 min−1) was initiated, and PG was allowed to increase to 3.9 mmol/l (70 mg/dl), maintained for 120 min, and thereafter to 5.5 mmol/l (100 mg/dl). Thick broken line, variable glucose infusion rate (GIR); thick unbroken line, fixed i.v. glucose infusion (5.5 mg kg−1 min−1)

Fig. 2

Flow of participants through the trial. FAS, full analysis set

Fig. 3

Mean time to PG targets (a) and mean glucose infusion rate (b) during development of, and recovery from, hypoglycaemia. In (a), time point zero has been defined as when PG = 4.5 mmol/l, because a decline in PG below 4.5 mmol/l is considered to be the threshold for hypoglycaemic response. Black circles, IDeg; white squares, IGlar. In (b), *denotes statistically significant estimated treatment difference in rate of glucose infusion (p < 0.05). Grey bars, IDeg; white bars, IGlar; narrow vertical black bars, 95% CI. GIR, glucose infusion rate

Fig. 4

Baseline-adjusted HSS during development of, and recovery from, hypoglycaemia. Black circles, IDeg; white squares, IGlar; vertical bars, SEM

Fig. 5

Baseline-adjusted cognitive function performance test scores during development of, and recovery from, hypoglycaemia for (a) trail making B, (b) digit symbol substitution test (DSST), (c) four-choice reaction time (percentage correct answers) and (d) four-choice reaction time (response time). Black circles, IDeg; white squares, IGlar; vertical bars, SEM. *denotes statistically significant estimated treatment difference in slopes (p < 0.05). TMB, trail making B; 4CRT, four-choice reaction time

Fig. 6

Counter-regulatory hormone response during development of, and recovery from, hypoglycaemia for (a) growth hormone, (b) cortisol, (c) adrenaline, (d) noradrenaline and (e) glucagon. Black circles, IDeg; white squares, IGlar; vertical bars, SEM. *denotes statistically significant estimated treatment difference in slopes (p < 0.05)