Similar risk of exercise-related hypoglycaemia for insulin degludec to that for insulin glargine in patients with type 1 diabetes: a randomized cross-over trial.

We compared changes in blood glucose (BG) and risk of hypoglycaemia during and after exercise in 40 patients with type 1 diabetes (T1D) treated with insulin degludec (IDeg) or insulin glargine (IGlar) in a randomized, open-label, two-period, crossover trial. After individual titration and a steady-state period, patients performed 30 min of moderate-intensity cycle ergometer exercise (65% peak rate of oxygen uptake). BG, counter-regulatory hormones and hypoglycaemic episodes were measured frequently during and for 24 h after exercise. BG changes during exercise were similar with IDeg and IGlar [estimated treatment difference (ETD) for maximum BG decrease: 0.14 mmol/l; 95% confidence interval (CI) -0.15, 0.42; p = 0.34], as was mean BG (ETD -0.16 mmol/l; 95% CI -0.36, 0.05; p = 0.13). No hypoglycaemic episodes occurred during exercise. Post-exercise mean BG, counter-regulatory hormone response and number of hypoglycaemic episodes in 24 h after starting exercise were similar with IDeg (18 events in 13 patients) and IGlar (23 events in 15 patients). This clinical trial showed that, in patients with T1D treated with a basal-bolus regimen, the risk of hypoglycaemia induced by moderate-intensity exercise was low with IDeg and similar to that with IGlar.

Faster-acting insulin aspart: earlier onset of appearance and greater early pharmacokinetic and pharmacodynamic effects than insulin aspart.

AIMS: To evaluate the pharmacokinetics and pharmacodynamics of faster-acting insulin aspart and insulin aspart in a randomized, single-centre, double-blind study. METHODS: Fifty-two patients with type 1 diabetes (mean age 40.3 years) received faster-acting insulin aspart, insulin aspart, or another faster aspart formulation (not selected for further development), each as a single 0.2 U/kg subcutaneous dose, under glucose-clamp conditions, in a three-way crossover design (3-12 days washout between dosing). RESULTS: Faster-acting insulin aspart had a faster onset of exposure compared with insulin aspart, shown by a 57% earlier onset of appearance [4.9 vs 11.2 min; ratio 0.43, 95% confidence interval (CI) 0.36; 0.51], a 35% earlier time to reach 50% maximum concentration (20.7 vs 31.6 min; ratio 0.65, 95% CI 0.59; 0.72) and a greater early exposure within 90 min after dosing. The greatest difference occurred during the first 15 min, when area under the serum insulin aspart curve was 4.5-fold greater with faster-acting insulin aspart than with insulin aspart. Both treatments had a similar time to maximum concentration, total exposure and maximum concentration. Faster-acting insulin aspart had a significantly greater glucose-lowering effect within 90 min after dosing [largest difference: area under the curve for the glucose infusion rate (AUC(GIR), 0-30 min) ratio 1.48, 95% CI 1.13; 2.02] and 17% earlier time to reach 50% maximum glucose infusion rate (38.3 vs 46.1 min; ratio 0.83, 95% CI 0.73; 0.94). The primary endpoint (AUC(GIR, 0-2 h)) was 10% greater for faster-acting insulin aspart, but did not reach statistical significance (ratio 1.10, 95% CI 1.00; 1.22). Both treatments had similar total and maximum glucose-lowering effects, indicating similar overall potency. CONCLUSIONS: Faster-acting insulin aspart was found to have earlier onset and higher early exposure than insulin aspart, and a greater early glucose-lowering effect, with similar potency.

Insulin degludec/insulin aspart produces a dose-proportional glucose-lowering effect in subjects with type 1 diabetes mellitus.

AIMS: To evaluate the pharmacodynamic dose-response relationship of insulin degludec/insulin aspart (IDegAsp), a novel, soluble co-formulation of the ultra-long-acting basal insulin, insulin degludec (IDeg), with the rapid-acting prandial insulin (IAsp), across different doses in patients with type 1 diabetes (T1DM). METHODS: This was a randomized, single-centre, double-blind, four-period, incomplete block, crossover trial. A cohort of 33 people with T1DM received single doses (0.4, 0.6 or 0.8 U/kg) of IDegAsp or the comparator, biphasic insulin aspart 30, in a randomized sequence of four treatment periods, each separated by a washout of 13-21 days. Pharmacodynamic response was assessed using a 26-h euglycaemic glucose clamp, with blood glucose stabilized at a target of 5.5 mmol/l (100 mg/dl). RESULTS: A rapid onset of action and a distinct peak attributable to IAsp was observed in the glucose infusion rate (GIR) profile, followed by a separate, flat and stable basal glucose-lowering effect attributable to the IDeg component. The mean area under the GIR curve over 24 h (AUC(GIR,0-24 h)), and the mean maximum GIR (GIR(max)) increased with increasing dose level of IDegAsp. A dose-response relationship for IDegAsp was demonstrated for AUC(GIR,0-24 h) and GIR(max), indicating dose proportionality. A dose-concentration relationship was also observed for both the basal and bolus components of IDegAsp. CONCLUSIONS: IDegAsp has a clear dose-response relationship, indicating the clinical potential for straightforward titration according to individual patient needs.

Ultra-long-acting insulin degludec has a flat and stable glucose-lowering effect in type 2 diabetes.

AIMS: Insulin degludec (IDeg) is a new-generation, ultra-long-acting basal insulin that forms soluble multihexamers upon subcutaneous injection, resulting in a depot from which IDeg is absorbed slowly and continuously into circulation. This double-blind, two-period, incomplete block cross-over trial investigated the pharmacodynamic and pharmacokinetic properties of IDeg at steady state (SS) in people with type 2 diabetes. METHODS: Forty-nine subjects treated with insulin without concomitant oral anti-diabetic drugs were given IDeg (0.4, 0.6 and/or 0.8 U/kg) once daily for two 6-day periods, separated by an interval of 13-21 days. Following dosing on Day 6, subjects underwent a 26-h euglycaemic glucose clamp (Biostator®; clamp blood glucose level: 90 mg/dl; 5.0 mmol/l). Pharmacokinetic samples were taken until 120 h after last dosing. RESULTS: For all dose levels, the mean glucose infusion rate (GIR) profiles were flat and stable. The glucose-lowering effect of IDeg was evenly distributed over the dosing interval τ, with area under the curve (AUC) for each of the four 6-h intervals being approximately 25% of the total AUC (AUC(GIR) (,τ,) (SS) ). Total glucose-lowering effect increased linearly with increasing dose. The blood glucose levels of all subjects stayed very close to the clamp target until end of clamp. The terminal half-life of IDeg was approximately 25 h at steady state. IDeg was well tolerated and no safety concerns were identified. No injection site reactions were reported. CONCLUSIONS: IDeg has a flat and consistent glucose-lowering effect in people with type 2 diabetes.

Insulin degludec: four times lower pharmacodynamic variability than insulin glargine under steady-state conditions in type 1 diabetes.

AIMS: Insulin degludec (IDeg) is a new-generation basal insulin with an ultra-long duration of action. We compared the pharmacodynamic (PD) variability of IDeg and insulin glargine (IGlar) under steady-state conditions. METHODS: Day-to-day variability in glucose-lowering effect was investigated in 54 subjects with type 1 diabetes who underwent a 24-h euglycaemic glucose clamp on the 6th, 9th and 12th day of treatment with 0.4 U/kg of IDeg or IGlar once daily. Within-subject variability was estimated using a linear mixed model on log-transformed PD endpoints derived from the glucose infusion rate (GIR) profiles during the clamps. RESULTS: For IDeg the day-to-day variability in glucose-lowering effect was four-times lower than for IGlar for total metabolic effect (AUC(GIR,0-24h,SS), CV 20% vs. 82%) and for the last 22 h [AUC(GIR,2-24h,SS) (not influenced by intravenous insulin during the clamp), CV 22% vs. 92%]. Furthermore, lower variability in the maximum effect was observed for IDeg vs. IGlar (GIR(max,SS), CV 18% vs. 60%). The lower within-subject variability of IDeg was consistent over time (CVs of 33% for AUC(GIR,0-2h,SS), 32% for AUC(GIR,10-12h,SS) and 33% for AUC(GIR,22-24h,SS)), whereas the variability of IGlar was higher and increased substantially 8 h post-dosing (CVs of 60% for AUC(GIR,0-2h,SS), 135% for AUC(GIR,10-12h,SS) and 115% for AUC(GIR,22-24h,SS)). CONCLUSIONS: These results show that IDeg has a significantly more predictable glucose-lowering effect from day to day than IGlar.

Differential effects of insulin detemir and neutral protamine Hagedorn (NPH) insulin on hepatic glucose production and peripheral glucose uptake during hypoglycaemia in type 1 diabetes.

AIMS/HYPOTHESIS: We compared the symptoms of hypoglycaemia induced by insulin detemir (NN304) (B29Lys(epsilon-tetradecanoyl),desB30 human insulin) and equally effective doses of neutral protamine Hagedorn (NPH) insulin in relation to possible differential effects on hepatic glucose production and peripheral glucose uptake. METHODS: After overnight intravenous infusion of soluble human insulin 18 participants with type 1 diabetes received subcutaneous injections of NPH insulin or insulin detemir (0.5 U/kg body weight) on separate occasions in random order. During the ensuing gradual development of hypoglycaemia cognitive function and levels of counter-regulatory hormones were measured and rates of endogenous glucose production and peripheral glucose uptake continuously evaluated using a primed constant infusion of [6,6-(2)H(2)]glucose. The study was terminated when plasma glucose concentration had fallen to 2.4 mmol/l or had reached a minimum at a higher concentration. RESULTS: During the development of hypoglycaemia no difference between the two insulin preparations was observed in symptoms or hormonal responses. Significant differences were seen in rates of glucose flux. At and below plasma glucose concentrations of 3.5 mmol/l suppression of endogenous glucose production was greater with insulin detemir than with NPH insulin, whereas stimulation of peripheral glucose uptake was greater with NPH insulin than with insulin detemir. CONCLUSIONS/INTERPRETATION: In participants with type 1 diabetes subcutaneously injected insulin detemir exhibits relative hepatoselectivity compared with NPH insulin, but symptoms of hypoglycaemia and hormonal counter-regulation are similar. TRIAL REGISTRATION: ClinicalTrials.gov NCT00760448.

Ultra-long pharmacokinetic properties of insulin degludec are comparable in elderly subjects and younger adults with type 1 diabetes mellitus.

BACKGROUND: Management of diabetes in elderly subjects is complex and careful management of glucose levels is of particular importance in this population because of an increased risk of diabetes-related complications and hypoglycaemia. OBJECTIVE: The aim of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of insulin degludec (IDeg), a basal insulin with an ultra-long duration of action, in elderly subjects with type 1 diabetes compared with younger adults. METHODS: This trial was a randomised, double-blind, two-period, crossover trial conducted in a single centre and included both inpatient and outpatient periods. Subjects were men and women aged 18-35 years inclusive (younger adult group) or ≥65 years (elderly group) with type 1 diabetes who received IDeg (0.4 U/kg) via subcutaneous injection in the thigh once-daily for six days. Following 6-day dosing, a 26-hour euglycaemic glucose clamp procedure was conducted to evaluate the steady-state pharmacodynamic effects of IDeg. Blood samples were taken for pharmacokinetic analysis up to 120 h post-dose. Pharmacokinetic endpoints included the total exposure of IDeg, ie the area under the IDeg serum concentration curve during one dosing interval at steady state (AUC(IDeg,τ,SS)) (τ = 0-24 h, equal to one dosing interval) and the maximum IDeg serum concentration at steady state (C(max,IDeg,SS)). Pharmacodynamic endpoints included the total glucose-lowering effect of IDeg, ie the area under the glucose infusion rate (GIR) curve at steady state (AUC(GIR,τ,SS)), and the maximum GIR at steady state (GIR(max,IDeg,SS)). RESULTS: Total exposure (AUC(IDeg,τ,SS)) and maximum concentration (C(max,IDeg,SS)) of IDeg were comparable between elderly subjects and younger adults. Estimated mean age group ratios (elderly/younger adult) for AUC(IDeg,τ,SS) and C(max,IDeg,SS) and corresponding two-sided 95 % confidence intervals (CIs) were 1.04 (95 % CI 0.73-1.47) and 1.02 (95 % CI 0.74-1.39), respectively. Mean AUC(IDeg,0-12h,SS)/AUC(IDeg,τ,SS) was 53 % in both younger adult and elderly subjects, showing that in both age groups IDeg exposure was evenly distributed across the first and second 12 h of the 24-hour dosing interval. No statistically significant differences were observed between younger adult and elderly subjects with regard to AUC(GIR,τ,SS) (the primary endpoint of this study) and GIR(max,IDeg,SS). Estimated mean age group ratios (elderly/younger adult) for AUC(GIR,τ,SS) and GIR(max,IDeg,SS) and corresponding two-sided 95 % CIs were 0.78 (95 % CI 0.47-1.31) and 0.80 (95 % CI 0.54-1.17), respectively. Duration of action was beyond the clamp duration of 26 h in all subjects. CONCLUSIONS: The exposure of IDeg at steady state during once-daily dosing was similar in younger adult and elderly subjects. The glucose-lowering effect of IDeg was numerically lower in elderly subjects compared with younger adults, but no significant differences were observed between age groups. The ultra-long pharmacokinetic and pharmacodynamic properties of IDeg observed in younger adults were preserved in elderly subjects with type 1 diabetes. Clinical trials.gov number: NCT00964418.

Time-action profile of insulin detemir and NPH insulin in patients with type 2 diabetes from different ethnic groups.

AIM: To evaluate the time-action profiles and the dose-response relationship of the long-acting insulin analogues insulin detemir (IDet) and NPH insulin (NPH) in type 2 diabetic patients belonging to different ethnic groups. METHODS: Forty-eight type 2 diabetic patients belonging to different ethnic groups (three groups of 16 African Americans (AA), 16 Hispanics/Latinos (HL) and 16 Caucasians) participated in this double-blind crossover trial. Each patient took part in six 16-h isoglycaemic glucose clamps (clamp target 7.2 mmol/l) and was randomly allocated to three doses (0.3, 0.6 and 1.2 (I)U/kg) of IDet and NPH, respectively. RESULTS: IDet and NPH showed comparable pharmacodynamic effects [the area under the glucose infusion rate curve (AUC(GIR 0-16 h)) (mg/kg)] in the investigated dose range: IDet, 0.3 U/kg, 207 AA, 535 HL, 285 Caucasians; 0.6 U/kg, 1203 AA, 824 HL and 1126 Caucasians; 1.2 U/kg, 1502 AA, 1977 HL and 2269 Caucasians; NPH, 0.3 IU/kg, 733 AA, 1148 HL and 1148 Caucasians; 0.6 IU/kg, 1395 AA, 1976 HL and 1077 Caucasians; 1.2 IU/kg, 2452 AA, 3296 HL and 2455 Caucasians. Both IDet and NPH showed a linear dose-response relationship in all three groups (p = 0.31), without any significant differences in slope (p = 0.71) or intercept (p = 0.51). Comparable results were obtained for pharmacokinetics. CONCLUSIONS: These results confirm a linear dose-response relationship of IDet, without any relevant differences between ethnic groups. This suggests that similar dosing recommendation can be used for IDet in type 2 diabetic patients belonging to different ethnic group.