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.

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.

OBJECTIVE -Insulin detemir is a soluble basal insulin analog with a unique mechanism of protracted action designed to reduce the variability associated with conventional basal insulins. This trial compared the glycemic control, risk of hypoglycemia, and effect on body weight of insulin detemir and NPH insulin in patients with type 1 diabetes treated with rapid-acting insulin aspart at meals. RESEARCH DESIGN AND METHODS-This study was a 6-month multinational open parallel-group comparison conducted at 46 centers in five countries and included 448 patients with type 1 diabetes randomized 2:1 to insulin detemir or NPH insulin, respectively. RESULTS -After 6 months, comparable HbA 1c levels were found between the two treatment groups. Fasting plasma glucose tended to be lower in patients treated with insulin detemir, but this difference was not statistically significant (Ϫ0.76 mmol/l, P ϭ 0.097). Within-subject variation in self-measured fasting blood glucose was lower with insulin detemir than with NPH insulin (SD 3.37 vs. 3.78 mmol/l, P Ͻ 0.001). Risk of hypoglycemia was 22% lower with insulin detemir than with NPH insulin (P Ͻ 0.05) and 34% lower for nocturnal (2300 -0600) hypoglycemia (P Ͻ 0.005). Nightly plasma glucose profiles were smoother and more stable with insulin detemir (P ϭ 0.05). Body weight was significantly lower with insulin detemir at the end of the trial (P Ͻ 0.001).CONCLUSIONS -Treatment with insulin detemir resulted in more predictable glycemic control, with smoother plasma glucose profiles than NPH insulin and a significant reduction in the risk of hypoglycemia. The reduction in body weight with insulin detemir is a potential additional advantage. Regimens optimized for insulin detemir may be able to improve glycemic control beyond that possible with NPH insulin.

BackgroundFast-acting insulin aspart (faster aspart) is insulin aspart (IAsp) in a new formulation aiming to mimic the fast endogenous prandial insulin release more closely than currently available insulin products. In a post hoc analysis of pooled data from six clinical pharmacology trials, the pharmacological characteristics of faster aspart and IAsp were compared.MethodsThe analysis included 218 adult subjects with type 1 diabetes from six randomised, double-blind, crossover trials in the faster aspart clinical development programme. Subjects received subcutaneous dosing (0.2 U/kg) of faster aspart and IAsp. In three trials, a 12-h euglycaemic clamp was performed (target 5.5 mmol/L; 100 mg/dL) to assess pharmacodynamics.ResultsThe pharmacokinetic and pharmacodynamic profiles were left-shifted for faster aspart versus IAsp. Onset of appearance occurred 4.9 min earlier (95% confidence interval [CI] faster aspart-IAsp: [−5.3 to −4.4], p < 0.001), early exposure (AUCIAsp,0–30min) was two times greater (estimated ratio faster aspart/IAsp 2.01 [1.87–2.17], p < 0.001) and offset of exposure (t Late 50% Cmax) occurred 12.2 min earlier [−17.9 to −6.5] (p < 0.001) for faster aspart versus IAsp. Accordingly, onset of action occurred 4.9 min earlier [−6.9 to −3.0] (p < 0.001), early glucose-lowering effect (AUCGIR,0–30min) was 74% greater (1.74 [1.47–2.10], p < 0.001) and offset of glucose-lowering effect (t Late 50% GIRmax) occurred 14.3 min earlier [−22.1 to −6.5] (p < 0.001) for faster aspart versus IAsp. Total exposure and total glucose-lowering effect did not differ significantly between treatments.ConclusionsFaster aspart has the potential to better mimic the physiologic prandial insulin secretion and thereby to improve postprandial glucose control compared with IAsp. ClinicalTrials.gov identifiers: NCT02035371, NCT01924637, NCT02131246, NCT02033239, NCT02003677, NCT01618188.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0514-8) contains supplementary material, which is available to authorized users.

Insulin degludec (IDeg) is a new-generation basal insulin with an ultra-long duration of action. To date, a large number of studies have been conducted to investigate the pharmacokinetic and pharmacodynamic properties of IDeg. Standardised methods for collection and analysis of blood samples (for pharmacokinetic endpoints) and euglycaemic clamp procedures (for pharmacodynamic endpoints) were applied across studies to enable cross-study evaluation of important pharmacokinetic and pharmacodynamic parameters. Data show that IDeg has a half-life of >25 h [compared with ~12 h for insulin glargine (IGlar)] and reaches steady state within 3 days of administration in all patient populations investigated. The pharmacokinetic profile of IDeg demonstrates an even distribution of exposure across one dosing interval. The pharmacodynamic profile of IDeg is flat and stable, demonstrated by an even distribution of glucose-lowering effect across all four 6-h intervals in a 24-h period (one dosing day). These properties were consistently demonstrated across different type 1 and type 2 diabetes mellitus patient populations, including those from different ethnic origins (both males and females with type 2 diabetes), the elderly, and patients with hepatic or renal impairment. IDeg has an ultra-long duration of action exceeding 42 h and demonstrates four times lower day-to-day within-subject variability in glucose-lowering effect than IGlar. This review discusses the pharmacokinetic and pharmacodynamic data accumulated thus far, and the relevance of these results from a clinical perspective.