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Pharmacology: Pharmacodynamics: Mechanism of action: Insulin degludec binds specifically to the human insulin receptor and results in the same pharmacological effects as human insulin.
The blood glucose-lowering effect of insulin is due to the facilitated uptake of glucose following the binding of insulin to receptors on muscle and fat cells and to the simultaneous inhibition of glucose output from the liver.
Pharmacodynamic effects: Tresiba is a basal insulin that forms soluble multi-hexamers upon subcutaneous injection, resulting in a depot from which insulin degludec is continuously and slowly absorbed into the circulation leading to a flat and stable glucose-lowering effect of Tresiba (see Figure 1). During a period of 24 hours with once-daily treatment, the glucose-lowering effect of Tresiba, in contrast to insulin glargine, was evenly distributed between the first and second 12 hours (AUCGIR,0-12h,SS/AUCGIR,total,SS = 0.5). (See Figure 1.)
Click on icon to see table/diagram/imageThe duration of action of Tresiba is beyond 42 hours within the therapeutic dose range. Steady state will occur after 2-3 days of dose administration.
The day-to-day variability, expressed as the coefficient of variation, in glucose-lowering effect during one dosing interval of 0-24 hours at steady state (AUCGIR,τ,SS) is 20% for insulin degludec, which is significantly lower than for insulin glargine (100 units/mL).
The total glucose-lowering effect of Tresiba increases linearly with increasing doses.
The total glucose-lowering effect is comparable for Tresiba 100 units/ml and 200 units/ml after administration of the same doses of the two products.
There is no clinically relevant difference in the pharmacodynamics of Tresiba between elderly and younger adult patients.
Clinical efficacy and safety: 11 multinational clinical trials of 26 or 52 weeks' duration were conducted as controlled, open-label, randomised, parallel, treat-to-target trials exposing 4,275 patients to Tresiba (1,102 in type 1 diabetes mellitus and 3,173 in type 2 diabetes mellitus).
In the open-label trials the effect of Tresiba was tested in patients with type 1 diabetes mellitus (Table 2), in insulin naïve patients (insulin initiation in type 2 diabetes mellitus, Table 3) and in previous insulin users (insulin intensification in type 2 diabetes mellitus, Table 4) with fixed as well as flexible dosing time (Table 5), and the reduction in HbA1c from baseline to end of trial was confirmed to be non-inferior in all trials against all comparators (insulin detemir and insulin glargine (100 units/ml)). While improvements in HbA1c were non-inferior compared to other insulin products, against sitagliptin Tresiba was statistically significantly superior in reducing HbA1c (Table 4). (See Tables 2-5)
In a prospectively planned meta-analysis across seven open-label treat-to-target confirmatory trials in patients with type 1 and type 2 diabetes mellitus, Tresiba was superior in terms of a lower number of treatment-emergent confirmed hypoglycaemic episodes (driven by a benefit in type 2 diabetes mellitus, see Table 1) and nocturnal confirmed hypoglycaemic episodes compared to insulin glargine (100 units/ml) (administered according to label). The reduction in hypoglycaemia was achieved at a lower average FPG level with Tresiba than with insulin glargine. (See Table 1.)
Click on icon to see table/diagram/imageThere is no clinically relevant development of insulin antibodies after long-term treatment with Tresiba.
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Click on icon to see table/diagram/imageIn a 104-week clinical trial, 57% of patients with type 2 diabetes treated with Tresiba (insulin degludec) in combination with metformin achieved a target HbA1c <7.0%, and the remaining patients continued in a 26-week open-label trial and were randomised to add liraglutide or a single dose of insulin aspart (with the largest meal). In the insulin degludec + liraglutide arm, the insulin dose was reduced by 20% in order to minimise the risk of hypoglycaemia. Addition of liraglutide resulted in a statistically significantly greater reduction of HbA1c (-0.73% for liraglutide versus -0.40% for comparator, estimated means) and body weight (-3.03 versus 0.72 kg, estimated means). The rate of hypoglycaemic episodes (per patient year of exposure) was statistically significantly lower when adding liraglutide compared to adding a single dose of insulin aspart (1.0 versus 8.15; ratio: 0.13; 95% CI: 0.08 to 0.21).
Furthermore, two 64-week controlled, double-blind, randomised, cross-over, treat-to-target trials were conducted in patients with at least one risk factor for hypoglycaemia and with type 1 diabetes mellitus (501 patients) or type 2 diabetes mellitus (721 patients). Patients were randomised to either Tresiba or insulin glargine (100 units/ml) followed by cross-over. The trials evaluated the rate of hypoglycaemia upon treatment with Tresiba compared to insulin glargine (100 units/ml) (see Table 6).
Click on icon to see table/diagram/imageCardiovascular evaluation: DEVOTE was a randomised, double-blind, and event-driven clinical trial with a median duration of 2 years comparing the cardiovascular safety of Tresiba versus insulin glargine (100 units/ml) in 7,637 patients with type 2 diabetes mellitus at high risk of cardiovascular events.
The primary analysis was time from randomisation to first occurrence of a 3-component major adverse cardiovascular event (MACE) defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. The trial was designed as a non-inferiority trial to exclude a pre-specified risk margin of 1.3 for the hazard ratio (HR) of MACE comparing Tresiba to insulin glargine. The cardiovascular safety of Tresiba as compared to insulin glargine was confirmed (HR 0.91 [0.78; 1.06]) (Figure 2).
Results from subgroup analyses (e.g. sex, diabetes duration, CV risk group and previous insulin regimen) were aligned with the primary analysis.
Click on icon to see table/diagram/imageAt baseline, HbA1c was 8.4% in both treatment groups and after 2 years HbA1c was 7.5% both with Tresiba and insulin glargine.
Tresiba was superior compared to insulin glargine in terms of a lower rate of severe hypoglycaemic events and a lower proportion of subjects experiencing severe hypoglycaemia. The rate of nocturnal severe hypoglycaemia was significantly lower for Tresiba compared to insulin glargine (Table 7).
Click on icon to see table/diagram/imagePregnancy: Tresiba has been studied in an open-label, randomised, active controlled clinical trial, in which pregnant women with type 1 diabetes mellitus were treated within a basal-bolus treatment regimen with Tresiba (92 women) or insulin detemir (96 women) as basal insulin, both in combination with insulin aspart as meal time insulin (EXPECT).
Tresiba was non-inferior to insulin detemir as measured by HbA1c at last planned HbA1c visit prior to delivery after gestational week (GW) 16. Moreover, no difference between treatment groups was observed for glycaemic control (change in HbA1c, FPG and postprandial glucose (PPG)) during pregnancy.
No clinically relevant differences were observed between Tresiba and insulin detemir for the maternal safety endpoints: hypoglycaemia, pre-term delivery and adverse events during the pregnancy. Pre-eclampsia was reported in 12 subjects treated with Tresiba (13.2%) and in 7 subjects (7.4%) who were treated with insulin detemir. Non-planned caesarean section was reported in 23 subjects (25.3%) treated with Tresiba and in 15 subjects (16.0%) treated with insulin detemir. The majority of the adverse events reported in both groups were non-serious, mild in severity, unlikely related to the trial product and had the outcome 'recovered/resolved'. No deaths were reported in the subjects who were randomised in the trial.
No perinatal or neonatal death was reported. No clinically relevant differences were observed between Tresiba and insulin detemir for the pregnancy endpoints (early foetal death, presence of major abnormalities, neonatal hypoglycaemia, perinatal mortality, neonatal mortality, foetal macrosomia, large for gestational age, and adverse events in the infant during the 30 days after birth).
Paediatric population: The efficacy and safety of Tresiba have been studied in a 1:1 randomised controlled clinical trial in children and adolescents with type 1 diabetes mellitus for a period of 26 weeks (n=350), followed by a 26-week extension period (n=280). Patients in the Tresiba arm included 43 children aged 1-5 years, 70 children aged 6-11 years and 61 adolescents aged 12-17 years. Tresiba dosed once daily showed similar reduction in HbA1c at week 52 and greater reduction in FPG from baseline versus the comparator insulin detemir dosed once or twice daily. This was achieved with 30% lower daily doses of Tresiba compared to insulin detemir.
The rates (events per patient-year of exposure) of severe hypoglycaemia (ISPAD definition; 0.51 versus 0.33), confirmed hypoglycaemia (57.71 versus 54.05) and nocturnal confirmed hypoglycaemia (6.03 versus 7.60) were comparable with Tresiba versus insulin detemir. In both treatment arms, children aged 6-11 years had a numerically higher rate of confirmed hypoglycaemia than in the other age groups. A numerically higher rate of severe hypoglycaemia in children aged 6-11 years in the Tresiba arm was observed. The rate of hyperglycaemic episodes with ketosis was significantly lower for Tresiba versus insulin detemir, 0.68 and 1.09, respectively. The frequency, type and severity of adverse reactions in the paediatric population do not indicate differences to the experience in the general diabetes population. Antibody development was sparse and had no clinical impact. Efficacy and safety data for adolescent patients with type 2 diabetes mellitus have been extrapolated from data for adolescent and adult patients with type 1 diabetes mellitus and adult patients with type 2 diabetes mellitus. Results support the use of Tresiba in adolescent patients with type 2 diabetes mellitus.
Pharmacokinetics: Absorption: After subcutaneous injection, soluble and stable multi-hexamers are formed creating a depot of insulin in the subcutaneous tissue. Insulin degludec monomers gradually separate from the multi-hexamers thus resulting in a slow and continuous delivery of insulin degludec into the circulation.
Steady-state serum concentration is reached after 2-3 days of daily Tresiba administration.
During a period of 24 hours with once-daily treatment, the exposure of insulin degludec was evenly distributed between the first and second 12 hours. The ratio between AUCIDeg,0-12h,SS and AUCIDeg,τ,SS was 0.5.
Distribution: The affinity of insulin degludec to serum albumin corresponds to a plasma protein binding of >99% in human plasma.
Biotransformation: Degradation of insulin degludec is similar to that of human insulin; all metabolites formed are inactive.
Elimination: The half-life after subcutaneous administration of Tresiba is determined by the rate of absorption from the subcutaneous tissue. The half-life of Tresiba is approximately 25 hours independent of dose.
Linearity: Dose proportionality in total exposure is observed after subcutaneous administration within the therapeutic dose range. In direct comparison, requirements for bioequivalence are met for Tresiba 100 units/ml and Tresiba 200 units/ml (based on AUCIDeg,τ,SS and Cmax,IDeg,SS).
Gender: There is no gender difference in the pharmacokinetic properties of Tresiba.
Elderly, race, renal and hepatic impairment: There is no difference in the pharmacokinetics of insulin degludec between elderly and younger adult patients, between races or between healthy subjects and patients with renal or hepatic impairment.
Paediatric population: The pharmacokinetic properties of insulin degludec in children (1-11 years) and adolescents (12-18 years) were at steady state comparable to those observed in adults with type 1 diabetes mellitus. Total exposure after a single dose was, however, higher in children and adolescents than in adults with type 1 diabetes mellitus.
Toxicology: Preclinical safety data: Non-clinical data reveal no safety concerns for humans based on studies of safety pharmacology, repeated dose toxicity, carcinogenic potential, and toxicity to reproduction.
The ratio of mitogenic relative to metabolic potency for insulin degludec is comparable to that of human insulin.
