Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes. Insulins and analogues for injection, long-acting.
ATC code: A10AE06.

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
Tregludec 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 Tregludec (see figure 1). During a period of 24 hours with once-daily treatment, the glucose-lowering effect of Tregludec , in contrast to insulin glargine, was evenly distributed between the first and second 12 hours (AUCGIR,0-12h,SS/AUCGIR,total,SS = 0.5).
Glucose Infusion Rate (mg/(kg*min))



Time since injection (hours)
Treatment       IDeg 0.6 units/kg
Figure 1 Glucose infusion rate profile, smoothed, steady state - Mean profile 0-24 hours - IDeg 100 units/mL 0.6 units/kg - Trial 1987

The duration of action of Tregludec 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 Tregludec increases linearly with increasing doses.

There is no clinically relevant difference in the pharmacodynamics of this medicinal product 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 Tregludec (1,102 in type 1 diabetes mellitus and 3,173 in type 2 diabetes mellitus).

In the open-label trials the effect of Tregludec was tested in patients with type 1 diabetes mellitus (Table 2), in insulin naïve patients (insulin initiation in type 2 diabetes mellitus, Table3) 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 Tregludec was statistically significantly superior in reducing HbA1c (Table4).

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, Tregludec 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 Tregludec than with insulin glargine.

Table 1 Hypoglycaemia meta-analysis outcomes
Confirmed hypoglycaemiaa
Estimated risk ratio (Insulin degludec/Insulin glargine)     Total           Nocturnal Type 1 + Type 2 diabetes mellitus (pooled)                   0.91*             0.74* Maintenance period b                                                   0.84*                   0.68* Geriatric patients ≥65 years                                           0.82                    0.65* Type 1 diabetes mellitus                                                      1.10                    0.83 Maintenance period b                                                   1.02                    0.75* Type 2 diabetes mellitus                                                      0.83*                   0.68* Maintenance period b                                                   0.75*                   0.62* Basal only therapy in previously insulin-naïve                         0.83*                   0.64* *Statistically significant a Confirmed hypoglycaemia was defined as episodes confirmed by plasma glucose <3.1 mmol/L or by the patient needing third party assistance. Nocturnal confirmed hypoglycaemia was defined as episodes between midnight and 6 a.m. b Episodes from week 16.

There is no clinically relevant development of insulin antibodies after long-term treatment with Tregludec.

Table 2 Results from open-label clinical trials in type 1 diabetes mellitus 52 weeks of treatment                  26 weeks of treatment
Tregludec 1            Insulin        Tregludec 1           Insulin glargine                             detemir1
(100 units/mL)1
N                               472                  157               302                153 HbA1c (%)
End of trial                    7.3                   7.3              7.3                7.3 Mean change                    -0.40                -0.39             -0.73              -0.65 Difference: -0.01 [-0.14; 0.11]        Difference: -0.09[-0.23; 0.05] FPG (mmol/L)
End of trial                    7.8                   8.3              7.3                8.9 Mean change                    -1.27                -1.39             -2.60              -0.62 Difference: -0.33 [-1.03; 0.36]       Difference: -1.66 [-2.37; -0.95] Rate of hypoglycaemia (per Patient year of exposure)
Severe                          0.21                 0.16              0.31               0.39 Confirmed2                     42.54                40.18             45.83              45.69 Ratio: 1.07 [0.89; 1.28]               Ratio: 0.98 [0.80; 1.20]
2
Nocturnal confirmed             4.41                 5.86              4.14               5.93 Ratio: 0.75 [0.59; 0.96]               Ratio: 0.66 [0.49; 0.88]
1 In a once-daily regimen + insulin aspart to cover mealtime insulin requirements 2 Confirmed hypoglycaemia was defined as episodes confirmed by plasma glucose <3.1 mmol/L or by the patient needing third party assistance. Nocturnal confirmed hypoglycaemia was defined as episodes between midnight and 6 a.m.

Table 3 Results from open-label clinical trials in insulin naïve type 2 diabetes mellitus (insulin initiation)
52 weeks of treatment                  26 weeks of treatment
Tregludec 1             Insulin        Tregludec 1           Insulin glargine                             glargine
(100 units/mL)1                       (100 units/mL)1
N                               773                  257               228                229 HbA1c (%)
End of trial                    7.1                  7.0               7.0                6.9 Mean change                    -1.06                -1.19             -1.30              -1.32 Difference: 0.09 [-0.04; 0.22]         Difference: 0.04 [-0.11; 0.19] FPG (mmol/L)
End of trial                    5.9                  6.4               5.9                6.3 Mean change                    -3.76                -3.30             -3.70              -3.38 Difference: -0.43 [-0.74; -0.13]       Difference: -0.42 [-0.78; -0.06] Rate of hypoglycaemia (per patient year of exposure)
Severe                           0                   0.02               0                  0 Confirmed2                             1.52               1.85                      1.22               1.42 Ratio: 0.82 [0.64; 1.04]                     Ratio: 0.86 [0.58; 1.28] Nocturnal confirmed2                   0.25               0.39                      0.18               0.28 Ratio: 0.64 [0.42; 0.98]                     Ratio: 0.64 [0.30; 1.37] 1 Once-daily regimen + metformin ± DPP-IV inhibitor
2 Confirmed hypoglycaemia was defined as episodes confirmed by plasma glucose <3.1 mmol/L or by the patient needing third party assistance. Nocturnal confirmed hypoglycaemia was defined as episodes between midnight and 6 a.m.

Table4 Results from open-label clinical trials in type 2 diabetes mellitus: left – prior basal insulin users, right – insulin naïve
52 weeks of treatment              26 weeks of treatment
Tregludec 1           Insulin      Tregludec 2         Sitagliptin2 glargine
(100 units/mL)1
N                                   744                248             225                222 HbA1c (%)
End of trial                        7.1                7.1             7.2                7.7 Mean change                        -1.17              -1.29           -1.56              -1.22 Difference: 0.08 [-0.05; 0.21]    Difference: -0.43 [-0.61; -0.24]
FPG (mmol/L)
End of trial                        6.8                7.1             6.2                8.5 Mean change                        -2.44              -2.14           -3.22              -1.39 Difference: -0.29 [-0.65; 0.06]    Difference: -2.17 [-2.59; -1.74]
Rate of hypoglycaemia (per patient year of exposure)
Severe hypoglycaemia               0.06                0.05           0.01                 0 Confirmed3                        11.09               13.63           3.07                1.26 Ratio: 0.82 [0.69; 0.99]           Ratio: 3.81 [2.40; 6.05]
3
Nocturnal confirmed                1.39                1.84           0.52                0.30 Ratio: 0.75 [0.58; 0.99]           Ratio: 1.93 [0.90; 4.10]
1 Once-daily regimen + insulin aspart to cover mealtime insulin requirements ± metformin ± pioglitazone 2 Once-daily regimen ± metformin SU/glinide ± pioglitazone
3 Confirmed hypoglycaemia was defined as episodes confirmed by plasma glucose <3.1 mmol/L or by the patient needing  third party assistance. Nocturnal confirmed hypoglycaemia was defined as episodes between midnight and 6 a.m.

Table 5 Results from an open-label clinical trial with flexible dosing of Tregludec in type 2 diabetes mellitus
26 weeks of treatment
Tregludec 1                    Tregludec Flex2        Insulin glargine (100 units/mL)3
N                         228                            229                    230 HbA1c (%)
End of trial              7.3                            7.2                    7.1 Mean change               -1.07                          -1.28                  -1.26 Difference: -0.13 [-0.29; 0.03]5          Difference: 0.04 [-0.12; 0.20] FPG (mmol/L)
End of trial              5.8                            5.8                    6.2 Mean change from          -2.91                          -3.15                  -2.78 baseline
Difference: -0.05 [-0.45; 0.35]5          Difference: -0.42 [-0.82; - 0.02]
Rate of hypoglycaemia (per patient year of exposure)
Severe                    0.02                           0.02                   0.02 Confirmed4                3.63                           3.64                   3.48 6
Ratio: 1.10 [0.79; 1.52]                  Ratio: 1.03 [0.75; 1.40]
Nocturnal confirmed4      0.56                           0.63                   0.75 Ratio: 1.18 [0.66; 2.12]6                 Ratio: 0.77 [0.44; 1.35]
1   Once-daily regimen (with main evening meal) + one or two of the following oral antidiabetes agents: SU, metformin or DPP-4 inhibitor
2 Flexible once-daily regimen (intervals of approximately 8–40 hours between doses) + one or two of the following oral
 antidiabetes agents SU, metformin or DPP-4 inhibitor
3 Once-daily regimen + one or two of the following oral antidiabetes agents: SU, metformin or DPP-4 inhibitor 4 Confirmed hypoglycaemia was defined as episodes confirmed by plasma glucose <3.1 mmol/L or by the patient needing
 third party assistance. Nocturnal confirmed hypoglycaemia was defined as episodes between midnight and 6 a.m.
5 The difference is for Tregludec Flex – Tregludec
6 The ratio is for Tregludec Flex/Tregludec.


In a 104-week clinical trial, 57% of patients with type 2 diabetes treated with Tregludec (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 vs -0.40% for comparator, estimated means) and body weight (-3.03 vs 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 vs 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 Tregludec or insulin glargine (100 units/mL) followed by cross-over. The trials evaluated the rate of hypoglycaemia upon treatment with Tregludec compared to insulin glargine (100 units/mL) (see Table 6).

Table 6 Results from the double-blind, cross-over clinical trials in type 1 and type 2 diabetes mellitus
Type 1 diabetes mellitus             Type 2 diabetes mellitus
Insulin glargine                     Insulin glargine
Tregludec 1                         Tregludec 2
(100 units/mL)1                      (100 units/mL)2
N                                     501                                  721 HbA1c (%)
Baseline                              7.6                                   7.6 End of treatment             6.9                6.9                7.1               7.0 FPG (mmol/L)
Baseline                              9.4                                   7.6 End of treatment             7.5                8.4                6.0               6.1 Rate of severe hypoglycaemia3
0.69               0.92               0.05              0.09
Maintenance period4
Ratio: 0.65 [0.48; 0.89]             Ratio: 0.54 [0.21; 1.42]
Rate of severe or BG confirmed symptomatic hypoglycaemia3,5
22.01              24.63              1.86              2.65
Maintenance period4
Ratio: 0.89 [0.85; 0.94]             Ratio: 0.70 [0.61; 0.80]
Rate of severe or BG confirmed symptomatic nocturnal hypoglycaemia3.5 2.77               4.29               0.55              0.94
Maintenance period4
Ratio: 0.64 [0.56; 0.73]             Ratio: 0.58 [0.46; 0.74]
1 In a once-daily regimen + insulin aspart to cover mealtime insulin requirements 2 In a once-daily regimen ± OADs (any combination of metformin, dipeptidyl peptidase-4 inhibitor, alpha-glucosidase inhibitor, thiazolidinediones, and sodium glucose cotransporter-2 inhibitor) 3 Per patient year of exposure
4 Episodes from week 16 in each treatment period
5 Blood glucose (BG) confirmed symptomatic hypoglycaemia was defined as episodes confirmed by a plasma glucose value  of less than 3.1 mmol/L, with symptoms consistent with hypoglycaemia. Nocturnal confirmed hypoglycaemia was defined as episodes between midnight and 6 a.m.

Cardiovascular evaluation
DEVOTE was a randomised, double-blind, and event-driven clinical trial with a median duration of 2 years comparing the cardiovascular safety of Tregludec 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 to insulin glargine. The cardiovascular safety of Tregludec 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) was aligned with the primary analysis.



N: Number of subjects with a first EAC confirmed event during trial. %: Percentage of subjects with a first EAC confirmed event relative to the number of randomised subjects. EAC: Event adjudication committee. CV: Cardiovascular. MI: Myocardial infarction. CI: 95% confidence interval.
Figure 2 Forest plot of analysis of the composite 3-point MACE and individual cardiovascular endpoints in DEVOTE

At baseline, HbA1c was 8.4% in both treatment groups and after 2 years HbA1c was 7.5% both with Tregludec and insulin glargine.
Tregludec 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 Tregludec compared to insulin glargine (Table 7).

Table 7 Results from DEVOTE
Tregludec 1 Insulin glargine
(100 units/mL)1
N                               3,818                    3,819
Rate of hypoglycaemia (per 100 patient years of observation)
Severe                          3.70                     6.25
Rate ratio: 0.60 [0.48; 0.76]
Nocturnal severe2               0.65                     1.40
Rate ratio: 0.47 [0.31; 0.73]
Proportions of patients with hypoglycaemia (percent of patients)
Severe                          4.9                      6.6
Odds ratio: 0.73 [0.60; 0.89]
1
In addition to standard of care for diabetes and cardiovascular disease 2
Nocturnal severe hypoglycaemia was defined as episodes between midnight and 6 a.m.


Pregnancy
Tregludec 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 Tregludec (92 women) or insulin detemir (96 women) as basal insulin, both in combination with insulin aspart as meal time insulin (EXPECT).

Tregludec was non-inferior to insulin detemir as measured by HbA1c at last planned HbA1c visit prior to delivery after gestational week 16. Moreover, no difference between treatment groups was observed for glycaemic control (change in HbA1c, FPG and PPG) during pregnancy.
No clinically relevant differences were observed between Tregludec 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 Tregludec (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 Tregludec 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 Tregludec 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 Tregludec 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 Tregludec arm included 43 children aged 1–5 years,
70 children aged 6–11 years and 61 adolescents aged 12–17 years. Tregludec 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 Tregludec compared to insulin detemir. The rates (events per patient-year of exposure) of severe hypoglycaemia (ISPAD definition; 0.51 vs 0.33), confirmed hypoglycaemia (57.71 vs 54.05) and nocturnal confirmed hypoglycaemia (6.03 vs 7.60) were comparable with Tregludec 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 Tregludec arm was observed. The rate of hyperglycaemic episodes with ketosis was significantly lower for Tregludec versus insulin detemir, 0.68 and 1.09, respectively.
No safety issues were identified with Tregludec with respect to adverse events and standard safety parameters. 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 Tregludec in adolescent patients with type 2 diabetes mellitus.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

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 Tregludec 100 units/mL 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 Tregludec 100 units/mL is determined by the rate of absorption from the subcutaneous tissue. The half-life of Tregludec 100 units/mL 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 Tregludec 100 units/mL (based on AUCIDeg,τ,SS and Cmax,IDeg,SS).

Gender
There is no gender difference in the pharmacokinetic properties of this medicinal product.

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
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.