TRESIBA Solution for injection Ref.[7517] Active ingredients: Insulin degludec

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

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 (AUC_GIR,0-12h,SS/AUC_GIR,total,SS = 0.5).

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 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 (AUC_GIR,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 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 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 HbA_1c 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 HbA_1c were non-inferior compared to other insulin products, against sitagliptin Tresiba was statistically significantly superior in reducing HbA_1c (Table 4).

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.

Table 1. Hypoglycaemia meta-analysis outcomes:

^* 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 Tresiba.

Table 2. Results from open-label clinical trials in type 1 diabetes mellitus:

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):

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.

Table 4. Results from open-label clinical trials in type 2 diabetes mellitus: left – prior basal insulin users, right – insulin naïve:

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 Tresiba in type 2 diabetes mellitus:

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 Tresiba Flex – Tresiba
⁶ The ratio is for Tresiba Flex/Tresiba.

In a 104-week clinical trial, 57% of patients with type 2 diabetes treated with Tresiba (insulin degludec) in combination with metformin achieved a target HbA_1c <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 HbA_1c (-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 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).

Table 6. Results from the double-blind, cross-over clinical trials in type 1 and type 2 diabetes mellitus:

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 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) was aligned with the primary analysis.

Figure 2. Forest plot of analysis of the composite 3-point MACE and individual cardiovascular endpoints in DEVOTE:

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.

At baseline, HbA_1c was 8.4% in both treatment groups and after 2 years HbA_1c 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).

Table 7. Results from DEVOTE:

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

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 HbA_1c at last planned HbA_1c visit prior to delivery after gestational week 16. Moreover, no difference between treatment groups was observed for glycaemic control (change in HbA_1c, FPG and 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. Preeclampsia 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 European Medicines Agency has waived the obligation to submit the results of trials with Tresiba in:

• Neonates and infants from birth to less than 12 months of age with type 1 diabetes mellitus and children from birth to less than 10 years of age with type 2 diabetes mellitus on the grounds that the disease or condition for which the specific medicinal product is intended does not occur in the specified paediatric subset (see section 4.2 for information on paediatric use).

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 HbA_1c 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 vs 0.33), confirmed hypoglycaemia (57.71 vs 54.05) and nocturnal confirmed hypoglycaemia (6.03 vs 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. No safety issues were identified with Tresiba 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 Tresiba in adolescent patients with type 2 diabetes mellitus.