1 Introduction
2 Mechanism of Protraction of Insulin Degludec (IDeg)
3 Main Data Collection Procedures
3.1 Pharmacological Considerations
3.2 Pharmacokinetic Sampling
3.3 Euglycaemic Clamp Methodology
4 Pharmacokinetic Characteristics of IDeg
4.1 Time to Steady State and the Half-Life of IDeg
(A)
| |||
---|---|---|---|
Type of diabetes | Study population | Half-life of IDeg (h) | |
T1DM | Adults (18–65 years) [23] | 25.4 | |
Older adults (≥65 years) [33] | 25.4 | ||
T2DM | Adults (18–70 years) [21] | 25.1 | |
Adults (18–70 years), Caucasian participants [25] | 27.1 | ||
Adults (18–70 years), African American participants [25] | 28.5 | ||
Adults (18–70 years), Hispanic/Latino participants [25] | 22.8 |
(B)
| |||
---|---|---|---|
Type of diabetes | Dose (U/kg) | Half-life of IDeg (h) | Half-life of IGlar (h) |
T1DM | 0.4 | 25.9 | 11.5 |
0.6 | 27.0 | 12.9 | |
0.8 | 23.6 | 11.9 |
4.2 Pharmacokinetic Profiles
5 Pharmacodynamic Characteristics of IDeg
5.1 Pharmacodynamic Profiles
Product | Dose (U/kg) | AUCGIR,0–6h,SS/AUCGIR,τ,SS
| AUCGIR,6–12h,SS/AUCGIR,τ,SS
| AUCGIR,12–18h,SS/AUCGIR,τ,SS
| AUCGIR,18–24h,SS/AUCGIR,τ,SS
|
---|---|---|---|---|---|
IDeg | 0.4 | 23 | 28 | 26 | 23 |
IGlar | 0.4 | 31 | 29 | 23 | 17 |
IDeg | 0.6 | 23 | 28 | 27 | 22 |
IGlar | 0.6 | 29 | 30 | 24 | 17 |
IDeg | 0.8 | 22 | 27 | 27 | 24 |
IGlar | 0.8 | 28 | 30 | 25 | 17 |
5.2 Duration of Action of IDeg
5.3 Variability in Glucose-Lowering Effect
6 Pharmacokinetic and Pharmacodynamic Characteristics of IDeg across Different Formulations, Special Patient Populations and Various Injection Sites
6.1 Comparison of Two Different Formulations of IDeg: 100 and 200 U/mL
6.2 Children and Adolescents
6.3 Renal or Hepatic Impairment
Comparison of grades of renal/hepatic impairment | Renal impairment study [28] | Hepatic impairment study [27] | ||
---|---|---|---|---|
AUCIDeg,0–∞
|
C
max,IDeg
| AUCIDeg,0–120h
|
C
max,IDeg
| |
Mild vs. normal | 1.11 (0.80–1.54) | 1.14 (0.81–1.61) | 0.95 (0.77–1.16) | 0.90 (0.67–1.20) |
Moderate vs. normal | 1.11 (0.80–1.53) | 1.06 (0.76–1.49) | 1.00 (0.82–1.22) | 0.77 (0.58–1.03) |
Severe vs. normal | 1.19 (0.86–1.65) | 1.23 (0.87–1.73) | 0.92 (0.74–1.14) | 0.75 (0.55–1.02) |
ESRD vs. normal | 1.02 (0.74–1.40) | 1.05 (0.75–1.46) | N/A | N/A |
6.4 Variation in Injection Site
7 Clinical Relevance of the Pharmacokinetic and Pharmacodynamic Characteristics of IDeg
Study name | Study population | Efficacy | Changes in the rate of hypoglycaemia with IDeg vs. IGlar (% reduction) | ||
---|---|---|---|---|---|
Reduction in HbA1c with IDeg vs. IGlar, ETD (%) | Reduction in FPG levels with IDeg vs. IGlar, ETD (mmol/L) | Overall confirmed hypoglycaemia | Nocturnal confirmed hypoglycaemia | ||
BEGIN®: T1 [48] | T1DM | −0.01; non-inferior | −0.33 | 7 ↑ |
25 ↓
|
BEGIN®: Flex T1 [49]a
| T1DM | 0.17; non-inferior | −0.05 | 3 ↑ |
40 ↓
|
BEGIN®: Once Long [50] | T2DM, insulin naive | 0.09; non-inferior |
−0.43
| 18 ↓ |
36 ↓
|
BEGIN®: LOW VOLUME [51] | T2DM, insulin naive | 0.04; non-inferior |
−0.42
| 14 ↓ | 36 ↓ |
BEGIN®: BB [52] | T2DM | 0.08; non-inferior | −0.29 |
18 ↓
|
25 ↓
|
BEGIN®: FLEX [53]b
| T2DM, insulin naive and insulin treated | 0.04; non-inferior |
−0.42
| 3 ↑ | 23 ↓ |
BEGIN®: ONCE ASIA [54] | T2DM, insulin naive | 0.11; non-inferior | −0.09 | 18 ↓ | 38 ↓ |
8 Potential Risk Factors and Limitations Associated with an Ultra-Long-Acting Basal Insulin
9 Conclusion
Clinical benefit | Relevant section(s) for further information |
---|---|
Long half-life of >25 h, leading to a flat pharmacokinetic profile and low fluctuations in glucose-lowering activity across one dosing interval (24 h) | Sect. 4
|
Ultra-long duration of action of >42 h | Sect. 5.2
|
Four times lower day-to-day within-subject variability in glucose-lowering effect than insulin glargine | Sect. 5.3
|
Stable and consistent pharmacokinetic and pharmacodynamic properties that are preserved across various patient populations including children, adolescents, elderly, patients from different race and ethnic backgrounds and those with renal or hepatic impairment | |
A 200 U/mL formulation with similar properties as the 100 U/mL formation, which can be useful for patients requiring a large dose of basal insulin | Sect. 6.1
|
Can be injected in different parts of the body as the total glucose-lowering effect of insulin degludec is comparable between the thigh, abdomen and deltoid | Sect. 6.4
|
Lower risk of hypoglycaemia, especially nocturnal hypoglycaemia, compared with insulin glargine | Sect. 7
|
Offers the potential for a more flexible dosing interval and a simpler titration algorithm | Sect. 7
|