Insulin aspart has an improved pharmacokinetic profile compared with regular human insulin and thus demonstrates a greater glucose-lowering effect. |
The safety and efficacy of insulin aspart has been demonstrated via randomized controlled trials in diverse patient populations with type 1 or type 2 diabetes mellitus. |
Step-wise intensification is an appropriate treatment option with insulin aspart. |
There is some evidence that patients with a history of recurrent hypoglycemia may have a lower incidence of severe episodes using insulin aspart. |
1 Introduction
2 Pharmacokinetic and Pharmacodynamic Properties of Insulin Aspart
2.1 Structure
2.2 Pharmacokinetics (PK)
2.2.1 Comparison with Regular Insulin
2.2.2 Comparison with Rapid-Acting Insulins
2.3 Pharmacodynamics (PD)
2.3.1 Comparison with Regular Insulin
Study | Number of subjects | Insulin | Peak glucose infusion rate (mg/min/kg)A ± SD | Time to peak glucose infusion (min) ± SD |
---|---|---|---|---|
Heinemann et al. 1993 [36] | 14 | Insulin aspart | 12.2 ± 3.1a
| 104 ± 27b
|
RHI | 10.6 ± 2.7 | 165 ± 42 | ||
Heinemann et al. 1996 [37] | 24 | Insulin aspart | 10.2 ± 2.3c
| 105 ± 18b
|
RHI | 8.4 ± 2.0 | 148 ± 27 | ||
Heinemann et al. 1998 [54] | 19 | Insulin aspart | 11.2 ± 2.8 | 104 ± 16 |
RHI | 9.5 ± 2.3 | 156 ± 29 | ||
Mudaliar et al. 1999 [38] | 20 | Insulin aspartB
| 94 ± 46b
| |
RHIB
| 173 ± 62 | |||
Insulin aspartC
| 111 ± 59b
| |||
RHIC
| 192 ± 51 | |||
Insulin aspartD
| 145 ± 122a
| |||
RHID
| 193 ± 60 | |||
Engwerda et al. 2011 [46] | 18 | Insulin aspart (needle-free device) | 6.49 ± 0.58 | 51 ± 3d
|
Insulin aspart (pen) | 6.09 ± 0.56 | 105 ± 11 |
2.3.2 Comparison with Rapid-Acting Analogs
2.4 PK/PD in Special Populations
2.4.1 Elderly Patients
2.4.2 Children and Adolescents with Type 1 Diabetes
2.4.3 In Continuous Subcutaneous Insulin Infusion
2.4.4 In Obesity and Renal/Hepatic Impairment
2.4.5 In Pregnancy
3 Clinical Efficacy of Insulin Aspart
Study (duration) | No. of patients | Insulin treatment (baseline)A
| Mean HbA1c at study end, % (baseline HbA1c) ± SD | Mean FPG at study end, mmol/L (baseline FPG) | Postprandial plasma glucose at study end, mmol/L (baseline)A ± SD | |||
---|---|---|---|---|---|---|---|---|
O/TM | B | L | D | |||||
(a) T1D: randomized studies | ||||||||
Home et al. (1998) (4 weeks) [73] | 90 | IAsp + NPH | 6.4 | 7.2 | ||||
HI + NPH | 8.1a,B
| 8.8a,B
| ||||||
Home et al. (2000) (6 months) [70] | 1065 | IAsp + NPH | 7.88 (7.96)b,B
| 8.5g,B
| 8.9c,B
| 8.0d,B
| 8.4d,B
| |
HI + NPH | 8.00 (7.98) | 7.7 | 10.1 | 8.5 | 9.0 | |||
Home et al. (2006) (36 months; extension of Home et al. (2000) [74] | 753 | IAsp + NPH | 7.97 | |||||
HI + NPH | 8.11 | |||||||
Raskin et al. (2000) (24 weeks)C [71] | 882 | IAsp + NPH | 7.78 (7.90)e,B
| 8.6a,B
| 7.57a,B
| 8.46a,B
| ||
HI + NPH | 7.93 (7.95) | 10.2 | 8.96 | 9.29 | ||||
Raskin et al. (2000) (52 weeks) [71] | 714 | IAsp ± NPH | 7.78 (7.90) | |||||
HI ± NPH | 7.91 (7.95)n,B
| |||||||
Tamás et al. (2001) (12 weeks)C [75] | 423 | IAsp + NPH | 8.02 (8.36)a,B
| 8.8 | 8.4c,B
| 8.6D
| 8.2d,B
| |
HI + NPH | 8.18 (8.29) | 9.3 | 10.1 | 8.6D
| 9.3 | |||
DeVries et al. (2003) (64 weeks) [72] | 368 | IAsp + NPH | 8.08 | 8.05 | 8.34f,B
| 7.56,B
| 7.45g,B
| |
HI + NPH | 8.22 | 8.29 | 9.62 | 8.79 | 9.14 | |||
Hermansen et al. (2004) (18 weeks) [78] | 595 | IAsp + IDet | 7.88 (8.48)g,B
| 7.58 (8.83) | ||||
HI + NPH | 8.11 (8.29) | 8.10 (9.17) | ||||||
Heller et al. (2004) (16 weeks) [77] | 155 | IAsp + NPH | 7.7 (7.9) | |||||
HI + NPH | 7.7 (7.9) | |||||||
Brock Jacobsen et al. (2011) (crossover study, 8-week periods) [76] | 16 | IAsp + NPH | 7.0 ± 0.2 | |||||
HI + NPH | 7.0 ± 0.2 | |||||||
(a) T1D: observational studies | ||||||||
Krzymień et al. (2010) (single-arm, follow-up study, 13 weeks) [85] | 950 | IAsp + NPH or IDet | 7.48 ± 1.00c,E
| 118.22 ± 27.60c,E
| 7.68 ± 1.45c,E
| 7.73 ± 1.45c,E
| 7.61 ± 1.56c,E
| |
(NPH or IDet) | (8.75 ± 1.93) | (161.70 ± 53.66) | (9.62 ± 3.19) | (9.59 ± 2.88) | (9.33 ± 2.69) | |||
(b) T2D: randomized studies | ||||||||
Bretzel et al. (2004) (3 months) [79] | 231 | IAsp ± NPH | Δ0.91 ± 1.00 (7.82)h,E
| |||||
HI ± NPH | Δ0.73 ± 0.87 (7.83) | |||||||
HPI | Δ0.65 ± 1.10 (7.78)i,E
| |||||||
Raslová et al. (2004) (22 weeks) [83] | 395 | IAsp + IDet | 7.46 (8.16) | 7.28 | ||||
HI + NPH | 7.52 (8.08) | 7.32 | ||||||
Gallagher and Home (2005) (crossover study, 6 week periods) [80] | 21 | IAsp ± NPH | 7.04 (7.8)g,E
| 7.9 ± 0.4j,E
| 9.2 ± 0.6 | 7.1 ± 0.5i,E
| ||
HI ± NPH | 7.15 (7.8)g,E
| 9.3 ± 0.4 | 10.2 ± 0.6 | 9.0 ± 0.6 | ||||
Gallagher and Home (2005) (crossover study, 6 week periods) [80] | 18 | IAsp | 6.94 (7.8 ± 0.7) | 7.0 | 7.5 | |||
HI | 7.07 (7.8 ± 0.7) | 6.5 | 8.20 | |||||
Pala et al. (2007) (crossover study, 90 day periods) [82] | 30 | IAsp | 7.3a,E,B (7.8) | 10.7 (11.3) | 17.5 (22.1) | |||
HI | 7.9 (7.7) | 11.3 (11.6) | 20.9 (20.2) | |||||
Meneghini et al. (2011) (48 weeks) STEP-Wise trial [91] | 296 | SimpleSTEP | 7.5 ± 1.1 (8.7 ± 1.0) | 7.49 ± 2.78 (8.10 ± 2.89) | Δ −2.0 ± 2.0 | |||
ExtraSTEP | 7.7 ± 1.2 (8.9 ± 1.2) | 7.38 ± 2.89 (8.27 ± 2.89) | Δ −1.77 ± 1.88 | |||||
Cucinotta et al. (2012) (26 weeks) [89] | 4099 | IAsp ± basal | 7.63 (8.02) | Δ −11.8 | Δ −7.2 | Δ −8.0 | Δ −6.5 | |
HI ± basal | 7.6 (7.82) | Δ −6.3 | Δ −5.8 | Δ −5.0 | Δ −3.7 | |||
Herrmann et al. (2013) (24 months) [81] | 29 | IAsp ± IDet | 7.3 ± 0.9a,E (8.7 ± 1.6) | |||||
HI ± IDet | 7.2 ± 0.9a,E (8.7 ± 1.6) | |||||||
Rodbard et al. (2014) (32 weeks) FullSTEP trial [92] | 401 | IAsp step-wise + IDet | Δ −0.98 (7.9 ± 0.6) | 7.01 (7.0 ± 1.9) | Δ1.28k,E
| |||
IAsp + IDet basal–bolus | Δ −1.12 (7.9 ± 0.6) | 7.12 (6.9 ± 1.6) | Δ1.64 | |||||
(b) T2D: observational studies | ||||||||
Chlup et al. (2007) (before-after study, 52 weeks) [84] | 57 | IAsp (HI) | 7.5 ± 0.20 (8.4 ± 0.23)g,E
| 9.7 (9.7) | 10.6 (11.2) | 10.3 (10.1) | 10.4 (10.5) | |
Krzymień et al. (2010) (single-arm, follow-up study, 13 weeks) [85] | 1332 | IAsp + NPH or IDet | 7.60 ± 0.90c,E (8.81 ± 1.4) | 6.94 ± 1.33c,E (9.12 ± 2.40) | 8.03 ± 1.44c,E (2.41 ± 2.73) | 8.35 ± 1.44c,E (11.08 ± 2.75) | 8.06 ± 1.42c,E (10.49 ± 2.64) | |
Randeree et al. (2013) (single arm, before/after study, 24 weeks; A1chieve study) [88] | Insulin-experienced: 561 | IAsp | 7.4g,E (9.1) | 7.1g,E (9.9) | 9.9g,E (13.4) | |||
Insulin-naïve: 1465 | 7.2g,E (9.5) | 7.4g,E (10.8) | 10.1 (15.8) | |||||
Latif et al. (2013) (single-arm, before/after study, 24 weeks, A1chieve study) [87] | ≤40 years: 571 | IAsp + basal (insulin-naïve) | 7.4C,g,E (9.75) | Δ −4.4 ± 4.5g,E (11.3 ± 4.5) | Δ −5.9 ± 4.9g,E (14.8 ± 5.0) | |||
>40–65 years: 2801 | 7.4C,g,E (9.65) | Δ −3.9 ± 3.7g,E (10.9 ± 3.6) | Δ −5.5 ± 4.7g,E (14.4 ± 4.7) | |||||
>65 years: 660 | 7.4C,g,E (9.60) | Δ −3.6 ± 4.3g,E (10.7 ± 4.2) | Δ −5.6 ± 4.3g,E (14.7 ± 5.1) | |||||
(c) T1D or T2D | ||||||||
Gao et al. (2009) [143] | 220 | IAsp + NPH | 7.7 ± 1.3 (9.3 ± 1.4) | Δ14.6 ± 5.3d,B
| ||||
HI + NPH | 7.7 ± 1.2 (9.2 ± 1.2) | Δ8.4 ± 4.1 |
Study (duration) | No. of patients | Insulin treatment (baseline)A
| Mean HbA1c at study end, % (baseline HbA1c) ± SD | Other endpoints (baseline) ± SD |
---|---|---|---|---|
(a) Insulin aspart (CSII) vs MDI: randomized trials | ||||
DeVries et al. (2002) (crossover, 16-week periods)B [119] | 79 Adults T1D | IAsp CSII | Δ −0.91 ± 1.28a,C (9.27 ± 1.4) | SD of 9-point SMBG values, −1.35 ± 1.88 mmol/Lh,D
|
IAsp + NPH | Δ −0.07 ± 0.70 (9.25 ± 1.4) | SD of 9-point SMBG values, −0.40 ± 1.77 mmol/L | ||
Raskin et al. (2003) (24 weeks) [117] | 132 Adults T2D | IAsp CSII | 7.6 ± 1.22 (8.2 ± 1.37)b,C
| PPG (90 min post-breakfast), 9.2 ± 2.6 mmol/Lj,D
|
IAsp + NPH | 7.5 ± 1.17 (8.0 ± 1.08)b,C
| PPG (90 min post-breakfast), 10.7 ± 3.6 mmol/L | ||
Doyle et al. (2004) (16 weeks) [113] | 32 Children (8–21 years) T1D | IAsp CSII | 7.2 ± 1.0 (8.1 ± 1.2)b,c,C,D
| SMBG at lunch, dinner and bedtime were all significantly lower for IAsp CSIId,D
|
IAsp + IGlar | 8.1 ± 1.2 (8.2 ± 1.1) | |||
Hirsch et al. (2005) (crossover, 5-week periods) [115] | 100 Adults T1D | IAsp CSII | Serum fructosamine, 343 ± 47 μmol/Lg,D
AUCglucose≥140mg/dL, 464 ± 452 mg∗h∗dL−1
d,D
| |
IAsp+IGlar | Serum fructosamine, 355 ± 50 μmol/L AUCglucose≥140mg/dL, 777 ± 746 mg∗h∗dL−1
| |||
Skogsberg et al. (2008) (24 months) [99] | 72 Children (7–17 years) T1D | IAsp CSII | 6.5 ± 0.4 (8.2 ± 04) | Treatment satisfaction scores, 3.5 ± 0.5k,D
|
IAsp MDI | 6.7 ± 0.5 (8.4 ± 0.5) | Treatment satisfaction scores, 2.5 ± 0.5 | ||
Pańkowska et al. (2010) (26 weeks) [98] | 61 Children (<7 years) T1D | IAsp CSII | 7.6 ± 0.6 (7.7 ± 0.7) | 24 h AUCglucose, 200.1 ± 12.7 |
IAsp+NPH | 7.6 ± 0.9 (7.6 ± 0.8) | 24 h AUCglucose, 219.8 ± 12.8 | ||
BRHI+NPH | 7.6 ± 1.0 (7.6 ± 1.1) | 24 h AUCglucose, 211.8 ± 10.9 | ||
Bergenstal et al. (2010) (1 year) [112] | 329 Adults T1D | IAsp CSII | Δ −1.0 ± 0.7d,D (8.3 ± 0.5) | Reach HbA1c ≤7.0 %, 57/166 (34 %)d,D
|
IAsp + IGlar MDI | Δ −0.4 ± 0.8 (8.3 ± 0.5) | Reach HbA1c ≤7.0 %, 19/163 (12 %) | ||
156 Children (7–18 years) T1D | IAsp CSII | Δ −0.4 ± 0.9d,D (8.3 ± 0.6) | Reach HbA1c ≤7.0 %, 10/78 (13 %) | |
IAsp + IGlar MDI | Δ + 0.2 ± 1.0 (8.3 ± 0.5) | Reach HbA1c ≤7.0 %, 4/78 (5 %) | ||
Lv et al. (2013) (<2 weeks; time to reach glucose target) [118] | 119 Adults T2D | IAsp CSII | (9.86 ± 1.69) | FBG, 6.03 ± 0.47 mmol/L |
IAsp + IGlar | (9.25 ± 1.54) | FBG, 5.98 ± 0.72 mmol/L | ||
IAsp + IDet | (9.56 ± 1.49) | FBG, 6.17 ± 0.53 mmol/L | ||
Gao et al. (2014) (12 weeks) [114] | 200 Adults T2D | IAsp CSII | 7.11 ± 1.32 (10.79 ± 1.42) | FBG, 6.76 ± 1.13 mmol/Ln,D (FBG, 8.61 ± 3.12 mmol/L) |
IAsp + IGlar | 7.51 ± 1.28 (10.86 ± 1.36) | FBG, 6.85 ± 1.26 mmol/Ln,D (FBG, 8.68 ± 3.32 mmol/L) | ||
Insulin aspart (CSII) vs MDI: observational studies | ||||
Kawamura et al. (2008) (6 months, single-arm, before/after study) [116] | 26 Children (6–18 years) T1D | IAsp CSII (MDI varied regimens) | 7.4 ± 0.8 (7.8 ± 1.8) | |
(b) Insulin aspart vs buffered RHI, both in CSII: randomized trials | ||||
Bode and Strange 2001 (7 weeks) [120] | 29 Adults T1D | IAsp CSII | 6.9 ± 0.6 (7.2 ± 0.8) | FBG, 7.9 ± 2.8 mmol/L |
BRHI CSII | 7.1 ± 0.6 (7.2 ± 0.9) | FBG, 8.0 ± 2.6 mmol/L | ||
Bode et al. (2002) (16 weeks) [121] | 146 Adults T1D | IAsp CSII | Δ0.00 ± 0.51 (7.3 ± 0.7) | |
BRHI CSII | Δ0.15 ± 0.63 (7.5 ± 0.8) | |||
ILisp CSII | Δ0.18 ± 0.84 (7.3 ± 0.7) | |||
Insulin aspart vs buffered RHI, both in CSII: observational studies | ||||
Chlup et al. (2004) (~90 weeks, single-arm before/after study) [122] | 21 Adults T1D | IAsp CSII (BR HI CSII) | 7.53b,D (7.89) | |
(c) Insulin aspart (CSII) vs insulin lispro and insulin glulisine: randomized trials | ||||
Weinzimer et al. (2008) (16 weeks) [128] | 298 Children (4–18 years) T1D | IAsp CSII | 7.9 ± 0.93 (8.0 ± 0.94) | FPG, 9.2 ± 3.7 mmol/L (FPG, 9.5 ± 4.3 mmol/L) |
ILisp CSII | 8.1 ± 0.85 (8.1 ± 0.84) | FPG, 10.0 ± 4.6 mmol/L (FPG, 9.9 ± 3.8 mmol/L) | ||
Bartolo et al. (2008) (crossover study, 3 days) [131] | 17 Adults T1D | IAsp CSII | ΔBG90 min 0.51 ± 2.03 mmol/Lc,D
ΔBG120 min 0.36 ± 2.11 mmol/Lo,D
%postprandial values0–120 min within target range, 59.8 ± 29.1 % | |
ILisp CSII | ΔBG90 min −0.67 ± 2.42 mmol/L ΔBG120 min −0.67 ± 2.11 mmol/L %postprandial values0–120 min within target range, 48.6 ± 30.6 % | |||
van Bon et al. (2011) (crossover study, 13-week periods) [127] | 288 Adults T1D | IAsp CSII | 7.26 ± 0.76 (7.33 ± 0.71) | Reach HbA1c <7.0, 31 % |
IGlu CSII | 7.32 ± 0.73 (7.31 ± 0.71) | Reach HbA1c <7.0, 28 % | ||
ILisp CSII | 7.31 ± 0.74 (7.28 ± 0.71) | Reach HbA1c <7.0, 30 % | ||
Thrasher et al. (2014) (crossover study, 16-week periods) [126] | 122 Adults T2D | IAsp CSII | 7.4 ± 0.12 (7.4 ± 0.9) | |
ILisp CSII | 7.5 ± 0.12 (7.4 ± 0.9) | |||
Dzygalo and Szypowska, (2014) (crossover study, 2 visits) [125] | 64 Children (10.3–17.9 years) T1D | IAsp CSII | PPG, iAUC ~338 ± 51.8 min × mmol/L | |
IGlu CSII | PPG, iAUC ~403 ± 48.9 min × mmol/L | |||
Tamborlane et al. (2015) (two crossover studies; 8- and 12-week periods, respectively) [130] | 132 Adults T1D | IAsp CSII | Δ0.0 (7.3 ± 0.7) | Mean difference, daily mean SMBG 0.22 mmol/L [95 % CI −0.07 to 0.52] |
ILisp CSII | Δ0.06 (7.3 ± 0.7) | |||
133 Adults T1D | IAsp CSII | Δ −0.31 (7.5 ± 0.7)m,C,D
| Mean difference, daily mean SMBG 0.18 mmol/L [95 % CI −0.10 to 0.47] | |
ILisp CSII | Δ −0.15 (7.5 ± 0.7) | |||
(c) Insulin aspart (CSII) vs insulin lispro and insulin glulisine: observational studies | ||||
Alemzadeh et al. (2007) (1-year, single-arm, before/after study) [124] | 14 Children (~3–5 years) T1D | IAsp CSII (IAsp + IGlar) | 7.8 ± 0.4 (8.0 ± 0.5) | Sensor MBG, 10.27 ± 4.38 mmol/L (Sensor MBG, 11.82 ± 5.22 mmol/L) MAGE, 9.32 ± 1.22 mmol/LC,m (MAGE, 11.65 ± 1.72 mmol/L) |
Wittlin et al. (2008) (16 weeks, single-arm, before/after study) [129] | 513 Adults T1D or T2D | IAsp CSII (ILisp CSII) | 7.9 ± 1.1e,D (8.1 ± 1.1) | FBG, 7.72 ± 3.33 mmol/Lf,D (FBG, 8.30 ± 3.59 mmol/L) |
3.1 Patients with Type 1 Diabetes (T1D)
3.2 Patients with Type 2 Diabetes (T2D)
3.3 Meta-Analysis in T1D and T2D
3.4 Intensification of Treatment with Insulin Aspart
3.4.1 Intensification with All-Analog Regimens
3.4.2 Step-Wise Addition of Insulin Aspart
3.5 Long-Term Microvascular and Macrovascular Complications
3.6 Special Populations
3.6.1 Children and Adolescents
3.6.2 Pregnancy
3.6.3 Hospitalized Patients
3.7 Insulin Aspart in Continuous Subcutaneous Insulin Infusion (CSII)
3.7.1 Insulin Aspart CSII Versus Multiple Daily Injection (MDI)
3.7.2 Insulin Aspart Compared with Buffered Regular Human Insulin (RHI), Both in CSII
3.7.3 Insulin Aspart Compared with Other Rapid-Acting Analogs in CSII
3.8 Flexible Dosing
3.9 Quality of Life/Treatment Satisfaction with Insulin Aspart
4 Safety and Tolerability of Insulin Aspart
4.1 General Adverse Event Profile
4.1.1 Receptor Binding and Mitogenicity
4.1.2 Anti-Insulin Antibodies
4.2 Hypoglycemia
4.2.1 In Patients with T1D
Study (duration) | No. of patients | Insulin treatment (baseline)A
| Incidence of hypoglycemic events (% of patients) | Rate of hypoglycemic episodes per patient—year (insulin aspart) | ||||
---|---|---|---|---|---|---|---|---|
All | Major | Nocturnal | All rate ratio [95 % CI] | Major relative risk [95 % CI] | Nocturnal rate ratio [95 % CI] | |||
(a) T1D: randomized trials | ||||||||
Home et al. (1998) (4 weeks) [73] | 90 | IAsp + NPH | 20a,B
| |||||
HI + NPH | 44 | |||||||
Home et al. (2000)C (6 months) [70]D
| 1065 | IAsp + NPH | 10,430 (80.9) | 314 (16) | 1520 (51.1) | 30.0 26.0 1.18 [0.98–1.42] | 0.81 0.97 0.83 [0.59; 1.18] | 4.4 5.9 0.75 [0.60–0.93]b
|
HI + NPH | 4480 (77.7) | 152 (18) | 1011 (57.3) | |||||
Home et al. (2006) (36 months; extension of Home et al. 2000) [74] | 753 | IAsp + NPH | 820 (29) | 0.48 0.47 1.00 [0.72; 1.39] | ||||
HI + NPH | 261 (31) | |||||||
Raskin et al. (2000)C (24 weeks) [71]D
| 882 | IAsp + NPH | 13,019 (89.9) | 1545 (59.9) | 45.2 47.5 0.94 [0.79–1.11] | 5.4 7.5 0.69 [0.56–0.86]c
| ||
HI + NPH | 6521 (87.1) | 1030 (66.4) | ||||||
Tamás et al. (2001)C (12 weeks) [75]D
| 423 | IAsp + NPH | 9037 (91.5) | 32 (7.1) | 1494 (73.0) | 36.9 44.8 0.84 [0.65–1.08] | 6.1 7.7 0.79 [0.59–1.06] | |
HI + NPH | 10,824 (91.0) | 31 (8.0) | 1870 (73.1) | |||||
DeVries et al. 2003C (64 weeks) [72]D
| 368 | IAsp + NPH | 5129 (89.8) | 796 (68.3) | 24.1 29.5 0.83 [0.64–1.08] | 0.91 0.79 1.29 [0.89–1.87] | 3.7 4.9 0.79 [0.59–1.06] | |
HI + NPH | 6167 (91.7) | 1029 (74.0) | ||||||
Hermansen et al. (2004) (18 weeks) [78] | 595 | IAsp + IDet | 2497 (75) | 40 (6.5) | 271 (38.7) | 0.79A [0.63–0.98]d
| 0.89 [0.35–2.22] | 0.45A [0.35–0.58]c
|
HI + NPH | 3192 (82.9) | 45 (6.3) | 608 (60.3) | |||||
Heller et al. (2004) (16 weeks) [77] | 155 | IAsp + NPH | 0.72 [0.47–1.09] | |||||
HI + NPH | ||||||||
Brock Jacobsen et al. (2011) (crossover, 8-week periods) [76] | 16 | IAsp + NPH | 214 | |||||
HI + NPH | 297 | |||||||
(a) T1D: observational studies | ||||||||
Krzymień et al. (2010) (13 weeks, single-arm, before/after study) [85] | 950 | IAsp + NPH or IDet (NPH or IDet) | 0.14 [0.10–0.20]a
| |||||
(b) T2D: randomized trials | ||||||||
Raslová et al. (2004) and correction (2006) (22 weeks) [83] | 395 | IAsp + IDet | 333 (38.7) | 2 (1.0) | 59 (16.2) | 0.87A [0.55; 1.37] | 0.54A [0.30–0.97]e
| |
HI + NPH | 400 (41.5) | 4 (1.0) | 113 (22.6) | |||||
Meneghini et al. (2011) (48 weeks) | 296 | SimpleSTEP regimen | 920 (74) | 4 (1.3) | 132 (32) | |||
STEP-Wise trial [91] | ExtraSTEP regimen | 825 (77.4) | 1 (0.7) | 91 (30.8) | ||||
Rodbard et al. (2014) (32 weeks) | 401 | Step-wise | 0.58 [0.45; 0.75]g
| |||||
FullSTEP trial [92] | Basal–bolus | |||||||
(b) T2D: observational studies | ||||||||
Krzymień et al. (2010) (single-arm follow-up study, 13 weeks) [85] | 1332 | IAsp + NPH or IDet (NPH or IDet) | 0.94E [0.68–1.31]a
| |||||
Randeree et al. (2013) (24 weeks) [88] | Insulin-experienced: 561 | IAsp | (7.8) | (0) | (0.9) | 1.6c,F
| 0 | 0.1 |
Insulin-naïve: 1465 | (2.8) | (0) | (0.5) | 0.9c,F
| 0 | 0.1 | ||
Latif et al. (2013) (single-arm before/after, 24 weeks) (A1cheive study) [87] | ≤40 years: 571 | Insulin-naïve switching to IAsp + basal | 12.7c,F (27.7) | 0.2c,F (6.7) | 4.9c,F (13.7) | 4.1 | 0 | 1.1 |
>40–65 years: 2801 | 11.1c,F (18.6) | 0c,F (3.6) | 4.1c,F (9.2) | 3.6 | 0 | 0.7 | ||
>65 years: 660 | 11.0c,F (18.3) | 0c,F (3.3) | 2.9c,F (9.8) | 3.4 | 0 | 0.6 | ||
(c) T1D and T2D | ||||||||
Gao et al. (2009)F (12 weeks) [143] | 220 | IAsp | 73 (23.6) | 0 | 3 (2.7) | 2.9 1.0 2.97 [1.40–6.32]f
| 0.1 0.2 0.97 [0.59–1.58] | |
RHI | 25 (15.5) | 5 (3.6) |
4.2.2 In Patients with T2D
4.2.3 Meta-Analysis of T1D and T2D
4.2.4 During Step-Wise Addition of Insulin Aspart
4.2.5 In Patients with Recurrent Hypoglycemia
4.2.6 In Children and Adolescents
4.2.7 In Hospitalized Patients
4.3 Safety and Tolerability During Pregnancy
5 Insulin Aspart in CSII
5.1 In Vitro/Stability Studies
5.1.1 Insulin Aspart CSII Compared with MDI
Study (duration) | No. of patients | Insulin treatment (baseline)A
| Safety findings |
---|---|---|---|
Insulin aspart (CSII) vs multiple daily doses: randomized trials | |||
DeVries et al. (2002) (crossover, 16 week periods) [119] | 79 Adults T1D | IAsp CSII | 0.98 ± 2.02 episodes of mild hypoglycemia per patient—week 3 episodes of severe hypoglycemia 1 episode of DKA |
IAsp + NPH | 0.02 ± 1.18 episodes of mild hyperglycemia per patient—week 6 episodes of severe hypoglycemia 1 episode of DKA | ||
Raskin et al. (2003) (24 weeks) [117] | 132 Adults T2D | IAsp CSII | 0.8 ± 1.6 hypoglycemic events/patient/30 days, none severe |
IAsp + NPH | 1.2 ± 3.1 hypoglycemic events/patient/30 days, none severe | ||
Doyle et al. (2004) (16 weeks) [113] | 32 Children (8–21 years) | IAsp CSII | 1 hospitalization for DKA |
IAsp + IGlar | 5 episodes of severe hypoglycemia in 4 patients 2 hospitalizations for ketosis in 1 patient | ||
Pańkowska et al. (2010) [98] | 61 Children (<7 years) | IAsp CSII | 0.3 major hypoglycemic events per year 21 minor hypoglycemic events per year 1.2 symptoms-only hypoglycemic events per year |
IAsp + NPH | 0.1 major hypoglycemic events per year 18 minor hypoglycemic events per year 1.1 symptoms-only hypoglycemic events per year | ||
BR HI + NPH | 0 major hypoglycemic events per year 20 minor hypoglycemic events per year 1.4 symptoms-only hypoglycemic events per year | ||
Bergenstal et al. (2010) (1 year) [112] | 329 Adults T1D | IAsp CSII, sensor-augmented | 15.31 episodes of severe hypoglycemia per 100 patient—years 0.01 episodes of DKA per 100 patient—years |
IAsp + IGlar MDI | 17.62 episodes of severe hypoglycemia per 100 patient—years 0 episodes of DKA per 100 patient—years | ||
156 Children (7–18 years) T1D | IAsp CSII, sensor-augmented | 8.98 episodes of severe hypoglycemia per 100 patient—years 0.02 episodes of DKA per 100 patient—years | |
IAsp + IGlar MDI | 4.95 episodes of severe hypoglycemia per 100 patient—years 0.02 episodes of DKA per 100 patient—years | ||
Insulin aspart (CSII) vs multiple daily doses: observational studies | |||
Kawamura et al. (2008) (6 months, single-arm, before/after study) [116] | 26 Children (6–18 years) T1D | IAsp CSII (MDI, varied regimens) | 7/22 patients had hypoglycemia, none severe |
8/22 patients had hypoglycemia, none severe | |||
Insulin aspart (CSII) vs buffered RHI: randomized trials | |||
Bode and Strange (2001) (7 weeks) [120] | 29 Adults T1D | IAsp CSII | 14 (74 %) patients experienced hypoglycemia 2.9 events/patient |
BR HI CSII | 6 (60 %) patients experienced hypoglycemia 6.2 events/patient | ||
Bode et al. (2002) (16 weeks) [121] | 146 Adults T1D | IAsp CSII | 3.7 ± 3.6 hypoglycemic episodes per patient per month |
BR HI CSII | 4.8 ± 4.2 hypoglycemic episodes per patient per month | ||
ILisp CSII | 4.4 ± 4.7 hypoglycemic episodes per patient per month | ||
Skogsberg et al. (2008) (24 months) [99] | 72 Children (7–17 years) T1D | IAsp CSII | 2.5 ± 0.5 perceived episodes of hypoglycemia No episodes of DKA |
IAsp MDI | 3.5 ± 0.5 perceived episodes of hypoglycemia No episodes of DKA | ||
Lv et al. (2013) (<2 weeks; time to reach glucose target) [118] | 119 Adults T2D | IAsp CSII | 0.10 episodes of hypoglycemia per person per day |
IAsp + IGlar | 0.07 episodes of hypoglycemia per person per day | ||
IAsp + IDet | 0.05 episodes of hypoglycemia per person per day | ||
Gao et al. (2014) (12 weeks) [114] | 200 Adults T2D | IAsp CSII | 1.62 % of patients had hypoglycemic eventsa
|
IAsp + IGlar | 5.93 % of patients had hypoglycemic events | ||
Insulin aspart (CSII) vs buffered RHI: observational studies | |||
Chlup et al. (2004) (~90 weeks, single-arm before/after study) [122] | 21 Adults T1D | IAsp CSII (BR HI CSII) | No change in frequency of hyper- or hypoglycemia after switching |
Insulin aspart vs insulin lispro and insulin glulisine, all in CSII: randomized trials | |||
Weinzimer et al. (2008) (16 weeks) [128] | 298 Children (4–18 years) T1D | IAsp CSII | 92.2 hypoglycemic events per patient—year 5.7 nocturnal hypoglycemic events per patient—year 0.4 major hypoglycemic events per patient—year 1 patient experienced DKA |
ILisp CSII | 81.3 hypoglycemic events per patient—year 5.7 nocturnal hypoglycemic events per patient—year 0.3 major hypoglycemic events per patient—year 2 patients experienced DKA | ||
van Bon et al. (2011) (crossover, 13-week periods) [127] | 288 Adults T1D | IAsp CSII | 65.01 symptomatic hypoglycemic events per patient—year 9.66 nocturnal hypoglycemic events per patient—year 1.38 severe hypoglycemic events per patient—year |
IGlu CSII | 73.84 symptomatic hypoglycemic events per patient—year 12.80 nocturnal hypoglycemic events per patient—year 1.63 severe hypoglycemic events per patient—year 1 patient experienced DKA | ||
ILisp CSII | 62.69 symptomatic hypoglycemic events per patient—year 9.48 nocturnal hypoglycemic events per patient—year 1.06 severe hypoglycemic events per patient—year | ||
Thrasher et al. (2014) (crossover, 16-week periods) [126] | 122 Adults T2D | IAsp CSII | 2.38 hypoglycemic events per patient per 30 days 1.52 documented symptomatic hypoglycemic events per patient per 30 days 0.52 nocturnal hypoglycemic events per patient per 30 days 1 case of DKA |
ILisp CSII | 2.24 hypoglycemic events per patient per 30 days 1.25 documented symptomatic hypoglycemic events per patient per 30 days 0.45 nocturnal hypoglycemic events per patient per 30 days | ||
Insulin aspart vs insulin lispro and insulin glulisine, all in CSII: observational studies | |||
Alemzadeh et al. (2007) (1-year, single-arm before/after) [124] | 14 Children (~3–5 years) | IAsp CSII (IAsp + IGlar) | 73.1 moderate hypoglycemic events per 100 patient—years 17.5 severe hypoglycemic events per 100 patient—years (92.3 moderate hypoglycemic events per 100 patient—years 22.5 severe hypoglycemic events per 100 patient—years) |
Wittlin et al. (2008) (16 weeks, single-arm, before/after) [129] | 513 Adults T1D or T2D | IAsp CSII (ILisp CSII) | 6 hypoglycemic events during 12 weeks of treatment (1 hypoglycemic event during 4 weeks of treatment) |