. 2020 Aug 12;22(11):1961–1975. doi: 10.1111/dom.14128

TABLE 1.

Key phase III clinical trials of IDegAsp in T2D

Study	Study design	Mean HbA1c	Mean FPG (mmol/L)	Hypoglycaemia (overall confirmed or nocturnal confirmed)	Baseline characteristics
Initiation of IDegAsp (insulin‐naïve people)
BOOST JAPAN Onishi et al. Diabetes Obes Metab 2013 ²¹ NCT01272193	Phase III 26‐wk, open‐label, treat‐to‐target n = 296 (Japanese) IDegAsp OD vs. IGlar U100 OD	ETD IDegAsp/IGlar U100: −0.28% [−0.46; −0.10]_{95% CI}; P < .01	ETD IDegAsp/IGlar U100: 0.15 [−0.29; 0.60]_{95% CI}; P = NS	Overall: ERR IDegAsp/IGlar U100 0.73 [0.50; 1.08]_{95% CI}; P = NS Nocturnal: ERR IDegAsp/IGlar U100 0.75 [0.34; 1.64]_{95% CI}; P = NS	Duration of diabetes, mean years (SD) IDegAsp: 10.9 (7.3) IGlar U100: 12.4 (8.6) Baseline HbA1c, mean % (SD) IDegAsp: 8.3% (0.8) IGlar U100: 8.5% (08) Pretrial concomitant therapies: any OAD In‐trial concomitant therapies: ≤2 OADs; SU, DPP‐4i, glinides discontinued
START TWICE DAILY Franek et al. Diabetic Med 2016 ²³ NCT01513590	Phase IIIb 26‐wk, open‐label, parallel‐group, treat‐to‐target n = 394 IDegAsp BID vs. BIAsp 30 BID	ETD IDegAsp/BIAsp 30: 0.02% [−0.12; 0.17]_{95% CI}	ETD IDegAsp/BIAsp 30 BID: −1.00 mmol/L [−1.4; −0.6]_{95% CI}; P < .001	Overall: ERR IDegAsp/BIAsp 30: 0.46 [0.35; 0.61]_{95% CI}; P < .001 Nocturnal: ERR IDegAsp/BIAsp 30: 0.25 [0.16; 0.38]_{95% CI}; P < .001	Duration of diabetes, mean years (SD) IDegAsp: 9.6 (6.1) BIAsp 30: 9.4 (5.7) Baseline HbA1c, mean % (SD) IDegAsp: 8.5% (0.8) BIAsp 30: 8.3% (0.7) Pretrial concomitant therapies: metformin ± one other OAD In‐trial concomitant therapies: metformin alone
Kumar et al. PLoS One 2016 ²⁴ NCT01045707 [core] NCT01169766 [ext]	Phase III 26‐wk core trial; 26‐wk extension; open‐label, parallel‐group, treat‐to‐target n = 530 IDegAsp OD vs. IGlar U100 OD	ETD IDegAsp/IGlar U100: –0.08% [−0.26; 0.09]_{95% CI}; P = NS^*	ETD IDegAsp/IGlar U100: 0.28 [−0.14; 0.69]_{95% CI} at week 52	Overall: ERR IDegAsp/IGlar U100: 1.86 [1.42; 2.44]_{95% CI}; P < .0001 Nocturnal: ERR IDegAsp/IGlar U100: 0.25 [0.14; 0.47]_{95% CI}; P < .0001	Core study phase Duration of diabetes, mean years (SD) IDegAsp: 8.7 (6.1) IGlar U100: 9.6 (6.1) Baseline HbA1c, mean % (SD) IDegAsp: 8.9% (1.0) IGlar U100: 8.9% (0.9) Pretrial permitted therapies: metformin and one other OAD In‐trial concomitant therapies: metformin alone
SIMPLE USE Park et al. Diabetic Med 2017 ²⁶ NCT01365507	Phase IIIb 26‐wk, open‐label, parallel‐group, treat‐to‐target n = 276 IDegAsp OD titrated Q2W using simple algorithm vs. IDegAsp OD titrated OW using step‐wise algorithm	ETD IDegAsp_{Simple/Stepwise}: −0.2% [−0.4; 0.02]_{95% CI}	ETD IDegAsp_{Simple/Stepwise}: −0.4 [−0.9; 0.09]_{95% CI}	Overall ERR IDegAsp_{Simple/Stepwise}: 1.8 [1.1; 2.9]_{95% CI} Nocturnal ERR IDegAsp_{Simple/Stepwise}: 1.1 [0.5; 2.4]_{95% CI}	Duration of diabetes, mean years (SD) IDegAsp_Simple: 10.1 (6.5) IDegAsp_Stepwise: 10.2 (6.5) Baseline HbA1c, mean % (SD) IDegAsp_Simple: 8.3% (0.8) IDegAsp_Stepwise: 8.2% (0.8) Pretrial therapies: Metformin +1 or 2 other OADs (inc. SU/glinide, DPP‐4‐i, α‐glucosidase inhibitor, SGLT2i) In‐trial therapies: metformin alone
Intensification from basal or premixed insulin to IDegAsp
Step‐by‐Step intensification trial Philis‐Tsimikas et al. Diabetes Res Clin Pract 2019 ²⁷ NCT02906917	Phase III 38‐wk, open‐label, treat‐to‐target n = 532 Inadequately controlled on basal insulin ± OADs IDegAsp OD vs. IGlar U100 OD + IAsp OD for 26 wk then IDegAsp OD/BID vs. IGlar U100 OD + IAsp OD/BID/TID, for 12 wk	Weeks 0–26 ETD IDegAsp/IGlar U100: 0.07% [−0.06; 0.21]_{95% CI} Weeks 0–38 ETD IDegAsp/IGlar U100: 0.09 [−0.04; 0.22]_{95% CI}	Weeks 0–26 ETD IDegAsp/IGlar U100: 0.04 [−0.34; 0.42]_{95% CI} Weeks 0–38 ETD IDegAsp/IGlar U100: −0.24 [−0.60; 0.13]_{95% CI}	Overall: Weeks 0–26 ERR IDegAsp/IGlar U100: 0.90 [0.67; 1.22]_{95% CI} Weeks 0–38: ERR IDegAsp/IGlar U100: 0.86 [0.65; 1.14]_{95% CI} Nocturnal Weeks 0–26: ERR 0.55 [0.34; 0.90]_{95% CI} Weeks 0–38: ERR 0.61 [0.40; 0.93]_{95% CI}	Duration of diabetes, mean years (SD) IDegAsp: 12.9 (6.9) IGlar U100: 13.0 (6.5) Baseline HbA1c, mean % (SD) IDegAsp: 8.2% (0.8) IGlar U100: 8.1% (0.7) Pretrial therapies: Basal insulin ± other OADs (biguanide, SU, glinide, DPP‐4i, α‐glucosidase inhibitor, SGLT‐2i) In‐trial concomitant therapies: SU/glinide discontinued
INTENSIFY ALL Kaneko et al. Diabetes Res Clin Pract 2015 ²⁰ NCT01059812	Phase III 26‐wk, open‐label, treat‐to‐target n = 424 (Asian) Inadequately controlled on basal or premixed insulin ± metformin IDegAsp BID vs. BIAsp 30 BID	ETD IDegAsp/BIAsp 30: 0.05% [−0.10; 0.20]_{95% CI}	ETD IDegAsp/BIAsp 30: −1.06 [−1.43; −0.70]_{95% CI}; P < .001	Overall ERR IDegAsp/BIAsp 30: 1.00 [0.76; 1.32]_{95% CI}; P = NS Nocturnal ERR IDegAsp/BIAsp 30: 0.67 [0.43; 1.06]_{95% CI}; P = NS	Duration of diabetes, mean years (SD) IDegAsp: 16.3 (7.9) BIAsp 30: 16.3 (8.2) Baseline HbA1c, mean % (SD) IDegAsp: 8.4% (0.8) BIAsp 30: 8.4% (0.9) Pretrial therapies: Basal, premixed or self‐mixed insulin ± metformin In‐trial concomitant therapies: metformin only
Kumar et al. Diabetic Med 2017 ²⁵ NCT01045447	Phase III 26‐wk, open‐label, treat‐to‐target n = 465 IDegAsp OD vs. IGlar U100 OD	ETD IDegAsp/IGlar U100: −0.03% [−0.20; 0.14]_{95% CI}; P = NS	ETD IDegAsp/IGlar U100: 0.33 [−0.11; 0.77]_{95% CI}; P = NS	Overall ERR IDegAsp/IGlar U100: 1.43 [1.07; 1.92]_{95% CI}; P < .05 Nocturnal ERR IDegAsp/IGlar U100: 0.80 [0.49; 1.30]_{95% CI}; P = NS	Duration of diabetes, mean years (SD) IDegAsp: 11.6 (6.8) IGlar U100: 11.4 (7.3) Baseline HbA1c, mean % (SD) IDegAsp: 8.3% (0.8) IGlar U100: 8.4% (1.0) Pretrial therapies: Basal insulin (IGlar U100; IDet; NPH insulin) + metformin ± other OADs In‐trial concomitant therapies: Metformin ± pioglitazone ± DPP‐4i; other OADs discontinued
Intensification from IDegAsp OD to IDegAsp BID
Step‐by‐Step intensification trial Philis‐Tsimikas et al. Diabetes Res Clin Pract 2019 ²⁷ NCT02906917	Phase III 38‐wk, open‐label, treat‐to‐target n = 532 Inadequately controlled on basal insulin ± OADs IDegAsp OD vs. IGlar U100 OD + IAsp OD for 26 wk then IDegAsp OD/BID vs. IGlar U100 OD + IAsp OD/BID/TID, for 12 wk	Weeks 0–26 ETD IDegAsp/IGlar U100: 0.07% [−0.06, 0.21]_{95% CI} Weeks 0–38 ETD IDegAsp/IGlar U100: 0.09 [−0.04; 0.22]_{95% CI}	Weeks 0–26 ETD IDegAsp/IGlar U100: 0.04 [−0.34; 0.42]_{95% CI} Weeks 0–38 ETD IDegAsp/IGlar U100: −0.24 [−0.60; 0.13]_{95% CI}	Overall: Weeks 0–26 ERR IDegAsp/IGlar U100: 0.90 [0.67; 1.22]_{95% CI} Weeks 0–38 ERR IDegAsp/IGlar U100: 0.86 [0.65; 1.14]_{95% CI} Nocturnal Weeks 0–26 ERR 0.55 [0.34; 0.90]_{95% CI} Weeks 0–38 ERR 0.61 [0.40; 0.93]_{95% CI}	Duration of diabetes, mean years (SD) IDegAsp: 12.9 (6.9) IGlar U100: 13.0 (6.5) Baseline HbA1c, mean % (SD) IDegAsp: 8.2% (0.8) IGlar U100: 8.1% (0.7) Pretrial therapies: Basal insulin ± other OADs (biguanide, SU, glinide, DPP‐4i, α‐glucosidase inhibitor, SGLT‐2i) In‐trial concomitant therapies: SU/glinide discontinued
Switching either from premixed insulin or self‐mixed insulin ± OAD, or from human insulin OD/BID, basal insulin OD/BID, premixed insulin or self‐mixed insulin ± metformin to IDegAsp
INTENSIFY PREMIX I Fulcher et al. Diabetic Care 2014 ¹⁹ NCT01009580	Phase IIIa 26‐wk, open‐label, treat‐to‐target n = 447 Inadequately controlled with premixed insulin ± OADs IDegAsp BID vs. BIAsp 30 BID	IDegAsp/BIAsp 30 ETD: −0.03% [−0.18; 0.13]_{95% CI}; P = NS	IDegAsp/BIAsp 30 ETD: −1.14 [−1.53; −0.76]_{95% CI}; P < .001	Overall IDegAsp/BIAsp30 ERR: 0.68 [0.52; 0.89]_{95% CI}; P = .0049 Nocturnal IDegAsp/BIAsp30 ERR: 0.27 [0.18; 0.41]_{95% CI}; P = .0001	Duration of diabetes, mean years (SD) IDegAsp: 12.8 (6.8) BIAsp 30: 13.1 (7.4) Baseline HbA1c, mean % (SD) IDegAsp: 8.3 (0.8) BIAsp 30: 8.4 (0.9) Pretrial therapies: Premixed or self‐mixed 20–40% rapid/short acting insulin OD/BID ± OADs (metformin, SU, glinide, α‐glucosidase inhibitor, DPP‐4i, pioglitazone) In‐trial concomitant therapies: all prior therapies discontinued except metformin, DPP‐4i and pioglitazone
INTENSIFY ALL Kaneko et al. Diabetes Res Clin Pract 2015 ²⁰ NCT01059812	Phase III 26‐wk, open‐label, treat‐to‐target (n = 424) (Asian) Inadequately controlled on basal or premixed insulin ± metformin IDegAsp BID vs. BIAsp 30 BID	ETD IDegAsp/BIAsp 30: 0.05% [−0.10; 0.20]_{95% CI}	ETD IDegAsp/BIAsp 30: −1.06 [−1.43; −0.70]_{95% CI}; P < .001	Overall ERR IDegAsp/BIAsp 30: 1.00 [0.76; 1.32]_{95% CI}; P = NS Nocturnal ERR IDegAsp/BIAsp 30: 0.67 [0.43; 1.06]_{95% CI}; P = NS	Duration of diabetes, mean years (SD) IDegAsp: 16.3 (7.9) BIAsp 30: 16.3 (8.2) Baseline HbA1c, mean % (SD) IDegAsp: 8.4% (0.8) BIAsp 30: 8.4% (0.9) Pretrial therapies: basal, premixed or self‐mixed insulin ± metformin In‐trial concomitant therapies: metformin only
INTENSIFY PREMIX I/INTENSIFY ALL pooled analysis Christiansen et al. J Diabetes 2016 ²²	Pooled analysis of INTENSIFY PREMIX I and INTENSIFY ALL Inadequately controlled with premixed insulin ± OADs OR basal or premixed insulin ± metformin, respectively IDegAsp BID vs. BIAsp 30 BID	IDegAsp vs. BIAsp 30: ETD 0.00% [−0.11; 0.10]_{95% CI}; P = NS	IDegAsp vs. BIAsp 30: ETD −1.12 [−1.38; −0.85]_{95% CI}; P < .0001	Overall ERR IDegAsp vs. BIAsp 30: 0.81 [0.67; 0.98]_{95% CI}; P = .03 Nocturnal ERR IDegAsp vs. BIAsp 30: 0.43 [0.31; 0.59]_{95% CI}; P < .0001	Duration of diabetes, mean years (SD) INTENSIFY PREMIX I IDegAsp: 12.8 (6.8) BIAsp 30: 13.1 (7.4) INTENSIFY ALL IDegAsp: 16.3 (7.9) BIAsp 30: 16.3 (8.2) Baseline HbA1c, mean % (SD) INTENSIFY PREMIX I IDegAsp: 8.3 (0.8) BIAsp 30: 8.4 (0.9) INTENSIFY ALL IDegAsp: 8.4 (0.8) BIAsp 30: 8.4 (0.9) Pretrial therapies: INTENSIFY PREMIX I Premixed insulin (OD or BID) ± OADs (metformin, DPP‐4i and pioglitazone) INTENSIFY ALL Basal, premixed or self‐mixed insulin ± metformin In‐trial concomitant therapies: INTENSIFY PREMIX I Metformin ± DPP‐4i ± pioglitazone INTENSIFY ALL Metformin

Study

Study design

Mean HbA1c

Mean FPG (mmol/L)

Hypoglycaemia (overall confirmed or nocturnal confirmed)

Baseline characteristics

Initiation of IDegAsp (insulin‐naïve people)

BOOST JAPAN

Onishi et al. Diabetes Obes Metab 2013 ²¹ NCT01272193

Phase III

26‐wk, open‐label, treat‐to‐target

n = 296 (Japanese)

IDegAsp OD vs. IGlar U100 OD

ETD IDegAsp/IGlar U100: −0.28% [−0.46; −0.10]_{95% CI}; P < .01

ETD IDegAsp/IGlar U100: 0.15 [−0.29; 0.60]_{95% CI}; P = NS

Overall:

ERR IDegAsp/IGlar U100 0.73 [0.50; 1.08]_{95% CI}; P = NS

Nocturnal:

ERR IDegAsp/IGlar U100 0.75 [0.34; 1.64]_{95% CI}; P = NS

Duration of diabetes, mean years (SD) IDegAsp: 10.9 (7.3) IGlar U100: 12.4 (8.6)

Baseline HbA1c, mean % (SD) IDegAsp: 8.3% (0.8) IGlar U100: 8.5% (08)

Pretrial concomitant therapies: any OAD

In‐trial concomitant therapies:

≤2 OADs; SU, DPP‐4i, glinides discontinued

START TWICE DAILY

Franek et al. Diabetic Med 2016 ²³ NCT01513590

Phase IIIb

26‐wk, open‐label, parallel‐group, treat‐to‐target

n = 394

IDegAsp BID vs. BIAsp 30 BID

ETD

IDegAsp/BIAsp 30: 0.02% [−0.12; 0.17]_{95% CI}

ETD IDegAsp/BIAsp 30 BID: −1.00 mmol/L [−1.4; −0.6]_{95% CI}; P < .001

Overall: ERR IDegAsp/BIAsp 30: 0.46 [0.35; 0.61]_{95% CI}; P < .001

Nocturnal: ERR IDegAsp/BIAsp 30: 0.25 [0.16; 0.38]_{95% CI}; P < .001

Duration of diabetes, mean years (SD) IDegAsp: 9.6 (6.1) BIAsp 30: 9.4 (5.7)

Baseline HbA1c, mean % (SD) IDegAsp: 8.5% (0.8) BIAsp 30: 8.3% (0.7)

Pretrial concomitant therapies: metformin ± one other OAD

In‐trial concomitant therapies: metformin alone

Kumar et al. PLoS One 2016 ²⁴ NCT01045707 [core] NCT01169766 [ext]

Phase III

26‐wk core trial; 26‐wk extension; open‐label, parallel‐group, treat‐to‐target

n = 530

IDegAsp OD vs. IGlar U100 OD

ETD IDegAsp/IGlar U100: –0.08% [−0.26; 0.09]_{95% CI}; P = NS^*

ETD IDegAsp/IGlar U100: 0.28 [−0.14; 0.69]_{95% CI} at week 52

Overall: ERR IDegAsp/IGlar U100: 1.86 [1.42; 2.44]_{95% CI}; P < .0001

Nocturnal: ERR IDegAsp/IGlar U100: 0.25 [0.14; 0.47]_{95% CI}; P < .0001

Core study phase

Duration of diabetes, mean years (SD) IDegAsp: 8.7 (6.1) IGlar U100: 9.6 (6.1)

Baseline HbA1c, mean % (SD) IDegAsp: 8.9% (1.0) IGlar U100: 8.9% (0.9)

Pretrial permitted therapies: metformin and one other OAD

In‐trial concomitant therapies: metformin alone

SIMPLE USE

Park et al. Diabetic Med 2017 ²⁶ NCT01365507

Phase IIIb

26‐wk, open‐label, parallel‐group, treat‐to‐target

n = 276

IDegAsp OD titrated Q2W using simple algorithm vs. IDegAsp OD titrated OW using step‐wise algorithm

ETD IDegAsp_{Simple/Stepwise}: −0.2% [−0.4; 0.02]_{95% CI}

ETD IDegAsp_{Simple/Stepwise}: −0.4 [−0.9; 0.09]_{95% CI}

Overall

ERR IDegAsp_{Simple/Stepwise}: 1.8 [1.1; 2.9]_{95% CI}

Nocturnal ERR IDegAsp_{Simple/Stepwise}: 1.1 [0.5; 2.4]_{95% CI}

Duration of diabetes, mean years (SD) IDegAsp_Simple: 10.1 (6.5) IDegAsp_Stepwise: 10.2 (6.5)

Baseline HbA1c, mean % (SD) IDegAsp_Simple: 8.3% (0.8) IDegAsp_Stepwise: 8.2% (0.8)

Pretrial therapies:

Metformin +1 or 2 other OADs (inc. SU/glinide, DPP‐4‐i, α‐glucosidase inhibitor, SGLT2i)

In‐trial therapies:

metformin alone

Intensification from basal or premixed insulin to IDegAsp

Step‐by‐Step intensification trial

Philis‐Tsimikas et al. Diabetes Res Clin Pract 2019 ²⁷ NCT02906917

Phase III

38‐wk, open‐label, treat‐to‐target

n = 532 Inadequately controlled on basal insulin ± OADs

IDegAsp OD vs. IGlar U100 OD + IAsp OD for 26 wk then IDegAsp OD/BID vs. IGlar U100 OD + IAsp OD/BID/TID, for 12 wk

Weeks 0–26 ETD IDegAsp/IGlar U100: 0.07% [−0.06; 0.21]_{95% CI}

Weeks 0–38 ETD IDegAsp/IGlar U100: 0.09 [−0.04; 0.22]_{95% CI}

Weeks 0–26 ETD IDegAsp/IGlar U100: 0.04 [−0.34; 0.42]_{95% CI}

Weeks 0–38 ETD IDegAsp/IGlar U100: −0.24 [−0.60; 0.13]_{95% CI}

Overall:

Weeks 0–26 ERR IDegAsp/IGlar U100: 0.90 [0.67; 1.22]_{95% CI}

Weeks 0–38: ERR IDegAsp/IGlar U100: 0.86 [0.65; 1.14]_{95% CI}

Nocturnal

Weeks 0–26: ERR 0.55 [0.34; 0.90]_{95% CI}

Weeks 0–38: ERR 0.61 [0.40; 0.93]_{95% CI}

Duration of diabetes, mean years (SD) IDegAsp: 12.9 (6.9) IGlar U100: 13.0 (6.5)

Baseline HbA1c, mean % (SD) IDegAsp: 8.2% (0.8) IGlar U100: 8.1% (0.7)

Pretrial therapies: Basal insulin ± other OADs (biguanide, SU, glinide, DPP‐4i, α‐glucosidase inhibitor, SGLT‐2i)

In‐trial concomitant therapies: SU/glinide discontinued

INTENSIFY ALL

Kaneko et al. Diabetes Res Clin Pract 2015 ²⁰ NCT01059812

Phase III

26‐wk, open‐label, treat‐to‐target

n = 424 (Asian) Inadequately controlled on basal or premixed insulin ± metformin

IDegAsp BID vs. BIAsp 30 BID

ETD IDegAsp/BIAsp 30: 0.05% [−0.10; 0.20]_{95% CI}

ETD IDegAsp/BIAsp 30: −1.06 [−1.43; −0.70]_{95% CI}; P < .001

Overall

ERR IDegAsp/BIAsp 30: 1.00 [0.76; 1.32]_{95% CI}; P = NS

Nocturnal ERR IDegAsp/BIAsp 30: 0.67 [0.43; 1.06]_{95% CI}; P = NS

Duration of diabetes, mean years (SD) IDegAsp: 16.3 (7.9) BIAsp 30: 16.3 (8.2)

Baseline HbA1c, mean % (SD) IDegAsp: 8.4% (0.8) BIAsp 30: 8.4% (0.9)

Pretrial therapies: Basal, premixed or self‐mixed insulin ± metformin

In‐trial concomitant therapies: metformin only

Kumar et al. Diabetic Med 2017 ²⁵ NCT01045447

Phase III

26‐wk, open‐label, treat‐to‐target

n = 465

IDegAsp OD vs. IGlar U100 OD

ETD IDegAsp/IGlar U100: −0.03% [−0.20; 0.14]_{95% CI}; P = NS

ETD IDegAsp/IGlar U100: 0.33 [−0.11; 0.77]_{95% CI}; P = NS

Overall

ERR IDegAsp/IGlar U100: 1.43 [1.07; 1.92]_{95% CI}; P < .05

Nocturnal ERR IDegAsp/IGlar U100: 0.80 [0.49; 1.30]_{95% CI}; P = NS

Duration of diabetes, mean years (SD) IDegAsp: 11.6 (6.8) IGlar U100: 11.4 (7.3)

Baseline HbA1c, mean % (SD) IDegAsp: 8.3% (0.8) IGlar U100: 8.4% (1.0)

Pretrial therapies: Basal insulin (IGlar U100; IDet; NPH insulin) + metformin ± other OADs

In‐trial concomitant therapies: Metformin ± pioglitazone ± DPP‐4i; other OADs discontinued

Intensification from IDegAsp OD to IDegAsp BID

Step‐by‐Step intensification trial

Philis‐Tsimikas et al. Diabetes Res Clin Pract 2019 ²⁷ NCT02906917

Phase III

38‐wk, open‐label, treat‐to‐target

n = 532

Inadequately controlled on basal insulin ± OADs

IDegAsp OD vs. IGlar U100 OD + IAsp OD for 26 wk then IDegAsp OD/BID vs. IGlar U100 OD + IAsp OD/BID/TID, for 12 wk

Weeks 0–26 ETD IDegAsp/IGlar U100: 0.07% [−0.06, 0.21]_{95% CI}

Weeks 0–38 ETD IDegAsp/IGlar U100: 0.09 [−0.04; 0.22]_{95% CI}

Weeks 0–26 ETD IDegAsp/IGlar U100: 0.04 [−0.34; 0.42]_{95% CI}

Weeks 0–38 ETD IDegAsp/IGlar U100: −0.24 [−0.60; 0.13]_{95% CI}

Overall:

Weeks 0–26 ERR IDegAsp/IGlar U100: 0.90 [0.67; 1.22]_{95% CI}

Weeks 0–38 ERR IDegAsp/IGlar U100: 0.86 [0.65; 1.14]_{95% CI}

Nocturnal

Weeks 0–26 ERR 0.55 [0.34; 0.90]_{95% CI}

Weeks 0–38 ERR 0.61 [0.40; 0.93]_{95% CI}

Duration of diabetes, mean years (SD) IDegAsp: 12.9 (6.9) IGlar U100: 13.0 (6.5)

Baseline HbA1c, mean % (SD) IDegAsp: 8.2% (0.8) IGlar U100: 8.1% (0.7)

Pretrial therapies: Basal insulin ± other OADs (biguanide, SU, glinide, DPP‐4i, α‐glucosidase inhibitor, SGLT‐2i)

In‐trial concomitant therapies: SU/glinide discontinued

Switching either from premixed insulin or self‐mixed insulin ± OAD, or from human insulin OD/BID, basal insulin OD/BID, premixed insulin or self‐mixed insulin ± metformin to IDegAsp

INTENSIFY PREMIX I

Fulcher et al. Diabetic Care 2014 ¹⁹ NCT01009580

Phase IIIa

26‐wk, open‐label, treat‐to‐target n = 447

Inadequately controlled with premixed insulin ± OADs

IDegAsp BID vs. BIAsp 30 BID

IDegAsp/BIAsp 30 ETD: −0.03% [−0.18; 0.13]_{95% CI}; P = NS

IDegAsp/BIAsp 30 ETD: −1.14 [−1.53; −0.76]_{95% CI}; P < .001

Overall

IDegAsp/BIAsp30 ERR: 0.68 [0.52; 0.89]_{95% CI}; P = .0049

Nocturnal

IDegAsp/BIAsp30

ERR: 0.27 [0.18; 0.41]_{95% CI}; P = .0001

Duration of diabetes, mean years (SD) IDegAsp: 12.8 (6.8) BIAsp 30: 13.1 (7.4)

Baseline HbA1c, mean % (SD) IDegAsp: 8.3 (0.8) BIAsp 30: 8.4 (0.9)

Pretrial therapies:

Premixed or self‐mixed 20–40% rapid/short acting insulin OD/BID ± OADs (metformin, SU, glinide, α‐glucosidase inhibitor, DPP‐4i, pioglitazone)

In‐trial concomitant therapies: all prior therapies discontinued except metformin, DPP‐4i and pioglitazone

INTENSIFY ALL

Kaneko et al. Diabetes Res Clin Pract 2015 ²⁰ NCT01059812

Phase III

26‐wk, open‐label, treat‐to‐target

(n = 424)

(Asian)

Inadequately controlled on basal or premixed insulin ± metformin

IDegAsp BID vs. BIAsp 30 BID

ETD IDegAsp/BIAsp 30: 0.05% [−0.10; 0.20]_{95% CI}

ETD IDegAsp/BIAsp 30: −1.06 [−1.43; −0.70]_{95% CI}; P < .001

Overall

ERR IDegAsp/BIAsp 30: 1.00 [0.76; 1.32]_{95% CI}; P = NS

Nocturnal ERR

IDegAsp/BIAsp 30: 0.67 [0.43; 1.06]_{95% CI}; P = NS

Duration of diabetes, mean years (SD) IDegAsp: 16.3 (7.9) BIAsp 30: 16.3 (8.2)

Baseline HbA1c, mean % (SD) IDegAsp: 8.4% (0.8) BIAsp 30: 8.4% (0.9)

Pretrial therapies: basal, premixed or self‐mixed insulin ± metformin

In‐trial concomitant therapies: metformin only

INTENSIFY PREMIX I/INTENSIFY ALL pooled analysis

Christiansen et al. J Diabetes 2016 ²²

Pooled analysis of INTENSIFY PREMIX I and INTENSIFY ALL

Inadequately controlled with premixed insulin ± OADs OR basal or premixed insulin ± metformin, respectively

IDegAsp BID vs. BIAsp 30 BID

IDegAsp vs. BIAsp 30: ETD 0.00% [−0.11; 0.10]_{95% CI}; P = NS

IDegAsp vs. BIAsp 30: ETD −1.12 [−1.38; −0.85]_{95% CI}; P < .0001

Overall

ERR IDegAsp vs. BIAsp 30: 0.81 [0.67; 0.98]_{95% CI}; P = .03

Nocturnal

ERR IDegAsp vs. BIAsp 30: 0.43 [0.31; 0.59]_{95% CI}; P < .0001

Duration of diabetes, mean years (SD) INTENSIFY PREMIX I IDegAsp: 12.8 (6.8) BIAsp 30: 13.1 (7.4)

INTENSIFY ALL IDegAsp: 16.3 (7.9)

BIAsp 30: 16.3 (8.2)

Baseline HbA1c, mean % (SD) INTENSIFY PREMIX I IDegAsp: 8.3 (0.8) BIAsp 30: 8.4 (0.9)

INTENSIFY ALL IDegAsp: 8.4 (0.8) BIAsp 30: 8.4 (0.9)

Pretrial therapies:

INTENSIFY PREMIX I Premixed insulin (OD or BID) ± OADs (metformin,

DPP‐4i and pioglitazone)

INTENSIFY ALL Basal, premixed or self‐mixed insulin ± metformin

In‐trial concomitant therapies:

INTENSIFY PREMIX I Metformin ± DPP‐4i ± pioglitazone INTENSIFY ALL Metformin

Abbreviations: BIAsp 30, biphasic insulin aspart 30; BID, twice daily; CI, confidence interval; DPP‐4i, dipeptidyl‐peptidase‐4 inhibitor; ERR, estimated rate ratio; ETD, estimated treatment difference; glargine, insulin glargine; glargine U100, insulin glargine 100 units/mL; IAsp, insulin aspart; IDegAsp, insulin degludec/insulin aspart co‐formulation; IGlar, insulin glargine; NPH, insulin neutral protamine Hagedorn; NS, not significant; OAD, oral antidiabetic drug; OD, once daily; OW, once weekly; SD, standard deviation; SGLT‐2i, sodium‐glucose co‐transporter‐2 inhibitor; SU, sulphonylurea; TID, three times daily; T2D, type 2 diabetes; Q2W, every 2 weeks.

The mean ETD (IDegAsp–glargine U100) was −0.08% (95% CI: −0.26, 0.09) after 52 weeks, as observed in the core phase at week 26. ²⁴