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Supplementary data tables

Table I: T1DM studies meeting all of the eligibility criteria (all regimens)

Study Total study population size, n

Study design & duration

Country Key inclusion criteria Hypoglycemia definition

Insulin regimen Glycemic targets (PG, HbA1c if applicable) & mean EOT HbA1c

Hypoglycemia event rates (episodes/patient/year)†

RCTs

Hirsch 2012 [1]

n=548 Phase III, open-label, treat-to-target, multicenter, RCT

26 weeks

Australia, Denmark, France, Israel, Poland, Romania, Russia, UK, USA

Aged ≥18 years Diagnosis of T1DM

for ≥1 year Treated with insulin

(BB, premix, self-mix) for ≥1 year

HbA1c 7.0–10.0% BMI ≤35 kg/m2

Patients with recurrent severe hypoglycemia or hypoglycemic unawareness were excluded.

Confirmed: PG <3.1 mmol/L (regardless of symptoms) or severe episodes requiring assistance

Nocturnal: occurring between midnight and 6:00 hours (inclusive)

Analogue co-formulation vs BB: IDegAsp + IAsp (n=366) vs IDet + IAsp (n=182)

PG target 4–5 mmol/L

HbA1c target <7%

EOT HbA1c

IDeg Asp: 7.6% IDet: 7.6%

Confirmed, including severe (IDegAsp vs IDet + IAsp): 39.17 vs 44.34, respectively

Severe (IDegAsp vs IDet + IAsp): 0.33 vs 0.42, respectively

Nocturnal - confirmed (IDegAsp vs IDet + IAsp):3.71 vs 5.72, respectively

Heller 2012 (BEGIN®: BB T1) [2]

n=629 Phase III, open-label, treat-to-target, non-inferiority, multicenter, RCT

52 weeks

France, Germany, Russia, South Africa, UK, USA


for ≥1 year Treated with BB

therapy for ≥1 year HbA1c ≤10% BMI ≤35 kg/m2


Confirmed: PG <3.1 mmol/L or severe episodes requiring assistance

Nocturnal: occurring from 00:01 to 05:59 hours (inclusive)

BB: IDeg + IAsp (n=472) vs IGlar + IAsp (n=157)

PG target 3.9–<5.0

mmol/L

HbA1c target <7%

EOT HbA1c‡

IDeg: 7.3% IGlar: 7.3%

Confirmed, including severe (IDeg vs IGlar): 42.54 vs 40.18, respectively

Severe (IDeg vs IGlar) 0.21 vs 0.16, respectively

Nocturnal - confirmed (IDeg vs IGlar): 4.41 vs 5.86, respectively

1






Bode 2013(BEGIN®: BB T1) [3]

n=469 Open-label, multicenter, extension study of BEGIN® BB T1

52 weeks

France, Germany, Russia, South Africa, UK, USA


for ≥1 year Treated with BB

therapy for ≥1 year HbA1c ≤10% BMI ≤35 kg/m2

Confirmed: PG <3.1 mmol/L or severe episodes requiring assistance

Nocturnal: occurring from 00:01 to 05:59 hours (inclusive)

BB: IDeg + IAsp (n=351) vs IGlar + IAsp (n=118)

PG target 3.9–4.9 mmol/L

HbA1c target <7%

EOT HbA1c


Confirmed: only reported graphically

Severe (IDeg vs IGlar): 0.17 vs 0.15, respectively

Nocturnal - confirmed (IDeg vs IGlar): 3.9 vs. 5.3, respectively

Mathieu 2013 (BEGIN®: Flex T1) [4]

Main trial: n=493

Extension:n=372

Open-label, treat-to-target, non-inferiority RCT

26 weeks with a 26-week extension

Europe, USA Aged ≥18 years On BB therapy HbA1c ≤10% BMI ≤35 kg/m2


Confirmed: BG <3.1 mmol/L or severe episodes requiring assistance

Nocturnal: occurring between 00:01 and 05:59 hours (inclusive)

Main trial, BB:

IDeg Forced-Flex + IAsp (IDeg at fixed intervals with 8–40 hrs between doses; n=164) vs IDeg + IAsp (n=165), vs IGlar + IAsp (n=164)

Extension, BB:

IDeg Free-Flex + IAsp (8–40 hrs between doses of IDeg; n=239) vs IGlar + IAsp (n=133)

PG target Basal titration:

4.0–5.0 mmol/L Bolus titration:

<5.0 mmol/L

HbA1c target NR

HbA1c at Week 26‡

IDeg Forced-Flex: 7.3%


HbA1c at Week 52 IDeg Free-Flex:

7.6% IGlar: 7.5%

Weeks 0–26 Confirmed (IDeg

Forced Flex vs IDeg vs IGlar): 82.4 vs 88.3 vs 79.7, respectively

Severe (IDeg Forced Flex vs IDeg vs IGlar): 0.3 vs 0.4 vs 0.5, respectively

Nocturnal - confirmed (IDeg Forced Flex vs IDeg vs IGlar): 6.2 vs 9.6 vs 10.0, respectively

Weeks 0–52 Confirmed (IDeg Free-

Flex vs IGlar): 68.1 vs 63.4, respectively

Severe (IDeg Free-Flex vs IGlar): 0.2 vs 0.4, respectively

Nocturnal - confirmed (IDeg Free-Flex vs IGlar): 6.4 vs 8.5, respectively

2






RWD studies

Kristensen 2012 [5]

n=3,861 Retrospective, cross-sectional questionnaire survey including patients from 6 hospital outpatient clinics

Data were collected from Nov 2006-June 2007. Severe hypo events were reported for the previous year

Denmark Aged ≥18 years Diagnosis of T1DM

Severe: requiring assistance of another to restore the BG level

Mild: symptomatic, self-treated episode with/without a BG measurement

Analogue (n=1,052) vs human insulin (n=2,085)

PG target NR

HbA1c target NR

EOT HbA1c

NR

Overall severe: 1.21 Overall mild: 123.8§

Severe (long-acting analogues vs long-acting human): 1.47 vs 1.09, respectively

Severe (IDet vs IGlar): 1.30 vs 1.59, respectively

Mild (long-acting analogues vs long-acting human): 136.8 vs 112.3, respectively§

Ostenson 2014 [6]

n=1,631 patients with T1DM

Retrospective, questionnaire-based survey

Patients recruited via consumer panels, websites, telephone, and GP clinics

4 weeks

Austria, Denmark, Finland, Norway, Sweden, Switzerland, the Netherlands

Aged ≥15 years Diagnosis of T1DM Current insulin

treatment

Severe: requiring the assistance of another to manage

Non-severe: symptomatic, self-treated, with/without a BG measurement or BG ≤3.1 mmol/L without symptoms and self-managed

Nocturnal: occurring while in bed/asleep

Basal only (n=134), BB (n=1,058), other (n=439)

PG target NR

HbA1c target NR

EOT HbA1c

NR

Mean non-severe: 91.0 Severe: 0.7 Nocturnal – non-

severe: 20.0¶

3

Abbreviations: BB, basal-bolus; BD, twice daily; BG, blood glucose; BMI, body mass index; EOT: end of treatment; HbA1c, glycated hemoglobin; IAsp, insulin aspart; IDeg, insulin degludec; IDegAsp, insulin degludec and insulin aspart co-formulation; IDet, insulin detemir; IGlar, insulin glargine; NR, not reported; OAD, oral anti-diabetic drug; OD, once daily; PG, plasma glucose; RCT, randomized controlled trial; T1DM, type 1 diabetes mellitus.†Event rates are reported as the mean number of episodes per patient per year unless otherwise specified.‡Calculated based on reported baseline values and decreases from baseline.§Rates of mild hypoglycemia are reported in the study as episodes per patient per week. ¶Calculated based on 22% of non-severe hypoglycemic episodes occurring during sleep.

4

Table II: T2DM studies meeting all of the eligibility criteria (basal-oral regimens)






RCTs

Buse 2011 (DURABLE) [7]

n=2,091 Open-label, multinational, parallel-group RCT

30 months

Argentina, Australia, Brazil, Canada, Greece, Hungary, India the Netherlands, Romania, Spain, USA

Aged 30–80 years Diagnosis of T2DM Insulin naïve HbA1c >7.0% Taking ≥two OADs

(MET, SU, pioglitazone, rosiglitazone) for ≥90 days

Patients with a history of severe hypoglycemia were excluded.

Severe: requiring assistance with oral carbohydrate, IV glucose or glucagon

Confirmed: PG ≤3.9 mmol/L or symptomatic

Nocturnal: occurring after bedtime and before morning meal/insulin dose

Basal-oral: IGlar + OADs (n=1,046)

PG target NR

HbA1c target ≤7.0%

EOT HbA1c

HbA1c for patients who maintained HbA1c goal: 6.5%

HbA1c for patients who did not maintain goal: 7.6%

Overall: 16.4‡

Confirmed (‘documented symptomatic’ with PG ≤3.9 mmol/L): 8.2‡

Severe: 0.07‡

Nocturnal - confirmed: 7.7‡

De Vries 2012 [8]

n=988 Open-label, parallel-group RCT

38 weeks

Belgium, Canada, France, Germany, Italy, the Netherlands, Spain, UK, USA

Aged 18–80 years Diagnosis of T2DM Insulin naïve HbA1c 7.0–10.0%

after treatment with MET for ≥3 months, or HbA1c 7.0–8.5% after treatment with MET and SU for ≥3 months

Minor: PG <3.1 mmol/L and self-treated

Basal-oral: IDet + MET + liraglutide (n=162)

PG target NR

HbA1c target <7.0% ≤6.5%

EOT HbA1c

7.1%

Minor: 0.286

Zinman n=1,030 Open-label, Austria, Aged ≥18 years Confirmed: BG Basal-oral: IDeg PG target Confirmed, including

5






2012 (BEGIN: Once Long) [9]

treat-to-target, non-inferiority, multicenter, parallel-group RCT

52 weeks

Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Norway, Serbia and Montenegro, Spain, USA

Diagnosis of T2DM for ≥6 months

Insulin naïve HbA1c 7–10%

(inclusive) BMI ≤40 kg/m2

Treated with unchanged doses of OADs for ≥3 months


<3.1 mmol/L or severe episodes requiring assistance


+ MET (n=773) vs IGlar + MET (n=257)

3.9–4.9 mmol/L

HbA1c target <7.0%

EOT HbA1c


severe (IDeg vs IGlar): 1.52 vs 1.85, respectively



6






Gough 2013 (BEGIN: Low Volume) [10]

n=460 Open-label, treat-to-target, non-inferiority, multicenter RCT

26 weeks

Canada, France, Ireland, Russia, South Africa, Ukraine, UK, USA


for ≥6 months Insulin naïve HbA1c 7–10%


Treated with MET ± additional OADs for ≥3 months

Patients with recurrent severe hypoglycemia (>1 event in last 12 months) or hypoglycemic unawareness were excluded.



Basal-oral: IDeg + MET ± DPP-4 inhibitor (n=228) vs IGlar + MET ± DPP-4 inhibitor (n=229)

PG target <5 mmol/L

HbA1c target <7.0%

EOT HbA1c§


Confirmed, including severe (IDeg vs IGlar): 1.22 and 1.42, respectively

Nocturnal - confirmed (IDeg vs IGlar): 0.18 and 0.28, respectively

Meneghini 2013 [11]

n=457 Open-label, treat-to-target, multicenter RCT

26 weeks

Argentina, India, Korea, Puerto Rico, Thailand, USA

Aged ≥18 years Diagnosis of T2DM ≥6

months Treated with MET ± a

second OAD for ≥3 months

HbA1c 7–9% BMI ≤35 kg/m2

Minor: able to self-treat and BG <3.1 mmol/L with/without symptoms

Major: unable to self-treat

Symptomatic: symptoms of hypoglycemia and BG >3.1 mmol/L or no BG measurement

Nocturnal: occurring between 23:00 and 05:59

Basal-oral: IDet + MET (n=228) vs IGlar + MET (n=229)

PG Target ≤5.0 mmol/L

HbA1c target ≤7.0% ≤6.5%

EOT IDet: 7.5% IGlar: 7.1%

All events (IDet vs IGlar): 3.19 vs 4.41, respectively

Minor (IDet vs IGlar): 1.15 vs 1.51, respectively

Symptomatic (IDet vs IGlar): 2.03 vs 2.89, respectively

Major (IDet vs IGlar): 0 vs 0.02, respectively

Nocturnal - confirmed (IDet vs IGlar): 1.11 vs 0.88, respectively

Nocturnal – non-severe (IDet vs IGlar): 0.38 vs

7






hours (inclusive) 0.29, respectively

Meneghini 2013 [12]

n=687 Phase III, open-label, treat-to-target, parallel-group RCT

26 weeks

Argentina, Finland, Hungary, India, Israel, Former Yugoslav Republic of Macedonia, Malaysia, Mexico, Norway, Russia, Serbia and Montenegro, South Africa, Taiwan, UK


for ≥6 months BMI ≤40 kg/m2

Previously treated with OADs (baseline HbA1c 7.0–11.0%) or any basal insulin + OADs (HbA1c 7.0–10.0%)

Patients with recurrent severe hypoglycemia (>1 event in last 12 months) or hypoglycemic unawareness were excluded.

Confirmed: PG <3.1 mmol/L (regardless of symptoms) and severe events requiring assistance

Nocturnal: onset between 00:01 and 05:59 hours (inclusive)

Basal-oral: IDeg Flex (8–40 hrs between doses (n=229) vs IDeg (n=228) vs IGlar (n=230)

PG target 3.9-<5.0 mmol/

L

HbA1c target <7.0%

EOT IDeg Flex: 7.2% IDeg: 7.3% IGlar: 7.1%

Confirmed, including severe (IDeg Flex vs IDeg vs IGlar): 3.6 vs 3.6 vs 3.5, respectively

Nocturnal - confirmed (IDeg Flex vs IDeg vs IGlar): 0.6 vs 0.6 vs 0.8, respectively

Onishi 2013 [13]

n=435 Phase III, open-label, treat-to-target, multicenter, non-inferiority RCT

26 weeks

Hong Kong, Japan, Malaysia, South Korea, Taiwan, Thailand

Aged ≥18 years (≥20 years for Japan)


Insulin naïve HbA1c 7.0–10.0%


Treated with 1–2 OADs at an unchanged dose for ≥3 months

Confirmed: PG <3.1 mmol/L (regardless of symptoms) or severe requiring assistance


Basal-oral: IDeg + ≥1 OAD (n=289) vs IGlar + ≥1 OAD (n=146)

PG target 3.9-<5.0 mmol/

L


EOT IDeg: 7.2% IGlar: 7.1%



8






Philis-Tsimikas 2013 [14]

n=458 Open-label, multicenter RCT

26 weeks

Argentina, Canada, India, Mexico, South Africa, Turkey, USA


for ≥6 months Insulin naïve HbA1c 7.5–11.0%

(7.5–10% for Argentina)

BMI ≤40 kg/m2

Treated with 1–2 OADs at an unchanged dose for ≥3 months

Confirmed: plasma glucose <3.1 mmol/L (regardless of symptoms) or severe requiring assistance


Basal-oral: IDeg + OADs (n=229)

PG target <5.0 mmol/L

HbA1c target <7.0%

EOT 7.2%

Confirmed, including severe: 3.07

Severe: 0.01 Nocturnal - confirmed:

0.52

Rodbard 2013 [15]

n=1,023 Open-label, treat-to-target, multinational RCT

52 week extension of BEGIN®: Once Long study

Austria, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Norway, Serbia and Montenegro, Spain, USA


for ≥6 months HbA1c 7–10%


Treated with unchanged doses of OADs for ≥3 months



Basal-oral: IDeg + OADs (n=551) vs IGlar + OADs (n=174)

PG target 3.9–4.9

mmol/L

HbA1c target <7.0%

EOT IDeg: 7.0% IGlar: 6.9%




Buse 2014(DUAL II) [16]

n=413 Phase III, parallel-group, double-blind RCT

26 weeks

Bulgaria, Denmark, Hungary, India, Slovenia, Switzerland, USA

Aged ≥18 years HbA1c 7.5–10.0%

(inclusive) BMI ≥27 kg/m2

Treated with basal insulin at a stable dose (20–40 units/day [±10%]) for ≥90 days + OADs

Confirmed: PG <3.1 mmol/L (regardless of symptoms) and severe requiring assistance

Nocturnal: Confirmed hypoglycemia with onset between

Basal-oral: IDeg + MET (n= 199) vs IDegLira + MET (n=199)

PG target NR


EOT

Confirmed – including severe (IDeg vs IDegLira): 2.6 vs 1.5, respectively

Nocturnal – confirmed (IDeg vs IDegLira): 0.32 vs 0.22, respectively

9






00:01 and 05:59 hours (inclusive)

IDeg: 8.0% IDegLira: 6.9%

RWD studies

Tsai 2011 (FINE) [17]

n=2,921 Prospective, multinational, observational

6 months

Bangladesh, China, Hong Kong, India, Indonesia, Korea, Pakistan, Singapore, Taiwan, Thailand, Vietnam

Aged ≥20 years Patients with T2DM

on OADs HbA1c ≥8% Required initiation of

basal insulin based on the judgement of their treating physician

Mild/moderate: asymptomatic with BG <3.9 mmol/L, or symptomatic with/without a BG measurement

Severe: BG <3.9 mmol/L requiring assistance

Basal +/- oral regimen: IDet (n=61), IGlar (n=2,016) or NPH +/- OADs (n=589)

PG target NR

HbA1c target <7.0%

EOT§

Overall: 7.7% IGlar: 7.5% IDet: 9.1% NPH: 8.2%

IGlar (mild-moderate vs severe): 0.224 vs 0.003, respectively

IDet (mild-moderate vs severe): 0.361 vs 0.000, respectively

NPH (mild-moderate vs severe): 0.458 vs 0.031, respectively

Home 2011 [18]

n=66,726 Non-interventional, prospective, international, observational

24 weeks

Africa, Asia, Europe, Latin America

Diagnosis of T2DM Minor: BG <3.1 mmol/L, with/without symptoms and able to self-manage

Major: symptomatic, requiring assistance and BG <3.1 mmol/L or reversal of symptoms following food intake, or glucagon or IV glucose

Nocturnal: symptomatic, occurring during

Insulin detemir:Insulin naïve n=12,078Prior insulin user n=3467

PG target NR

HbA1c target <7.0%

EOTNR

Insulin naïve: Overall: 1.33 Minor: 1.33 Major: 0.00 Nocturnal: 0.38

Prior insulin: Overall: 1.83 Minor: 1.83 Major: 0.01 Nocturnal: 0.47

10






sleep between bedtime after the evening insulin injection and before getting up

Verges 2012 (LIGHT) [19]

n=2,541 Longitudinal, prospective, multicenter, observational

3 months

France Aged >40 years Diagnosis of T2DM Insulin naïve HbA1c >7% Receiving OADs

Minor (diurnal or nocturnal): patient reported

Severe: requiring assistance and BG <2.8 mmol/L and relief of symptoms following food intake, glucagon or IV glucose

Insulin analogue (IDet or IGlar)

PG target NR

HbA1c target <7.0%

EOT Overall: 7.5% IDet: 7.5% IGlar: 7.5%

Overall: 5.6 Nocturnal: 1.04 Severe: 0.12

Khunti 2012 (SOLVE) [20]

n=17,374 Prospective, open-label, observational

24 weeks

Canada, China, Germany, Israel, Italy, Poland, Portugal, Spain, Turkey, UK

Diagnosis of T2DM Receiving ≥1 OAD

Minor: BG <3.1 mmol/L with/without symptoms

Severe: requiring assistance to administer food, glucagon or IV glucose

Basal-oral: IDet + OADs

PG target NR

HbA1c target <7.0%

EOT 7.5%

Minor: 1.832 Severe: 0.005 Nocturnal - non-severe:

0.277

Brod 2012 (GAPP2) [21]

n=3,042 Online, multinational, cross-sectional survey

30 days

Canada, Denmark, Germany, Japan, UK, US

Aged ≥40 years Received a diagnosis

of T2DM >40 years of age

Receiving insulin therapy (excluding

Self-treated (diurnal or nocturnal)

Basal (n=1,460) PG target NR

HbA1c target NR

Overall basal¶: 35.3 Diurnal basal¶: 23.1 Nocturnal basal¶: 13.4

11






premix, bolus only or pumps)

EOT NR

Echtay 2013 [22]

n=2,155 Multinational, prospective, observational

24 weeks

Israel, Jordan, Lebanon, Pakistan

Diagnosis of T2DM Previously treated

with ≥1 OAD or newly diagnosed starting IDet ± OAD therapy

Minor: self-treated with/without symptoms and BG <3.1 mmol/L

Major: symptomatic and requiring assistance or reversal of symptoms following glucagon or IV glucose administration

Nocturnal: symptomatic occurring during sleep, after evening insulin injection

Basal ± OAD: IDet

PG target NR


EOT IDet: 7.6%

Overall: 1.37 Minor: 1.30 Major: 0.02 Nocturnal: 0.39

Ostenson 2014 [6]

n=2,196 Retrospective, questionnaire based survey


4–7 weeks


Aged ≥15 years Diagnosis of T2DM Current insulin

treatment

Non-severe: symptomatic self-treated, with/without a BG measurement or BG ≤3.1 mmol/L without symptoms, self-managed

Severe: requiring assistance to manage


Basal PG target NR

HbA1c target NR

EOT NR

Non-severe: 20.3 Severe: 0.1 Nocturnal – non-

severe††: 6.5

12

Abbreviations: BG, blood glucose; BMI, body mass index; EOT, end of treatment; HbA1c, glycated hemoglobin; IDet insulin detemir; IDeg, insulin degludec; IGlar, insulin glargine; IV, intravenous; MET, metformin; NPH, neutral protamine Hagedorn; NR, not reported; OAD, oral anti-diabetic drug; PG, plasma glucose; RCT, randomized controlled trial; SU, sulphonylurea; T2DM, type 2 diabetes mellitus.†Event rates are reported as the mean number of episodes per patient per year unless otherwise specified.‡For all non-severe hypoglycemia, values were calculated at endpoint for the period between the previous office visit and endpoint office visit. For severe hypoglycemia, incidence and rate were calculated over the entire study duration due to the rare occurrence of severe hypoglycemia.§Calculated based mean change from baseline.¶Calculated based on the rates of events per patient per 30 days.††Calculated based on the percentage of non-severe hypoglycemic events reported during sleep.

13

Table III: T2DM studies meeting all of the eligibility criteria (basal-bolus regimens)



Country Key inclusion criteria Hypoglycemia definition Insulin regimen

HbA1c target (if applicable) & EOT levels (mean, SD)


RCTs

Jain 2010 [23]

n=484 Randomized, open-label, active-controlled RCT

36 weeks

Australia, Canada, France, Greece, India, Republic of Korea, Mexico, Russian Federation, Spain

Aged 30–80 years Diagnosis of T2DM Insulin naïve HbA1c 7.5–12.0% BMI ≤40 kg/m2

Taking ≥2 OADs for ≥90 days

Capable and willing to use insulin injections and SMPG

Excluded if recent history of severe hypoglycemia

Confirmed: symptomatic or BG <3.9 mmol/L (regardless of symptoms)

Severe: symptomatic and requiring assistance with either BG <2.8 mmol/L or prompt recovery after oral carbohydrate, glucagon or IV glucose

Nocturnal: occurring between bedtime and waking

Basal-bolus: IGlar + insulin lispro (n=242)

PG target NA

HbA1c target ≤7.0% <7.0% ≤6.5%

EOT IGlar:

7.50%

Overall: 26.6‡

Miser 2010 [24]

n=744 Open-label, parallel-group, non-inferiority intensification sub study of the DURABLE RCT

6 months

Argentina, Australia, Brazil, Canada, Greece, Hungary, India, the Netherlands, Puerto Rico, Romania, Spain

Aged 30–80 years Diagnosis of T2DM Insulin naïve HbA1c >7.0% Treated with ≥2

OADs for 90 days


Confirmed: plasma glucose ≤3.9 mmol/L§ or symptomatic

Severe: requiring assistance

Nocturnal: events occurring after bedtime and before the morning meal or insulin dose

Basal-bolus: IGlar + ILis + OADs (n=370)

PG target NA

HbA1c target ≤7.0% ≤6.5%

EOT Arm A and

B: 8.1% and 8.2%, respectively

Overall (Arm A and B): 11.2 and 12.1, respectively

Nocturnal IGlar (Arm A and B): 3.0 and 2.4, respectively

Garber n=1,006 Phase III, Bulgaria, Aged ≥18 years Confirmed: BG Basal bolus: PG target Confirmed, including

14






2012 (BEGIN®: BB T2) [25]

randomized. open-label, treat-to-target, parallel-group, non-inferiority

52 weeks

Germany, Hong Kong, Ireland, Italy, Romania, Russia, Slovakia, South Africa, Spain, Turkey, USA


HbA1c 7.0–10.0% (inclusive)

BMI ≤40.0 kg/m2

Treated with any insulin regimen for ≥3 months

<3.1 mmol/L (irrespective of symptoms)


Diurnal: occurring between 06:00 and 00:00


IDeg + IAsp (n=755) vs IGlar + IAsp (n=251)

NR

HbA1c target <7.0%

EOT††


severe (IDeg vs IGlar): 11.09 vs 13.63, respectively

Diurnal (IDeg vs IGlar): 9.28 vs 11.39, respectively

Nocturnal - confirmed (IDeg vs IGlar):1.39 vs 1.84, respectively


Bowering 2012 [26]

n=426 Randomized open-label, multinational, active-controlled, parallel RCT

48 weeks

Australia, Brazil, Canada, China, India, South Korea, Mexico

Aged 30–80 years Diagnosis of T2DM HbA1c ≥7% and

<11.0% Taking OADs without

insulin for ≥90 days


Overall: symptomatic or BG <3.9 mmol/L (regardless of symptoms)

Severe: symptomatic and requiring assistance with either BG <2.8 mmol/L, or prompt recovery after oral carbohydrate, glucagon or IV glucose

Nocturnal: any event occurring between bedtime and waking

Basal bolus: IGlar + ILis with OAD (n=212)

PG target NR


EOT 7.3%

Overall¶: 23.85 Nocturnal¶: 10.34

RWD studies

15






Home 2011 [18]

n=66,726 Non-interventional, prospective, international, observational

24 weeks



Major: symptomatic, requiring assistance and BG <3.1 mmol/L or reversal of symptoms following food intake, or glucagon or IV glucose

Nocturnal: symptomatic, occurring during sleep between bedtime after the evening insulin injection and before getting up

Basal-bolus: Insulin naïve n=1593Prior insulin user n=2512

PG target NR

HbA1c target <7.0%

EOT NR

Insulin naïve: Overall: 2.95 Minor: 2.95 Major: 0.00 Nocturnal: 0.42


Brod 2012 (GAPP2) [21]

n=3,042 Online, multinational, cross sectional survey

30 days

Canada, Denmark, Germany, Japan, UK, US

Aged ≥40 years Diagnosis of T2DM Currently on insulin

treatment (excluding premix, bolus only or pumps)

Self-treated (diurnal or nocturnal)

Basal-bolus (n=1,582)

PG target NR

HbA1c target NR

EOT NR

Overall¶: 38.9 Diurnal¶: 30.4 Nocturnal¶: 8.5

Ostenson 2014 [6]

n=2,196 Retrospective, questionnaire-based survey

4–7 weeks



treatment



Nocturnal: occurring

Basal-bolus PG target NR

HbA1c target NR

EOT NR

Non-severe: 35.4 Severe: 0.2 Nocturnal – non-

severe‡‡: 7.8

16






while in bed/asleep

Abbreviations: BID, twice daily; BG, blood glucose; BMI, body mass index; EOT, end of treatment; HbA1c, glycated hemoglobin; IAsp, insulin aspart; IDet insulin detemir; IDeg, insulin degludec; IGlar, insulin glargine; ILis, insulin lispro; IV, intravenous; NR, not reported; OAD, oral anti-diabetic drug; OD, once daily; PG, plasma glucose; QD, four times daily; RCT, randomized controlled trial; SU, sulphonylurea; T2DM, type 2 diabetes mellitus.†Event rates are reported as the mean number of episodes per patient per year unless otherwise specified.‡Hypoglycemia rates are reported in the study as episodes per patient per week. § Converted from mg/dL to mmol/L¶Hypoglycemia rates are reported in the study as episodes per 30 days. †† Calculated based on the mean change from baseline.‡‡ Calculated based on the percentage of non-severe hypoglycemic events reported during sleep.

17

Table IV: T2DM studies meeting all of the eligibility criteria (premix regimens)






RCTs

Jain 2010 [23]

n=484 Randomized, open-label, active-controlled RCT

36 weeks

Australia, Canada, France, Greece, India, Republic of Korea, Mexico, Russian Federation, Spain

Aged 30–80 years Diagnosis of T2DM Insulin naïve HbA1c 7.5–12.0% BMI ≤40 kg/m2

Taking ≥2 OADs for ≥90 days


Severe: symptomatic and requiring assistance with either BG <2.8 mmol/L or prompt recovery after oral carbohydrate, glucagon or IV glucose


Premix: Insulin lispro mix 50/50

PG target NR

HbA1c target ≤7.0% <7.0% ≤6.5%

EOT 7.58%

All events¶: 19.1

Miser 2010 [24]

n=744 Open-label, parallel-group, non-inferiority intensification sub study of the DURABLE RCT

6 months

Argentina, Australia, Brazil, Canada, Greece, Hungary, India, the Netherlands, Puerto Rico, Romania, Spain

Aged 30–80 years Diagnosis of T2DM Insulin naïve HbA1c >7.0% Treated with ≥2

OADs for 90 days Excluded if recent

history of severe hypoglycemia

Confirmed: plasma glucose ≤70 mg/dL or symptomatic


Nocturnal: events occurring after bedtime and before the morning meal or insulin dose

Premix: insulin lispro mix 75/25 (Arm A) (n=200) or insulin lispro 50/50 (Arm B) (n=174)

PG target NR

HbA1c target ≤7.0% <7.0%

EOT Arm A:

8.0% Arm B:

8.2%

Arm A (insulin lispro 75/25) Overall: 10.1 Nocturnal - confirmed:

2.5Arm B (insulin lispro 50/50) Overall: 11.1 Nocturnal - confirmed:

2.5

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Rosenstock 2010 [27]

n=677 Randomized, open-label, parallel-group RCT

52 weeks

Argentina, Brazil, Canada, Chile, Mexico, Poland, Russia, Spain, UK, USA

Aged 18–80 years Diagnosis of T2DM HbA1c >7.0% and

≤11.0% BMI ≤40 kg/m2

Taking any standard insulin regimen of 2 or 3 injections daily

Required <1.4 U insulin per kg bodyweight

Non-smoking for ≥6 months

FEV1 and DLco ≥70% Total lung capacity

≥80%

Excluded if experienced ≥2 episodes of hypoglycemia or related admission to hospital within 6 months

Mild/moderate: symptomatic and BG ≤3.5 mmol/L; symptoms in the absence of BG measurements that are relieved by carbohydrate administration; or BG >2.0 mmol/L or ≤2.7 mmol/L with/without symptoms

Severe: BG ≤2 mmol/L or symptomatic requiring assistance and BG <2.7 mmol/L. In the absence of BG measurement, symptoms to be reversed by oral carbohydrates or SC glucagon

Premix: Biphasic IAsp 70/30 (n=316)

PG target NR


EOT§

8.0%

Mild/moderate: 7.08††

Severe: 0.26‡‡

Overall: 7.32††

Buse 2011 (DURABLE) [7]

n=2,091 Randomized, open-label, multicenter, parallel-group RCT

30 months

Argentina, Australia, Brazil, Canada, Greece, Hungary, India the Netherlands, Puerto Rico, Romania,

Aged 30–80 years Diagnosis of T2DM Insulin naïve HbA1c >7.0% Taking two or more

OADs (Met, SU, pioglitazone, rosiglitazone) for ≥90 days

Excluded if history of

Severe: requiring assistance with oral carbohydrate, IV glucose or glucagon

Confirmed: plasma glucose ≤3.9 mmol/L or symptomatic

Nocturnal: occurring after bedtime and before morning

Premix: lispro mix 75/25 + OADs (n=1,045)

PG target NR


EOT 7.1%

Overall, including severe: 18.6

Severe: 0.03 Nocturnal - confirmed:

5.9

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Spain, USA severe hypoglycemia meal/insulin dose

Bowering 2012 [26]

n=426 Randomized, open-label, active-controlled, parallel RCT

48 weeks

Australia, Brazil, Canada, China, India, South Korea, Mexico

Aged 30–80 years Diagnosis of T2DM HbA1c ≥7% and

<11.0% Taking OADs without

insulin for ≥90 days


Severe: symptomatic and requiring assistance with either BG <2.8 mmol/L, or prompt recovery after oral carbohydrate, glucagon or IV glucose


Premix: insulin lispro mix 75/25

PG target NR


EOT 7.1%

Overall¶: 20.8 Nocturnal¶: 8.15

RWD studies

Berntorp 2011 [28]

n=1,154 Prospective, observational, multicenter study in routine clinical practice

6 months

Sweden Diagnosis of T2DM Insulin naïve Treating physician

decision to initiate biphasic IAsp30

Major: requiring assistance and either plasma glucose <3.1 mmol/L or reversal of symptoms upon glucose/glucagon administration

Nocturnal: symptomatic occurring after bedtime and before the morning determination of fasting plasma glucose/insulin injection

Premix: Biphasic IAsp30

PG target NR

HbA1c target ≤7%

EOT 7.2%

Overall event : 4.1 Nocturnal: 0.9

Home 2011 [18]

n=66,726 Non-interventional, prospective, international,



Major: symptomatic,

Premix: Insulin naïve n=27,591

PG target NR

Insulin naïve: Overall: 1.04 Minor: 1.04

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observational 24 weeks

requiring assistance and BG <3.1 mmol/L or reversal of symptoms following food intake, or glucagon or IV glucose

Nocturnal: symptomatic, occurring during sleep between bedtime after the evening insulin injection and before getting up

Prior insulin user n=13,318

HbA1c target <7.0%

EOT NR

Major: 0.00 Nocturnal: 0.20


Makela 2012 [29]

n=493 Non-randomized, non-interventional, prospective, open-label, observational study in primary care

26 weeks

Finland Diagnosis of T2DM Insulin naïve or

previously treated with basal-only insulin and requiring improved glycemic control as judged by the treating physician

Minor: BG <3.1 mmol/L or symptomatic with BG ≥3.1 mm/L

Major: requiring assistance to administer carbohydrate, glucagon, or IV glucose

Nocturnal: occurring after bedtime and before getting up in the morning

Premix: Biphasic IAsp30 (insulin naïve: 215. prior insulin: 342)

PG target NR

HbA1c target <7.0%

EOT Insulin

naïve: 7.1% Prior

insulin: 7.5%

Major: Insulin naïve: 0.2 Prior insulin: 0.13

Minor: Insulin naïve: 6.45 Prior insulin: 8.58

Nocturnal – non-severe Insulin naïve: 1.25 Prior insulin: 2.56

Pirags 2012 [30]

n=1,139 Prospective, observational, multicenter study

12 months

10 countries in Africa, Asia, and Europe

Aged ≥18 years Diagnosis of T2DM BMI <40 kg/m2

Prior treatment with ≥1 OADs for ≥3 months

Requirement of a premixed insulin to achieve metabolic control as judged by

Severe: requiring assistance to administer carbohydrate, glucagon, or other resuscitative actions and BG <3.9 mmol/L or prompt recovery after restoring normoglycemia

Premix: insulin lispro 25/75 or biphasic IAsp 30/70

PG target NR


EOT

Severe: 0.04

21






the treating physician

7.3%

Ostenson 2014 [6]

n=2,196 Questionnaire based survey


4–7 weeks



treatment




Other, including mixed insulin

PG target NR

HbA1c target NR

EOT NR

Non-severe§§: 27.0 Severe§§: 0.2 Nocturnal – non-

severe§§: 7.3

Abbreviations: BG, blood glucose; BMI, body mass index; DLco, diffusing capacity of the lungs for carbon monoxide; EOT, end of treatment; FEV1, forced expiratory volume in 1 second; HbA1c, glycated hemoglobin; IAsp, insulin aspart; IV, intravenous; MET, metformin; NR, not reported; OAD, oral anti-diabetic drug; OD, once daily; PG, plasma glucose; RCT, randomized controlled trial; SC, subcutaneous; SU, sulphonylurea; T2DM, type 2 diabetes mellitus.†Event rates are reported as the mean number of episodes per patient per year unless otherwise specified.§ Calculated based on the mean change from baseline.¶Hypoglycemia rates are reported in the study as episodes per 30 days. ††Hypoglycemia rates are reported in the study as episodes per patient per month. ‡‡Severe hypoglycemia rates are reported in the study as episodes per 100 patient months. §§ Calculated based on the percentage of non-severe hypoglycemic events reported during sleep.

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