Supplementary Material

Table S1.1: Search strategy for the systematic literature review - Database: Ovid MEDLINE(R) <1946 to January Week 3 2016>

Database: Ovid MEDLINE(R) <1946 to January Week 3 2016>
1 / exp Diabetes Mellitus, Type 2/
2 / (NIDDM or T2DM or T2D or MODY).tw,ot.
3 / (((late or adult$ or matur$ or slow or stabl$) adj3 onset) and diabet$).ab,ti.
4 / ((typ$ 2 or typ$ II) adj3 diabet$).tw,ot.
5 / or/1-4
6 / (Alogliptin or Vipidia or Nesina or Sitagliptin or Januvia or Saxagliptin or Onglyza or Vildagliptin or Galvus or Linagliptin or Trajenta or Tradjenta or Trazenta).af.
7 / exp Sulfonylurea Compounds/
8 / (sulfonylurea$ or sulphonylurea$).tw,ot.
9 / exp Glyburide/
10 / (Acetohexamid$ or Carbutamid$ or Chlorpropamid$ or Tolbutamid$ or Tolazamid$ or Glipizid$ or Gliclazid$ or Glibenclamid$ or Glyburid$ or Gliquidon$ or Glyclopyramid$ or Glimepirid$ or Meglitinid$ or Repaglinid$ or Nateglinid$ or Glynase$).tw,ot.
11 / or/7-10 (25090)
12 / exp Metformin/ or Metformin.tw,ot.
13 / and/6,11-12
14 / 5 and 13
15 / (animals not (animals and humans)).sh.
16 / 14 not 15
17 / limit 16 to english language

Also searched Databases: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations January 29, 2016 and Ovid MEDLINE(R) Daily Update January 29, 2016

Table S1.2: Search strategy for the systematic literature review - Database: Ovid Embase <1974 to 2016 January 29>

Database: Ovid Embase <1974 to 2016 January 29> /
1 / exp non insulin dependent diabetes mellitus/
2 / (NIDDM or T2DM or T2D or MODY).tw,ot.
3 / (((late or adult$ or matur$ or slow or stabl$) adj3 onset) and diabet$).ab,ti.
4 / ((typ$ 2 or typ$ II) adj3 diabet$).tw,ot.
5 / or/1-4
6 / (Alogliptin or Vipidia or Nesina or Sitagliptin or Januvia or Saxagliptin or Onglyza or Vildagliptin or Galvus or Linagliptin or Trajenta or Tradjenta or Trazenta).af.
7 / exp sulfonylurea derivative/
8 / (sulfonylurea$ or sulphonylurea$).tw,ot.
9 / *glibenclamide/
10 / (Acetohexamid$ or Carbutamid$ or Chlorpropamid$ or Tolbutamid$ or Tolazamid$ or Glipizid$ or Gliclazid$ or Glibenclamid$ or Glyburid$ or Gliquidon$ or Glyclopyramid$ or Glimepirid$ or Meglitinid$ or Repaglinid$ or Nateglinid$ or Glynase$).tw,ot.
11 / or/7-10
12 / *metformin/ or Metformin.tw,ot.
13 / and/6,11-12
14 / 5 and 13
15 / limit 14 to (human and english language)

Table S1.3: Search strategy for the systematic literature review - The Cochrane Library - searched: 31/01/16

Database: The Cochrane Library - searched: 31/01/16
#1 / MeSH descriptor: [Diabetes Mellitus, Type 2] explode all trees
#2 / diabetes mellitus type 2:ti,ab,kw
#3 / #1 or #2
#4 / (Alogliptin or Vipidia or Nesina or Sitagliptin or Januvia or Saxagliptin or Onglyza or Vildagliptin or Galvus or Linagliptin or Trajenta or Tradjenta or Trazenta):ti,ab,kw
#5 / MeSH descriptor: [Sulfonylurea Compounds] explode all trees
#6 / (sulfonylurea* or sulphonylurea*):ti,ab,kw
#7 / (Acetohexamie or Carbutamide or Chlorpropamide or Tolbutamide or Tolazamide or Glipizide or Gliclazide or Glibenclamide or Glyburide or Gliquidone or Glyclopyramide or Glimepiride or Glynase):ti,ab,kw
#8 / #5 or #6 or #7
#9 / metformin:ti,ab,kw
#10 / MeSH descriptor: [Metformin] explode all trees
#11 / #4 and #8 and #9
#12 / #3 and #11

Table S1.4: Search strategy for the systematic literature review – Web of Science – searched: 31/01/16

Database: Web of Science – searched: 31/01/16
TOPIC: (Alogliptin or Vipidia or Nesina or Sitagliptin or Januvia or Saxagliptin or Onglyza or Vildagliptin or Galvus or Linagliptin or Trajenta or Tradjenta or Trazenta) AND TOPIC: (sulfonylurea* or sulphonylurea* or Acetohexamie or Carbutamide or Chlorpropamide or Tolbutamide or Tolazamide or Glipizide or Gliclazide or Glibenclamide or Glyburide or Gliquidone or Glyclopyramide or Glimepiride or Glynase)
AND TOPIC: (metformin)

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Table S2: Quality assessment results for RCTs

Study / Was randomisation carried out appropriately? / Was the concealment of treatment allocation adequate? / Were the care providers, and participants blind to treatment allocation?* / Were the groups similar at the outset of the study in terms of prognostic factors? / No unexpected imbalances in drop-outs between groups? (YES=no unexpected imbalances) / Is there any evidence to suggest that all key outcomes have been reported? / Did the analysis include an adequate intention-to-treat analysis? If so, was this appropriate and were appropriate methods used to account for missing data? / Overall quality assessment = Good, Moderate or Poor* /
Chen et al., 2015 [1]b / NC / NC / NO / YES / NC / YES / NC / Poor
EXAMINE Heller et al., 2016 [2]a / YES / YES / YES / YES / NC / YES / NC / Moderate
Hermansen et al., 2007 [3]a / YES / YES / YES / YES / NC / YES / YES / Moderate
Hong et al., 2015 [4]b / YES / NC / NO / YES / NC / YES / NC / Poor
Lukashevich et al., 2014 [5]a / YES / YES / YES / YES / YES / YES / YES / Good
Moses et al., 2014 [6]a / YES / YES / YES / YES / YES / YES / YES / Good
NCT01590771. Record accessed March 2016 [7]a / YES / YES / YES / YES / NC / YES / NC / Moderate
Owens et al., 2011 [8]a / YES / YES / YES / YES / YES / YES / YES / Good
NC = not clear
*All YES = Good; YES and max of two NC = Moderate; Any NO = Poor
a Studies included in the main analysis group
b Studies excluded from the main analysis group due to being non-FAS (ITT) studies
Source: National Institute for Health and Clinical Excellence (NICE). STA specification for manufacturer/sponsor submission of evidence. June 2012. Adapted from Centre for Reviews and Dissemination (2008) Systematic reviews. CRD’s guidance for undertaking reviews in health care. York: Centre for Reviews and Dissemination.

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Table S3: Study design and patient characteristics of studies included in the NMA

Study / Study design characteristics / Patient baseline characteristics /
Study Design / Patient population / Duration (wks) / Patient No.s (ITT) / Countries / Treatment arms in the NMA (dose/day) / Mean age (yrs) / % Male / %
Caucasian / Mean duration of T2DM (yrs) / Baseline HbA1c /
Chen et al., 2015a [1] / Prospective, randomised, open label study / Chinese patients with T2DM inadequately controlled on metformin + SU / 24 / 73 / China / Saxagliptin 5mg
Vildagliptin 50mg
Met
SU (gliclazide) / 62.9 / NR / 0.0 / 7.0 / 8.35
EXAMINE Heller et al., 2016 [2] / Post-hoc subgroup analysis from a multicentre, randomised, double-blind trial / T2DM inadequately controlled on metformin + SU / 40 monthsc / 1398 / Multiple: As, Au, C, E (inc. UK), N and S America / Alogliptin 25mg
Met
SU / 59.8 / 70.9 / 69.12 / 8.5 / 8.15
Hermansen et al., 2007b [3] / Multinational, randomised, double-blind, parallel-group study / T2DM inadequately controlled on metformin + SU / 24 / 441 / Not known / Sitagliptin 100mg
Met
SU (glimepiride) / 56.6 / 52.6 / 64.7 / 9.3 / 8.27
Hong et al., 2015a [4] / randomised, single centre study / Korean patients with T2DM inadequately controlled on metformin + SU / 24 / 344 / Korea / Vildagliptin 100mg
Met
SU (glimepiride or gliclazide) / 59.0 / 60.5 / 0.0 / 12.9 / 8.60
Lukashevich et al., 2014 [5] / Multicentre, double-blind, placebo-controlled study / T2DM inadequately controlled on metformin + SU / 24 / 318 / Multiple: As, Au, E, and M / Vildagliptin 100mg
Met
SU (glimepiride) / 55.3 / 50.6 / 21.5 / 7.1 / 8.75
Moses et al., 2014 [6] / Multicentre, randomised, parallel-group, double-blind study / T2DM inadequately controlled on metformin + SU / 24 / 257 / Multiple: As, Au, C, UK / Saxagliptin 5mg
Met
SU / 57.2 / 62.0 / 45.7 / NR / 8.37
NCT01590771. Record accessed March 2016 [7] / Multicentre, randomised, double-blind, placebo-controlled study / T2DM inadequately controlled on SU ± metformin / 24 / 223 / China / Sitagliptin 100mg
Met
SU / 57.5 / 47.0 / 0.0 / NR / 8.61
Owens et al., 2011 [8] / randomised, double-blind, parallel-group study, placebo-controlled, multi-centre / T2DM inadequately controlled on metformin + SU / 24 / 1055 / Multiple: As, E (inc. UK), C, and S America / Linagliptin 5mg
Met
SU / 58.3 / 46.8 / 47.5 / NR / 8.15
Abbreviations: As = Asia; Au = Australia; C = Canada; E = Europe; N = North; S = South; UK = United Kingdom; NR = not reported; ITT = intention-to-treat; Met = metformin; SU = sulfonylurea; T2DM = type 2 diabetes mellitus
a These studies were not included in the main group analysis due to the analysis being carried out per protocol
b The study by Hermansen et al.,[3] contained an additional treatment arm consisting of sitagliptin + SU (dual therapy) that was excluded as dual therapy was outside of the decision-focused scope of the NMA
c The EXAMINE trial study duration was 40 months. However, efficacy assessments for the EXAMINE trial were carried out at 6 months (26 weeks).[2]

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Table S4: Raw data: Baseline and mean change from baseline HbA1c among randomised clinical trials included in the triple therapy NMA for add-on to metformin + SU

Author / Drug (added to met +SU) / Number included / Baseline HbA1c (%) / Mean change in HbA1c (%) / Standard error
Arm 1 / Arm 2 / Arm 1 / Arm 2 / Arm 1 / Arm 2 / Arm 1 / Arm 2 / Arm 1 / Arm 2
Chen / Vilda / Saxa / 36 / 37 / 8.35 / 8.35 / 1.07 / 1.22 / 0.06 / 0.065759595
EXAMINE / Pbo / Alo / 606 / 604 / 8.16 / 8.15 / -0.16 / -0.78 / 0.05 / 0.05
Hermansen* / Pbo / Sita / 105-109 / 115 / 8.26 / 8.27 / 0.30 / -0.59 / 0.078180275 / 0.072400968
Hong / SU dose increase** / Vilda / 152 / 157 / 8.60 / 8.60 / -0.5 / -1.2 / 0.075918657 / 0.092191546
Lukashevich / Pbo / Vilda / 160 / 152 / 8.80 / 8.75 / -0.25 / -1.01 / 0.0866 / 0.085790734
Moses / Pbo / Saxa / 127 / 127 / 8.17 / 8.37 / -0.08 / -0.74 / 0.075796982 / 0.063706757
NCT01590771 / Pbo / Sita / 112 / 111 / 8.48 / 8.61 / -0.45 / -0.86 / 0.075697677 / 0.078559652
Owens / Pbo / Lina / 262 / 778 / 8.14 / 8.15 / -0.1 / -0.72 / 0.05 / 0.03
* Hermansen et al., was a four-arm study, but we only report the two triple therapy arms (placebo + met + SU [Arm 1] and sitagliptin + me t + SU [Arm 2] as the dual therapy arms fall outside the scope of the decision-focused NMA
** Hong et al., was an open-label randomised study; thus there was no placebo
Abbreviations: Pbo = placebo; Alo = alogliptin; Vilda = vildagliptin; Saxa = saxagliptin; Lina = linagliptin; Sita = sitagliptin

Table S5: Raw data: Mean change from baseline weight (kg) among randomised clinical trials included in the triple therapy NMA for add-on to metformin + SU

Author / Drug (added to met + SU) / Number included / Baseline Weight (kg) / Mean change in Weight (kg) / Standard error
Arm 1 / Arm 2 / Arm 1 / Arm 2 / Arm 1 / Arm 2 / Arm 1 / Arm 2 / Arm 1 / Arm 2
EXAMINE / Pbo / Alo / 612 / 610 / 80.62 / 80.40 / 0.61 / 0.75 / 0.144713 / 0.147379
Hermansen* / Pbo / Sita / 113 / 116 / 86.7 / 87.2 / -0.7 / 0.4 / 0.32806 / 0.25242
Lukashevich / Pbo / Vilda / 160 / 152 / 72.4 / 73.1 / -0.1 / 0.5 / 0.247724 / 0.249287
Moses / Pbo / Saxa / 128 / 129 / 80.3 / 82.4 / -0.6 / 0.2 / 0.185616 / 0.193699
Owens / Pbo / Lina / 222 / 714 / 77.4 / 76.6 / -0.06 / 0.27 / 0.16 / 0.09
* Hermansen et al., was a four-arm study, but we only report the two triple therapy arms (placebo + met + SU [Arm 1] and sitagliptin+ met + SU [Arm 2] as the dual therapy arms fall outside the scope of the decision-focused NMA
Pbo = placebo; Alo = alogliptin; Vilda = vildagliptin; Saxa = saxagliptin; Lina = linagliptin; Sita = sitagliptin

Table S6: Raw data: Mean change from baseline FPG among randomised clinical trials included in the triple therapy NMA for add-on to metformin + SU

Author / Drug (added to met + SU) / Number included / Baseline FPG (mg/dL) / Mean change in FPG (mg/dL) / Standard error /
Arm 1 / Arm 2 / Arm 1 / Arm 2 / Arm 1 / Arm 2 / Arm 1 / Arm 2 / Arm 1 / Arm 2 /
Heller et al., 2016 [2] / Pbo / Alo / 595 / 598 / 155.56 / 156.73 / 9.89 / -6.49 / 2.06 / 2.05
Hermansen et al., 2007 [3]* / Pbo / Sita / 105-109 / 115 / 178.4 / 179.4 / 12.9 / -7.8 / 3.984672 / 3.908355
Lukashevich et al., 2014 [5] / Pbo / Vilda / 160 / 158 / 171.0 / 167.4 / 0.36 / -19.98 / 4.600844 / 4.629872
Moses et al., 2014 [6] / Pbo / Saxa / 128 / 129 / 154.8 / 162.0 / 2.7 / -5.22 / 3.591635 / 2.824097
NCT01590771. Record accessed March 2016 [7] / Pbo / Sita / 114 / 113 / 179.8 / 181.5 / -5.7 / -22.2 / 3.129448 / 3.150128
Owens et al., 2011 [8] / Pbo / Lina / 262 / 778 / 162.0 / 158.4 / 7.2 / -5.4 / 1.8 / 1.8
* Hermansen et al.,(2007)[3] was a four-arm study, but we only report the two triple therapy arms (placebo + met + SU [Arm 1] and sitagliptin + met + SU [Arm 2] as the dual therapy arms fall outside the scope of the decision-focused NMA
Abbreviations: Pbo = placebo; Alo = alogliptin; Vilda = vildagliptin; Saxa = saxagliptin; Lina = linagliptin; Sita = sitagliptin

Table S7: Raw data: Number and proportion of individuals experiencing at least one hypoglycaemic episode (any severity/type) among RCTs included in the triple therapy NMA for add-on to metformin + SU

Author / Drug (added to met + SU) / No. of patients (Safety set) / N (%) patients experiencing ≥1 hypoglycaemic event
Arm 1 / Arm 2 / Arm 1 / Arm 2 / Arm 1 / Arm 2
Heller et al., 2016 [2] / Pbo / Alo / 705 / 693 / 29 (4.1) / 44 (6.4)
Hermansen et al., 2007 [3]* / Pbo / Sita / 113 / 116 / 1 (0.9) / 19 (16.4)
Lukashevich et al., 2014 [5] / Pbo / Vilda / 160 / 157 / 3 (1.9) / 8 (5.1)
Moses et al., 2014 [6] / Pbo / Saxa / 128 / 129 / 8 (6.3) / 13 (10.1)
Owens et al., 2011 [8] / Pbo / Lina / 263 / 792 / 39 (14.8) / 180 (22.7)
* Hermansen et al.,(2007)[3] was a four-arm study, but we only report the two triple therapy arms (placebo + met + SU [Arm 1] and sitagliptin + met + SU [Arm 2] as the dual therapy arms fall outside the scope of the decision-focused NMA
Abbreviations: Pbo = placebo; Alo = alogliptin; Vilda = vildagliptin; Saxa = saxagliptin; Sita = sitagliptin

Table S8: Raw data: Adverse events leading to study discontinuation among RCTs included in the triple therapy NMA for add-on to metformin + SU