Supplementary materials
FIGURES
Figure 1S – Trial flow summary.
1 2 Figure 2S – Funnel plot for 24-week HbA1c in placebo-controlled trials.
3 Table 1S – Quality assessment of trials included in the meta-analysis.
Description of First author ID code Age Diabetes BMI Trial duration Randomization Allocation Blinding Dropouts ITT (year)* duration (weeks) (years) (years) (Kg/m2) Albiglutide Ahrén 2014 (1) NCT00838903 54 6 33 104 NA A A A YES Rosenstock NCT00976391 55 11 NR 26 NA NA OL A YES 2014 (2) NCT01733758 NCT01733758 58 NR NR 26 NR NR A NR YES (3) Nauck 2016 (4) NCT00849017 53 4 34 52 A A A A YES Home 2015 (5) NCT00839527 55 9 32 52 A A OL A YES Dulaglutide Giorgino 2015 (6) NCT01075282 57 9 31 78 A A OL A YES Blonde 2015 (7) NCT01191268 60 12 33 52 A A OL A YES Umpierrez 2014 (8) NCT01126580 56 3 33 52 A A A A YES Weinstock 2015 (9) NCT00734474 54 7 31 104 A A OL A YES NCT01149421 (10) NCT01149421 56 8 33 26 NA NA A A YES Wysham 2014 (11) NCT01064687 56 9 33 26 NA NA A A YES NCT01644500 (12) NCT01644500 53 NR NR 26 NR NR A NR YES NCT01648582 (13) NCT01648582 55 NR NR 52 NA NA OL A YES NCT01769378 (14) NCT01769378 58 NR NR 24 NA NA A A YES Exenatide 4 Nauck 2007 (15) NCT00082407 58 10 30 52 A A OL A YES Jaiswal 2015 (16) NCT00855439 52 7 36 78 NA NA OL A YES Derosa 2011 (17) NR 55 NR 28 52 A A OL A YES Derosa 2010 (18) NR 56 NR 29 52 A A A A YES Liang 2013 (19) NCT01435980 51 7 30 52 A NA OL A YES Bunck 2009 (20) NCT00097500 58 5 31 64 A NA OL A YES Sathyanarayan a 2011 (21) NCT01432405 52 NR 32 52 A NA OL A NO Gallwitz 2012 (22) NCT00359762 56 6 32 208 A A OL A YES Xu 2015 (23) NCT01147627 50 NR 26 48 A A OL NA YES Gudipaty 2014 (24) NCT00775684 54 4 32 26 NA NA OL A NO Barnett 2007 (25) NCT00099619 55 7 31 16 A A OL A YES Bergenstal 2009 (26) NCT00097877 52 9 34 24 A A OL A YES Davies 2009 (27) NCT00360334 56 9 34 26 NA NA OL A YES Davis 2007 (28) NCT00099333 53 11 34 16 A A OL NA YES Diamant 2014 (29) NCT00960661 59 11 33 30 A NA OL A YES Gallwitz 2011 (30) NCT00434954 57 5 33 26 A NA OL A YES Gurkan 2014 (31) NR 53 7 35 26 A A OL A YES Heine 2005 NCT00082381 59 9 31 26 A A OL A YES
5 (32) NCT00313001 (33) NCT00313001 53 NR 34 24 A A OL A YES Yuan 2012 (34) NR 57 NR 30 26 NA NA OL A YES Apovian 2010 (35) NR 55 5 34 24 A A A A YES Buse 2004 (36) NCT00039026 55 6 34 30 A NA A A YES DeFronzo 2005 (37) NCT00039013 53 6 34 30 A NA A A YES Gao 2009 (38) NCT00324363 54 8 26 16 A A A A YES Kadowaki 2012 (39) NCT00577824 58 NR NR 24 NA NA OL A YES Kendall 2005 (40) NCT00035984 55 9 34 30 NA NA A A YES Liutkus 2010 (41) NCT00603239 54 6 34 26 A A A A YES Moretto 2008 (42) NCT00381342 54 1 32 24 A A A A YES NCT00375492 (43) NCT00375492 55 NR NR 24 NR NR A A YES Wu 2011 (44) NR 55 6 26 16 NA NA A A YES NCT00667732 (45) NCT00667732 NR NR NR 24 NR NR A A YES NCT00701935 (46) NCT00701935 58 NR NR 26 NA NA NA A YES Derosa 2013 (47) NR 57 1 32 52 A NA NA A YES Buse 2011 (48) NCT00765817 59 12 33 30 A A A A YES DeFronzo 2010 (49) NCT00135330 56 5 33 20 A NA OL A YES Zinman 2007 (50) NCT00099320 56 7 34 16 A A A A YES Exenatide Once-Weekly Diamant 2012 NCT00641056 58 8 32 84 A A OL A YES 6 (51) Davies 2013 (52) NCT01003184 58 7 34 26 A A OL A YES Inagaki 2012 (53) NCT00935532 57 9 26 52 A A OL A YES Kim 2007 (54) NCT00103935 53 4 36 16 A A A A YES NCT01652729 (55) NCT01652729 54 NR NR 28 NA NA OL A YES Bergenstal 2010 (56) NCT00637273 52 6 32 26 A A A A YES Russell-Jones 2012 (57) NCT00676338 54 3 31 26 A A A A YES Frias 2016 (58) NCT02229396 54 7 33 28 A A A A YES Liraglutide Gouch 2015 (59) NCT01336023 55 7 31 52 A A OL A YES Pratley 2011 (60) NCT00700817 55 6 33 52 A A OL A YES Garber 2011 (61) NCT00294723 53 5 33 104 A A A A YES Davies 2016 (62) NCT01272232 55 8 37 56 A A A A YES Retnakaran 2014 (63) NCT01270789 58 2 30 48 A A A A YES Bailey 2016 (64) NCT01907854 56 7 32 26 A A A A YES Charbonnel 2013 (65) NCT01296412 57 8 33 26 A A OL A YES Zang 2016 (66) NCT02008682 52 5 27 26 A A OL A YES D'Alessio 2015 (67) NCT01117350 57 8 32 24 A A OL NA YES Mathieu 2014 (68) NCT01388361 61 12 32 28 A NA OL A YES Davies 2016 NCT01620489 67 15 34 26 A A A A YES
7 (69) De Wit 2014 (70) NCT01392898 58 NR 33 52 A A OL A YES Lind 2015 (71) NCT02113332 64 17 34 24 A A A A YES Marre 2009 (72) NCT00318422 56 7 30 26 NA NA A A YES Nauck 2009 (73) NCT00318461 57 7 31 104 A A A A YES NCT01617434 (74) NCT01617434 58 NR 32 26 NA NA A A YES Russell-Jones 2009 (75) NCT00331851 57 9 30 26 A A A A YES Vanderheiden 2016 (76) NCT01505673 54 17 41 26 NA NA NA A YES Zinman 2009 (77) NCT00333151 55 9 34 26 A A A A YES NCT00614120 (78) NCT00614120 53 7 26 16 NR NR A A YES Lixisenatide Bolli 2014 (79) NCT00763451 56 6 33 24 A A A A YES NCT00976937 (80) NCT00976937 43 4 37 24 NA NA A A YES Ahrén 2013 (81) NCT00712673 55 6 33 24 NA A NA A YES NCT01798706 (82) NCT01798706 74 14 30 24 NA NA A A YES Pinget 2013 (83) NCT00763815 56 8 34 24 A A A A YES Riddle 2013 (84) NCT00715624 57 12 32 24 A A A A YES Seino 2015 (85) NCT00866658 58 14 25 24 A A A A YES Yu Pan 2014 (86) NCT01169779 55 7 27 24 A A A A YES
8 Rosenstock 2013 (87) NCT00707031 58 7 34 26 A A OL A YES Riddle 2013 (88) NCT00975286 56 9 32 24 A A A A YES Rosenstock 2014 (89) NCT00713830 57 9 30 24 A A A A YES
Head-to-head comparisons Albiglutide Pratley 2014 NCT01128894 55 8 33 32 A A OL A YES (90) Dulaglutide Dungan 2014 (91) NCT01624259 57 7 34 26 A A OL A YES Wysham 2014 (11) NCT01064687 56 9 33 26 NA NA A A YES Liraglutide Buse 2009 NCT01029882 57 8 26 A A OL A YES (92) Exenatide LAR Buse 2013 (93) NCT01029886 57 8 32 26 A A OL A YES Blevins 2011 NCT00877890 55 7 33 24 A A OL A YES (94) Drucker 2008 (95) NCT00308139 55 6 35 30 A A OL A YES Ji 2013 (96) NCT00917267 55 8 27 26 A A OL A YES
*For reference: see Web appendix. ITT: Intention To Treat; A: Adequately described; NA: Not Adequately described; OL: Open Label; NR: Not
reported.
9 Table 2S – 52-week HbA1c (median [Interquartile]) in placebo- and active comparator- controlled trials.
Comparator # trials HbA1c p Exenatide b.i.d Placebo 3 -0.76[-1.12;-0.40] <0.001 Thiazolidinediones 1 -0.60[-0.83;-0.36] <0.001 Sulphonylureas 3 0.07[-0.11;0.25] 0.47 Insulin 4 0.04[-0.08;0.17] 0.52 Liraglutide Placebo 2 -0.57[-0.86;-0.28] <0.001 DPP-4 Inhibitors 1 -0.70[-0.85;-0.55] <0.001 Sulphonylureas 1 -0.70[-0.88;-0.52] <0.001 Insulin 1 0.20[0.07;0.33] 0.003 Lixisenatide Placebo 1 -0.40[-0.56;-0.23] <0.001 Exenatide OW Insulin 1 -0.20[-0.39;-0.01] 0.042 Albiglutide Placebo 3 -0.90[-1.00;-0.78] <0.001 DPP-4 Inhibitors 1 -0.30[-0.46;-0.14] <0.001 Thiazolidinediones 3 0.10[-0.05;0.25] 0.19 Sulphonylureas 4 -0.40[-0.56;-0.23] <0.001 Dulaglutide DPP-4 Inhibitors 1 -0.70[-0.90;-0.50] <0.001 Metformin 1 -0.20[-0.34;-0.06] 0.007 Insulin 2 -0.40[-0. 95;-0.20] <0.001 Exenatide bid 1 -0.60[-0.82;-0.38] <0.001 bid.: bis in die; OW: Once-Weekly.
10 Table 3S – Metaregression analysis to explore relationship between 24-week HbA1c and possible moderators at baseline.
Moderator (mean) Slope p Exenatide b.i.d Age (years) 0.00[-0.03;0.03] 0.95 Duration of diabetes (years) 0.00[-0.03;0.04] 0.86 HbA1c (%) 0.03[-0.07;0.12] 0.61 Fasting plasma glucose (mg/dl) 0.13 [0.06;0.20] <0.001 Body Mass Index (Kg/m2) -0.01[-0.03;0.02] 0.62 Liraglutide Age (years) -0.02[-0.08;0.03] 0.41 Duration of diabetes (years) -0.05[-0.09;-0.01] 0.001 HbA1c (%) -0.08[-0.18;0.03] 0.14 Fasting plasma glucose (mg/dl) -0.06[-0.15;0.04] 0.26 Body Mass Index (Kg/m2) -0.05[-0.08;-0.01] 0.001
11 Table 4S – Efficacy in subgroups on the basis of the patients’ characteristics.
Comparat Older vs Female Caucasian vs Higher vs Higher vs Longer vs shorter First author (year)* or Younger vs male non-caucasian lower BMI lower HbA1c duration DM
EXENATIDE Buse 2004 (36) Placebo Buse 2011 (48) Placebo Glimepirid Gallwitz 2012 (30) e Xu 2015 (23) Insulin LIXISENATIDE Pinget 2013 (83) Placebo LIRAGLUTIDE Marre 2009 (72) Placebo Zinman 2009 (77) Placebo Placebo/S Nauck 2009 (73) U Placebo/In Russel-Jones 2009 (75) s. Garber 2011 (60) SU NCT00614120 (78) SU ** Pratley 2011 (60) DPP-4i EXENATIDE OW Pioglitazon Bergenstal 2010 (56) e Placebo/S Frias 2016 (58) GLT2i ALBIGLUTIDE Nauck 2016 (4) Placebo NCT01733758 (3) Placebo Placebo/Pi Home 2015 (5) og. Pbo/SU/DP Ahren 2014 (1) P4i Rosenstock 2014 (2) Lispro *See Web-Appendix; **All Asians. White cell: not explored; red cell: lower efficacy; green cell: higher efficacy; yellow cell: equal efficacy. DM:
Diabetes Mellitus; Pbo: Placebo; SU: Sulfonylureas; DPP4i: Dypeptidyl-Peptidase-4 inhibitors; Piog.: Pioglitazone.
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