Risk of pancreatic adverse events associated with the use of glucagon-like peptide-1 receptor agonist and dipeptidyl peptidase-4 inhibitor drugs: A systematic review and meta-analysis of randomized trials

Table 1 Characteristics of glucagon-like peptide-1 based agents in randomized controlled trials included in analysis of pancreatic events

Ref.	Location (No. of centers)	Year of study completion	Total duration (wk)	Duration of GLP-1 exposure (wk)	Participant disease	Arms	No. of participants	Mean age, yr (SD)	Female, n (%)
Ross et al[21]	Multi-national (84 centers in 9 countries)	2010	43	12	Type 2 diabetes	Linagliptin 2.5 mg bid	223	58.7 (9.9)	85 (38.1)
						Linagliptin 5 mg qd	224	58.4 (10.6)	103 (46.0)
						Placebo	44	59.9 (10.7)	23 (52.3)
Haak et al[22]	Multi-national (133 clinics in 14 countries)	2010	73	24	Type 2 diabetes	Linagliptin 5 mg qd	142	56.2 (10.8)	62 (43.7)
						Metformin 500 mg bid	144	52.9 (10.4)	62 (43.1)
						Metformin 1000 mg bid	147	55.2 (10.6)	69 (46.9)
						Linagliptin 2.5 mg qd + Metformin 500 mg bid	143	55.6 (11.2)	73 (49.0)
						Linagliptin 2.5 mg qd + Metformin 1000 mg bid	143	56.4 (10.7)	66 (46.2)
						Placebo	72	55.7 (11.0)	36 (50)
NCT00328172[23]	Multi-national (71 sites in 6 countries)	2007	65	12	Type 2 diabetes	Linagliptin 0.5 mg	58	58.0 (9.4)	13 (22.4)
						Linagliptin 2.5 mg	57	59.8 (10.3)	30 (52.6)
						Linagliptin 5.0 mg	55	56.6 (9.6)	24 (43.6)
						Metformin	65	53.7 (10.7)	26 (40.0)
						Placebo	67	58.6 (8.9)	34 (50.7)
Yki-Jarvinen et al[24,25]	Multi-national (169 sites in 19 countries)	2011	108	52	Type 2 diabetes	Linagliptin 5.0 mg	631	59.7 (9.9)	302 (47.9)
						Placebo	630	60.4 (10.0)	301 (47.8)
NCT00654381[26]	Japan	2010	91	12	Type 2 diabetes	Linagliptin 5.0 mg	159	60.3 (9.4)	48 (30.2)
						Linagliptin 10.0 mg	160	61.3 (10.0)	48 (30.0)
						Voglibose	162	58.5 (9.9)	47 (29.0)
						Placebo	80	59.7 (8.9)	23 (28.7)
NCT00622284[27]	Multi-national (221 sites in 16 countries)	2010	146	104	Type 2 diabetes	Linagliptin	776	59.8 (9.4)	314 (40.5)
						Glimepiride	775	59.8 (9.4)	304 (39.2)
BI Trial No: 1218.15/ U09-2519-01[28]	Multi-national (43 sites in 7 countries)	2009	61	24	Type 2 diabetes	Linagliptin 5 mg + Pioglitazone 30 mg	259	NR	NR
						Pioglitazone 30 mg + Placebo	130	NR	NR
BI Trial No: 1218.52/U11-1782-01[29]	Multi-national (101 sites in 14 countries)	2011	102	54	Type 2 diabetes	Linagliptin 2.5 mg + Metformin (500 mg and 1000 mg bid)	396	NR	NR
						Metformin 1000 mg bid	170	NR	NR
BI Trial No: 1218.63/U11-1781-02[30]	Multi-national (33 sites in 5 countries)	2011	67	24	Type 2 diabetes	Linagliptin 5 mg	162	NR	46 (28.4)
						Placebo	79	NR	30 (38.0)
BI Trial No: 1218.75/U12-3204-01[31]	Multi-center study (Black/African American patients only)	2011	55	24	Type 2 diabetes	Linagliptin 5 mg	106	NR	NR
						Placebo	120	NR	NR
BI Trial No: 1218.61/U13-3124-01[32]	Multi-national study (4 countries)	2012	123	24	Type 2 diabetes	Linagliptin 5 mg	183	NR	NR
						Placebo	89	NR	NR
BI Trial No: 1218.65/U12-2143-01[33]	Multi-national study (19 sites in 3 countries)	2012	74	24	Type 2 diabetes	Linagliptin 5 mg	205	82%(< 65 yr)	NR
						Placebo	100	83% (< 65 yr)	NR
BI Trial No: 1218.64/U13-1283-01[34]	Multi-national study (52 sites in 9 countries)	2012	117	52	Type 2 diabetes	Linagliptin 5 mg	113	NR	43 (38.1)
						Placebo (first 12 wk)/ Glimepiride (next 40 wk)	122	NR	43 (35.2)
BI Trial No: 1218.66/U12-2076-01[35]	Multi-national study (19 sites in 3 countries	2012	80	24	Type 2 diabetes	Linagliptin 5 mg	200	84.0% (< 65 yr)	NR
						Placebo	99	89.9% (< 65 yr)	NR
Rosenstock et al[36]	Multi-national study (110 sites in 13 countries)	2007	65	26	Type 2 diabetes	Alogliptin 12.5 mg	131	55.4 (9.8)	76 (58)
						Alogliptin 25 mg	129	55.9 (10.2)	85 (66)
						Placebo	130	55.0 (10.6)	68 (52)
White et al[37]	Multi-national study (898 centers in 49 countries)	2013	193	76 (median)	Type 2 diabetes	Alogliptin	2701	36.0% (≥ 65 yr)	873 (32.3)
						Placebo	2679	34.9% (≥ 65 yr)	856 (32.0)
NCT01318135[38]	Japan (58 sites)	2010	52	52	Type 2 diabetes	Alogliptin 12.5 mg qd + Glimepiride 1-6 mg qd or bid	150	38.0% (≥ 65 yr)	53 (35.3)
						Alogliptin 25 mg qd + Glimepiride 1-6 mg qd or bid	152	30.9% (≥ 65 yr)	52 (34.2)
NCT01289119[39]	Multi-national study (21 sites in 3 countries)	2011	52	16	Type 2 diabetes	Alogliptin monotherapy	92	51.6 (10.41)	37 (40.2)
						Metformin	98	53.2 (9.46)	50 (51.0)
						Metformin + Alogliptin Add-on Therapy	99	53.0 (9.88)	48 (48.5)
						Pioglitazone	63	51.8 (10.37)	24 (38.1)
						Pioglitazone + Alogliptin Add-on Therapy	61	52.6 (9.44)	33 (54.1)
						Placebo	93	53.1 (8.88)	39 (41.9)
NCT01263496[40]	Japan (58 sites)	2008	72	52	Type 2 diabetes	Alogliptin 6.25 mg qd	96	28.1 (≥ 65 yr)	26 (27.1)
						Alogliptin 12.5 mg qd	101	33.7 (≥ 6 5 yr)	29 (28.7)
						Alogliptin 25 mg qd	97	34.0 (≥ 65 yr)	22 (22.7)
						Alogliptin 50 mg qd	97	32.9 (≥ 65 yr)	29 (29.9)
						Voglibose 0.2 mg tid	83	38.6 (≥ 65 yr)	27 (32.5)
NCT00328627[41]	Multi-national study (90 sites in 19 countries)	2008	93	26	Type 2 diabetes	Alogliptin 12.5 mg + Placebo	128	53.1 (9.59)	61 (47.6)
						Alogliptin 25 mg + Placebo	129	53.7 (9.31)	79 (61.2)
						Placebo	129	55.2 (9.89)	68 (52.7)
NCT00395512[42]	Multi-national study (268 sites in 23 countries)	2008	67	26	Type 2 diabetes	Alogliptin 25 mg + Pioglitazone 30 mg	164	52.8 (11.01)	91 (55.5)
						Alogliptin 12.5 mg + Pioglitazone 30 mg	164	53.5 (11.37)	83 (50.6)
						Pioglitazone 30 mg	163	51.5 (10.72)	73 (44.8)
Kikuchi et al[43]	Japan (26 sites)	2007	52	12	Type 2 diabetes	Vildagliptin 50 mg bid + glimepiride	102	59.2 (9.8)	27 (26.5)
						Placebo + glimepiride	100	60.3 (10.1)	31 (31.0)
Lukashevich et al[44]	Multi-national study (12 countries)	2010	291	24	Type 2 diabetes	Vildagliptin 50 mg qd (moderate RI)	165	67.7 (8.8)	69 (41.8)
						Placebo (moderate RI)	129	69.7 (7.3)	49 (38.0)
						Vildagliptin 50 mg qd (severe RI)	124	64.1 (9.2)	59 (47.6)
						Placebo (severe RI)	97	64.5 (10.8)	44 (45.4)
Strain et al[45]	Multi-national study (45 centers in 7 countries)	2012	64	24	Type 2 diabetes	Vildagliptin	139	75.1 (4.3)	66 (47.5)
						Placebo	139	74.4 (4.0)	86 (61.9)
NCT00106340[46] (CLAF237A2308)	Multi-national study (402 centers in 25 countries)	2008	166	104	Type 2 diabetes	Vildagliptin 50 mg bid + Metformin	1562	57.5 (9.07)	733 (46.9)
						Glimepiride up to 6 mg qd + Metformin	1556	57.5 (9.19)	718 (46.1)
NCT00300287[47] (CLAF237A2307)	Multi-national study (69 centers in 6 countries)	2006	85	52	Type 2 diabetes	Vildagliptin 50 mg qd	156	63.27 (10.18)	63 (40.4)
						Placebo	150	62.84 (11.03)	61 (40.7)
CLAF237A1301[48]	Japan (51 centers)	2007	44	12	Type 2 diabetes	Vildagliptin 50 mg bid	188	60.3 (10.48)	67 (35.6)
						Voglibose 0.2 mg tid	192	58.0 (9.32)	62 (32.3)
CLAF237A23119[49]	United States (796 centers)	2007	53	12	Type 2 diabetes	Vildagliptin 100 mg + Metformin	1776	55.3	864 (48.6)
						Thiazolinedione + Metformin	888	56.2	467 (52.6)
NCT00110240[50] (CLAF237A2323)	Multi-national study (31 centers in 3 countries)	2006	87	24	Type 2 diabetes	Vildagliptin 50 mg bid	441	51.79 (10.13)	176 (40.0)
						Acarbose up to 100 mg tid	220	51.93 (10.34)	81 (37.0)
NCT00327015[51]	Multi-national study (211 sites in 13 countries)	2007	78	24	Type 2 diabetes	Saxagliptin 5 mg + Metformin 500 mg	320	51.95 (10.43)	155 (48.4)
						Saxagliptin 10 mg + Metformin 500 mg	323	52.08 (11.59)	177 (54.8)
						Metformin 500 mg + Placebo	328	51.83 (10.74)	165 (50.3)
Hollander et al[52]	Multi-national study (133 sites in 7 countries)	2007	82	24	Type 2 diabetes	Saxagliptin 2.5 mg + TZD	195	54.9 (9.7)	89 (45.6)
(NCT00295633)						Saxagliptin 5 mg + TZD	186	53.2 (10.6)	97 (52.2)
						Placebo + TZD	184	54.0 (10.1)	99 (53.8)
NCT00757588[53]	Multi-national study (80 sites in 10 countries)	2010	73	24	Type 2 diabetes	Saxagliptin 5 mg + Insulin	304	57.2 (9.4)	184 (60.5)
						Placebo + Insulin	151	57.3 (9.3)	83 (54.9)
Scirica et al[54]	Multi-national study (788 sites in 26 countries)	2013	156	109	Type 2 diabetes	Saxagliptin	8280	65.1 (8.5)	2768 (33.4)
						Placebo	8212	65 (8.6)	2687 (32.7)
Göke et al[55]	Multi-national study (130 sites in 11 countries)	2010	139	104	Type 2 diabetes	Saxagliptin + Metformin	428	57.5 (10.26)	216 (50.5)
						Glipizide + Metformin	430	57.59 (10.37)	198 (46.1)
NCT00316082[56]	Multi-national study (74 sites in 4 countries)	2007	74	24	Type 2 diabetes	Saxagliptin 2.5/5 mg QAM	71	54.28 (10.93)	34 (47.9)
						Saxagliptin 2.5 mg QAM	74	55.24 (10.44)	49 (66.2)
						Saxagliptin 5 mg QAM	74	54.66 (9.71)	36 (48.6)
						Saxagliptin 5 mg QPM	72	55.11 (10.35)	39 (54.2)
						Placebo	74	55.57 (10.32)	39 (52.7)
NCT00614939[57]	Multi-national study (74 sites in 14 countries)	2009	74	12	Type 2 diabetes	Saxagliptin	85	66.8 (8.3)	53 (62.4)
						Placebo	85	66.2 (9.1)	44 (51.8)
Chan et al[58,59]	Multi-national study (30 sites in 13 countries)	2006	NR	54	Type 2 diabetes	Sitagliptin 50 mg or 25 mg once daily	65	68.9 (9.8)	34 (52.3)
						Glipizide	26	65.3 (9.7)	10 (38.5)
Kojima et al[60]	Japan (Japanese Red Cross Medical Center)	2011	65	12	Type 2 diabetes	Sitagliptin	20	63.85 (12.92)	5 (0.25)
						Nateglinide	16	66.44 (9.02)	4 (0.25)
NCT00509262	Multi-national study	2011	178	54	Type 2 diabetes	Sitagliptin	211	64.2 (10.7)	80 (37.9)
(Arjona Ferreira et al[61,62])
						Glipizide	212	64.2 (9.4)	90 (42.5)
Henry et al[63,64]	Multi-national study	2010	108	54	Type 2 diabetes	Sitagliptin 100 mg/Pioglitazone 15 mg	230	NR	112 (48.7)
						Sitagliptin 100 mg/Pioglitazone 30 mg	231	NR	96 (41.6)
						Sitagliptin 100 mg/Pioglitazone 45 mg	230	NR
									95 (41.3)
						Pioglitazone 15 mg	230	NR	82 (35.7)
						Pioglitazone 30 mg	233	NR	106 (45.5)
						Pioglitazone 45 mg	230	NR	117 (50.9)
Raz et al[65,66]	Multi-national study (30 sites in 13 countries)	2007	47	30	Type 2 diabetes	Sitagliptin 100 mg	96	53.6 (9.5)	47 (48.9)
						Placebo	94	56.1 (9.5)	55 (58.5)
NCT01131182[67]	NR	2010	22	4	Type 2 diabetes	Sitagliptin	507	55.0 (11.0)	238 (46.9)
						Sulfonylurea	514	55.0 (11.0)	259 (50.4)
Goldstein et al[68,69]	Multi-national study	2006	69	54	Type 2 diabetes	Sitagliptin 50 mg bid + Metformin 500 mg bid	190	54.1 (10.0)	85 (44.7)
						Sitagliptin 50 mg bid + Metformin 1000 mg bid	182	53.3 (9.6)	105 (57.7)
						Sitagliptin 50 mg bid + Metformin 1000 mg bid (Open Label Cohort)	117	52.6 (10.0)	50 (42.7)
						Metformin 500 mg bid	182	53.4 (10.2)	93 (51.1)
						Metformin 1000 mg bid	182	53.2 (9.6)	100 (54.9)
						Placebo/Metformin 1000 mg bid	176	53.6 (10.0)	83 (47.2)
Arechavaleta et al[70,71]	Multi-national study	2009	74	30	Type 2 diabetes	Sitagliptin	516	56.3 (9.7)	232 (44.9)
						Glimepiride	519	56.2 (10.1)	240 (46.2)
NCT00086515 et al[72,73]	Multi-national study	2007	135	24	Type 2 diabetes	Sitagliptin 100 mg	464	54.4 (10.4)	205 (44.2)
						Placebo/Glipizide 5 mg	237	54.7 (9.7)	96 (40.5)
Bergenstal et al[74,75]	Multi-national study (62 sites in 3 countries)	2009	56	26	Type 2 diabetes	Exenatide once weekly	160	52.4 (10.41)	71 (44.4)
						Sitagliptin	166	52.2 (10.54)	80 (48.2)
						Pioglitazone	165	53.0 (9.92)	86 (52.1)
NCT00094757[76]	Multi-national study	2006	78	54	Type 2 diabetes	Sitagliptin 100 mg	205	54.5 (10.0)	95 (46.3)
						Sitagliptin 200 mg	206	55.4 (9.2)	102 (49.5)
						Placebo/Pioglitazone	110	55.5 (10.1)	41 (37.3)
NCT00094770[77]	Multi-national study (173 sites in 27 countries)	2006	139	104	Type 2 diabetes	Sitagliptin 100 mg	588	56.8 (9.3)	252 (42.8)
						Glipizide	584	56.6 (9.8)	226 (38.7)
NCT01137812[78,79]	Multi-national study (182 sites in 17 countries)	2012	87	52	Type 2 diabetes	Sitagliptin 100 mg	378	56.6 (9.33)	163 (43.1)
						Canagliflozin 300 mg	377	56.5 (9.62)	170 (45.1)
NCT00482729[80]	Multi-national study (209 sites in United States)	2008	74	44	Type 2 diabetes	Sitagliptin/Meformin-Fixed Dose Combination	625	49.5 (10.5)	272 (43.5)
						Metformin	621	50.0 (10.5)	266 (42.8)
Bunck et al[81]	Multi-national study (3 sites in 3 countries)	2007	154	52	Type 2 diabetes	Exenatide	36	58.4 (1.4)	13 (36.1)
						Insulin glargine	33	58.3 (1.3)	11 (33.3)
Diamant et al[82]	Multi-national study (72 sites in 7 countries)	2009	53	26	Type 2 diabetes	Exenatide	233	58.0 (10.0)	113 (48.0)
						Insulin glargine	223	58 (9.0)	100 (45.0)
Inagaki et al[83]	Japan (22 sites)	2010	61	26	Type 2 diabetes	Exenatide once weekly	215	57.07 (10.44)	73 (34.0)
						Insulin glargine once daily	212	56.44 (11.16)	64 (30.2)
Russell-Jones et al[84]	Multi-national study (106 sites in 22 countries)	2010	82	26	Type 2 diabetes	Exenatide 2 mg once weekly + Oral placebo	248	53.7 (10.91)	109 (43.9)
						Sitagliptin 100 mg/d + SC placebo	163	52.3 (11.05)	69 (42.3)
						Metformin starting at 1000 mg/d + SC placebo	246	53.7 (11.08)	92 (37.4)
						Pioglitazone starting at 30 mg/d+ SC placebo	163	55.3 (10.96)	66 (40.5)
NCT01003184[85]	34 sites in Ireland and United Kingdom	2011	91	26	Type 2 diabetes	Exenatide once weekly	111	59.2 (9.86)	40 (36.04)
						Insulin Detemir twice daily	105	57.8 (9.48)	33 (31.4)
Astrup et al[86]	Multi-national study (19 sites in 8 European countries)	2009	117	104	Type 2 diabetes	Liraglutide 1.2 mg	95	47.18 (9.72)	73 (76.8)
						Liraglutide 1.8 mg	90	45.53 (10.9)	68 (75.6)
						Liraglutide 2.4 mg	93	45.01 (11.09)	71 (76.3)
						Liraglutide 3.0 mg	93	45.91 (10.71)	70 (75.3)
						Placebo	98	45.86 (10.28)	74 (75.5)
Garber et al[87]	126 sites in United States and 12 sites in Mexico	2007	91	52	Type 2 diabetes	Liraglutide 1.2 mg	251	53.7 (11.0)	134 (53.4)
						Liraglutide 1.8 mg	247	52.0 (10.8)	126 (51.0)
						Glimepiride 8 mg	248	53.4 (10.9)	115 (46.4)
Nauck et al[88]	Multi-national study (170 sites in 21 countries)	2007	52	26	Type 2 diabetes	Once daily Liraglutide (0.6 mg)	242	56.0 (11.0)	91 (37.6)
						Once daily Liraglutide (1.2 mg)	241	57 (9.0)	111 (46.1)
						Once daily Liraglutide (1.8 mg)	242	57 (9.0)	100 (41.3)
						Once daily Glimepiride (4 mg)	244	57 (9.0)	103 (42.2)
						Placebo	122	56 (9.0)	49 (40.2)
Marre et al[89]	Multi-national study (116 sites in 21 countries)	NR	NR	26	Type 2 diabetes	Liraglutide 0.6 mg	233	55.7 (9.9)	107 (46.0)
						Liraglutide 1.2 mg	228	57.7 (9.0)	125 (55.0)
						Liraglutide 1.8 mg	234	55.6 (10.0)	110 (47.0)
						Placebo	114	54.7 (10.0)	60 (53.0)
Zinman et al[90]	90 sites in United States and Canada	2007	65	26	Type 2 diabetes	Liraglutide 1.2 mg	178	55.0 (10.0)	77 (43.0)
						Liraglutide 1.8 mg	178	55.0 (11.0)	87 (49.0)
						Placebo	177	55.0 (10.0)	67 (38.0)
Raz et al[91]	Multi-national study (53 centers in 11 countries)	2011	134	24	Type 2 diabetes	Taspoglutide 10 mg	116	NR	NR
						Taspoglutide 20 mg	129	NR	NR
						Placebo	123	NR	NR
Rosenstock et al[92]	Multi-national study (118 sites in 4 countries)	2008	56	16	Type 2 diabetes	Albiglutide 4 mg weekly	35	50.4 (10.3)	20 (57.1)
						Albiglutide 15 mg weekly	35	55.5 (10.5)	17 (48.6)
						Albiglutide 30 mg weekly	31	54.2 (9.7)	23 (74.2)
						Albiglutide 15 mg biweekly	33	52.5 (9.6)	19 (57.6)
						Albiglutide 30 mg biweekly	32	55.5 (9.9)	16 (50.0)
						Albiglutide 50 mg biweekly	35	51.1 (10.3)	16 (45.7)
						Albiglutide 50 mg monthly	35	54.1 (11.3)	18 (51.4)
						Albiglutide 100 mg monthly	34	54.4 (9.9)	15 (44.1)
						Placebo	51	54.0 (10.6)	23 (45.1)
Seino et al[93]	Multi-national study (57 centers in 4 Asian countries)	NR	NR	24	Type 2 diabetes	Lixisenatide (10 ug for 1 wk, 15 mg for 1 wk, then 20 mg-maintenance dose)	154	58.7 (10.2)	85 (55.2)
						Placebo	157	58.0 (10.1)	77 (49.0)
Umpierrez et al[94]	36 sites in United States and 3 in Puerto Rico	2008	39	16	Type 2 diabetes	LY2189265 (LY 0.5/1.0)	66	59.0 (12.0)	31 (47.0)
						LY2189265 (LY 1.0/1.0)	65	57.0 (12.0)	30 (46.0)
						LY2189265 (LY 1.0/2.0)	65	54.0 (11.0)	31 (48.0)
						Placebo	66	56.0 (12.0)	37 (56.0)

Table 2 Quality assessment of glucagon-like peptide-1 based agents in randomized controlled trials included in analysis of pancreatic events

Ref.	Sequence generation	Blinding	Allocation concealment	Was Pancreatitis an AE or SAE?	Adverse event monitoring	Arms	Withdrawal rate (%)	Loss to follow- up (%)
Ross et al[21]	Central computer based; randomization: block in a 5:5:1 ratio	Double blind	Adequate	AE	Safety and tolerability end-points were the incidence of adverse events (including adverse changes observed during physical examinations or ECGs), protocol-specified significant AEs, hypoglycemia and changes from baseline in vital signs, clinical laboratory parameters and body weight	Linagliptin 2.5 mg bid	7.2	0
						Linagliptin 5 mg qd	4.5	0
						Placebo	2.3	0
Haak et al[22]	NR	Double blind	Adequate	AE	Incidence of AEs, serious AEs, discontinuation due to AEs,12-lead ECGs, vital signs and clinical laboratory parameters. The causal relationships between study medications and AEs were evaluated by the investigators at the site	Linagliptin 5 mg qd	14.8	2.1
						Metformin 500 mg bid	11.8	2.1
						Metformin 1000 mg bid	14.3	2.7
						Linagliptin 2.5 mg qd + Metformin 500 mg bid	11.2	2.8
						Linagliptin 2.5 mg qd + Metformin 1000 mg bid	7.7	0
						Placebo	25.0	1.4
NCT00328172[23]	NR	Double blind	NR	SAE	NR	Linagliptin 0.5 mg	24.1	1.7
						Linagliptin 2.5 mg	17.5	3.5
						Linagliptin 5.0 mg	23.6	1.8
						Metformin	7.7	1.5
						Placebo	32.8	1.5
Yki-Jarvinen et al[24,25]	NR	Double blind	NR	SAE	NR	Linagliptin 5.0 mg	13.9	2.2
						Placebo	17.5	1.3
NCT00654381[26]	NR	Double blind	NR	SAE	NR	Linagliptin 5.0 mg	1.89	0
						Linagliptin 10.0 mg	3.13	0
						Voglibose	2.5	0
						Placebo	7.5	0
NCT00622284[27]	NR	Double blind	NR	SAE	NR	Linagliptin	24.4	1.4
						Glimepiride	22.1	1.7
BI Trial No: 1218.15/ U09-2519-01[28]	Randomized into 1;2 ratio to receive either placebo or linagliptin	Double blind	Adequate	SAE	Incidence and intensity of AEs, withdrawals due to AEs, physical examination, 12-lead ECG, vital signs, clinical laboratory parameters	Linagliptin 5 mg + Pioglitazone 30 mg	5.8	NR
						Pioglitazone 30 mg + Placebo	14.6	NR
BI Trial No: 1218.52/U11-1782-01[29]	NR	Double blind	NR	SAE	Safety endpoints were the incidence and intensity of AEs, withdrawals due to AEs, clinically relevant new or worsening findings in physical examination, 12-lead ECG, vital signs and clinical laboratory parameters	Linagliptin 2.5 mg + Metformin (500 mg and 1000 mg bid)	0.0	NR
						Metformin 1000 mg bid	0.6	NR
BI Trial No: 1218.63/U11-1781-02[30]	NR	Double blind	NR	SAE	Incidence and intensity of AEs, withdrawals due to AEs, physical examination, 12-lead ECG, vital signs, clinical laboratory parameters	Linagliptin 5 mg	1.23	NR
						Placebo	1.26	NR
BI Trial No: 1218.75/U12-3204-01[31]	NR	Double blind	NR	AE	Incidence and intensity of AEs, withdrawals due to AEs, clinically relevant changes from baseline in vital signs (blood pressure and pulse rate), clinically relevant new or worsening findings in 12-lead ECG as reported as AEs, clinically relevant changes from baseline in clinical laboratory assessments, cardiac and cerebrovascular events adjudicated CEC	Linagliptin 5 mg	12.3	NR
						Placebo	12.5	NR
BI Trial No: 1218.61/U13-3124-01[32]	NR	Double blind	NR	AE	Incidence and intensity of AEs, primarily based on spontaneous AEs; withdrawal due to AEs; clinically relevant new or worsening findings in physical examination reported as AEs; changes from baseline in vital signs (BP and pulse); clinically relevant new or worsening findings in 12 lead ECG reported as AEs; changes from baseline in clinical lab assessments; and hypoglycemic events	Linagliptin 5 mg	2.2	NR
						Placebo	0.0	NR
BI Trial No: 1218.65/U12-2143-01[33]	NR	Double blind	NR	SAE	Incidence and intensity of adverse events, withdrawals due to AEs, physical examination, ECGs, change from baseline in clinical lab parameters and cardiovascular events (Clinical Event Committee adjudication results)	Linagliptin 5 mg	0.98	NR
						Placebo	3.0	NR
BI Trial No: 1218.64/U13-1283-01[34]	NR	Double blind	NR	AE	Incidence and intensity of adverse events (AEs), withdrawals due to AEs, physical examination, vital signs, 12 lead ECG, change from baseline in clinical lab parameters	Linagliptin 5 mg	0.0	NR
						Placebo (first 12 wk)/ Glimepiride (next 40 wk)	1.64	NR
BI Trial No: 1218.66/U12-2076-01[35]	NR	Double blind	NR	SAE	Incidence and intensity of adverse events, withdrawals due to AEs, physical examination and vital signs, 12-lead ECG, clinical laboratory assessments	Linagliptin 5 mg	5.1	NR
						Placebo	2.0	NR
Rosenstock et al[36]	Automated interactive voice response system using a randomization schedule	Double blind	NR	SAE	During the treatment period, patients were reviewed for adverse event evaluations. Further safety assessments included clinical examination of skin and digits. Hematology, serum chemistry, vital signs, physical exam and ECG parameters were done	Alogliptin 12.5 mg	36.6	3.05
						Alogliptin 25 mg	40.3	2.33
						Placebo	57.7	1.54
White et al[37]	NR	Double blind	NR	SAE	The principal secondary safety end point was the primary composite end point with the addition of urgent revascularization due to unstable angina within 24 h after hospital admission. Additional safety end points included angioedema, hypoglycemia, pancreatitis, cancer, and the results of laboratory testing	Alogliptin	NR	NR
						Placebo	NR	NR
NCT01318135[38]	NR	Open Label	Inadequate	SAE (Pancreatic cancer only)		Alogliptin 12.5 mg qd + Glimepiride 1-6 mg qd or bid	NR	NR
						Alogliptin 25 mg qd + Glimepiride 1-6 mg qd or bid	NR	NR
NCT01289119[39]	NR	Double blind	NR	SAE	TEAE were defined as any adverse events that started on or after the date of the first dose of double-blind study drug and within 14 d after the date of the last dose of double-blind study drug	Alogliptin monotherapy	9.78	3.26
						Metformin	9.18	0
						Metformin + Alogliptin Add-on Therapy	6.06	0
						Pioglitazone	7.94	0
						Pioglitazone + Alogliptin Add-on Therapy	6.56	1.64
						Placebo	9.78	0
NCT01263496[40]	NR	Open Label	Inadequate	SAE	A TEAE is defined as an adverse event with an onset that occurs after receiving study drug and within 30 d after receiving the last dose of study drug	Alogliptin 6.25 mg qd	NR	NR
						Alogliptin 12.5 mg qd	NR	NR
						Alogliptin 25 mg qd	NR	NR
						Alogliptin 50 mg qd	NR	NR
						Voglibose 0.2 mg tid	NR	NR
NCT00328627[41]	NR	Double blind	NR	SAE	NR	Alogliptin 12.5 mg + Placebo	24.2	1.56
						Alogliptin 25 mg + Placebo	21.7	1.55
						Placebo	45.7	3.1
NCT00395512[42]	NR	Double blind	Adequate	SAE	NR	Alogliptin 25 mg + Pioglitazone 30 mg	17.1	3.05
						Alogliptin 12.5 mg + Pioglitazone 30 mg	23.2	3.05
						Pioglitazone 30 mg	22.7	3.68
Kikuchi et al[43]	Dynamic randomization	Double blind	NR	SAE	Adverse events were recorded at each visit, and these AEs were assessed for severity and suspected relationship to the study drug. Hematology, biochemistry and urinalysis were performed at each scheduled visit. All laboratory assessments were processed at a central testing to ensure consistency	Vildagliptin 50 mg bid + glimepiride	2.9	NR
						Placebo + glimepiride	4	NR
Lukashevich et al[44]	NR	Double blind	NR	SAE	All treatment emergent AEs were recorded and assessed by the investigator as to severity and potential relationship to study drug. Particular attention was paid to hepatic, infections, skin, pancreatitis as well as edema and cardiovascular safety	Vildagliptin 50 mg qd (moderate RI)	10.3	2.4
						Placebo (moderate RI)	10.9	1.6
						Vildagliptin 50 mg qd (severe RI)	13.7	1.6
						Placebo (severe RI)	13.4	2.1
Strain et al[45]	Validated automated system	Double blind	Adequate	AE	All AEs and their severity, serious AEs, and their presumed relation with the study drug were monitored and recorded at each study visit	Vildagliptin	5.8	0.72
						Placebo	5.8	0
NCT00106340[46] (CLAF237A2308)	NR	Double blind	NR	SAE	Safety assessments included monitoring and recording all AEs, SAEs and pregnancies; regular monitoring of hematology, blood chemistry, and urine (performed at a central lab); and regular assessments of vital signs, ECG, physical condition and body weight. Severity and relationship to study drug were recorded for all AEs and SAEs	Vildagliptin 50 mg bid + Metformin	36.4	0
						Glimepiride up to 6 mg qd + Metformin	38.8	0
NCT00300287[47]	NR	Double blind	NR	SAE	Safety assessments included monitoring and recording all AEs, SAEs with their severity and presumed relationship to study drug and pregnancies, recording of hypoglycemic events, the regular monitoring of hematology, blood chemistry and urine, and regular assessments of vital signs, physical condition, body weight, and ECGs	Vildagliptin 50 mg qd	14.7	0.6
						Placebo	12.7	0.7
(CLAF237A2307) CLAF237A1301[48]	NR	Double blind	NR	AE (elevated pancreatic enzymes)	Safety assessments included monitoring and recording all AEs, SAEs with their severity and presumed relationship to study drug and pregnancies, recording of hypoglycemic events, the regular monitoring of hematology, blood chemistry and urine, and regular assessments of vital signs, physical condition, body weight, and ECGs	Vildagliptin	4.8	NR
						50 mg bid Voglibose 0.2 mg tid	5.2	NR
CLAF237A23119[49]	NR	Open Label	NA	SAE	Safety assessments included monitoring and recording all AEs, SAEs with their severity and presumed relationship to study drug and pregnancies, recording of hypoglycemic events, the regular monitoring of hematology, blood chemistry and urine, and regular assessments of vital signs, physical condition, body weight, and ECGs	Vildagliptin 100 mg + Metformin	10.4	2.5
						Thiazolinedione + Metformin	11.8	2.1
NCT00110240[50] (CLAF237A2323)	NR	Double Blind	NR	SAE	Safety assessments included adverse events, hypoglycemic events and serious adverse events, physical examination, vital signs, laboratory evaluations, and ECGs	Vildagliptin 50 mg bid	9.5	1.6
						Acarbose up to 100 mg tid	12.7	1.4
NCT00327015[51]	NR	Double Blind	NR	SAE	Safety and tolerability end-points included incidence of AEs, SAEs, discontinuation due to AEs, physical and ECG examinations, vital signs and results of clinical laboratory tests	Saxagliptin 5 mg + Metformin 500 mg	28.4	6.9
						Saxagliptin 10 mg + Metformin 500 mg	28.5	7.1
						Metformin 500 mg + Placebo	33.2	6.7
Hollander et al[52] (NCT00295633)	NR	Double Blind	NR	SAE	Safety assessments included incidence of AEs, SAEs and discontinuation due to AEs, changes from baseline lab parameters; changes from baseline vital signs; and incidence of marked clinical laboratory abnormalities	Saxagliptin 2.5 mg + TZD	31.8	NR
						Saxagliptin 5 mg + TZD	36	NR
						Placebo + TZD	41.3	NR
NCT00757588[53]	Interactive voice response system	Double Blind	NR	SAE	Safety end points included AEs, hypoglycemia and weight gain	Saxagliptin 5 mg + Insulin	11.8	0.98
						Placebo + Insulin	11.3	3.31
Scirica et al[54]	Central computerized telephone or web based system	Double Blind	NR	NR (Safety End Point)	A clinical events committee comprising specialists in cardiovascular and pancreatic medicine, all of whom were unaware of the study group assignments, adjudicated	Saxagliptin	NR	NR
						Placebo	NR	NR
Goke et al[55]	NR	Double Blind	NR	SAE	Safety and tolerability assessments included AEs and SAEs, lab measurements, vital signs, physical examination and ECG testing	Saxagliptin + Metformin	61.4	0.23
						Glipizide + Metformin	65.8	0.69
NCT00316082[56]	NR	Double Blind	NR	SAE	NR	Saxagliptin 2.5/5 mg QAM	38.0	9.9
						Saxagliptin 2.5 mg QAM	44.6	9.5
						Saxagliptin 5 mg QAM	29.7	8.1
						Saxagliptin 5 mg QPM	36.1	11.1
						Placebo	35.1	8.1
NCT00614939[57]	Interactive voice response system	Double Blind	NR	SAE	Safety and tolerability assessments included AEs, SAEs, treatment-related AEs, discontinuations of randomized study medication because of AEs, deaths, AEs of special interest and hypoglycemic events	Saxagliptin	71.8	NR
						Placebo	80.0	NR
Chan et al[58,59]	Computer generated randomization schedule	Double Blind	Adequate	SAE	Assessment of safety and tolerability included evaluation of the data from physical examinations, vital signs and ECGs collected at specified study visits. All adverse experiences were rated by the investigators for intensity and relationship to study drug	Sitagliptin 50 mg or 25 mg once daily	29.2	NR
						Placebo/Glipizide	23.1	NR
Kojima et al[60]	Random allocation sequence performed centrally	Open label	NA	AE	NR	Sitagliptin	NR	NR
						Nateglinide	NR	NR
NCT00509262 (Arjona Ferreira JC et al[61,62])	Computer generated randomization schedule	Double	NR	SAE	Safety measurements included evaluation of AEs, physical exam and vital signs, and ECG. Lab safety studies included serum chemistry, hematology and urinalysis. All AEs were rated by the investigator for intensity and relationship to study drug	Sitagliptin	210
						Glipizide	212
Henry RR et al[63,64]	NR	Blind Double blind	NR	SAE	Safety and tolerability were evaluated throughout the study by physical examination, monitoring of vital signs and safety lab measurements that included serum chemistry, hematology and urinalysis. AEs were monitored and evaluated by the investigators for intensity (severity), duration, outcome and relationship to study drug	Sitagliptin 100 mg/Pioglitazone 15 mg	20.9	3.5
						Sitagliptin 100 mg/Pioglitazone 30 mg	22.9	6.9
						Sitagliptin 100 mg/Pioglitazone 45 mg	22.2	5.7
						Pioglitazone 15 mg	31.3	6.1
						Pioglitazone 30 mg	27.9	9
						Pioglitazone 45 mg	27.4	5.7
Raz I et al[65,66]	Computer generated schedule	Double blind	NR	SAE	Safety and tolerability were evaluated by physical examination, vital signs and lab measurements that included routine serum chemistry, hematology, urinalysis and pregnancy testing. AEs were monitored through the study for intensity, duration, outcome, relationship to study drug and level of severity	Sitagliptin 100 mg	17.7
								3.13
						Placebo	14.9	3.19
NCT01131182[67]	NR	Open label	NA	SAE	NR	Sitagliptin	NR	NR
						Sulfonylurea	NR	NR
Goldstein et al[68,69]	NR	Double blind	NR	SAE	Data were collected regarding AEs, physical exam, vital signs, ECGs and body weight throughout the study. All AEs were rated by investigators for intensity and relationship to study drug	Sitagliptin 50 mg bid + Metformin 500 mg bid	22.1	2.6
						Sitagliptin 50 mg bid + Metformin 1000 mg bid	22.5	5.5
						Sitagliptin 50 mg bid + Metformin 1000 mg bid (OLC)	32.5	2.6
						Metformin 500 mg bid	30.8	2.2
						Metformin 1000 mg bid	25.8	3.8
						Placebo/Metformin 1000 mg bid	34.7	5.1
Arechavaleta et al[70,71]	Concealed computer-generated allocation schedule	Double blind	Adequate	SAE	Safety and tolerability were assessed by a review of all safety parameters including adverse experiences, laboratory safety parameters, body weight and vital signs	Sitagliptin	9.3	1.7
						Glimepiride	9.8	1.7
NCT00086515 et al[72,73]	NR	Double blind	NR	SAE	Safety and tolerability were assessed throughout the study. Monitoring for adverse experiences, physical examinations, vital signs, body weight, 12-lead ECGs (read at a central reading laboratory), and safety laboratory measurements comprising routine hematology, serum chemistry, and urinalysis were performed	Sitagliptin 100 mg	10.6	0.86
						Placebo/Glipizide 5 mg	18.9	2.11
Bergenstal et al[74,75]	Interactive voice response system	Double blind	Adequate	SAE	NR	Exenatide once weekly	26.9	5
						Sitagliptin	16.9	5.4
						Pioglitazone	24.8	7.8
NCT00094757[76]	NR	Double blind	NR	SAE	Data for adverse experiences, physical examinations, vital signs, ECGs, and body weight were collected throughout the study	Sitagliptin 100 mg	25.8	1.5
						Sitagliptin 200 mg	30.1	2.4
						Placebo/Pioglitazone	27.3	5.4
NCT00094770[77]	NR	Double blind	NR	SAE	Data on adverse experiences, physical examinations, vital signs, ECGs and body weight were collected throughout the study. All adverse experiences were rated by the study site investigators for intensity and relationship to study drug. Laboratory safety evaluations included blood chemistry, haematology and urinalysis	Sitagliptin 100 mg	34.4	3.2
						Glipizide	29.5	1.7
NCT01137812[78,79]	Interactive Voice Response System/Interactive Web Response System	Double blind	Adequate	SAE	Safety evaluations included AEs, clinical laboratory tests, vital sign measurements, physical examinations, self-monitored blood glucose, 12-lead electrocardiograms, and documentation of hypoglycemic episodes	Sitagliptin 100 mg	44.4	2.1
						Canagliflozin 300 mg	32.6	1.6
NCT00482729[80]	NR	Double blind	NR	SAE	NR	Sitagliptin/Meformin-Fixed Dose Combination	34.7 (217/626)	13.7 (86/626)
						Metformin	34.9 (218/624)	10.6 (66/624)
Bunck et al[81]	NR	Open label	NA	SAE	NR	Exenatide	16.7	0
						Insulin glargine	9.1	3.03
Diamant et al[82]	Computer generated randomization sequence	Open label	NA	SAE	Safety endpoints were adverse events, clinical lab assessments, vital signs, and hypoglycemia. We defined adverse events as those occurring at or after randomization or worsening during the study	Exenatide	10.3	0.86
						Insulin glargine	6.3	0.45
Inagaki et al[83]	Computer generated randomization sequence	Open label	NA	AE	Safety profile end points included AEs and hypoglycemia	Exenatide once weekly	10.2	0.47
						Insulin glargine once daily	5.2	0
Russell-Jones et al[84]	Computer generated randomization sequence	Double blind	Adequate	SAE	Safety end points were adverse events, clinical lab assessments, vital signs, hypoglycemia and antibodies to exenatide. Treatment emergent adverse events were defined as those occurring or worsening after the first dose of study drug	Exenatide 2 mg once weekly + Oral placebo	15.3	1.6
						Sitagliptin 100 mg/d + SC placebo	14.1	2.4
						Metformin starting at 1000 mg/d + SC placebo	13.4	0.4
						Pioglitazone starting at 30 mg/d + SC placebo	1.8	1.8
NCT01003184[85]	NR	Open label	NR	SAE	NR	Exenatide once weekly	17.1	0.9
						Insulin Detemir twice daily	11.4	0
Astrup et al[86]	NR	Double blind (first 20 wk) Weeks 20-104: Open label	NR	SAE	Safety assessments included adverse events, recorded at every visit, standard lab tests and serum liraglutide antibodies. A safety committee for data surveillance was established	Liraglutide 1.2 mg	10.5	0
						Liraglutide 1.8 mg	17.8	0
						Liraglutide 2.4 mg	21.5	0
						Liraglutide 3.0 mg	11.8	0
						Placebo	19.4	0
Garber et al[87]	Telephone based or web-based systems	Double blind	Adequate	SAE	Key safety assessments were tolerability (including nausea and other gastrointestinal adverse events), serum calcitonin and hypoglycemic episodes	Liraglutide 1.2 mg	35.5	NR
						Liraglutide 1.8 mg	29.7	NR
						Glimepiride 8 mg	38.7	NR
Nauck et al[88]	Telephone based or web-based randomization systems	Double blind	Adequate	SAE	Safety variables included adverse events, vital signs, ECG, biochemical and hematology measures and subject reported hypoglycemic episodes	Once daily Liraglutide (0.6 mg)	14.0	0
						Once daily Liraglutide (1.2 mg)	18.0	0.4
						Once daily Liraglutide (1.8 mg)	21.0	0
						Once daily Glimepiride (4 mg)	14.0	0
						Placebo	39.0	0
Marre et al[89]	NR	Double blind	NR	SAE	Safety variables included hypoglycemic episodes, liraglutide antibodies, tolerability (gastrointestinal complaints) and pulse. AEs, vital signs, ECG, biochemical and hematology measures including calcitonin were also monitored	Liraglutide 0.6 mg	10.7	NR
						Liraglutide 1.2 mg	14.0	NR
						Liraglutide 1.8 mg	8.9	NR
						Placebo	27.2	NR
Zinman et al[90]	Telephone based or web-based randomization systems	Double blind	Adequate	SAE	Safety variables included AEs, vital signs, ECG, biochemical and hematology measures and subject reported hypoglycemic episodes	Liraglutide 1.2 mg	14.0	NR
						Liraglutide 1.8 mg	25.0	NR
						Placebo	32.0	NR
Raz et al[91]	NR	Double blind	NR	SAE	Safety assessments included AEs, vital signs, physical examinations, clinical lab tests, ECG and hypoglycemia	Taspoglutide 10 mg	11.2	NR
						Taspoglutide 20 mg	13.2	NR
						Placebo	3.3	NR
Rosenstock et al[92]	NR	Double blind	NR	SAE	Adverse event assessments and safety analyses were conducted throughout the study	Albiglutide 4 mg weekly	48.6	5.7
						Albiglutide 15 mg weekly	31.4	8.6
						Albiglutide 30 mg weekly	32.3	3.2
						Albiglutide 15 mg biweekly	45.5	9.1
						Albiglutide 30 mg biweekly	24.2	0
						Albiglutide 50 mg biweekly	42.9	2.9
						Albiglutide 50 mg monthly	14.3	2.9
						Albiglutide 100 mg monthly	44.1	2.9
						Placebo	23.5	0
Seino et al[93]	Interactive voice response system	Double blind	Adequate	SAE	Safety and tolerability included reported AEs and other safety information such as symptomatic hypoglycemia	Lixisenatide (10 ug for 1 wk, 15 ug for 1 wk, then 20 ug-maintenance dose)	NR	NR
						Placebo	NR	NR
Umpierrez et al[94]	Computer generated random sequence	Double blind	Adequate	SAE	Safety measures included AEs, vital signs, hypoglycemia events and lab tests	LY2189265 (LY 0.5/1.0)	12.1	1.5
						LY2189265 (LY 1.0/1.0)	10.8	1.5
						LY2189265 (LY 1.0/2.0)	13.8	1.5
						Placebo	9.1	1.5

NR: Not reported; AE: Adverse event; SAE: Serious adverse event; ECGs: Electrocardiograms; TEAE: Treatment-emergent adverse events; CEC: Clinical events committee.

Table 3 Pancreatic cancer events in randomized controlled trials of glucagon-like peptide-1 agents

Ref.	Duration of GLP-1 exposure (wk)	Arms	No. of participants	No. of cases
NCT00654381[26]	52	Linagliptin 5 mg	159	0
		Linagliptin 10 mg	160	1
		Voglibose	162	0
		Placebo	80	0
NCT00622284[27]	104	Linagliptin	776	1
		Glimepiride	775	2
BI Trial No: 1218.15/U09-2519-01[28]	24	Linagliptin 5 mg + Pioglitazone 30 mg	130	0
		Pioglitazone 30 mg + Placebo	259	1
White et al[37]	76	Alogliptin	2701	0
		Placebo	2679	0
NCT01318135[38]	52	Alogliptin 12.5 mg qd + Metformin 500 mg bid or 750 mg tid	142	1
		Metformin 500 mg bid or 750 mg tid	145	0
NCT01263496[40]	52	Alogliptin 6.25 mg qd	96	0
		Alogliptin 12.5 mg qd	101	0
		Alogliptin 25 mg qd	97	1
		Alogliptin 50 mg qd	97	0
		Voglibose 0.2 mg tid	83	0
CLAF237A23119[49]	12	Vildagliptin 100 mg + Metformin	1756	1
		Thiazolinedione + Metformin	871	NR
NCT00757588[53]	52	Saxagliptin 5 mg + Insulin	304	1
		Placebo + Insulin	151	0
Scirica et al[54]	109	Saxagliptin	8280	5
		Placebo	8212	12
NCT00316082[56]	24	Saxagliptin 2.5/5 mg QAM	71	1
		Saxagliptin 2.5 mg QAM	74	0
		Saxagliptin 5 mg QAM	74	0
		Saxagliptin 5 mg QPM	72	0
		Placebo	74	0
Chan et al[58,59]	54	Sitagliptin 50 mg or 25 mg once daily	65	1
		Placebo/Glipizide	26	0
Ferreira et al[61,62]	54	Sitagliptin	210	1
		Glipizide	212	0
Henry et al[63,64]	54	Pioglitazone 15 mg	230	0
		Pioglitazone 30 mg	233	0
		Pioglitazone 45 mg	230	0
		Sitagliptin 100 mg/Pioglitazone 15 mg	230	0
		Sitagliptin 100 mg/Pioglitazone 30 mg	231	1
		Sitagliptin 100 mg/Pioglitazone 45 mg	230	0
Raz et al[65,66]	30	Sitagliptin 100 mg	96	0
		Placebo	94	1
Goldstein et al[68,69]	104	Metformin 500 mg bid	182	0
		Metformin 1000 mg bid	182	0
		Sitagliptin 50 mg bid + Metformin 500 mg bid	190	0
		Sitagliptin 50 mg bid + Metformin 1000 mg bid	182	0
		Sitagliptin 50 mg bid + Metformin 1000 mg bid	117	0
		Placebo/Metformin 1000 mg bid	176	1
Arechavaleta et al[70,71]	30	Sitagliptin	516	1
		Glimepiride	518	0
Charbonnel et al[72,73]	104	Sitagliptin 100 mg	464	1
		Placebo/Glipizide 5 mg	237	0
NCT00094757[76]	54	Sitagliptin 100 mg	205	0
		Sitagliptin 200 mg	206	0
		Placebo/Pioglitazone	110	1

GLP-1: Glucagon-like peptide-1.