Efficacy and Safety of DPP-4 Inhibitors and Metformin Combinations in Type 2 Diabetes: A Systematic Literature Review and Network Meta-Analysis

Figures & data

Table 1 Baseline Characteristics of the Included Studies

Study no.	Author(s) and year	No. of Arms	Intervention	Comparator	I (n)	C (n)	N (study)	Median follow-up	Age (years)		Gender
									Mean (SD) or median (range)		Male		Female
									I	C	I	C	I	C
1	Yang et al,^Citation18 2011	2	Saxagliptin + Met	Met	283	287	570	Week 24 study	53.8 (10.4)	54.4 (10.1)	136 (48.1)	139 (48.4)	147 (51.9)	148 (51.6)
2	Pfützner et al,^Citation19 2011	4	Arm 1: saxagliptin 5 mg + 500 mg Met; Arm 2: saxagliptin 10 mg + 500 mg Met	Arm 3: saxagliptin 10 mg + placebo; Arm 4: 500 mg Met + placebo	Arm 1: 320; Arm 2: 323	Arm 3: 335; Arm 4: 328	1306	76 week study	Arm 1: 52.0 (10.4); Arm 2: 52.1 (11.6)	Arm 3: 52.1 (10.2); Arm 4: 51.8 (10.7)	Arm 1: 165 (51.6); Arm 2: 146 (45.2)	Arm 3: 169 (50.4); Arm 4: 163 (49.7)
3	Phillips et al,^Citation20 2003	2	Met + acarbose	Met	40	43	83	169 days	58.37 (10.7)	62.39 (8.02)	65%	76.70%	35%	23.30%
4	Chiasson et al,^Citation21 2001	4	Arm 1: Met alone; Arm 2: miglitol + Met	Arm 3: placebo; Arm 4: miglitol alone	Arm 1: 83; Arm 2: 76	Arm 3: 83; Arm 4: 82	324		Arm 1: 57.9 (8.6); Arm 2: 58.9 (7.9)	Arm 3: 57.7 (9.9); Arm 4: 57.3 (9.0)	Arm 1: 61; Arm 2: 59	Arm 3: 56; Arm 4: 64	Arm 1: 22; Arm 2: 17	Arm 3: 27; Arm 4: 18
5	Gu et al,^Citation22 2019	2	Met + saxagliptin	Met + glimepiride	187	186	388	48 weeks	54.2 (9.4)	52.8 (9.5)	119 (63.6%)	109 (58.6%)
6	Du et al,^Citation23 2017	2	Met + saxagliptin	Met + acarbose	238	243	488	24 weeks	54.7 (10.51)	56.5 (10.81)			91 (38.2)	105 (43.2)
7	Van Gaal et al,^Citation24 2001	2	Met + miglitol	Met	77	75	153	32 weeks	57.9 (10.0)	57.9 (8.5)	32	37	45	38
8	Dou et al,^Citation25 2018	3	Arm 1: saxa 5 mg + Met	Arm 2: saxa 5 mg + pbo; Arm 3: Met + pbo	Arm 1: 210	Arm 2: 213; Arm 3: 207	630	24 weeks	Arm 1: 50.8 (10.4)	Arm 2: 49.5 (10.9); Arm 3: 50.1 (11.0)	136 (64.8)	Arm 2: 151 (70.9); Arm 3: 132 (63.8)	74 (35.2)	Arm 2: 62 (29.1); Arm 3: 75 (36.2)
9	Hanefeld et al,^Citation26 2004	–	Sulfonylurea + pioglitazone 15 mg	Sulfonylurea + Met 850 mg	319	320	639	11 months	60 (8.8) (36–75)	60 (8.0) (36–75)	171 (53.6)	175 (54.7)	148 (46.4)	145 (45.3)
10	Wang et al,^Citation27 2013	2	Acarbose + Met	Acarbose 50 mg tablet	117	116	233		55.9 (9.5)	55.6 (9.5)	60 (51.3)	51 (44.0)
11	Cai et al,^Citation28 2015	2	Rosiglitazone + Met	Met	198	200	398	48 weeks	51.38 (9.57)	51.25 (8.84)	57.70%	59.80%
12	Rosenstock et al,^Citation29 2006	3	Arm 1: rsg/Met fixed-dose combination [rosiglitazone maleate/Met hydrochloride (avandamet)]	Arm 2: Met (Met hydrochloride); Arm 3: rsg [rosiglitazone maleate (avandia)]	155	Arm 2: 154; Arm 3: 159	468		Arm 1: 50.1 (10.7)	Arm 2: 51.5 (10.4); Arm 3: 50.6 (10.26)	Arm 1: 66 (43)	Arm 2: 67 (44); Arm 3: 66 (42)	Arm 1: 89 (57)	Arm 2: 87 (56); Arm 3: 93 (58)
13	Oh et al,^Citation30 2019	2	Voglibose + Met	Met	88	84	187	24 weeks	51.9±8.8	53.4±8.8	55 (62.5)	44 (52.4)
14	Moses et al,^Citation31 1999	3	Arm 1: Met repaglinide	Arm 2: repaglinide + placebo; Arm 3: Met + placebo	Arm 1: 27	Arm 2: 28; Arm 3: 27	83		Arm 1: 57.2±8.3	Arm 2: 60.3±7.7; Arm 3: 57.8±9.5	Arm 1: 18	Arm 2: 15; Arm 3: 17	Arm 1: 9	Arm 2: 13; Arm 3: 10
15	Marre et al,^Citation32 2002	3	Arm 1: 60 mg nateglinide + Met; Arm 2: 120 mg nateglinide + Met	Placebo + Met	Arm 1: 155; Arm 2: 160	152	467	24 weeks	Arm 1: 57.9 (9.9); Arm 2: 57.3 (10.5)	56.4 (10.3)	Arm 1: 95 (61.3); Arm 2: 98 (61.3)	84 (55.3)	Arm 1: 60 (38.7); Arm 2: 62 (38.8)	68 (44.7)
16	Horton et al,^Citation33 2000	4	Arm 1: nateglinide; Arm 2: Met; Arm 3: nateglinide + Met	Placebo	Arm 1: 179; Arm 2: 178; Arm 3: 172	172	701	24 weeks	Arm 1: 58.6 (10.7); Arm 2: 56.8 (10.9); Arm 3: 58.4 (10.9)	59.6 (10.9)	Arm 1: 110; Arm 2: 121; Arm 3: 101	104	Arm 1: 69; Arm 2: 57; Arm 3: 71	68
17	Raskin et al,^Citation34 2009	3	Arm 1: repaglinide/Met fdc, bid; Arm 2: repaglinide/Met fdc, tid	Arm 3: rosiglitazone/Met fdc tablet bid	Arm 1: 187 Arm 2: 187	Arm 3: 187	561	26 weeks	Arm 1: 54.8 (11.5); Arm 2: 54.5 (10.5)	Arm 3: 55.5 (10.3)	Arm 1: 108 (57.8); Arm 2: 110 (58.8)	Arm 3: 95 (50.8)	Arm 1: 79 (42.2); Arm 2: 77 (41.2)	Arm 3: 92 (49.2)
18	Lewin et al,^Citation35 2007	4	Arm 1: mer 1500 mg qd + sulfonylurea; Arm 2: mer 1000 mg bid + sulfonylurea; Arm 3: mer 2000 mg qd + sulfonylurea	Arm 4: sulfonylurea monotherapy	Arm 1: 144; Arm 2: 141; Arm 3: 146	Arm 4: 144	607	24 weeks	Arm 1: 54.0 (10.3); Arm 2: 53.0 (10.5); Arm 3: 53.0 (10.9)	Arm 4: 53.0 (10.7)	Arm 1: 77 (53.5); Arm 2: 83 (58.9); Arm 3: 75 (51.4)	Arm 4: 79 (54.9)	Arm 1: 67 (46.5); Arm 2: 58 (41.1); Arm 3: 71 (48.6)	Arm 4: 65 (45.1)
19	Jin et al,^Citation36 2015	2	Lobeglitazone + Met	Pioglitazone + Met	128	125			1.4%
20	Wang et al,^Citation37 2016	2	Met + glibenclamide	Met + acarbose	23	27	50		54.7 (8.3)	52.5 (8.2)	10 (43.5)	14 (51.9)
21	Perez et al,^Citation38 2009		Arm 1: pioglitazone 15 mg/Met 850 mg bid; Arm 2: pioglitazone 15 mg bid	Arm 3: Met 850 mg bid	Arm 1: 201; Arm 2: 190	Arm 3: 209	600		Arm 1: 54.7 (12.2); Arm 2: 54.0 (12.1)	Arm 3: 53.7 (12.0)			Arm 1: 111 (55.2); Arm 2: 123 (65.1)	Arm 3: 112 (53.3)
22	Kawamori et al,^Citation39 2014	2	Met + repaglinide	Met + placebo	Repaglinide (n =94)	Placebo (n =36)	133	Phase III study: 16 weeks; long‐term study: 52 weeks	55.1±11.1	Placebo: 53.6±12.1	61	21	31	15
23	Wang et al,^Citation40 2011	2	Repaglinide + Met	Repaglinide	218	214	588	6-week dose titration period and 10-week dose maintenance period	50.4±9.6	49.4±10	158 (72.5%)	155 (72.4%)	60 (27.5%)	59 (27.6%)
24	Raskin et al,^Citation41 2003	2	Repaglinide + Met	Nateglinide + Met	96	96	192	16 weeks	55.8±10.7	55.0±10.6	50	60	46	36
25	Moses,^Citation42 1999	3	Arm 1: Met + repaglinide	Arm 2: repaglinide + placebo; Arm 3: Met + placebo	Arm 1: 27	Arm 2: 28; Arm 3: 27	83	Baseline period: 4–5 weeks; treatment period: 4–5 months	Arm 1: 57.2	Arm 2: 60.3; Arm 3: 57.8	Arm 1: 18	Arm 2: 15; Arm 3: 17	Arm 1: 9	Arm 2: 13; Arm 3: 10
26	Vaccaro et al,^Citation43 2017	2	Met + pioglitazone	Met + sulfonylurea	1535	1493	4956	Follow-up visits were scheduled at 1, 3, and 6 months after randomization and every 6 months thereafter until study end	62.4 (6.4)	62.2 (6.5)	909 (59%)	865 (58%)	626 (41%)	628 (42%)
27	Handelsman et al,^Citation44 2017	2	Omarigliptin + Met	Glimepiride + Met	376	375	1197	Study duration up to 57 weeks	58±10	58±9	203 (54.0%)	211 (56.3%)
28	Derosa et al,^Citation45 2014	2	Vildagliptin + Met	Glimepiride + Met	86	81	178	6 months	59.8±9.9	57.2±9.0	42	40	44	41
29	Kim et al,^Citation46 2017	2	Vildagliptin + Met	Glimepiride + Met	17	17	39	12 weeks	55.6±8.4	56.3±5.7			7 (41.2)	7 (41.2)
30	Derosa et al,^Citation47 2007	2	Nateglinide + Met	Glibenclamide + Met	119	114	248	12 months	55±5	56±4	58	58	61	56
31	González-Ortiz et al,^Citation48 2009	2	Glimepiride/Met	Glibenclamide/Met	76	76	152	12 months	52.3±7.6	52.9±7.6	28	31	48	45
32	Chien et al,^Citation49 2007	4	Arm 1: glyburide + Met (2.5 mg/500 mg); Arm 2: glyburide + Met (5 mg/500)	Arm 3: glyburide; Arm 4: Met	Arm 1: 21; Arm 2: 21	Arm 3: 17; Arm 4: 17	100	16 weeks	Arm 1: 60±7; Arm 2: 57±8	Arm 3: 63±7; Arm 4: 59±9	Arm 1: 15; Arm 2: 13	Arm 3: 9; Arm 4: 7	Arm 1: 6; Arm 2: 8	Arm 3: 8; Arm 4: 10
33	Garber et al,^Citation50 2006	2	Met + glibenclamide	Met + rosiglitazone	160	158	356	24 weeks	56 (31–78)	56 (24–78)	90 (56%)	102 (65%)	70 (44%)	56 (35%)
34	Kim et al,^Citation51 2013	2	Met + sitagliptin	Met + glimepiride	16	17	34	4 weeks	59.6±6.7	55.8±6.6	12	7	4	10
35	Schernthaner et al,^Citation52 2015	2	Saxagliptin + Met	Glimepiride + Met	360	360	720	52 weeks	72.5 (5.7)	72.7 (5.4)	217 (60.3)	228 (63.3)
36	Garber et al,^Citation53 2003	3	Arm 1: glyburide/Met	Arm 2: Met; Arm 3: glyburide	Arm 1: 171	Arm 2: 164; Arm 3: 151	513	16 weeks	Arm 1: 55.6 (11.2)	Arm 2: 54.7 (11.8); Arm 3: 55.3 (12.2)	Arm 1: 76 (44.4)	Arm 2: 71 (43.3); Arm 3: 66 (43.7)	Arm 1: 95 (55.6)	Arm 2: 93 (56.7); Arm 3: 85 (56.3)
37	Del Prato et al,^Citation54 2014	3	Arm 1: alogliptin 12.5 mg + Met	Arm 2: alogliptin 25 mg + Met; Arm 3: glipizide 5 mg + Met	Arm 1: 880	Arm 2: 885; Arm 3: 874	5789	104 weeks	Arm 1: 55.2 (9.60)	Arm 2: 55.5 (9.81); Arm 3: 55.4 (9.60)	Arm 1: 419 (47.6)	Arm 2: 452 (51.1); Arm 3: 441 (50.5)	Arm 1: 461 (52.4)	Arm 2: 433 (48.9); Arm 3: 433 (49.5)
38	Schwarz et al,^Citation55 2008	2	Nateglinide + Met	Glyburide + Met	35	40	75	104 weeks	70.1±2.9	70.4±3.8	17 (51.5)	18 (50.0)	16 (48.5)	18 (50.0)
39	Umpierrez et al,^Citation56 2006	2	Glimepiride + Met	Pioglitazone + Met	96	107	203	28 weeks	51.6±11.8	55.7±9.7	53±55.2	56±52.3	43±44.8	51±47.7
40	Göke et al,^Citation57 2013	2	Saxagliptin + Met	Glipizide + Met	428	430	858	52 weeks	57.5 (27–83)	57.6 (25–80)	212 (49.5)	232 (54.0)	216 (50.5)	198 (46.0)
41	Gerich et al,^Citation58 2005	2	Nateglinide/Met	Glyburide/Met	219	209	428	104 weeks	52.6±11.6	53.5±11.6	106 (51.0)	95 (48.0)	102 (49.0)	103 (52.0)
42	Forst et al,^Citation59 2014	2	Linagliptin + Met	Glimepiride + Met	19	20	39	12 weeks	65±8	63±7	13	14	6	6
43	Seck et al,^Citation60 2010	2	Sitagliptin + Met	Glipizide + Met	248	256	504	2 years	57.6 (8.5)	57.0 (9.1)	142 (57.3)	161 (62.9)	106 (42.7)	95 (37.1)
44	Ristic et al,^Citation61 2006	2	Nateglinide + Met	Gliclazide + Met	133	129	262	24 weeks	62.0±11.0	61.6±10.1	72 (54.1)	65 (50.4)	61 (45.9)	64 (49.6)
45	Göke et al,^Citation62 2010	2	Saxagliptin + Met	Glipizide + Met	428	430	891	52 weeks	57.5 (10.26)	57.6 (10.37)	212 (49.5)	232 (54.0)	216 (50.5)	198 (46.0)
46	Matthews et al,^Citation63 2010	2	Vildagliptin + Met	Glimepiride + Met	1562	1556	3118	2	57.5±9.07	57.5±9.19	829 (53.1%)	838 (53.9%)	733 (46.9%)	718 (46.1%)
47	Arechavaleta et al,^Citation64 2011	2	Sitagliptin + Met	Glimepiride + Met	516	519	1035	30 weeks	56.3±9.7	56.2±10.1	284 (55.0)	279 (53.8)
48	Nauck et al,^Citation65 2007	2	Sitagliptin + Met	Glipizide + Met	588	584	1172	52 weeks	56.8 (9.3)	56.6 (9.8)	336 (57.1)	358 (61.3)	252 (42.9)	226 (38.7)
49	Ferrannini et al,^Citation66 2009	2	Vildagliptin + Met	Glimepiride + Met	1396	1393	2789	52 weeks	57.50±9.06	57.46±9.28	737 (52.8%)	753 (54.1%)	659 (47.2%)	640 (45.9%)
50	Ristic et al,^Citation67 2007	2	Nateglinide + Met	Gliclazide + Met	133	129	262	52 weeks	61.9 (11.1)	61.5 (10.2)	63 (56.3)	51 (50.5)	49 (43.8)	50 (49.5)
51	Derosa et al,^Citation68 2014	2	Vildagliptin + Met	Glimepiride + Met	81	86	167	6 months	59.8±9.9	56.8±8.9	42	36	44	34
52	Charpentier et al,^Citation69 2001	3	Arm 1: Met + glimepiride	Arm 2: glimepiride; Arm 3: Met	Arm 1: 147	Arm 2: 150; Arm 3: 75	379	20 weeks	Arm 1: 56.8 (36–70)	Arm 2: 55.4 (35–70); Arm 3: 56.7 (36–69)	Arm 1: 87 (59)	Arm 2: 87 (58); Arm 3: 45 (60)
53	Feinglos et al,^Citation70 2005	2	Met + glipizide	Met + placebo	61	61	122	16 weeks	57.7±10.7	58.8±10.0	28	25	33	36
54	Lin et al,^Citation71 2011	2	Acarbose	Glibenclamide	20	20	51	16 weeks	51.5 (8.0)	53.9 (8.5)	13	10	7	10
55	Garber et al,^Citation72 2002	5	Glyburide/Met (1.25 mg/250 mg), glyburide/Met (2.5 mg/500 mg)	Placebo, glyburide, Met	Glyburide/Met (1.25/250): 158; glyburide/Met (2.5/500): 165	Placebo: 161; glyburide: 161; Met: 161	847	20 weeks	Gly/Met (1.25/250): 56.9 (12.0); gly/Met (2.5/500): 58.1 (9.8)	Placebo: 55.4 (10.5); glyburide: 56.5 (10.5); Met: 56.0 (11.0)	Glyburide/Met (1.25/250): 91 (57.6%); glyburide/Met (2.5/500): 96 (58.2%)	Placebo: 76 (47.2%); glyburide: 82 (50.9%); Met: 93 (57.8%)	Glyburide/Met (1.25/250): 67 (42.4%); glyburide/Met (2.5/500): 69 (41.8%)	Placebo: 85 (52.8%); glyburide: 79 (49.1%); Met: 68 (42.2%)
56	Home et al,^Citation73 2007	2	Met + rosiglitazone	Met + sulfonylurea	259	311	1122	18 months	57 (8)	57 (8)	141 (54)	139 (52)
57	Wang et al,^Citation74 2015	2	Saxagliptin + Met	Acarbose + Met	41	40	90	12 months	64.3 (2.6)	65.1 (3.1)	18	19	23	21
58	Rosenstock et al,^Citation75 2011	3	Gosogliptin 20 mg + Met, gosogliptin 30 mg + Met	Placebo + Met	Pf-734,200: 116; pf-734,200: 116	57	289	12 weeks
59	Shankar et al,^Citation76 2017	2	Omarigliptin + Met	Placebo + Met	201	201	659	24 weeks	57.5 (8.1)	56.8 (9.1)	101 (50.2)	102 (50.7)
60	Filozof and Gautier,^Citation77 2010	2	Vildagliptin + Met	Gliclazide + Met	513	494	1007	52 weeks	59.2 (9.9)	59.7 (10.2)	268 (52.2%)	256 (51.8%)
61	Forst et al,^Citation78 2010	5	Linagliptin (1 mg, 5 mg, 10 mg)	Placebo	Linagliptin 1 mg: 65; 5 mg: 66; 10 mg: 66	Placebo: 71	333	12 weeks	Linagliptin 1 mg: 59.2 (8.4); 5 mg: 59.6 (9.8); 10 mg: 61.8 (8.8)	Placebo: 60.1 (8.1)	Linagliptin 1 mg: 36 (55.4); 5 mg: 37 (56.1); 10 mg: 35 (53.0)	Placebo: 44 (62.0)
62	Scheen et al,^Citation6 2010	2	Saxagliptin + Met	Sitagliptin + Met	403	398	822	18 weeks	58.8 (10.1)	58.1 (10.5)	190 (47.1)	202 (50.8)	213 (52.9)	196 (49.2)

Abbreviations: n, number; I, intervention; C, comparator; Met, metformin.

Figure 1 Study flowchart diagram.

Table 2 Effect Estimates for Efficacy Outcomes (Mean Difference and 95% CI)

(A) Change in HbA1c from Baseline
AGI	−1.35 (−2.85, 0.1273)	−1.214 (−2.849, 0.404)	−1.239 (−2.957, 0.4606)	−0.884 (−2.506, 0.721)	−0.4199 (−2.675, 1.799)	−1.163 (−2.814, 0.4661)	−1.005 (−3.225, 1.224)	−0.5204 (−2.26, 1.205)
1.35 (−0.1273, 2.85)	AGI + Met	0.1363 (−0.5322, 0.7954)	0.111 (−0.7439, 0.9393)	0.4673 (−0.1594, 1.089)	0.9184 (−0.75, 2.602)	0.1865 (−0.5233, 0.8783)	0.3482 (−1.301, 1.965)	0.8292 (−0.04071, 1.701)
1.214 (−0.404, 2.849)	−0.1363 (−0.7954, 0.5322)	DPP4i + Met	−0.02803 (−0.6915, 0.654)	0.3303 (−0.1174, 0.781)	0.7871 (−0.7532, 2.347)	0.0502 (−0.2966, 0.3965)	0.2134 (−1.303, 1.711)	0.6903 (0.01619, 1.39)
1.239 (−0.4606, 2.957)	−0.111 (−0.9393, 0.7439)	0.02803 (−0.654, 0.6915)	Gli + Met	0.3572 (−0.2428, 0.951)	0.8076 (−0.8225, 2.476)	0.07739 (−0.579, 0.7264)	0.2379 (−1.374, 1.836)	0.7193 (−0.06438, 1.506)
0.884 (−0.721, 2.506)	−0.4673 (−1.089, 0.1594)	−0.3303 (−0.781, 0.1174)	−0.3572 (−0.951, 0.2428)	Met	0.4531 (−1.117, 2.059)	−0.2789 (−0.767, 0.1972)	−0.1168 (−1.683, 1.421)	0.3616 (−0.3024, 1.037)
0.4199 (−1.799, 2.675)	−0.9184 (−2.602, 0.75)	−0.7871 (−2.347, 0.7532)	−0.8076 (−2.476, 0.8225)	−0.4531 (−2.059, 1.117)	SU	−0.7379 (−2.262, 0.7718)	−0.5745 (−2.711, 1.518)	−0.09394 (−1.744, 1.536)
1.163 (−0.4661, 2.814)	−0.1865 (−0.8783, 0.5233)	−0.0502 (−0.3965, 0.2966)	−0.07739 (−0.7264, 0.579)	0.2789 (−0.1972, 0.767)	0.7379 (−0.7718, 2.262)	SU + Met	0.1611 (−1.313, 1.628)	0.6411 (−0.001001, 1.299)
1.005 (−1.224, 3.225)	−0.3482 (−1.965, 1.301)	−0.2134 (−1.711, 1.303)	−0.2379 (−1.836, 1.374)	0.1168 (−1.421, 1.683)	0.5745 (−1.518, 2.711)	−0.1611 (−1.628, 1.313)	SU + TZD	0.4784 (−1.105, 2.099)
0.5204 (−1.205, 2.26)	−0.8292 (−1.701, 0.04071)	−0.6903 (−1.39, −0.01619)	−0.7193 (−1.506, 0.06438)	−0.3616 (−1.037, 0.3024)	0.09394 (−1.536, 1.744)	−0.6411 (−1.299, 0.001001)	−0.4784 (−2.099, 1.105)	TZD + Met
(B) Change in FPG from Baseline
AGI	−29.61 (−56, −3.235)	−38.48 (−67.98, −8.616)	−37.32 (−67.97, −6.168)	−22.02 (−51.38, 8.132)	−44.18 (−74.16, −14.06)	−42.43 (−82.6, −1.973)	−51.18 (−84.74, −17.6)
29.61 (3.235, 56)	AGI + Met	−8.82 (−22.25, 4.974)	−7.764 (−23.37, 8.417)	7.615 (−5.875, 21.77)	−14.61 (−28.68, −0.1557)	−12.82 (−42.79, 17.58)	−21.6 (−42.4, −0.6941)
38.48 (8.616, 67.98)	8.82 (−4.974, 22.25)	DPP4i + Met	1.089 (−9.305, 11.77)	16.47 (8.243, 24.91)	−5.78 (−11.96, 0.4052)	−4.011 (−31.17, 23.34)	−12.84 (−29.42, 3.808)
37.32 (6.168, 67.97)	7.764 (−8.417, 23.37)	−1.089 (−11.77, 9.305)	Gli + Met	15.37 (5.854, 25.09)	−6.924 (−16.71, 2.852)	−5.155 (−33.25, 22.87)	−13.95 (−30.82, 2.683)
22.02 (−8.132, 51.38)	−7.615 (−21.77, 5.875)	−16.47 (−24.91, −8.243)	−15.37 (−25.09, −5.854)	Met	−22.26 (−31.12, −13.82)	−20.45 (−48.46, 7.209)	−29.34 (−46.71, −12.23)
44.18 (14.06, 74.16)	14.61 (0.1557, 28.68)	5.78 (−0.4052, 11.96)	6.924 (−2.852, 16.71)	22.26 (13.82, 31.12)	SU + Met	1.778 (−24.78, 28.35)	−7.02 (−22.66, 8.568)
42.43 (1.973, 82.6)	12.82 (−17.58, 42.79)	4.011 (−23.34, 31.17)	5.155 (−22.87, 33.25)	20.45 (−7.209, 48.46)	−1.778 (−28.35, 24.78)	SU + TZD	−8.778 (−39.47, 21.82)
51.18 (17.6, 84.74)	21.6 (0.6941, 42.4)	12.84 (−3.808, 29.42)	13.95 (−2.683, 30.82)	29.34 (12.23, 46.71)	7.02 (−8.568, 22.66)	8.778 (−21.82, 39.47)	TZD + Met
(C) Change in 2h-PPG from Baseline
AGI	−41.77 (−74.87, −7.878)	−33.79 (−73.86, 8.621)	−40.81 (−86.22, 9.382)	−9.858 (−49.73, 35.21)	−23.58 (−65.64, 22.76)
41.77 (7.878, 74.87)	AGI + Met	7.966 (−15.64, 33.17)	0.9272 (−31.27, 36.62)	31.78 (7.794, 59.75)	18.12 (−9.178, 48.8)
33.79 (−8.621, 73.86)	−7.966 (−33.17, 15.64)	DPP4i + Met	−7.015 (−32.26, 20.55)	23.84 (10.34, 40.49)	10.1 (−5.548, 27.66)
40.81 (−9.382, 86.22)	−0.9272 (−36.62, 31.27)	−7.015 (−20.55, 32.26)	Gli + Met	30.85 (9.246, 53.05)	17.27 (−12.08, 45.61)
9.858 (−35.21, 49.73)	−31.78 (−59.75, −7.794)	−23.84 (−40.49, −10.34)	−30.85 (−53.05, −9.246)	Met	−13.61 (−33.31, 4.934)
23.58 (−22.76, 65.64)	−18.12 (−48.8, 9.178)	−10.1 (−27.66, 5.548)	−17.27 (−45.61, 12.08)	13.61 (−4.934, 33.31)	SU + Met
33.79 (−8.621, 73.86)	−7.966 (−33.17, 15.64)	DPP4i + Met	−7.015 (−32.26, 20.55)	23.84 (10.34, 40.49)	10.1 (−5.548, 27.66)

Abbreviations: AGI, α-glucosidase inhibitor; DPP4i, dipeptidyl peptidase-4 inhibitors; Gli, glinides; Met, metformin; SU, sulfonylurea; TZD, thiazolidinedione.

Figure 2 Forest plot of efficacy outcomes: (a) change in HbA1c levels from baseline; (b) change in FPG levels from baseline; (c) change in 2h-PPG levels from baseline.

Table 3 Effect Estimates for Safety Outcomes (Risk Ratio and 95% CI)

(A) Serious Adverse Events
AGI	0.7115 (0.1334, 3.282)	0.9052 (0.1448, 5.016)	4.046e+08 (0.6909, 5.051e+29)	0.752 (0.1157, 4.357)	0.7327 (0.1204, 4.003)	1.635e+04 (1.034e-10, 3.948e+33)	0.9198 (0.146, 5.117)	0.6192 (0.09142, 3.899)	0.916 (0.146, 5.169)
1.406 (0.3047, 7.499)	AGI + Met	1.275 (0.5901, 2.856)	5.486e+08 (1.118, 7.769e+29)	1.059 (0.4522, 2.539)	1.034 (0.5018, 2.174)	2.364e+04 (1.762e-10, 6.107e+33)	1.295 (0.5958, 2.91)	0.8727 (0.3264, 2.466)	1.287 (0.5708, 2.989)
1.105 (0.1994, 6.906)	0.7844 (0.3502, 1.695)	DPP4i + Met	4.168e+08 (0.8913, 1.37e+30)	0.8323 (0.5387, 1.263)	0.8145 (0.5533, 1.162)	2.054e+04 (1.533e-10, 5.328e+33)	1.02 (0.8749, 1.162)	0.6914 (0.357, 1.289)	1.018 (0.7173, 1.364)
2.471e-09 (1.98e-30, 1.447)	1.823e-09 (1.287e-30, 0.8944)	2.399e-09 (7.298e-31, 1.122)	Gli	1.943e-09 (6.001e-31, 0.9284)	1.977e-09 (6.046e-31, 0.8974)	0.0014 (3.552e-36, 2.364e+24)	2.448e-09 (7.668e-31, 1.143)	1.588e-09 (5.897e-31, 0.7828)	2.443e-09 (8.165e-31, 1.148)
1.33 (0.2295, 8.641)	0.9439 (0.3938, 2.211)	1.201 (0.7919, 1.856)	5.147e+08 (1.077, 1.666e+30)	Gli + Met	0.9787 (0.5875, 1.626)	2.353e+04 (1.824e-10, 5.993e+33)	1.225 (0.8183, 1.847)	0.8277 (0.3912, 1.754)	1.217 (0.762, 1.947)
1.365 (0.2498, 8.305)	0.967 (0.46, 1.993)	1.228 (0.8603, 1.807)	5.059e+08 (1.114, 1.654e+30)	1.022 (0.6152, 1.702)	Met	2.504e+04 (1.913e-10, 6.615e+33)	1.249 (0.8634, 1.863)	0.8477 (0.4114, 1.758)	1.242 (0.8012, 1.961)
6.115e-05 (2.533e-34, 9.671e+09)	4.23e-05 (1.637e-34, 5.676e+09)	4.868e-05 (1.877e-34, 6.522e+09)	714.1 (4.23e-25, 2.815e+35)	4.25e-05 (1.669e-34, 5.483e+09)	3.994e-05 (1.512e-34, 5.227e+09)	SU	4.986e-05 (1.921e-34, 6.648e+09)	3.388e-05 (1.263e-34, 4.592e+09)	4.969e-05 (2.063e-34, 6.658e+09)
1.087 (0.1954, 6.847)	0.7723 (0.3436, 1.679)	0.9808 (0.8604, 1.143)	4.086e+08 (0.8752, 1.304e+30)	0.8164 (0.5415, 1.222)	0.8007 (0.5369, 1.158)	2.006e+04 (1.504e-10, 5.205e+33)	SU + Met	0.6785 (0.3577, 1.252)	0.9976 (0.7285, 1.313)
1.615 (0.2564, 10.94)	1.146 (0.4055, 3.064)	1.446 (0.776, 2.801)	6.297e+08 (1.277, 1.696e+30)	1.208 (0.5702, 2.556)	1.18 (0.5689, 2.431)	2.952e+04 (2.178e-10, 7.917e+33)	1.474 (0.7988, 2.796)	SU + TZD	1.471 (0.73, 2.917)
1.092 (0.1935, 6.847)	0.7767 (0.3346, 1.752)	0.9823 (0.733, 1.394)	4.093e+08 (0.8713, 1.225e+30)	0.8215 (0.5137, 1.312)	0.8051 (0.5099, 1.248)	2.012e+04 (1.502e-10, 4.847e+33)	1.002 (0.7615, 1.373)	0.6799 (0.3428, 1.37)	TZD + Met
(B) Hypoglycemia
AGI + Met	1.013 (0.2922, 3.656)	1.463 (0.02851, 38.73)	3.64 (0.9584, 14.1)	0.9943 (0.2983, 3.335)	2.573 (0.2998, 22.66)	6.263 (1.794, 22.86)	8.38 (1.173, 62.49)	0.7622 (0.1824, 3.035)
0.9867 (0.2735, 3.422)	DPP4i + Met	1.473 (0.03253, 30)	3.608 (1.732, 7.197)	0.9858 (0.5337, 1.733)	2.538 (0.4132, 15.31)	6.206 (4.127, 9.371)	8.293 (1.704, 40.64)	0.7535 (0.3086, 1.656)
0.6835 (0.02582, 35.07)	0.6791 (0.03333, 30.74)	Gli	2.432 (0.1286, 103.4)	0.6716 (0.03234, 28.85)	1.738 (0.05017, 115.4)	4.212 (0.2075, 186.5)	5.721 (0.1951, 325.1)	0.5123 (0.02303, 22.25)
0.2748 (0.07094, 1.043)	0.2771 (0.1389, 0.5773)	0.4112 (0.009673, 7.773)	Gli + Met	0.2735 (0.1418, 0.5121)	0.7061 (0.1095, 4.619)	1.721 (0.9324, 3.278)	2.292 (0.4546, 12.37)	0.2094 (0.08592, 0.4676)
1.006 (0.2999, 3.352)	1.014 (0.577, 1.874)	1.489 (0.03466, 30.92)	3.656 (1.953, 7.051)	Met	2.587 (0.4176, 16.61)	6.289 (3.769, 11.15)	8.411 (1.695, 44.33)	0.7654 (0.3465, 1.608)
0.3887 (0.04414, 3.335)	0.394 (0.06534, 2.42)	0.5755 (0.008665, 19.93)	1.416 (0.2165, 9.128)	0.3866 (0.06022, 2.394)	SU	2.443 (0.4262, 14.5)	3.258 (0.315, 34.9)	0.2959 (0.04134, 1.976)
0.1597 (0.04375, 0.5573)	0.1611 (0.1067, 0.2423)	0.2374 (0.005362, 4.819)	0.5811 (0.3051, 1.073)	0.159 (0.08972, 0.2653)	0.4093 (0.06895, 2.346)	SU + Met	1.339 (0.29, 6.168)	0.1216 (0.05351, 0.2471)
0.1193 (0.016, 0.8529)	0.1206 (0.02461, 0.5868)	0.1748 (0.003076, 5.125)	0.4363 (0.08085, 2.2)	0.1189 (0.02256, 0.59)	0.307 (0.02865, 3.174)	0.7469 (0.1621, 3.449)	SU + TZD	0.09142 (0.01549, 0.4745)
1.312 (0.3295, 5.482)	1.327 (0.6039, 3.241)	1.952 (0.04495, 43.42)	4.775 (2.139, 11.64)	1.306 (0.6218, 2.886)	3.38 (0.5061, 24.19)	8.225 (4.047, 18.69)	10.94 (2.108, 64.56)	TZD + Met
(C) Gastrointestinal Events
AGI	1.251 (0.4181, 3.674)	0.6112 (0.1591, 2.133)	1.268 (0.1899, 7.579)	0.6391 (0.1526, 2.389)	0.6571 (0.1778, 2.22)	0.3591 (0.05929, 1.909)	0.629 (0.1605, 2.241)	1.227 (0.2183, 6.161)	0.4638 (0.1129, 1.724)
0.7996 (0.2722, 2.392)	AGI + Met	0.4906 (0.2312, 0.9448)	1.012 (0.2149, 4.322)	0.512 (0.2064, 1.127)	0.528 (0.2651, 0.9552)	0.2887 (0.07173, 1.044)	0.5053 (0.2308, 0.9922)	0.9864 (0.2607, 3.349)	0.3722 (0.1564, 0.7972)
1.636 (0.4688, 6.285)	2.038 (1.058, 4.325)	DPP4i + Met	2.064 (0.5078, 8.491)	1.043 (0.5325, 2.003)	1.075 (0.707, 1.65)	0.5866 (0.1774, 1.917)	1.028 (0.7163, 1.46)	2.003 (0.6597, 6.001)	0.7579 (0.4041, 1.412)
0.7885 (0.1319, 5.267)	0.9881 (0.2314, 4.654)	0.4846 (0.1178, 1.969)	Gli	0.5052 (0.1454, 1.72)	0.5207 (0.1337, 2.038)	0.2838 (0.04688, 1.712)	0.4965 (0.1228, 1.994)	0.9655 (0.1707, 5.601)	0.3669 (0.08578, 1.564)
1.565 (0.4187, 6.552)	1.953 (0.887, 4.845)	0.9587 (0.4993, 1.878)	1.979 (0.5814, 6.879)	Gli + Met	1.03 (0.6001, 1.832)	0.563 (0.1548, 2.073)	0.9855 (0.522, 1.881)	1.914 (0.5668, 6.529)	0.7264 (0.3465, 1.553)
1.522 (0.4504, 5.625)	1.894 (1.047, 3.773)	0.9301 (0.606, 1.414)	1.921 (0.4907, 7.479)	0.9712 (0.5459, 1.666)	Met	0.5458 (0.1607, 1.818)	0.956 (0.6164, 1.463)	1.864 (0.5925, 5.635)	0.7059 (0.4152, 1.177)
2.785 (0.5237, 16.87)	3.464 (0.9582, 13.94)	1.705 (0.5215, 5.637)	3.523 (0.5842, 21.33)	1.776 (0.4824, 6.459)	1.832 (0.55, 6.223)	SU	1.753 (0.566, 5.452)	3.412 (0.7295, 16.17)	1.286 (0.3578, 4.677)
1.59 (0.4462, 6.229)	1.979 (1.008, 4.332)	0.9724 (0.6851, 1.396)	2.014 (0.5014, 8.143)	1.015 (0.5316, 1.916)	1.046 (0.6833, 1.622)	0.5704 (0.1834, 1.767)	SU + Met	1.95 (0.6835, 5.579)	0.738 (0.4056, 1.337)
0.815 (0.1623, 4.58)	1.014 (0.2986, 3.836)	0.4992 (0.1666, 1.516)	1.036 (0.1785, 5.857)	0.5225 (0.1532, 1.764)	0.5366 (0.1775, 1.688)	0.2931 (0.06186, 1.371)	0.5129 (0.1793, 1.463)	SU + TZD	0.3788 (0.1143, 1.267)
2.156 (0.58, 8.857)	2.687 (1.254, 6.396)	1.319 (0.7082, 2.475)	2.726 (0.6394, 11.66)	1.377 (0.6438, 2.886)	1.417 (0.8499, 2.409)	0.7777 (0.2138, 2.795)	1.355 (0.7481, 2.466)	2.64 (0.7895, 8.746)	TZD + Met
(D) Cardiovascular Events
AGI + Met	1325 (0.2804, 1.724e+11)	1683 (0.3257, 2.068e+11)	1421 (0.3059, 1.725e+11)	1112 (0.2083, 1.328e+11)	1359 (0.2775, 1.68e+11)
0.000755 (5.802e-12, 3.566)	DPP4i + Met	1.229 (0.5189, 3.693)	1.06 (0.6103, 2.06)	0.8201 (0.2301, 3.029)	1.014 (0.4583, 2.454)
0.0005943 (4.836e-12, 3.07)	0.8136 (0.2708, 1.927)	Met	0.8669 (0.3152, 2.062)	0.6619 (0.1393, 2.662)	0.8289 (0.3379, 1.713)
0.0007038 (5.798e-12, 3.269)	0.9438 (0.4854, 1.638)	1.154 (0.4851, 3.173)	SU + Met	0.7702 (0.2421, 2.35)	0.9597 (0.4743, 1.892)
0.0008996 (7.531e-12, 4.802)	1.219 (0.3301, 4.345)	1.511 (0.3757, 7.178)	1.298 (0.4255, 4.13)	SU + TZD	1.249 (0.334, 4.762)
0.0007359 (5.952e-12, 3.603)	0.9862 (0.4075, 2.182)	1.206 (0.5838, 2.959)	1.042 (0.5286, 2.108)	0.8005 (0.21, 2.994)	TZD + Met

Abbreviations: AGI, α-glucosidase inhibitor; DPP4i, dipeptidyl peptidase-4 inhibitors; Gli, glinides; Met, metformin; SU, sulfonylurea; TZD, thiazolidinedione.

Figure 3 Forest plot of safety outcomes: (a) serious adverse events; (b) hypoglycemia; (c) gastrointestinal events; (d) cardiovascular events.

Table 4 Summary Table of the Efficacy and Safety Outcomes of DPP4i + Met Combination with Other OAD-Based Met Combination Drug Classes

Drug Class Outcomes	SU + Met	TZD + Met	Gli + Met	AGI + Met
HbA1c	*	*	X
FPG			X	*
2h-PPG	*
SAE	*	X
Hypoglycemia	*		*	X
GI events	*		*	*
CV events	*	X

Notes: X: DPP4i + Met combination is comparable to other OAD-based metformin combinations. *: DPP4i + Met combination is better than other OAD-based metformin combinations.

Abbreviations: DPP4i dipeptidyl peptidase-4 inhibitors; Met, metformin; OADs, oral antidiabetic drugs; SU, sulfonylurea; TZD, thiazolidinedione; Gli, glinides; AGI, α-glucosidase inhibitor; HbA1c, glycated hemoglobin; FPG, fasting plasma glucose; 2h-PPG, 2-hour post-prandial blood glucose; SAE, serious adverse event; GI, gastrointestinal; CV, cardiovascular.

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