Overview of saxagliptin efficacy and safety in patients with type 2 diabetes and cardiovascular disease or risk factors for cardiovascular disease

Figures & data

Figure 1 Role of incretin hormones in glucose regulation.

Note: Reproduced with permission from Drucker DJ. The role of gut hormones in glucose homeostasis. J Clin Invest. 2007;117:24–32.²³
Abbreviations: CCK, cholecystokinin; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1.

Table 1 Saxagliptin clinical trials

Study	N*	Treatment	Mean baseline HbA1c, %†	Mean duration of T2DM, years†
Five-study pool
NCT00121641^Citation25	401	SAXA 2.5, 5, or 10 mg/day versus PBO	7.8–8.0	2.3–3.1
NCT00316082^Citation24	365	SAXA 2.5 mg QAM ± titration to 5 mg, 5 mg QAM, or 5 mg QPM versus PBO	7.8–8.0	1.2–2.0
NCT00121667^Citation26	743	SAXA 2.5, 5, or 10 mg/day + MET versus PBO + MET	8.0	6.5
NCT00313313^Citation27	768	SAXA 2.5 or 5 mg/day + GLY versus PBO + uptitrated GLY	8.4–8.5	6.8–7.1
NCT00295633^Citation28	565	SAXA 2.5 or 5 mg/day + TZD versus PBO + TZD	8.2–8.4	5.1–5.3
Three side-by-side
NCT00327015‡^Citation34	1,306	SAXA 5 or 10 mg/day + MET versus SAXA 10 mg/day + PBO or MET + PBO	9.4–9.6	1.4–2.0
NCT00575588^Citation35	858	SAXA 5 mg/day + MET versus glipizide + MET	7.7	5.4–5.5
NCT00757588^Citation29	455	SAXA 5 mg/day + INS ± MET versus PBO + INS ± MET	8.6–8.7	11.8–12.2
Nine-study pool
NCT00121641^Citation25	401	SAXA 2.5, 5, or 10 mg/day versus PBO	7.8–8.0	2.3–3.1
NCT00316082^Citation24	365	SAXA 2.5 mg QAM ± titration to 5 mg, 5 mg QAM, or 5 mg QPM versus PBO	7.8–8.0	1.2–2.0
NCT00698932^Citation42	568	SAXA 5 mg/day versus PBO	8.1–8.2	0.8–1.2
NCT00918879^Citation43	213	SAXA 5 mg/day versus PBO	8.3	0.9
NCT00121667^Citation26	743	SAXA 2.5, 5, or 10 mg/day + MET versus PBO + MET	8.0	6.5
NCT00661362^Citation44	570	SAXA 5 mg/day + MET versus PBO + MET	7.9	5.1
NCT00313313^Citation27	768	SAXA 2.5 or 5 mg/day + GLY versus PBO + uptitrated GLY	8.4–8.5	6.8–7.1
NCT00295633^Citation28	565	SAXA 2.5 or 5 mg/day + TZD versus PBO + TZD	8.2–8.4	5.1–5.3
NCT00757588^Citation29	455	SAXA 5 mg/day + INS ± MET versus PBO + INS ± MET	8.6–8.7	11.8–12.2
Additional studies in eleven-study safety pool
NCT01006590^Citation45	286	SAXA 5 mg/day + MET versus MET uptitration	7.7–7.8	6.0–6.9
NCT00327015‡^Citation34	1,306	SAXA 5 or 10 mg/day + MET versus SAXA 10 mg/day + PBO or MET + PBO	9.4–9.6	1.4–2.0
Additional studies in the 20-study safety pool
NCT00614939^Citation46	170	SAXA 2.5 mg/day versus PBO (± other OADs or INS)	8.1–8.5	15.1–18.2
NCT00950599^Citation48	338	SAXA 2.5, 5, 10, 20, 40, or 100 mg/day versus PBO	7.5–8.0	0.3–1.8
NCT00374907^Citation49	36	SAXA 5 mg/day versus PBO	6.6–6.9	2.7–3.7
NCT00575588^Citation35	858	SAXA 5 mg/day + MET versus glipizide + MET	7.7	5.4–5.5
NCT00666458^Citation50	801	SAXA 5 mg/day + MET versus SITA 100 mg/day + MET	7.7	6.3
NCT00683657^Citation51	93	SAXA 5 mg/day + MET XR versus PBO + MET XR	8.1	6.9
NCT00885378^Citation52	160	SAXA (2.5 mg twice daily) + MET versus PBO + MET	7.9–8.0	5.8–6.2
NCT00918138^Citation53	93	SAXA 5 mg/day + MET XR versus MET XR uptitration	8.4–8.6	5.1–6.2
NCT00960076^Citation54	282	SAXA 5 mg/day + MET XR versus MET XR uptitration	8.3–8.4	5.9–6.5

Notes:

* Randomized and treated patients.

† Range of values where indicated.

‡ Only the saxagliptin + metformin and metformin + placebo arms were included in the analyses.

Abbreviations: GLY, glyburide; HbA_1c, glycated hemoglobin; INS, insulin; MET, metformin; OAD, oral antihyperglycemic drug; PBO, placebo; QAM, once daily AM; QPM, once daily PM; SAXA, saxagliptin; SITA, sitagliptin; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione; XR, extended release.

Table 2 Efficacy of saxagliptin in patients with cardiovascular disease history or cardiovascular risk factors: five-study pool

	Adjusted mean change from baseline									Patients achieving HbA1c <7.0%, %
	HbA1c, %			FPG, mg/dL			PPG, mg/dL
	SAXA (n)	PBO (n)	Difference (95% CI)	SAXA (n)	PBO (n)	Difference (95% CI)	SAXA (n)	PBO (n)	Difference (95% CI)	SAXA (n)	PBO (n)	Difference (95% CI)
CVD history
Yes	−0.70 (110)	−0.06 (96)	−0.64 (−0.90, −0.38)	−18 (110)	−2 (96)	−16 (−26.2, −5.3)	−55 (88)	−16 (64)	−38 (−60.2, −31.2)	44 (110)	20 (96)	22 (8.2, 35.4)
No	−0.70 (746)	−0.01 (680)	−0.68 (−0.78, −0.58)	−13 (756)	1 (686)	−14 (−18.3, −10.4)	−52 (574)	−11 (520)	−41 (−49.2, −33.7)	35 (747)	18 (680)	16 (10.9, 20.4)
Treatment-by-subgroup interaction	P=0.95			P=0.41			P=0.52
CV risk factors
≥2	−0.75 (459)	−0.02 (410)	−0.73 (−0.85, −0.60)	−15 (463)	0 (411)	−15 (−19.8, −9.7)	−53 (354)	−17 (308)	−36 (−46.0, −26.2)	38 (460)	20 (410)	17 (10.4, 23.0)
≤1	−0.64 (402)	−0.02 (369)	−0.62 (−0.75, −0.48)	−12 (408)	2 (374)	−15 (−20.1, −9.4)	−52 (312)	−5 (278)	−47 (−57.5, −36.5)	35 (402)	17 (369)	16 (9.8, 22.6)
Treatment-by-subgroup interaction	P=0.49			P=0.65			P=0.06
Hypertension
Yes	−0.73 (457)	−0.04 (437)	−0.69 (−0.82, −0.57)	−15 (461)	−1 (439)	−14 (−19.2, −9.2)	−54 (351)	−13 (327)	−41 (−50.5, −30.9)	38 (458)	20 (437)	17 (10.6, 22.7)
No	−0.66 (402)	0 (340)	−0.66 (−0.80, −0.52)	−12 (408)	3 (344)	−16 (−21.2, −10.3)	−51 (313)	−9 (257)	−42 (−52.6, −31.2)	34 (402)	17 (340)	16 (9.6, 23.0)
Treatment-by-subgroup interaction	P=0.80			P=0.74			P=0.39
Statin use
Yes	−0.66 (211)	0.04 (211)	−0.70 (−0.89, −0.52)	−13 (211)	3 (211)	−16 (−23.3, −8.8)	−56 (158)	−10 (150)	−46 (−60.2, −31.2)	38 (211)	18 (211)	18 (9.0, 27.3)
No	−0.71 (650)	−0.05 (568)	−0.66 (−0.77, −0.56)	−14 (660)	0 (574)	−14 (−18.5, −10.0)	−51 (508)	−12 (436)	−40 (−48.2, −31.6)	36 (651)	19 (568)	16 (10.6, 20.9)
Treatment-by-subgroup interaction	P=0.92			P=0.86			P=0.54

Note: Data from Cook et al.³²

Abbreviations: CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; FPG, fasting plasma glucose; HbA_1c, glycated hemoglobin; PBO, placebo; PPG, postprandial glucose; SAXA, saxagliptin.

Table 3 Change in HbA_1c with saxagliptin in patients with cardiovascular disease history or cardiovascular risk factors: three side-by-side studies

	Adjusted mean change from baseline in HbA1c
	SAXA + MET (n)	PBO +MET (n)	Difference (95% CI)	SAXA + MET (n)	GLIP + MET (n)	Difference (95% CI)	SAXA + INS ± MET (n)	PBO + INS ± MET (n)	Difference (95% CI)
CVD history
Yes	−2.14 (32)	−1.76 (52)	−0.38 (−0.91, 0.15)	−0.49 (76)	−0.70 (89)	0.21 (−0.04, 0.46)	−0.73 (84)	−0.50 (39)	−0.23 (−0.57, 0.10)
No	−2.53 (274)	−1.97 (261)	−0.56 (−0.77, −0.36)	−0.58 (347)	−0.64 (334)	0.06 (−0.06, 0.18)	−0.73 (216)	−0.25 (110)	−0.48 (−0.68, −0.27)
Treatment-by-subgroup interaction	P=0.53			P=0.28			P=0.22
CV risk factors
≥2	−2.54 (124)	−2.16 (124)	−0.38 (−0.68, −0.08)	−0.56 (259)	−0.64 (273)	0.08 (−0.06, 0.22)	−0.70 (145)	−0.43 (80)	−0.26 (−0.50, −0.02)
≤1	−2.45 (182)	−1.78 (189)	−0.67 (−0.91, −0.42)	−0.58 (164)	−0.68 (150)	0.10 (−0.08, 0.28)	−0.76 (155)	−0.18 (69)	−0.58 (−0.83, −0.33)
Treatment-by-subgroup interaction	P=0.15			P=0.84			P=0.07
Hypertension
Yes	−2.50 (154)	−2.02 (167)	−0.47 (−0.74, −0.21)	−0.58 (313)	−0.69 (305)	0.11 (−0.02, 0.24)	−0.75 (232)	−0.33 (112)	−0.41 (−0.61, −0.21)
No	−2.48 (152)	−1.82 (145)	−0.66 (−0.93, −0.38)	−0.52 (109)	−0.56 (118)	0.03 (−0.18, 0.25)	−0.65 (66)	−0.27 (36)	−0.38 (−0.75, −0.02)
Treatment-by-subgroup interaction	P=0.34			P=0.54			P=0.89
Statin use
Yes	−2.40 (19)	−1.84 (27)	−0.56 (−1.28, 0.15)	−0.50 (177)	−0.63 (169)	0.13 (−0.04, 0.30)	−0.82 (102)	−0.40 (71)	−0.42 (−0.69, −0.15)
No	−2.49 (287)	−1.94 (286)	−0.55 (−0.75, −0.36)	−0.61 (246)	−0.67 (254)	0.06 (−0.08, 0.20)	−0.69 (198)	−0.25 (78)	−0.44 (−0.67, −0.21)
Treatment-by-subgroup interaction	P=0.98			P=0.56			P=0.93

Note: Data from Minervini et al³³ and Cook et al.³⁶

Abbreviations: CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; GLIP, glipizide; HbA_1c, glycated hemoglobin; INS, insulin; MET, metformin; PBO, placebo; SAXA, saxagliptin.

Table 4 Change in fasting plasma glucose with saxagliptin in patients with cardiovascular disease history or cardiovascular risk factors: three side-by-side studies

	Adjusted mean change from baseline in FPG, mg/dL
	SAXA + MET (n)	PBO + MET (n)	Difference (95% CI)	SAXA + MET (n)	GLIP + MET (n)	Difference (95% CI)	SAXA + INS ± MET (n)	PBO + INS ± MET (n)	Difference (95% CI)
CVD history
Yes	−47 (34)	−45 (52)	−2 (−19.9, 15.7)	−7 (74)	−19 (87)	12 (1.8, 22.0)	−5 (84)	−13 (39)	8 (−10.3, 25.7)
No	−60 (281)	−46 (268)	−14 (−21.0, −7.3)	−10 (346)	−15 (333)	5 (−0.3, 9.5)	−12 (216)	−4 (110)	−8 (−19.2, 2.5)
Treatment-by-subgroup interaction	P=0.22			P=0.20			P=0.13
CV risk factors
≥2	−61 (127)	−47 (124)	−14 (−24.2, 5.19)	−8 (257)	−16 (272)	8 (2.2, 13.3)	−4 (144)	−10 (80)	6 (−7.4, 18.4)
≤1	−57 (188)	−45 (196)	−12 (−20.4, −3.9)	−11 (163)	−14 (148)	3 (−4.1, 10.4)	−16 (156)	−2 (69)	−14 (−27.0, −0.3)
Treatment-by-subgroup interaction	P=0.77			P=0.32			P=0.04
Hypertension
Yes	−60 (158)	−45 (169)	−14 (−23.3, −5.4)	−9 (310)	−16 (304)	8 (2.4, 12.7)	−9 (231)	−8 (112)	−1 (−11.2, 10.2)
No	−58 (157)	−47 (150)	−11 (−20.7, −2.2)	−12 (109)	−14 (116)	2 (−6.4, 10.6)	−15 (67)	−1 (36)	−15 (−33.8, 4.6)
Treatment-by-subgroup interaction	P=0.66			P=0.29			P=0.21
Statin use
Yes	−55 (19)	−49 (27)	−7 (−30.8, 17.7)	−9 (175)	−18 (167)	10 (2.8, 16.6)	−18 (102)	−9 (71)	−9 (−23.3, 5.4)
No	−59 (296)	−46 (293)	−13 (−20.1, −6.8)	−10 (245)	−14 (253)	4 (−2.1, 9.4)	−7 (198)	−4 (78)	−2 (−14.8, 10.0)
Treatment-by-subgroup interaction	P=0.59			P=0.19			P=0.50

Note: Data from Minervini et al³³ and Cook et al.³⁶

Abbreviations: CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; FPG, fasting plasma glucose; GLIP, glipizide; INS, insulin; MET, metformin; PBO, placebo; SAXA, saxagliptin.

Table 5 Proportion of patients with cardiovascular disease history or cardiovascular risk factors achieving HbA_1c <7.0%: three side-by-side studies

	Patients achieving HbA1c <7.0%, % (n/N)
	SAXA + MET	PBO + MET	Difference (95% CI)	SAXA + MET	GLIP + MET	Difference (95% CI)	SAXA + INS ± MET	PBO + INS ± MET	Difference (95% CI)
CVD history
Yes	41 (13/32)	35 (18/52)	6 (−16.0, 27.7)	47 (36/76)	55 (49/89)	−8 (−22.8, 7.7)	13 (11/84)	10 (4/39)	3 (−12.0, 17.6)
No	63 (173/274)	42 (110/261)	21 (12.6, 29.2)	56 (193/347)	57 (191/334)	−2 (−9.1, 6.0)	19 (41/216)	6 (6/110)	14 (6.7, 20.4)
CV risk factors
≥2	63 (78/124)	48 (59/124)	15 (2.5, 27.8)	54 (140/259)	59 (160/273)	−5 (−13.0, 4.0)	17 (25/145)	10 (8/80)	7 (−2.5, 17.0)
≤1	59 (108/182)	37 (69/189)	23 (12.7, 32.6)	54 (89/164)	53 (80/150)	1 (−10.1, 12.0)	17 (27/155)	3 (2/69)	15 (7.5, 21.5)
Hypertension
Yes	63 (97/154)	44 (74/167)	19 (7.8, 29.3)	54 (168/313)	61 (185/305)	−7 (−14.8, 1.0)	17 (40/232)	8 (9/112)	9 (1.4, 17.0)
No	59 (89/152)	37 (53/145)	22 (10.7, 33.0)	55 (60/109)	47 (55/118)	8 (−4.7, 21.3)	17 (11/66)	3 (1/36)	14 (3.9, 23.8)
Statin use
Yes	63 (12/19)	37 (10/27)	26 (−3.8, 52.6)	51 (91/177)	58 (98/169)	7 (−17.1, 4.0)	20 (20/102)	11 (8/71)	8 (−2.5, 19.2)
No	61 (174/287)	41 (118/286)	19 (11.1, 27.4)	56 (138/246)	56 (142/254)	0.2 (−8.6, 9.0)	16 (32/198)	3 (2/78)	14 (7.3, 19.9)

Note: Data from Minervini et al³³ and Cook et al.³⁶

Abbreviations: CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; GLIP, glipizide; HbA_1c, glycated hemoglobin; INS, insulin; MET, metformin; n/N, number of patients achieving target/total number of patients in that group; PBO, placebo; SAXA, saxagliptin.

Table 6 Adverse events and incidence of hypoglycemia in patients with cardiovascular disease history or cardiovascular risk factors: five-study pool

n (%)	CVD history				CV risk factors				Hypertension				Statin use
	Yes		No		≥2		≥1		Yes		No		Yes		No
	SAXA n=111	PBO n=97	SAXA n=766	PBO n=699	SAXA n=468	PBO n=419	SAXA n=414	PBO n=380	SAXA n=466	PBO n=448	SAXA n=414	PBO n=349	SAXA n=214	PBO n=212	SAXA n=668	PBO n=587
≥1 AE	78 (70)	70 (72)	554 (72)	491 (70)	353 (75)	306 (73)	284 (69)	258 (68)	331 (71)	325 (73)	305 (74)	237 (68)	165 (77)	160 (76)	472 (71)	404 (69)
≥1 SAE	5 (5)	7 (7)	24 (3)	20 (3)	18 (4)	17 (4)	12 (3)	10 (3)	17 (4)	20 (5)	13 (3)	7 (2)	10 (5)	8 (4)	20 (3)	19 (3)
Hypoglycemia
Reported	8 (7)	6 (6)	60 (8)	48 (7)	36 (8)	29 (7)	33 (8)	25 (7)	39 (8)	29 (7)	30 (7)	25 (7)	24 (11)	15 (7)	45 (7)	39 (7)
Confirmed*	0	2 (2)	4 (0.5)	1 (0.1)	3 (0.6)	3 (0.7)	1 (0.2)	0	3 (0.6)	3 (0.7)	1 (0.2)	0	1 (0.5)	2 (0.9)	3 (0.4)	1 (0.2)

Note:

* Fingerstick glucose ≤50 mg/dL with symptoms. Data from Cook et al.³²

Abbreviations: AE, adverse event; CV, cardiovascular; CVD, cardiovascular disease; PBO, placebo; SAE, serious adverse event; SAXA, saxagliptin.

Table 7 Adverse events and confirmed hypoglycemia in patients with cardiovascular disease history or cardiovascular risk factors: three side-by-side studies

Subgroup	SAXA + MET n=320	PBO + MET n=328	SAXA + MET n=428	GLIP + MET n=430	SAXA + INS ± MET n=304	PBO + INS ± MET n=151
CVD history
Yes	n=34	n=53	n=79	n=91	n=85	n=39
≥1 AE	20 (59)	31 (59)	39 (49)	61 (67)	40 (47)	22 (56)
≥1 SAE	2 (6)	6 (11)	8 (10)	14 (15)	3 (4)	4 (10)
Confirmed hypoglycemia*	0	0	0	6 (7)	1 (1)	0
No	n=286	n=275	n=349	n=339	n=219	n=112
≥1 AE	158 (55)	161 (59)	224 (64)	233 (69)	133 (61)	68 (61)
≥1 SAE	6 (2)	2 (1)	31 (9)	21 (6)	9 (4)	3 (3)
Confirmed hypoglycemia	0	1 (0)	0	29 (9)	15 (7)	6 (5)
CV risk factor
≥2	n=129	n=127	n=262	n=277	n=145	n=81
≥1 AE	81 (63)	76 (60)	168 (64)	200 (72)	78 (54)	47 (58)
≥1 SAE	5 (4)	2 (2)	28 (11)	25 (9)	7 (5)	5 (6)
Confirmed hypoglycemia	0	0	0	28 (10)	7 (5)	3 (4)
≤1	n=191	n=201	n=166	n=153	n=159	n=70
≥1 AE	97 (51)	116 (58)	95 (57)	94 (61)	95 (60)	43 (61)
≥1 SAE	3 (2)	6 (3)	11 (7)	10 (7)	5 (3)	2 (3)
Confirmed hypoglycemia	0	1 (1)	0	7 (5)	9 (6)	3 (4)
Hypertension
Yes	n=160	n=172	n=318	n=311	n=234	n=113
≥1 AE	91 (57)	101 (59)	196 (62)	208 (67)	126 (54)	63 (56)
≥1 SAE	5 (3)	6 (4)	32 (10)	29 (9)	7 (3)	5 (4)
Confirmed hypoglycemia	0	0	0	26 (8)	11 (5)	3 (3)
No	n=160	n=155	n=109	n=119	n=68	n=37
≥1 AE	87 (54)	90 (58)	67 (62)	86 (72)	45 (66)	27 (73)
≥1 SAE	3 (2)	2 (1)	7 (6)	6 (5)	4 (6)	2 (5)
Confirmed hypoglycemia	0	1 (1)	0	9 (8)	5 (7)	3 (8)
Statin use
Yes	n=20	n=27	n=180	n=172	n=103	n=71
≥1 AE	13 (65)	17 (63)	121 (67)	122 (71)	57 (55)	48 (68)
≥1 SAE	0	2 (7)	23 (13)	13 (8)	6 (6)	5 (7)
Confirmed hypoglycemia	0	0	0	16 (9)	8 (8)	4 (6)
No	n=300	n=301	n=248	n=258	n=201	n=80
≥1 AE	165 (55)	175 (58)	142 (57)	172 (67)	116 (58)	42 (53)
≥1 SAE	8 (3)	6 (2)	16 (7)	22 (9)	6 (3)	2 (3)
Confirmed hypoglycemia	0	1 (0)	0	19 (7)	8 (4)	2 (3)

Notes: Data from Minervini et al³³ and Cook et al.³⁶ Data are n (%).

* Fingerstick glucose ≤50 mg/dL with symptoms.

Abbreviations: AE, adverse event; CV, cardiovascular; CVD, cardiovascular disease; GLIP, glipizide; INS, insulin; MET, metformin; PBO, placebo; SAE, serious adverse event; SAXA, saxagliptin.

Table 8 Efficacy of saxagliptin in patients with high Framingham 10-year cardiovascular risk: five-study pool

	Adjusted mean change from baseline						Patients achieving HbA1c <7.0%, % (n/N)
	HbA1c, % (n)		FPG, mg/dL (n)		PPG, mg/dL (n)
	SAXA	PBO	SAXA	PBO	SAXA	PBO	SAXA	PBO
Framingham CV risk <20%	−0.61 (443)	−0.07 (390)	−13 (447)	0.2 (396)	−50 (347)	−9 (297)	35 (154/443)	19 (73/390)
Difference versus PBO (95% CI)	−0.54 (−0.67, −0.41)		−13 (−18.1, −7.8)		−42 (−51.7, −31.6)		14 (8.1, 20.7)
Framingham CV risk ≥20%	−0.81 (400)	0 (374)	−16 (404)	0.6 (374)	−56 (306)	−15 (278)	38 (152/400)	19 (72/374)
Difference versus PBO (95% CI)	−0.81 (−0.94, −0.67)		−16 (−21.5, −10.8)		−41 (−51.3, −30.2)		18 (11.4, 24.6)
Treatment-by-subgroup interaction	P=0.01		P=0.55		P=0.85

Note: Data from Bonora et al.³⁸

Abbreviations: CI, confidence interval; CV, cardiovascular; FPG, fasting plasma glucose; HbA_1c, glycated hemoglobin; n/N, number of patients achieving target/total number of patients in that group; PBO, placebo; PPG, postprandial glucose; SAXA, saxagliptin.

Table 9 Adverse events and confirmed hypoglycemia in patients with high Framingham 10-year cardiovascular risk

	Framingham 10-year CV risk score
	<20%		≥20%
	SAXA (n=454)	PBO (n=404)	SAXA (n=408)	PBO (n=380)
≥1 AE	318 (70)	275 (68)	302 (74)	277 (73)
≥1 SAE	13 (3)	9 (2)	16 (4)	18 (5)
Hypoglycemia
Reported	36 (8)	28 (7)	29 (7)	26 (7)
Confirmed*	2 (0)	0	2 (1)	3 (1)

Notes: Data are n (%).

* Fingerstick glucose ≤50 mg/dL with symptoms. Data from Bonora et al.³⁸

Abbreviations: AE, adverse event; CV, cardiovascular; PBO, placebo; SAE, serious adverse event; SAXA, saxagliptin.

Table 10 Efficacy of saxagliptin in patients with or without statin use at baseline

	HbA1c, %			FPG, mg/dL			PPG, mg/dL			Patients achieving HbA0 <7.0%, % (n/N)
	SAXA 2.5 mg (n)	SAXA 5 mg (n)	PBO (n)	SAXA 2.5 mg (n)	SAXA 5 mg (n)	PBO (n)	SAXA 2.5 mg (n)	SAXA 5 mg (n)	PBO (n)	SAXA 2.5 mg	SAXA 5 mg	PBO
Any statin use	−0.64 (177)	−0.73 (337)	−0.10 (318)	−11 (179)	−19 (337)	−3 (318)	−49 (131)	−58 (230)	−18 (186)	36 (64/181)	34 (113/342)	17 (55/322)
Difference versus PBO (95% CI)	−0.53 (−0.71, −0.36)	−0.62 (−0.77, −0.48)		−9 (−15.7, −1.4)	−16 (−22.1, −10.3)		−31 (−45.3, −16.6)	−40 (−52.3, −27.8)		18 (8.5, 27.7)	17 (9.4, 23.7)
No statin	−0.66 (614)	−0.70 (1,480)	−0.16 (1,268)	−14 (620)	−13 (1,498)	−2 (1,280)	−51 (501)	−46 (905)	−13 (718)	33 (200/630)	36 (529/1,518)	22 (278/1,305)
Difference versus PBO (95% CI)	−0.51 (−0.60, −0.41)	−0.54 (−0.61, −0.47)		−12 (−16.0, −8.1)	−11 (−14.0, −8.3)	−2	−37 (−44.7, −29.7)	−33 (−38.9, −26.4)		13 (8.3, 18.2)	15 (11.7, 18.5)
Treatment-by-subgroup interaction	P=0.47			P=0.81			P=0.93

Note: Data from Bryzinski et al.⁴¹

Abbreviations: CI, confidence interval; FPG, fasting plasma glucose; HbA_1c, glycated hemoglobin; PBO, placebo; PPG, postprandial glucose; SAXA, saxagliptin.

Table 11 Adverse events and confirmed hypoglycemia in patients with or without statin use at baseline: eleven-study pool

n (%)	Any statin use			No statin use
	SAXA		PBO	SAXA		PBO
	2.5 mg (n=192)	5 mg (n=436)	(n=418)	2.5 mg (n=690)	5 mg (n=1,891)	(n=1,676)
≥1 AE	150 (78)	279 (64)	264 (63)	487 (71)	1,094 (58)	921 (55)
≥1 SAE	11 (6)	19 (4)	16 (4)	20 (3)	57 (3)	38 (2)
Hypoglycemia
Reported	22 (12)	50 (12)	40 (10)	47 (7)	107 (6)	71 (4)
Confirmed*	0	9 (2)	10 (2)	7 (1)	10 (1)	4 (0)

Notes: Data from Bryzinski et al.⁴¹

* Fingerstick glucose ≤50 mg/dL with symptoms.

Abbreviations: AE, adverse event; PBO, placebo; SAE, serious adverse event; SAXA, saxagliptin.

DruckerDJThe role of gut hormones in glucose homeostasisJ Clin Invest20071171243217200703

 PubMed Web of Science ®Google Scholar

RosenstockJAguilar-SalinasCKleinENepalSListJChenREffect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetesCurr Med Res Opin200925102401241119650754

 PubMed Web of Science ®Google Scholar

FrederichRMcNeillRBerglindNFlemingDChenRThe efficacy and safety of the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment-naive patients with type 2 diabetes mellitus: a randomized controlled trialDiabetol Metab Syndr2012413622828124

 PubMed Web of Science ®Google Scholar

DeFronzoRAHissaMNGarberAJThe efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin aloneDiabetes Care20093291649165519478198

 PubMed Web of Science ®Google Scholar

ChacraARTanGHApanovitchARavichandranSListJChenRSaxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trialInt J Clin Pract20096391395140619614786

 PubMed Web of Science ®Google Scholar

HollanderPLiJAllenEChenRCV181-013 InvestigatorsSaxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione aloneJ Clin Endocrinol Metab200994124810481919864452

 PubMed Web of Science ®Google Scholar

JadzinskyMPfutznerAPaz-PachecoEXuZAllenEChenRSaxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trialDiabetes Obes Metab200911661162219515181

 PubMed Web of Science ®Google Scholar

GökeBGallwitzBErikssonJHellqvistAGause-NilssonISaxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trialInt J Clin Pract201064121619163120846286

 PubMed Web of Science ®Google Scholar

BarnettAHCharbonnelBDonovanMFlemingDEffect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metforminCurr Med Res Opin201228451352322313154

 PubMed Web of Science ®Google Scholar

PanCYYangWTouCGause-NilssonIZhaoJEfficacy and safety of saxagliptin in drug-naive Asian patients with type 2 diabetes mellitus: a randomized controlled trialDiabetes Metab Res Rev201228326827522081481

 PubMed Web of Science ®Google Scholar

KumarKMPJainSTouCSchützerKMSaxagliptin as initial therapy in treatment-naive Indian adults with type 2 diabetes mellitus inadequately controlled with diet and exercise alone: a randomized, double-blind, placebo-controlled, phase IIIb clinical studyInt J Diabetes Dev Ctries201419

 Web of Science ®Google Scholar

YangWPanCYTouCZhaoJGause-NilssonIEfficacy and safety of saxagliptin added to metformin in Asian people with type 2 diabetes mellitus: a randomized controlled trialDiabetes Res Clin Pract201194221722421871686

 PubMed Web of Science ®Google Scholar

HermansMPDelibasiTFarmerIEffects of saxagliptin added to sub-maximal doses of metformin compared with uptitration of metformin in type 2 diabetes: the PROMPT studyCurr Med Res Opin201228101635164523020253

 PubMed Web of Science ®Google Scholar

NowickiMRychlikIHallerHWarrenLSuchowerLGause-NilssonISaxagliptin improves glycaemic control and is well tolerated in patients with type 2 diabetes mellitus and renal impairmentDiabetes Obes Metab201113652353221332627

 PubMed Web of Science ®Google Scholar

RosenstockJSankohSListJFGlucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetesDiabetes Obes Metab200810537638618355324

 PubMed Web of Science ®Google Scholar

HenryRRSmithSRSchwartzSLEffects of saxagliptin on beta-cell stimulation and insulin secretion in patients with type 2 diabetesDiabetes Obes Metab201113985085821554520

 PubMed Web of Science ®Google Scholar

ScheenAJCharpentierGOstgrenCJHellqvistAGause-NilssonIEfficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitusDiabetes Metab Res Rev201026754054920824678

 PubMed Web of Science ®Google Scholar

StenlofKRazINeutelJRavichandranSBerglindNChenRSaxagliptin and metformin XR combination therapy provides glycemic control over 24 hours in patients with T2DM inadequately controlled with metforminCurr Med Res Opin201026102355236320804445

 PubMed Web of Science ®Google Scholar

WhiteJLBuchananPLiJFrederichRA randomized controlled trial of the efficacy and safety of twice-daily saxagliptin plus metformin combination therapy in patients with type 2 diabetes and inadequate glycemic control on metformin monotherapyBMC Endocr Disord20141411724565221

 PubMedGoogle Scholar

NeutelJMZhaoCKaryekarCSAdding saxagliptin to metformin extended release (XR) or uptitration of metformin XR: efficacy on daily glucose measuresDiabetes Ther20134226928323881432

 PubMed Web of Science ®Google Scholar

FonsecaVZhuTKaryekarCHirshbergBAdding saxagliptin to extended-release metformin vs. uptitrating metformin dosageDiabetes Obes Metab201214436537122192246

 PubMed Web of Science ®Google Scholar

CookWBryzinskiBSlaterJFrederichRAllenESaxagliptin efficacy and safety in patients with type 2 diabetes mellitus and cardiovascular disease history or cardiovascular risk factors: results of a pooled analysis of phase 3 clinical trialsPostgrad Med2013125314515423748515

 PubMed Web of Science ®Google Scholar

MinerviniGCookWAllenEEfficacy and tolerability of saxagliptin in patients with type 2 diabetes mellitus and a history of cardiovascular diseaseDiabetes201362Suppl 1A306

 Google Scholar

CookWBryzinskiBAllenEHirshbergBSaxagliptin (SAXA) efficacy and safety in patients with type 2 diabetes mellitus (T2DM) stratified by cardiovascular (CV) risk factorsEndocr Rev201334SUN-849

 Google Scholar

BonoraEAllenEBryzinskiBHirshbergBCookWSaxagliptin reduces HbA1c and is well tolerated in patients with type 2 diabetes and high Framingham 10-year cardiovascular riskDiabetes201362Suppl 1A295

 Google Scholar

BryzinskiBAllenECookWHirshbergBSaxagliptin efficacy and safety in patients with type 2 diabetes receiving concomitant statin therapyJ Diabetes Complications7172014 Epub ahead of print

 PubMed Web of Science ®Google Scholar