Safety and efficacy of vildagliptin: 52-week post-marketing surveillance of Japanese patients with type 2 diabetes in combination with other oral antidiabetics and insulin

Figures & data

Figure 1. Patient disposition

^aSome patients had more than one reason for exclusion from the safety analysis population. CRF: case report form.

Table 1. Patient baseline characteristics

		Safety and Efficacy Analysis Population (N = 3006)
Sex	Male	1793 (59.7)
Age (years)	Mean (SD)	63.8 (12.8)
	<65	1467 (48.8)
	≥65	1539 (51.2)
Disease duration (years)	<5	496 (16.5)
	5 to <10	515 (17.1)
	≥10	849 (28.2)
	Unknown	1146 (38.1)
Complications		2441 (81.2)
Diabetic retinopathy		390 (13.0)
Diabetic nephropathy^a		677 (22.5)
	Pre-nephropathy	109 (16.1)
	Early nephropathy	304 (44.9)
	Early overt nephropathy	165 (24.4)
	Late overt nephropathy	56 (8.3)
	Renal failure	25 (3.7)
	Dialysis	16 (2.4)
	Unknown/not recorded	2 (0.3)
Diabetic neuropathy		397 (13.2)
Hypertension		1771 (58.9)
Dyslipidemia		1725 (57.4)
Renal impairment^a		396 (13.2)
	Mild	266 (67.2)
	Moderate	74 (18.7)
	Severe	39 (9.9)
	Unknown	17 (4.3)
Cardiac impairment		434 (14.4)
Hepatic impairment		438 (14.6)
BMI (kg/m^2)	N	2273
	Mean (SD)	25.8 (4.6)
	<25.0	1089 (36.2)
	≥25.0	1184 (39.4)
	Unknown	733 (24.4)
Smoking history		653 (21.7)
	Unknown	456 (15.2)
Prior treatment with DPP-4 inhibitors^b		236 (7.9)
Concomitant use of antidiabetics^c		3006 (100.0)
	SUs	789 (26.3)
	BGs	1640 (54.6)
	Met (≥1000 mg/day)	658 (21.9)
	Unknown	65 (2.2)
	TZDs	419 (13.9)
	αGIs	789 (26.3)
	Glinides	245 (8.2)
	Insulin products	687 (22.9)
	DPP-4 inhibitors	9 (0.3)
	SGLT2 inhibitors	28 (0.9)
	Other antidiabetics	137 (4.6)
Concomitant drugs other than antidiabetics^c		1476 (49.1)
HbA1c (NGSP value)	Baseline (mean (SD))	8.04 (1.44)

Data are shown as n (%), unless otherwise indicated.

^aSeverity is calculated with the number of patients with this complication as the denominator.

^bFrom 12 weeks prior to start of treatment.

^cConcomitant use at the start of vildagliptin treatment.

αGI; α-glucosidase inhibitor; BG: biguanide; BMI: body mass index; DPP-4: dipeptidyl peptidase 4; HbA1c: glycated hemoglobin; Met: metformin; NGSP: National Glycohemoglobin Standardization Program; SD: standard deviation; SGLT2: sodium glucose co-transporter 2 inhibitor; SU: sulfonylurea; TZD: thiazolidine derivative

Table 2. Summary of adverse events observed in ≥5 patients

	All	By type of concomitant antidiabetic^a
		BGs
		All	Met ≥1000 mg/day	Met <1000 mg/day	TZDs	αGIs	Glinides	Insulin products	SGLT2 inhibitors
No. of patients analyzed	3006	1640	658	911	419	789	245	687	28
No. of adverse events	609	309	130	165	105	144	78	176	0
No. of patients with adverse events; n (%)	409 (13.61)	212 (12.93)	85 (12.92)	115 (12.62)	70 (16.71)	104 (13.18)	50 (20.41)	109 (15.87)	0 (0.0)
No. of serious adverse events	89	38	17	19	17	17	21	17	0
No. of patients with serious adverse events; n (%)	66 (2.20)	24 (1.46)	8 (1.22)	14 (1.54)	12 (2.86)	15 (1.90)	14 (5.71)	17 (2.47)	0 (0.0)
Preferred Term	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)
Diabetes mellitus	25 (0.83)	14 (0.85)	10 (1.52)	4 (0.44)	6 (1.43)	8 (1.01)	2 (0.82)	7 (1.02)	－
Diabetes mellitus inadequate control	20 (0.67)	15 (0.91)	8 (1.22)	6 (0.66)	3 (0.72)	4 (0.51)	1 (0.41)	2 (0.29)	－
Hyperglycemia	17 (0.57)	8 (0.49)	3 (0.46)	3 (0.33)	5 (1.19)	7 (0.89)	1 (0.41)	5 (0.73)	－
Hypoglycemia	13 (0.43)	7 (0.43)	2 (0.30)	4 (0.44)	2 (0.48)	2 (0.25)	1 (0.41)	5 (0.73)	－
Hypertriglyceridemia	8 (0.27)	6 (0.37)	1 (0.15)	5 (0.55)	1 (0.24)	2 (0.25)	1 (0.41)	2 (0.29)	－
Hyperuricemia	6 (0.20)	3 (0.18)	－	3 (0.33)	－	3 (0.38)	1 (0.41)	3 (0.44)	－
Insomnia	6 (0.20)	3 (0.18)	2 (0.30)	1 (0.11)	2 (0.48)	2 (0.25)	－	1 (0.15)	－
Dizziness	5 (0.17)	2 (0.12)	－	2 (0.22)	2 (0.48)	1 (0.13)	－	1 (0.15)	－
Angina pectoris	7 (0.23)	1 (0.06)	－	－	2 (0.48)	2 (0.25)	－	6 (0.87)	－
Hypertension	17 (0.57)	5 (0.30)	4 (0.61)	1 (0.11)	5 (1.19)	10 (1.27)	2 (0.82)	3 (0.44)	－
Upper respiratory tract inflammation	5 (0.17)	－	－	－	3 (0.72)	－	1 (0.41)	3 (0.44)	－
Constipation	14 (0.47)	6 (0.37)	2 (0.30)	4 (0.44)	3 (0.72)	2 (0.25)	4 (1.63)	5 (0.73)	－
Gastroesophageal reflux disease	6 (0.20)	3 (0.18)	1 (0.15)	2 (0.22)	1 (0.24)	4 (0.51)	－	1 (0.15)	－
Hepatic function abnormal	21 (0.70)	11 (0.67)	3 (0.46)	7 (0.77)	1 (0.24)	6 (0.76)	3 (1.22)	6 (0.87)	－
Rash	5 (0.17)	2 (0.12)	1 (0.15)	1 (0.11)	－	－	1 (0.41)	2 (0.29)	－
Renal impairment	9 (0.30)	5 (0.30)	－	5 (0.55)	1 (0.24)	2 (0.25)	1 (0.41)	3 (0.44)	－
Glycosylated hemoglobin increased	30 (1.00)	17 (1.04)	8 (1.22)	8 (0.88)	4 (0.95)	7 (0.89)	4 (1.63)	5 (0.73)	－
Blood pressure increased	25 (0.83)	16 (0.98)	9 (1.37)	7 (0.77)	4 (0.95)	3 (0.38)	2 (0.82)	6 (0.87)	－
Blood triglycerides increased	17 (0.57)	11 (0.67)	5 (0.76)	6 (0.66)	1 (0.24)	－	－	7 (1.02)	－
Blood glucose increased	15 (0.50)	5 (0.30)	1 (0.15)	3 (0.33)	1 (0.24)	3 (0.38)	5 (2.04)	5 (0.73)	－
Glucose urine present	15 (0.50)	7 (0.43)	4 (0.61)	3 (0.33)	3 (0.72)	2 (0.25)	2 (0.82)	5 (0.73)	－
Blood creatine phosphokinase increased	9 (0.30)	6 (0.37)	3 (0.46)	3 (0.33)	3 (0.72)	2 (0.25)	－	3 (0.44)	－
Alanine aminotransferase increased	7 (0.23)	3 (0.18)	2 (0.30)	1 (0.11)	－	1 (0.13)	－	5 (0.73)	－
Aspartate aminotransferase increased	7 (0.23)	2 (0.12)	2 (0.30)	－	－	2 (0.25)	－	5 (0.73)	－
Weight increased	7 (0.23)	4 (0.24)	1 (0.15)	3 (0.33)	1 (0.24)	3 (0.38)	1 (0.41)	1 (0.15)	－
Blood creatinine increased	5 (0.17)	3 (0.18)	－	1 (0.11)	2 (0.48)	1 (0.13)	－	－	－
Blood uric acid increased	5 (0.17)	3 (0.18)	2 (0.30)	1 (0.11)	－	1 (0.13)	－	3 (0.44)	－
Low density lipoprotein increased	5 (0.17)	3 (0.18)	1 (0.15)	2 (0.22)	－	－	－	2 (0.29)	－

MedDRA/J (Version 20.0)

^aThe number of patients analyzed by type of concomitant antidiabetics is based on the concomitant medication used at the start of vildagliptin treatment.

Patients receiving multiple antidiabetics were counted in the respective antidiabetic categories.

Multiple episodes of an event (preferred term) in the same patient are counted only once.

αGIs; α-glucosidase inhibitors; BGs: biguanides; Met: metformin; SGLT2: sodium glucose co-transporter 2; TZDs: thiazolidine derivatives

Table 3. Summary of risk management plan-related ADRs

		By type of concomitant antidiabetic^a
		BGs
	All	All	Met ≥1000 mg/day	Met <1000 mg/day	TZDs	αGIs	Glinides	Insulin products	SGLT2 inhibitors
No. of patients analyzed^a	3006	1640	658	911	419	789	245	687	28
No. of ADRs	42	25	7	15	6	8	3	13	0
No. of patients with ADRs; n (%)	41 (1.36)	25 (1.52)	7 (1.06)	15 (1.65)	5 (1.19)	8 (1.01)	3 (1.22)	13 (1.89)	0 (0.00)
Type of ADR	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)
Transaminase increased and drug-induced hepatitis	7 (0.23)	3 (0.18)	1 (0.15)	2 (0.22)	1 (0.24)	4 (0.51)	1 (0.41)	2 (0.29)	－
Hepatic function abnormal	5 (0.17)	2 (0.12)	－	2 (0.22)	1(0.24)	3 (0.38)	1 (0.41)	1 (0.15)	－
Liver disorder	1 (0.03)	－	－	－	－	1 (0.13)	－	－	－
Blood alkaline phosphatase increased	1 (0.03)	1 (0.06)	1 (0.15)	－	－	－	－	1 (0.15)	－
Angioedema	5 (0.17)	2 (0.12)	1 (0.15)	1 (0.11)	1 (0.24)	1 (0.13)	－	2 (0.29)	－
Rash	3 (0.10)	2 (0.12)	1 (0.15)	1 (0.11)	－	－	－	1 (0.15)	－
Pruritus	1 (0.03)	－	－	－	1 (0.24)	－	－	－	－
Urticaria	1 (0.03)	－	－	－	－	1 (0.13)	－	1 (0.15)	－
Acute pancreatitis	6 (0.20)	4 (0.24)	2 (0.30)	1 (0.11)	－	－	1 (0.41)	2 (0.29)	－
Abdominal distension	2 (0.07)	1 (0.06)	－	－	－	－	1 (0.41)	1 (0.15)	－
Nausea	2 (0.07)	2 (0.12)	1 (0.15)	1 (0.11)	－	－	－	－	－
Abdominal pain	1 (0.03)	1 (0.06)	1 (0.15)	－	－	－	－	－	－
Amylase increased	1 (0.03)	－	－	－	－	－	－	1 (0.15)	－
Skin lesion	11 (0.37)	6 (0.37)	1 (0.15)	5 (0.55)	1 (0.24)	2 (0.25)	－	4 (0.58)	－
Drug eruption	3 (0.10)	2 (0.12)	－	2 (0.22)	－	－	－	1 (0.15)	－
Rash	3 (0.10)	2 (0.12)	1 (0.15)	1 (0.11)	－	－	－	1 (0.15)	－
Alopecia	1 (0.03)	1 (0.06)	－	1 (0.11)	－	1 (0.13)	－	－	－
Dermatitis	1 (0.03)	－	－	－	－	－	－	1 (0.15)	－
Pruritus	1 (0.03)	－	－	－	1 (0.24)	－	－	－	－
Skin exfoliation	1 (0.03)	1 (0.06)	－	1 (0.11)	－	－	－	－	－
Urticaria	1 (0.03)	－	－	－	－	1 (0.13)	－	1 (0.15)	－
Hypoglycemia	12 (0.40)	7 (0.43)	2 (0.30)	4 (0.44)	3 (0.72)	1 (0.13)	1 (0.41)	4 (0.58)	－
Hypoglycemia	11 (0.37)	7 (0.43)	2 (0.30)	4 (0.44)	2 (0.48)	1 (0.13)	1 (0.41)	4 (0.58)	－
Blood glucose decreased	1 (0.03)	－	－	－	1 (0.24)	－	－	－	－
Serious infection	0 (0.00)	－	－	－	－	－	－	－	－
Cardiovascular risks	2 (0.07)	2 (0.12)	1 (0.15)	1 (0.11)	－	－	－	－	－
Atrial fibrillation	1 (0.03)	1 (0.06)	－	1 (0.11)	－	－	－	－	－
Palpitations	1 (0.03)	1 (0.06)	1 (0.15)	－	－	－	－	－	－
Muscular events	4 (0.13)	3 (0.18)	－	2 (0.22)	1 (0.24)	1 (0.13)	－	1 (0.15)	－
Blood creatine phosphokinase increased	2 (0.07)	1 (0.06)	－	1 (0.11)	1 (0.24)	1 (0.13)	－	－	－
Blood creatinine increased	1 (0.03)	1 (0.06)	－	－	－	－	－	－	－
Rhabdomyolysis	1 (0.03)	1 (0.06)	－	1(0.11)	－	－	－	1 (0.15)	－
Neuropsychiatry events	0 (0.00)	－	－	－	－	－	－	－	－
Breast cancer	0 (0.00)	－	－	－	－	－	－	－	－
Pancreatic cancer	0 (0.00)	－	－	－	－	－	－	－	－

MedDRA/J (Version 20.0)

^aThe number of patients analyzed by type of concomitant antidiabetics is based on the concomitant medication used at the start of vildagliptin treatment.

Patients receiving multiple antidiabetics were counted in the respective antidiabetic categories.

Multiple episodes of an event (preferred term) in the same patient are counted only once.

αGIs; α-glucosidase inhibitors; ADR: adverse drug reaction; BGs: biguanides; Met: metformin; SGLT2: sodium glucose co-transporter 2; TZDs: thiazolidine derivatives.

Figure 2. Changes in HbA1c over time from baseline to endpoint

αGI: α-glucosidase inhibitor; BG: biguanide; GND: rapid-acting insulin secretagogue (glinide); HbA1c: glycated hemoglobin; INS: insulin; Met: metformin; NGSP: National Glycohemoglobin Standardization Program; SD: standard deviation; TZD: thiazolidine derivative.

Table 4. Change in HbA1c from baseline stratified by concomitant antidiabetic medication

		HbA1c (mean ± SD)
	N	Baseline	Endpoint	Change	p-value^a
All	2686	8.03 ± 1.42	7.27 ± 1.20	−0.76 ± 1.27	<0.0001
BGs	1493	8.05 ± 1.38	7.31 ± 1.17	−0.74 ± 1.29	<0.0001
Met ≥1000 mg/day	614	8.04 ± 1.33	7.40 ± 1.15	−0.64 ± 1.20	<0.0001
Met <1000 mg/day	815	8.06 ± 1.42	7.24 ± 1.17	−0.81 ± 1.32	<0.0001
TZDs	375	7.81 ± 1.23	7.16 ± 1.17	−0.65 ± 1.12	<0.0001
αGIs	683	7.83 ± 1.37	7.11 ± 1.11	−0.72 ± 1.20	<0.0001
Glinides	218	7.76 ± 1.22	7.08 ± 1.11	−0.68 ± 1.22	<0.0001
Insulin	627	8.45 ± 1.56	7.79 ± 1.28	−0.66 ± 1.34	<0.0001

^apaired t-test

αGIs: α-glucosidase inhibitors; BGs: biguanides; HbA1c: glycated hemoglobin; Met: metformin; SD: standard deviation; TZDs: thiazolidine derivatives.

Table 5. Mean change in HbA1c over time stratified by patient characteristics

			HbA1c (mean)
		N (%)	Baseline	Endpoint	95% CI	Change	95% CI
Overall		2686	8.03	7.27	7.22, 7.31	−0.76	−0.81, −0.71
Sex	Male	1604 (59.7)	8.06	7.27	7.22, 7.33	−0.78	−0.85, −0.72
	Female	1082 (40.3)	7.98	7.26	7.18, 7.33	−0.72	−0.79, −0.65
Age (years)	<65	1324 (49.3)	8.31	7.46	7.39, 7.53	−0.85	−0.93, −0.78
	≥65	1362 (50.7)	7.75	7.08	7.02, 7.13	−0.67	−0.72, −0.61
Body mass index (kg/m^2)	<25.0	984 (36.6)	7.93	7.17	7.1, .24	−0.76	−0.84, −0.68
	≥25.0	1091 (40.6)	8.17	7.38	7.31, 7.46	−0.79	−0.86, −0.72
	Unknown	611 (22.8)	7.92	7.21	7.12, 7.31	−0.7	−0.8, −0.6
Prior treatment with DPP-4 inhibitors^a	No	2470 (92.0)	8.04	7.25	7.2. 7.3	−0.79	−0.84, −0.74
	Yes	216 (8.0)	7.88	7.48	7.33, 7.62	−0.41	−0.55, −0.27

Patients analyzed were those with values measured on the start date of treatment (or immediately before start) and at the last assessment.

^aStatus of use during the period from 12 weeks (84 days) before to the day before the start of vildagliptin treatment.

CI: confidence interval; DPP-4: dipeptidyl peptidase 4; HbA1c: glycated hemoglobin.

Figure 3. Mean change in fasting blood glucose over time from baseline to endpoint

αGI: α-glucosidase inhibitor; BG: biguanide; GND: rapid-acting insulin secretagogue (glinide); INS: insulin; Met: metformin; SD: standard deviation; TZD: thiazolidine derivative.