Safety and effectiveness of empagliflozin and linagliptin fixed-dose combination therapy in Japanese patients with type 2 diabetes: final results of a one-year post-marketing surveillance study

Figures & data

Table 1. Patient baseline characteristics by age group (safety analysis set).

Characteristic		Age group, years
	All patients (N = 1146)	<65 (N = 572)	≥65 to <75 (N = 321)	≥75 (N = 253)
Age, mean ± SD, years	63.8 12.8	53.3 8.1	69.5 2.7	80.3 4.5
Sex, n (%)
Male	752 (65.62)	414 (72.38)	203 (63.24)	135 (53.36)
Female	394 (34.38)	158 (27.62)	118 (36.76)	118 (46.64)
Body weight, n	1064	542	296	226
kg, mean ± SD	70.73 ± 15.49	77.42 ± 14.91	66.44 ± 12.54	60.28 ± 12.33
BMI, n	1003	519	276	208
kg/m^2, mean ± SD	26.53 ± 4.45	27.87 ± 4.47	25.56 ± 4.05	24.48 ± 3.72
BMI category, n (%)
<20 kg/m^2	49 (4.28)	8 (1.40)	20 (6.23)	21 (8.30)
≥20 to <25 kg/m^2	345 (30.10)	136 (23.78)	106 (33.02)	103 (40.71)
≥25 to <30 kg/m^2	405 (35.34)	222 (38.81)	113 (35.20)	70 (27.67)
≥30 kg/m^2	204 (17.80)	153 (26.75)	37 (11.53)	14 (5.53)
Time since T2D diagnosis, n	666	361	186	119
years, mean ± SD	10.5 ± 8.2	8.3 ± 6.8	12.6 ± 8.7	13.9 ± 9.1
Time since T2D diagnosis category, n (%)
≤1 year	45 (3.93)	35 (6.12)	7 (2.18)	3 (1.19)
>1 to 5 years	152 (13.26)	99 (17.31)	29 (9.03)	24 (9.49)
>5 to 10 years	179 (15.62)	113 (19.76)	46 (14.33)	20 (7.91)
>10 years	290 (25.31)	114 (19.93)	104 (32.40)	72 (28.46)
Unknown	480 (41.88)	211 (36.89)	135 (42.06)	134 (52.96)
HbA1c, n	1118	562	312	244
%, mean ± SD	7.66 ± 1.21	7.80 ± 1.36	7.52 ± 1.01	7.51 ± 1.01
HbA1c category, n (%)
<7.0%	297 (25.92)	136 (23.78)	91 (28.35)	70 (27.67)
≥7.0 to <8.0%	491 (42.84)	242 (42.31)	145 (45.17)	104 (41.11)
≥8.0 to <9.0%	212 (18.50)	101 (17.66)	57 (17.76)	54 (21.34)
≥9.0%	118 (10.30)	83 (14.51)	19 (5.92)	16 (6.32)
Fasting plasma glucose, n	313	158	86	69
mg/dl, mean ± SD	142.90 ± 43.75	141.84 ± 42.38	144.88 ± 43.87	142.84 ± 47.15
Hepatic function status^a, n	1146	572	321	253
Normal, n (%)	891 (77.75)	413 (72.20)	264 (82.24)	214 (84.58)
Mild, n (%)	207 (18.06)	143 (25.00)	44 (13.71)	20 (7.91)
Moderate, n (%)	12 (1.05)	8 (1.40)	2 (0.62)	2 (0.79)
Severe, n (%)	0	0	0	0
Unknown, n (%)	36 (3.14)	8 (1.40)	11 (3.43)	17 (6.72)
eGFR, n	1083	547	305	231
ml/min/1.73 m^2, mean ± SD	74.43 ± 21.81	83.54 ± 21.01	68.04 ± 18.51	61.32 ± 17.69
eGFR category, ml/min/1.73 m^2, n (%)
≥90	244 (21.29)	195 (34.09)	36 (11.21)	13 (5.14)
≥60 to <90	560 (48.87)	298 (52.10)	167 (52.02)	95 (37.55)
≥30 to <60	261 (22.77)	49 (8.57)	96 (29.91)	116 (45.85)
<30	18 (1.57)	5 (0.87)	6 (1.87)	7 (2.77)
Systolic blood pressure, n	1033	510	290	233
mmHg, mean ± SD	131.18 ± 15.74	130.37 ± 14.51	130.70 ± 16.41	133.57 ± 17.23
Diastolic blood pressure, n	1032	509	290	233
mmHg, mean ± SD	75.11 ± 11.44	78.11 ± 11.13	72.54 ± 10.89	71.74 ± 11.11
Concomitant diseases, n (%)	918 (80.10)	448 (78.32)	266 (82.87)	204 (80.63)
Dyslipidemia	644 (56.20)	316 (55.24)	196 (61.06)	132 (52.17)
Hypertension	631 (55.06)	280 (48.95)	192 (59.81)	159 (62.85)
CVD and CeVD	184 (16.06)	53 (9.27)	66 (20.56)	65 (25.69)
Gout/hyperuricemia	132 (11.52)	61 (10.66)	34 (10.59)	37 (14.62)
Diabetic nephropathy	121 (10.56)	58 (10.14)	30 (9.35)	33 (13.04)
Diabetic retinopathy	68 (5.93)	35 (6.12)	20 (6.23)	13 (5.14)
Diabetic neuropathy	66 (5.76)	37 (6.47)	18 (5.61)	11 (4.35)
Osteoporosis	42 (3.66)	3 (0.52)	12 (3.74)	27 (10.67)
Malignant tumor	15 (1.31)	5 (0.87)	4 (1.25)	6 (2.37)
Urinary tract infection	4 (0.35)	1 (0.17)	1 (0.31)	2 (0.79)
Genital infection	2 (0.17)	0	1 (0.31)	1 (0.40)
Previous medication use, n (%)
Empagliflozin	734 (64.05)	400 (69.93)	198 (61.68)	136 (53.75)
Linagliptin	579 (50.52)	272 (47.55)	165 (51.40)	142 (56.13)
Empagliflozin and Linagliptin	272 (23.73)	143 (25.00)	74 (23.05)	55 (21.74)
Number of glucose-lowering agents^b
0	523 (45.64)	234 (40.91)	146 (45.48)	143 (56.52)
1	375 (32.72)	203 (35.49)	105 (32.71)	67 (26.48)
2	188 (16.40)	99 (17.31)	54 (16.82)	35 (13.83)
≥3	60 (5.24)	36 (6.29)	16 (4.98)	8 (3.16)
Glucose-lowering agents
Biguanide	467 (40.75)	285 (49.83)	127 (39.56)	55 (21.74)
Sulfonylurea	166 (14.49)	74 (12.94)	47 (14.64)	45 (17.79)
Insulin	112 (9.77)	60 (10.49)	34 (10.59)	18 (7.11)
Alpha-glucosidase inhibitor	109 (9.51)	43 (7.52)	38 (11.84)	28 (11.07)
Glinide	60 (5.24)	32 (5.59)	13 (4.05)	15 (5.93)
Thiazolidinedione	53 (4.62)	30 (5.24)	12 (3.74)	11 (4.35)

^aNormal: normal AST/ALT; mild: AST/ALT > ULN and <3 x ULN; moderate: AST/ALT ≥3 x ULN and <5 x ULN + total Bil ≤2 x ULN; severe: AST/ALT ≥5 x ULN, or AST/ALT ≥3 x ULN and <5 x ULN + total bilirubin >2 x ULN. ^bThe number of glucose-lowering agents other than empagliflozin/linagliptin at the start of empagliflozin/linagliptin FDC administration.

AST: aspartate transaminase; ALT: alanine aminotransferase; BMI: body mass index; CeVD: cerebrovascular disease; CVD, cardiovascular disease; eGFR: estimated glomerular filtration rate; FDC: fixed-dose combination; HbA1c: glycated hemoglobin; SD: standard deviation; T2D: type 2 diabetes; ULN: upper limit of normal

Table 2. Adverse drug reactions (ADRs) of important identified and potential risk by age group (safety analysis set).

		Age group, years
	All patients	<65	≥65 to <75	≥75
Total population
N	1146	572	321	253
ADR, n (%)
Total ADRs of important identified risk	15 (1.31)	6 (1.05)	8 (2.49)	1 (0.40)
Urinary tract infection^a	7 (0.61)	3 (0.52)	3 (0.93)	1 (0.40)
Hypoglycemia^b	2 (0.17)	1 (0.17)	1 (0.31)	0
Urine ketone body present^c	2 (0.17)	0	2 (0.62)	0
Ketoacidosis^d	0	0	0	0
Genital infection^e	1 (0.09)	0	1 (0.31)	0
Volume depletion^f	1 (0.09)	1 (0.17)	0	0
Liver injury^g	1 (0.09)	1 (0.17)	0	0
Polyuria/pollakiuria^h	1 (0.09)	0	1 (0.31)	0
Pancreatitis^i	0	0	0	0
Intestinal obstruction^j	0	0	0	0
Total ADRs of important potential risk	0	0	0	0
Malignant tumor^k	0	0	0	0
Infection^l	0	0	0	0
Lower limb amputation^m	0	0	0	0
Renal disorder^n	0	0	0	0
Bone fracture^o	0	0	0	0
Skin lesion^p	0	0	0	0
Bullous pemphigoid^q	0	0	0	0
Interstitial pneumonitis^r	0	0	0	0
Cardiac failure^s	0	0	0	0
AP (empagliflozin 10 mg/linagliptin 5 mg)
N	1017	508	283	226
ADR, n (%)
Total ADRs of important identified risk	12 (1.18)	5 (0.98)	7 (2.47)	0
Urinary tract infection^a	5 (0.49)	2 (0.39)	3 (1.06)	0
Hypoglycemia^b	2 (0.20)	1 (0.20)	1 (0.35)	0
Urine ketone body present^c	1 (0.10)	0	1 (0.35)	0
Ketoacidosis^d	0	0	0	0
Genital infection^e	1 (0.10)	0	1 (0.35)	0
Volume depletion^f	1 (0.10)	1 (0.20)	0	0
Liver injury^g	1 (0.10)	1 (0.20)	0	0
Polyuria/pollakiuria^h	1 (0.10)	0	1 (0.35)	0
Pancreatitis^i	0	0	0	0
Intestinal obstruction^j	0	0	0	0
Total ADRs of important potential risk	0	0	0	0
Malignant tumor^k	0	0	0	0
Infection^l	0	0	0	0
Lower limb amputation^m	0	0	0	0
Renal disorder^n	0	0	0	0
Bone fracture^o	0	0	0	0
Skin lesion^p	0	0	0	0
Bullous pemphigoid^q	0	0	0	0
Interstitial pneumonitis^r	0	0	0	0
Cardiac failure^s	0	0	0	0
BP (empagliflozin 25 mg/linagliptin 5 mg)
N	129	64	38	27
ADR, n (%)
Total ADRs of important identified risk	3 (2.33)	1 (1.56)	1 (2.63)	1 (3.70)
Urinary tract infection^a	2 (1.55)	1 (1.56)	0	1 (3.70)
Hypoglycemia^b	0	0	0	0
Urine ketone body present^c	1 (0.78)	0	1 (2.63)	0
Ketoacidosis^d	0	0	0	0
Genital infection^e	0	0	0	0
Volume depletion^f	0	0	0	0
Liver injury^g	0	0	0	0
Polyuria/pollakiuria^h	0	0	0	0
Pancreatitis^i	0	0	0	0
Intestinal obstruction^j	0	0	0	0
Total ADRs of important potential risk	0	0	0	0
Malignant tumor^k	0	0	0	0
Infection^l	0	0	0	0
Lower limb amputation^m	0	0	0	0
Renal disorder^n	0	0	0	0
Bone fracture^o	0	0	0	0
Skin lesion^p	0	0	0	0
Bullous pemphigoid^q	0	0	0	0
Interstitial pneumonitis^r	0	0	0	0
Cardiac failure^s	0	0	0	0

^aBased on 100 MedDRA preferred terms.

^bBased on the narrow SMQ: Hypoglycemia.

^cBased on the following MedDRA preferred terms: Urine ketone body; Blood ketone body increased; Blood ketone body; Blood ketone body present; Ketonuria; Ketosis.

^dBased on the MedDRA preferred term: Urine ketone body present.

^eBased on 94 MedDRA preferred terms.

^fBased on 18 MedDRA preferred terms.

^gBased on the following narrow SMQs: Liver related investigations, signs and symptoms; Cholestasis and jaundice of hepatic origin; Hepatitis, noninfectious; Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions.

^hBased on the following MedDRA preferred terms: Polyuria; Pollakiuria; Nocturia.

ⁱBased on the narrow SMQ: Pancreatitis chronic.

^jBased on 24 MedDRA preferred terms.

^kBased on the following narrow SMQs: Malignant or unspecified tumors (excluding the preferred term Acanthosis nigricans); Malignancy related conditions (excluding the preferred term Acanthosis nigricans).

^lBased on 319 MedDRA preferred terms.

^mBased on 9 MedDRA preferred terms.

ⁿBased on the narrow SMQ: Acute renal failure.

^oBased on 114 MedDRA preferred terms.

^pBased on the narrow SMQ: Severe cutaneous adverse reactions

^qBased on the MedDRA preferred term: Pemphigoid.

^rBased on the narrow SMQ: Interstitial pneumonia.

^sBased on the narrow SMQ: Cardiac failure.

ADR: adverse drug reaction; MedDRA: Medical Dictionary for Regulatory Activities version 24.0; SMQ: Standardized MedDRA Query.

Figure 1. Change from baseline in body weight over time by age group (safety analysis set). Data are for patients who received ≥1 dose of empagliflozin/linagliptin FDC. CI: confidence interval; FDC: fixed-dose combination; SD: standard deviation.

Figure 2. Mean change in a) HbA1c and b) FPG over time by age category (effectiveness analysis set). CI: confidence interval; FPG: fasting plasma glucose; HbA1c: glycated hemoglobin; SD: standard deviation.