J Endocrinol Metab

Journal of Endocrinology and Metabolism, ISSN 1923-2861 print, 1923-287X online, Open Access

Article copyright, the authors; Journal compilation copyright, J Endocrinol Metab and Elmer Press Inc

Journal website http://www.jofem.org

Original Article

Volume 8, Number 6, December 2018, pages 126-138

Add-On Sitagliptin Therapy for Insulin-Treated Type 2 Diabetes: An Analysis of Hemoglobin A1c and Other Variables Using ASSIST-K Follow-Up Data

**Table 1.** Profile of the Subjects: All Patients Receiving Insulin vs. Patients Included in Factor Analysis
	Patients receiving insulin	Patients included in factor analysis
Men: 194 × serum creatinine^-1.094 × age^-0.287; Women: 194 × serum creatinine^-1.094 × age^-0.287 × 0.739. Data are shown as the mean ± standard deviation unless otherwise noted. eGFR: estimated glomerular filtration rate; HbA1c: hemoglobin A1c; NGSP: National Glycohemoglobin Standardization Program.
No. of patients	937 (100.0%)	412 (100.0%)
Sex
Male	508 (54.2%)	216 (52.4%)
Female	429 (45.8%)	196 (47.6%)
Age at registration	63.9 ± 12.3	64.2 ± 12.1
Diabetic complications
Retinopathy
No	508 (54.2%)	238 (57.8%)
Yes	315 (33.6%)	174 (42.2%)
Unknown	114 (12.2%)	0 (0.0%)
Neuropathy
No	496 (52.9%)	221 (53.6%)
Yes	324 (34.6%)	191 (46.4%)
Unknown	117 (12.5%)	0 (0.0%)
Nephropathy
No	457 (48.8%)	207 (50.2%)
Yes	367 (39.2%)	205 (49.8%)
Unknown	113 (12.1%)	0 (0.0%)
Atherosclerotic diseases
Cerebrovascular disease
No	731 (78.0%)	378 (91.7%)
Yes	72 (7.7%)	34 (8.3%)
Unknown	134 (14.3%)	0 (0.0%)
Myocardial infarction/Angina
No	647 (69.1%)	324 (78.6%)
Yes	162 (17.3%)	88 (21.4%)
Unknown	128 (13.7%)	0 (0.0%)
Arteriosclerosis obliterans
No	702 (74.9%)	353 (85.7%)
Yes	87 (9.3%)	59 (14.3%)
Unknown	148 (15.8%)	0 (0.0%)
Other complications
Hypertension
No	325 (34.7%)	154 (37.4%)
Yes	531 (56.7%)	258 (62.6%)
Unknown	81 (8.6%)	0 (0.0%)
Dyslipidemia
No	274 (29.2%)	128 (31.1%)
Yes	588 (62.8%)	284 (68.9%)
Unknown	75 (8.0%)	0 (0.0%)
Duration of diabetes (years)
	17.0 ± 9.2	16.9 ± 9.0
N	795	412
Baseline body weight
	66.23 ± 15.51	66.36 ± 14.75
N	936	412
Baseline body mass index
	25.38 ± 4.61	25.48 ± 4.40
N	906	412
Baseline HbA1c (NGSP, %)
	8.50 ± 1.35	8.53 ± 1.35
N	922	412
Baseline eGFR (mL/min/1.73 m²)
	75.9 ± 22.9	75.3 ± 22.5
N	675	412

Table 1. Profile of the Subjects: All Patients Receiving Insulin vs. Patients Included in Factor Analysis

Patients receiving insulin

Patients included in factor analysis

Men: 194 × serum creatinine^-1.094 × age^-0.287; Women: 194 × serum creatinine^-1.094 × age^-0.287 × 0.739. Data are shown as the mean ± standard deviation unless otherwise noted. eGFR: estimated glomerular filtration rate; HbA1c: hemoglobin A1c; NGSP: National Glycohemoglobin Standardization Program.

No. of patients

937 (100.0%)

412 (100.0%)

Sex

Male

508 (54.2%)

216 (52.4%)

Female

429 (45.8%)

196 (47.6%)

Age at registration

63.9 ± 12.3

64.2 ± 12.1

Diabetic complications

Retinopathy

508 (54.2%)

238 (57.8%)

Yes

315 (33.6%)

174 (42.2%)

Unknown

114 (12.2%)

0 (0.0%)

Neuropathy

496 (52.9%)

221 (53.6%)

Yes

324 (34.6%)

191 (46.4%)

Unknown

117 (12.5%)

0 (0.0%)

Nephropathy

457 (48.8%)

207 (50.2%)

Yes

367 (39.2%)

205 (49.8%)

Unknown

113 (12.1%)

0 (0.0%)

Atherosclerotic diseases

Cerebrovascular disease

731 (78.0%)

378 (91.7%)

Yes

72 (7.7%)

34 (8.3%)

Unknown

134 (14.3%)

0 (0.0%)

Myocardial infarction/Angina

647 (69.1%)

324 (78.6%)

Yes

162 (17.3%)

88 (21.4%)

Unknown

128 (13.7%)

0 (0.0%)

Arteriosclerosis obliterans

702 (74.9%)

353 (85.7%)

Yes

87 (9.3%)

59 (14.3%)

Unknown

148 (15.8%)

0 (0.0%)

Other complications

Hypertension

325 (34.7%)

154 (37.4%)

Yes

531 (56.7%)

258 (62.6%)

Unknown

81 (8.6%)

0 (0.0%)

Dyslipidemia

274 (29.2%)

128 (31.1%)

Yes

588 (62.8%)

284 (68.9%)

Unknown

75 (8.0%)

0 (0.0%)

Duration of diabetes (years)

17.0 ± 9.2

16.9 ± 9.0

795

412

Baseline body weight

66.23 ± 15.51

66.36 ± 14.75

936

412

Baseline body mass index

25.38 ± 4.61

25.48 ± 4.40

906

412

Baseline HbA1c (NGSP, %)

8.50 ± 1.35

8.53 ± 1.35

922

412

Baseline eGFR (mL/min/1.73 m²)

75.9 ± 22.9

75.3 ± 22.5

675

412

**Table 2.** Use of Antidiabetic Agents
	Before sitagliptin	At initiation of sitagliptin	After 12 months of sitagliptin
OHA: oral hypoglycemic agent; SD: standard deviation.
No. of patients	412 (100.0%)	412 (100.0%)	412 (100.0%)
Sitagliptin dose
Mean ± SD	-	46.6 ± 9.6	52.0 ± 15.7
N	-	412	405
Daily no. of insulin injections
0	0 (0.0%)	1 (0.2%)	8 (1.9%)
1	78 (18.9%)	83 (20.1%)	77 (18.7%)
2	99 (24.0%)	99 (24.0%)	96 (23.3%)
3	99 (24.0%)	97 (23.5%)	101 (24.5%)
4	136 (33.0%)	132 (32.0%)	130 (31.6%)
Mean	2.7	2.7	2.7
OHAs
Sulfonylureas	79 (19.2%)	80 (19.4%)	70 (17.0%)
Biguanides	172 (41.7%)	160 (38.8%)	136 (33.0%)
Thiazolidinediones	48 (11.7%)	29 (7.0%)	30 (7.3%)
Alpha-glucosidase inhibitors	101 (24.5%)	83 (20.1%)	83 (20.1%)
Glinides	5 (1.2%)	0 (0.0%)	0 (0.0%)
Number of concomitant OHAs
0	159 (38.6%)	179 (43.4%)	199 (48.3%)
1	136 (33.0%)	134 (32.5%)	117 (28.4%)
2	87 (21.1%)	80 (19.4%)	86 (20.9%)
3 or more	30 (7.3%)	19 (4.6%)	10 (2.4%)
Mean	1.0	0.9	0.8

Table 2. Use of Antidiabetic Agents

Before sitagliptin

At initiation of sitagliptin

After 12 months of sitagliptin

OHA: oral hypoglycemic agent; SD: standard deviation.

No. of patients

412 (100.0%)

Sitagliptin dose

Mean ± SD

46.6 ± 9.6

52.0 ± 15.7

412

405

Daily no. of insulin injections

0 (0.0%)

1 (0.2%)

8 (1.9%)

78 (18.9%)

83 (20.1%)

77 (18.7%)

99 (24.0%)

96 (23.3%)

99 (24.0%)

97 (23.5%)

101 (24.5%)

136 (33.0%)

132 (32.0%)

130 (31.6%)

Mean

2.7

OHAs

Sulfonylureas

79 (19.2%)

80 (19.4%)

70 (17.0%)

Biguanides

172 (41.7%)

160 (38.8%)

136 (33.0%)

Thiazolidinediones

48 (11.7%)

29 (7.0%)

30 (7.3%)

Alpha-glucosidase inhibitors

101 (24.5%)

83 (20.1%)

Glinides

5 (1.2%)

0 (0.0%)

Number of concomitant OHAs

159 (38.6%)

179 (43.4%)

199 (48.3%)

136 (33.0%)

134 (32.5%)

117 (28.4%)

87 (21.1%)

80 (19.4%)

86 (20.9%)

3 or more

30 (7.3%)

19 (4.6%)

10 (2.4%)

Mean

1.0

0.9

0.8

**Table 3.** Adverse Events
	No. of adverse events (incidence rate), N = 412
Severe hypoglycemia	14 (3.4%)
Gastrointestinal symptoms	3 (0.7%)
Constipation	13 (3.2%)
Others	8 (1.9%)

Table 3. Adverse Events

No. of adverse events (incidence rate), N = 412

Severe hypoglycemia

14 (3.4%)

Gastrointestinal symptoms

3 (0.7%)

Constipation

13 (3.2%)

Others

8 (1.9%)

**Table 4.** Factor Analysis of the 12-Month Change in HbA1c (ANOVA)
	HbA1c (%) change over 12 months	Univariate model	Initial multivariable model (univariate at P < 0.10)	Final multivariable model (stepwise section at P < 0.05)
Factors investigated: age at registration, sex, diabetic complications (retinopathy, neuropathy, and nephropathy), atherosclerotic diseases (cerebrovascular disease, myocardial infarction/angina, and arteriosclerosis obliterans), other complications (hypertension and dyslipidemia), duration of diabetes, baseline profile (body weight, body mass index, HbA1c, serum creatinine, and eGFR), and baseline concomitant antidiabetic agents (daily no. of insulin injections and use of sulfonylureas, biguanides, thiazolidinediones, and alpha-glucosidase inhibitors). ANOVA: analysis of variance; CI: confidence interval; eGFR: estimated glomerular filtration rate; HbA1c: hemoglobin A1c; NGSP: National Glycohemoglobin Standardization Program; PE: point estimate; Ref: reference. *P < 0.050.
Dyslipidemia
No	128	-0.83	1.16	Ref	-	-	Ref	-	-	Ref	-	-
Yes	284	-0.59	1.13	0.239	0.001, 0.477	0.049*	0.307	0.085, 0.529	0.007*	0.343	0.124, 0.563	0.002*
Duration of diabetes (years)
0.0 - < 10.0	87	-0.97	1.57	Ref	-	0.027*	Ref	-	0.485
10.0 - < 15.0	92	-0.67	1.21	0.301	-0.032, 0.634	0.077	0.172	-0.135, 0.479	0.272
15.0 - < 22.0	121	-0.54	0.88	0.435	0.122, 0.748	0.007*	0.228	-0.065, 0.520	0.127
22.0 - 48.0	112	-0.54	0.89	0.431	0.113, 0.749	0.008*	0.139	-0.159, 0.437	0.359
Baseline daily no. of insulin injections
0 - 1	84	-0.94	1.39	Ref	-	-	Ref	-	-
2 - 4	328	-0.59	1.06	0.355	0.082, 0.627	0.011*	0.200	-0.055, 0.454	0.124
Baseline HbA1c (NGSP, %)
5.60 - < 7.50	94	-0.15	0.54	Ref	-	< 0.001*	Ref	-	< 0.001*	Ref	-	< 0.001*
7.50 - < 8.30	106	-0.46	0.70	-0.313	-0.604, -0.021	0.036*	-0.283	-0.575, 0.008	0.057	-0.268	-0.558, 0.021	0.069
8.30 - < 9.30	108	-0.58	1.11	-0.437	-0.728, -0.147	0.003*	-0.428	-0.716, -0.139	0.004*	-0.415	-0.702, -0.127	0.005*
9.30 - 13.90	104	-1.41	1.51	-1.267	-1.559, -0.974	< 0.001*	-1.249	-1.545, -0.953	< 0.001*	-1.289	-1.579, -0.999	< 0.001*

Table 4. Factor Analysis of the 12-Month Change in HbA1c (ANOVA)

HbA1c (%) change over 12 months

Univariate model

Initial multivariable model (univariate at P < 0.10)

Final multivariable model (stepwise section at P < 0.05)

Mean

95% CI

P value

95% CI

P value

95% CI

P value

Factors investigated: age at registration, sex, diabetic complications (retinopathy, neuropathy, and nephropathy), atherosclerotic diseases (cerebrovascular disease, myocardial infarction/angina, and arteriosclerosis obliterans), other complications (hypertension and dyslipidemia), duration of diabetes, baseline profile (body weight, body mass index, HbA1c, serum creatinine, and eGFR), and baseline concomitant antidiabetic agents (daily no. of insulin injections and use of sulfonylureas, biguanides, thiazolidinediones, and alpha-glucosidase inhibitors). ANOVA: analysis of variance; CI: confidence interval; eGFR: estimated glomerular filtration rate; HbA1c: hemoglobin A1c; NGSP: National Glycohemoglobin Standardization Program; PE: point estimate; Ref: reference. *P < 0.050.

Dyslipidemia

128

-0.83

1.16

Ref

Yes

284

-0.59

1.13

0.239

0.001, 0.477

0.049*

0.307

0.085, 0.529

0.007*

0.343

0.124, 0.563

0.002*

Duration of diabetes (years)

0.0 - < 10.0

-0.97

1.57

Ref

0.027*

Ref

0.485

10.0 - < 15.0

-0.67

1.21

0.301

-0.032, 0.634

0.077

0.172

-0.135, 0.479

0.272

15.0 - < 22.0

121

-0.54

0.88

0.435

0.122, 0.748

0.007*

0.228

-0.065, 0.520

0.127

22.0 - 48.0

112

-0.54

0.89

0.431

0.113, 0.749

0.008*

0.139

-0.159, 0.437

0.359

Baseline daily no. of insulin injections

0 - 1

-0.94

1.39

Ref

2 - 4

328

-0.59

1.06

0.355

0.082, 0.627

0.011*

0.200

-0.055, 0.454

0.124

Baseline HbA1c (NGSP, %)

5.60 - < 7.50

-0.15

0.54

Ref

< 0.001*

Ref

< 0.001*

Ref

< 0.001*

7.50 - < 8.30

106

-0.46

0.70

-0.313

-0.604, -0.021

0.036*

-0.283

-0.575, 0.008

0.057

-0.268

-0.558, 0.021

0.069

8.30 - < 9.30

108

-0.58

1.11

-0.437

-0.728, -0.147

0.003*

-0.428

-0.716, -0.139

0.004*

-0.415

-0.702, -0.127

0.005*

9.30 - 13.90

104

-1.41

1.51

-1.267

-1.559, -0.974

< 0.001*

-1.249

-1.545, -0.953

< 0.001*

-1.289

-1.579, -0.999

< 0.001*

**Table 5.** Factor Analysis of the 12-Month Change in Body Weight (ANOVA)
	Body weight (kg) Change over 12 months	Univariate model	Initial multivariable model (univariate at P < 0.10)	Final multivariable model (stepwise selection at P < 0.05)
Factors investigated: age at registration, sex, diabetic complications (retinopathy, neuropathy, and nephropathy), atherosclerotic diseases (cerebrovascular disease, myocardial infarction/angina, and arteriosclerosis obliterans), other complications (hypertension and dyslipidemia), duration of diabetes, baseline profile (body weight, body mass index, HbA1c, serum creatinine, and eGFR), and baseline concomitant antidiabetic agents ( daily no. of insulin injections and use of sulfonylureas, biguanides, thiazolidinediones, and alpha-glucosidase inhibitors). ANOVA: analysis of variance; CI: confidence interval; eGFR: estimated glomerular filtration rate; HbA1c: hemoglobin A1c; NGSP: National Glycohemoglobin Standardization Program; PE: point estimate; Ref: reference. P < 0.05, P < 0.01 and **P < 0.001.
Myocardial infarction/angina
No	316	0.25	3.63	Ref	-	-	Ref	-	-
Yes	88	-0.71	3.62	-0.955	-1.814, -0.096	0.030*	-0.693	-1.546, 0.160	0.111
Hypertension
No	151	0.63	3.67	Ref	-	-	Ref	-	-
Yes	253	-0.31	3.58	-0.940	-1.672, -0.209	0.012*	-0.573	-1.312, 0.165	0.128
Baseline daily no. of insulin injections
0 - 1	81	0.65	4.37	Ref	-	-	Ref	-	-
2 - 4	323	-0.12	3.43	-0.771	-1.658, 0.117	0.089	-0.321	-1.205, 0.563	0.476
Baseline biguanide use
No	247	0.47	3.73	Ref	-	-	Ref	-	-
Yes	157	-0.64	3.40	-1.109	-1.832, -0.385	0.003**	-0.634	-1.379, 0.112	0.096
Baseline body weight (kg)
36.9 - < 56.4	101	0.79	3.43	Ref	-	0.036*	Ref	-	0.597
56.4 - < 64.9	100	0.25	2.71	-0.540	-1.543, 0.464	0.291	-0.241	-1.343, 0.862	0.668
64.9 - < 74.5	102	-0.31	3.84	-1.098	-2.097, -0.100	0.031*	-0.698	-1.971, 0.575	0.282
74.5 - 119.5	101	-0.58	4.29	-1.374	-2.374, -0.373	0.007**	-0.095	-1.629, 1.439	0.903
Baseline body mass index
13.6 - < 22.6	100	0.78	3.66	Ref	-	< 0.001***	Ref	-	0.061	Ref	-	< 0.001***
22.6 - < 25.2	100	0.14	2.40	-0.634	-1.629, 0.361	0.211	-0.057	-1.203, 1.089	0.922	-0.612	-1.591, 0.367	0.220
25.2 - < 27.9	103	0.43	3.98	-0.345	-1.333, 0.642	0.492	0.205	-1.083, 1.493	0.755	-0.424	-1.401, 0.553	0.394
27.9 - 43.8	101	-1.19	4.02	-1.969	-2.962, -0.977	< 0.001***	-1.368	-2.943, 0.206	0.088	-1.984	-2.971, -0.997	< 0.001***
Baseline HbA1c (NGSP, %)
5.60 - < 7.55	101	-0.11	3.39	Ref	-	0.001**	Ref	-	0.014*	Ref	-	0.001**
7.55 - < 8.40	100	-0.18	2.30	-0.072	-1.065, 0.922	0.887	0.162	-0.825, 1.148	0.747	0.013	-0.965, 0.991	0.980
8.40 - < 9.30	99	-0.78	4.13	-0.672	-1.668, 0.324	0.186	-0.298	-1.290, 0.694	0.555	-0.393	-1.384, 0.598	0.436
9.30 - 13.90	104	1.18	4.17	1.294	0.309, 2.278	0.010*	1.258	0.266, 2.249	0.013*	1.460	0.485, 2.435	0.003**

Table 5. Factor Analysis of the 12-Month Change in Body Weight (ANOVA)

Body weight (kg) Change over 12 months

Univariate model

Initial multivariable model (univariate at P < 0.10)

Final multivariable model (stepwise selection at P < 0.05)

Mean

95% CI

P value

95% CI

P value

95% CI

P value

Factors investigated: age at registration, sex, diabetic complications (retinopathy, neuropathy, and nephropathy), atherosclerotic diseases (cerebrovascular disease, myocardial infarction/angina, and arteriosclerosis obliterans), other complications (hypertension and dyslipidemia), duration of diabetes, baseline profile (body weight, body mass index, HbA1c, serum creatinine, and eGFR), and baseline concomitant antidiabetic agents ( daily no. of insulin injections and use of sulfonylureas, biguanides, thiazolidinediones, and alpha-glucosidase inhibitors). ANOVA: analysis of variance; CI: confidence interval; eGFR: estimated glomerular filtration rate; HbA1c: hemoglobin A1c; NGSP: National Glycohemoglobin Standardization Program; PE: point estimate; Ref: reference. *P < 0.05, **P < 0.01 and ***P < 0.001.

Myocardial infarction/angina

316

0.25

3.63

Ref

Yes

-0.71

3.62

-0.955

-1.814, -0.096

0.030*

-0.693

-1.546, 0.160

0.111

Hypertension

151

0.63

3.67

Ref

Yes

253

-0.31

3.58

-0.940

-1.672, -0.209

0.012*

-0.573

-1.312, 0.165

0.128

Baseline daily no. of insulin injections

0 - 1

0.65

4.37

Ref

2 - 4

323

-0.12

3.43

-0.771

-1.658, 0.117

0.089

-0.321

-1.205, 0.563

0.476

Baseline biguanide use

247

0.47

3.73

Ref

Yes

157

-0.64

3.40

-1.109

-1.832, -0.385

0.003**

-0.634

-1.379, 0.112

0.096

Baseline body weight (kg)

36.9 - < 56.4

101

0.79

3.43

Ref

0.036*

Ref

0.597

56.4 - < 64.9

100

0.25

2.71

-0.540

-1.543, 0.464

0.291

-0.241

-1.343, 0.862

0.668

64.9 - < 74.5

102

-0.31

3.84

-1.098

-2.097, -0.100

0.031*

-0.698

-1.971, 0.575

0.282

74.5 - 119.5

101

-0.58

4.29

-1.374

-2.374, -0.373

0.007**

-0.095

-1.629, 1.439

0.903

Baseline body mass index

13.6 - < 22.6

100

0.78

3.66

Ref

< 0.001***

Ref

0.061

Ref

< 0.001***

22.6 - < 25.2

100

0.14

2.40

-0.634

-1.629, 0.361

0.211

-0.057

-1.203, 1.089

0.922

-0.612

-1.591, 0.367

0.220

25.2 - < 27.9

103

0.43

3.98

-0.345

-1.333, 0.642

0.492

0.205

-1.083, 1.493

0.755

-0.424

-1.401, 0.553

0.394

27.9 - 43.8

101

-1.19

4.02

-1.969

-2.962, -0.977

< 0.001***

-1.368

-2.943, 0.206

0.088

-1.984

-2.971, -0.997

< 0.001***

Baseline HbA1c (NGSP, %)

5.60 - < 7.55

101

-0.11

3.39

Ref

0.001**

Ref

0.014*

Ref

0.001**

7.55 - < 8.40

100

-0.18

2.30

-0.072

-1.065, 0.922

0.887

0.162

-0.825, 1.148

0.747

0.013

-0.965, 0.991

0.980

8.40 - < 9.30

-0.78

4.13

-0.672

-1.668, 0.324

0.186

-0.298

-1.290, 0.694

0.555

-0.393

-1.384, 0.598

0.436

9.30 - 13.90

104

1.18

4.17

1.294

0.309, 2.278

0.010*

1.258

0.266, 2.249

0.013*

1.460

0.485, 2.435

0.003**

**Table 6.** Factor Analysis of the 12-Month Change in eGFR (ANOVA)
	eGFR (mL/min/1.73 m²) change over 12 months	Univariate model	Initial multivariable model (univariate at P < 0.10)	Final multivariable model (stepwise selection at P < 0.05)
Factors investigated: age at registration, sex, diabetic complications (retinopathy, neuropathy, and nephropathy), atherosclerotic diseases (cerebrovascular disease, myocardial infarction/angina, and arteriosclerosis obliterans), other complications (hypertension and dyslipidemia), duration of diabetes, baseline profile (body weight, body mass index, HbA1c, serum creatinine, and eGFR), and baseline concomitant antidiabetic agents (daily no. of insulin injections and use of sulfonylureas, biguanides, thiazolidinediones, and alpha-glucosidase inhibitors). ANOVA: analysis of variance; CI: confidence interval; eGFR: estimated glomerular filtration rate; HbA1c: hemoglobin A1c; NGSP: National Glycohemoglobin Standardization Program; PE: point estimate; Ref: reference. P < 0.05, P < 0.01 and **P < 0.001.
Myocardial infarction/angina
No	226	-4.62	11.14	Ref	-	-	Ref	-	-
Yes	55	-1.91	9.50	2.714	-0.496, 5.924	0.097	1.546	-1.688, 4.779	0.347
Dyslipidemia
No	81	-6.05	10.80	Ref	-	-	Ref	-	-	Ref	-	-
Yes	200	-3.30	10.84	2.757	-0.049, 5.564	0.054	2.851	0.065, 5.637	0.045*	3.163	0.443, 5.883	0.023*
Baseline daily no. of insulin injections
0 - 1	65	-7.49	11.79	Ref	-	-	Ref	-	-
2 - 4	216	-3.07	10.40	4.421	1.431, 7.411	0.004**	0.657	-2.815, 4.130	0.710
Baseline sulfonylurea use
No	218	-3.14	10.88	Ref	-	-	Ref	-	-	Ref	-	-
Yes	63	-7.40	10.28	-4.262	-7.289, -1.234	0.006**	-3.986	-7.408, -0.564	0.023*	-4.199	-7.087, -1.310	0.005**
Baseline body weight (kg)
36.9 - < 57.2	70	-6.79	13.65	Ref	-	0.040*	Ref	-	0.200	Ref	-	0.019*
57.2 - < 65.2	68	-2.35	10.60	4.439	0.827, 8.051	0.016*	3.448	-0.364, 7.259	0.076	4.571	1.138, 8.003	0.009**
65.2 - < 74.0	70	-2.31	9.28	4.485	0.900, 8.070	0.014*	3.083	-1.289, 7.455	0.166	4.816	1.405, 8.226	0.006**
74.0 - 115.0	73	-4.83	9.00	1.959	-1.589, 5.507	0.278	0.632	-4.525, 5.789	0.810	2.226	-1.176, 5.629	0.199
Baseline body mass index
13.6 - < 22.6	69	-7.30	13.59	Ref	-	0.015*	Ref	-	0.694
22.6 - < 25.0	69	-2.56	11.25	4.739	1.142, 8.336	0.010*	2.003	-1.949, 5.955	0.319
25.0 - < 27.8	72	-1.94	8.54	5.362	1.802, 8.921	0.003**	2.563	-1.871, 6.998	0.256
27.8 - 43.8	71	-4.65	8.93	2.646	-0.926, 6.218	0.146	1.968	-3.345, 7.282	0.466
Baseline eGFR (mL/min/1.73 m²)
22.67 - < 61.30	70	-1.20	7.80	Ref	-	< 0.001***	Ref	-	< 0.001***	Ref	-	< 0.001***
61.30 - < 74.03	70	-2.08	9.47	-0.874	-4.367, 2.619	0.623	-0.008	-3.543, 3.528	0.997	-0.462	-3.875, 2.950	0.790
74.03 - < 90.44	70	-3.96	8.39	-2.758	-6.251, 0.735	0.121	-1.070	-4.621, 2.481	0.554	-1.573	-5.036, 1.890	0.372
90.44 - 173.50	71	-9.05	14.77	-7.850	-11.331, -4.370	< 0.001***	-6.452	-10.015, -2.890	< 0.001***	-7.206	-10.606, -3.806	< 0.001***

Table 6. Factor Analysis of the 12-Month Change in eGFR (ANOVA)

eGFR (mL/min/1.73 m²) change over 12 months

Univariate model

Initial multivariable model (univariate at P < 0.10)

Final multivariable model (stepwise selection at P < 0.05)

Mean

95% CI

P value

95% CI

P value

95% CI

P value

Myocardial infarction/angina

226

-4.62

11.14

Ref

Yes

-1.91

9.50

2.714

-0.496, 5.924

0.097

1.546

-1.688, 4.779

0.347

Dyslipidemia

-6.05

10.80

Ref

Yes

200

-3.30

10.84

2.757

-0.049, 5.564

0.054

2.851

0.065, 5.637

0.045*

3.163

0.443, 5.883

0.023*

Baseline daily no. of insulin injections

0 - 1

-7.49

11.79

Ref

2 - 4

216

-3.07

10.40

4.421

1.431, 7.411

0.004**

0.657

-2.815, 4.130

0.710

Baseline sulfonylurea use

218

-3.14

10.88

Ref

Yes

-7.40

10.28

-4.262

-7.289, -1.234

0.006**

-3.986

-7.408, -0.564

0.023*

-4.199

-7.087, -1.310

0.005**

Baseline body weight (kg)

36.9 - < 57.2

-6.79

13.65

Ref

0.040*

Ref

0.200

Ref

0.019*

57.2 - < 65.2

-2.35

10.60

4.439

0.827, 8.051

0.016*

3.448

-0.364, 7.259

0.076

4.571

1.138, 8.003

0.009**

65.2 - < 74.0

-2.31

9.28

4.485

0.900, 8.070

0.014*

3.083

-1.289, 7.455

0.166

4.816

1.405, 8.226

0.006**

74.0 - 115.0

-4.83

9.00

1.959

-1.589, 5.507

0.278

0.632

-4.525, 5.789

0.810

2.226

-1.176, 5.629

0.199

Baseline body mass index

13.6 - < 22.6

-7.30

13.59

Ref

0.015*

Ref

0.694

22.6 - < 25.0

-2.56

11.25

4.739

1.142, 8.336

0.010*

2.003

-1.949, 5.955

0.319

25.0 - < 27.8

-1.94

8.54

5.362

1.802, 8.921

0.003**

2.563

-1.871, 6.998

0.256

27.8 - 43.8

-4.65

8.93

2.646

-0.926, 6.218

0.146

1.968

-3.345, 7.282

0.466

Baseline eGFR (mL/min/1.73 m²)

22.67 - < 61.30

-1.20

7.80

Ref

< 0.001***

Ref

< 0.001***

Ref

< 0.001***

61.30 - < 74.03

-2.08

9.47

-0.874

-4.367, 2.619

0.623

-0.008

-3.543, 3.528

0.997

-0.462

-3.875, 2.950

0.790

74.03 - < 90.44

-3.96

8.39

-2.758

-6.251, 0.735

0.121

-1.070

-4.621, 2.481

0.554

-1.573

-5.036, 1.890

0.372

90.44 - 173.50

-9.05

14.77

-7.850

-11.331, -4.370

< 0.001***

-6.452

-10.015, -2.890

< 0.001***

-7.206

-10.606, -3.806

< 0.001***

**Table 7.** Factor Analysis of Severe Hypoglycemia (Logistic Regression Model)
	Severe hypoglycemia	Univariate model	Initial multivariable model (univariate at P < 0.10)	Final multivariable model (stepwise selection at P < 0.05)
Factors investigated: age at registration, sex, diabetic complications (retinopathy, neuropathy, and nephropathy), atherosclerotic diseases (cerebrovascular disease, myocardial infarction/angina, and arteriosclerosis obliterans), other complications (hypertension and dyslipidemia), duration of diabetes, baseline profile (body weight, body mass index, HbA1c, serum creatinine, and eGFR), and baseline concomitant antidiabetic agents ( daily no. of insulin injections and use of sulfonylureas, biguanides, thiazolidinediones, and alpha-glucosidase inhibitors). ANOVA: analysis of variance; CI: confidence interval; eGFR: estimated glomerular filtration rate; HbA1c: hemoglobin A1c; NGSP: National Glycohemoglobin Standardization Program; PE: point estimate; Ref: reference. *P < 0.050.
Sex
Male	216	11	5.1%	Ref	-	-	Ref	-	-
Female	196	3	1.5%	0.290	0.080, 1.054	0.060	0.304	0.082, 1.130	0.075
Baseline HbA1c (NGSP, %)
5.60 - < 7.50	94	8	8.5%	Ref	-	0.044*	Ref	-	0.042*			0.044*
7.50 - < 8.30	106	2	1.9%	0.207	0.043, 0.999	0.050*	0.219	0.044, 1.083	0.063	0.207	0.043, 0.999	0.050*
8.30 - < 9.30	108	2	1.9%	0.203	0.042, 0.980	0.047*	0.211	0.043, 1.046	0.057	0.203	0.042, 0.980	0.047*
9.30 - 13.90	104	2	1.9%	0.211	0.044, 1.019	0.053	0.170	0.034, 0.859	0.032*	0.211	0.044, 1.019	0.053

Table 7. Factor Analysis of Severe Hypoglycemia (Logistic Regression Model)

Severe hypoglycemia

Univariate model

Initial multivariable model (univariate at P < 0.10)

Final multivariable model (stepwise selection at P < 0.05)

No. of events

Incidence of events

OR PE

OR 95% CI

P value

OR PE

OR 95% CI

P value

OR PE

OR 95% CI

P value

Factors investigated: age at registration, sex, diabetic complications (retinopathy, neuropathy, and nephropathy), atherosclerotic diseases (cerebrovascular disease, myocardial infarction/angina, and arteriosclerosis obliterans), other complications (hypertension and dyslipidemia), duration of diabetes, baseline profile (body weight, body mass index, HbA1c, serum creatinine, and eGFR), and baseline concomitant antidiabetic agents ( daily no. of insulin injections and use of sulfonylureas, biguanides, thiazolidinediones, and alpha-glucosidase inhibitors). ANOVA: analysis of variance; CI: confidence interval; eGFR: estimated glomerular filtration rate; HbA1c: hemoglobin A1c; NGSP: National Glycohemoglobin Standardization Program; PE: point estimate; Ref: reference. *P < 0.050.

Sex

Male

216

5.1%

Ref

Female

196

1.5%

0.290

0.080, 1.054

0.060

0.304

0.082, 1.130

0.075

Baseline HbA1c (NGSP, %)

5.60 - < 7.50

8.5%

Ref

0.044*

Ref

0.042*

0.044*

7.50 - < 8.30

106

1.9%

0.207

0.043, 0.999

0.050*

0.219

0.044, 1.083

0.063

0.207

0.043, 0.999

0.050*

8.30 - < 9.30

108

1.9%

0.203

0.042, 0.980

0.047*

0.211

0.043, 1.046

0.057

0.203

0.042, 0.980

0.047*

9.30 - 13.90

104

1.9%

0.211

0.044, 1.019

0.053

0.170

0.034, 0.859

0.032*

0.211

0.044, 1.019

0.053

**Table 8.** Factor Analysis of Constipation (Logistic Regression Model)
	Constipation	Univariate model	Initial multivariable model (univariate at P < 0.10)	Final multivariable model (stepwise selection at P < 0.05)
Factors investigated: age at registration, sex, diabetic complications (retinopathy, neuropathy, and nephropathy), atherosclerotic diseases (cerebrovascular disease, myocardial infarction/angina, and arteriosclerosis obliterans), other complications (hypertension and dyslipidemia), duration of diabetes, baseline profile (body weight, body mass index, HbA1c, serum creatinine, and eGFR), and baseline concomitant antidiabetic agents ( daily no. of insulin injections and use of sulfonylureas, biguanides, thiazolidinediones, and alpha-glucosidase inhibitors). ANOVA: analysis of variance; CI: confidence interval; eGFR: estimated glomerular filtration rate; HbA1c: hemoglobin A1c; NGSP: National Glycohemoglobin Standardization Program; PE: point estimate; Ref: reference. *P < 0.050.
Cerebrovascular disease
No	378	10	2.6%	Ref	-	-	Ref	-	-
Yes	34	3	8.8%	3.561	0.931, 13.618	0.063	3.253	0.816, 12.962	0.094
Baseline HbA1c (NGSP, %)
5.60 - < 7.50	94	8	8.5%	Ref	-	0.028*	Ref	-	0.035*	Ref	-	0.028*
7.50 - < 8.30	106	1	0.9%	0.102	0.013, 0.835	0.033*	0.104	0.013, 0.854	0.035*	0.102	0.013, 0.835	0.033*
8.30 - < 9.30	108	2	1.9%	0.203	0.042, 0.980	0.047*	0.211	0.043, 1.028	0.054	0.203	0.042, 0.980	0.047*
9.30 - 13.90	104	2	1.9%	0.211	0.044, 1.019	0.053	0.222	0.046, 1.083	0.063	0.211	0.044, 1.019	0.053

Table 8. Factor Analysis of Constipation (Logistic Regression Model)

Constipation

Univariate model

Initial multivariable model (univariate at P < 0.10)

Final multivariable model (stepwise selection at P < 0.05)

No. of events

Incidence of events

OR PE

OR 95% CI

P value

OR PE

OR 95% CI

P value

OR PE

OR 95% CI

P value

Factors investigated: age at registration, sex, diabetic complications (retinopathy, neuropathy, and nephropathy), atherosclerotic diseases (cerebrovascular disease, myocardial infarction/angina, and arteriosclerosis obliterans), other complications (hypertension and dyslipidemia), duration of diabetes, baseline profile (body weight, body mass index, HbA1c, serum creatinine, and eGFR), and baseline concomitant antidiabetic agents ( daily no. of insulin injections and use of sulfonylureas, biguanides, thiazolidinediones, and alpha-glucosidase inhibitors). ANOVA: analysis of variance; CI: confidence interval; eGFR: estimated glomerular filtration rate; HbA1c: hemoglobin A1c; NGSP: National Glycohemoglobin Standardization Program; PE: point estimate; Ref: reference. *P < 0.050.

Cerebrovascular disease

378

2.6%

Ref

Yes

8.8%

3.561

0.931, 13.618

0.063

3.253

0.816, 12.962

0.094

Baseline HbA1c (NGSP, %)

5.60 - < 7.50

8.5%

Ref

0.028*

Ref

0.035*

Ref

0.028*

7.50 - < 8.30

106

0.9%

0.102

0.013, 0.835

0.033*

0.104

0.013, 0.854

0.035*

0.102

0.013, 0.835

0.033*

8.30 - < 9.30

108

1.9%

0.203

0.042, 0.980

0.047*

0.211

0.043, 1.028

0.054

0.203

0.042, 0.980

0.047*

9.30 - 13.90

104

1.9%

0.211

0.044, 1.019

0.053

0.222

0.046, 1.083

0.063

0.211

0.044, 1.019

0.053