J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website http://www.jocmr.org

Original Article

Volume 12, Number 3, March 2020, pages 200-208

A Study of Seasonal Variation in the Effect of Add-On Sitagliptin on Blood Glucose Control in Insulin-Treated Patients With Type 2 Diabetes

Figure 2. Change in HbA1c by period in which sitagliptin was started. Data are presented as mean ± standard deviation. ‡P < 0.05 versus 0 months paired t-test. HbA1c: hemoglobin A1c.

Figure 3. The amount of change in HbA1c by the period in which sitagliptin was started. Data are presented as mean ± standard deviation. §P < 0.05 Tukey-Kramer test. HbA1c: hemoglobin A1c.

Figure 4. The amount of change in HbA1c at 6 months from baseline (analysis of covariance). Data are presented as least squares mean ± standard error. ¶P < 0.05 ANCOVA. Groups 1 versus 2: P = 0.009, groups 1 versus 3: P = 0.001, groups 1 versus 4: P = 0.002, groups 2 versus 3: P = 0.677, groups 2 versus 4: P = 0.965, groups 3 versus 4: P = 0.662. Covariates: HbA1c and BMI at baseline, sex, age, the amount of change in BMI at 6 months from baseline, the number of insulin administrations per day, the amount of insulin per day, the use of long-acting insulin, the change in the amount of insulin administered per day at 6 months from baseline, and the concomitant use of sulfonylureas. HbA1c: hemoglobin A1c; ANCOVA: analysis of covariance; BMI: body mass index.

**Table 1.** Patient Characteristics
Item	Group 1	Group 2	Group 3	Group 4	P
Data are presented as number (%) or mean ± SD. BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; TG: triglyceride; GOT: glutamate oxaloacetate transaminase; GPT: glutamate pyruvate transaminase; γ-GTP: γ-glutamyl transpeptidase; BUN: blood urea nitrogen; HbA1c: hemoglobin A1c; SD: standard deviation. P < 0.05 ANOVA; *P < 0.05 Chi-squared test.
N	172	113	151	194
Age, years	67.1 ± 10.4	64.4 ± 10.0	63.4 ± 12.1	63.0 ± 12.8	0.003*
Men/women	92 (53.5%)/80 (46.5%)	51 (45.1%)/62 (54.9%)	73 (48.3%)/78 (51.7%)	79 (40.7%)/115 (59.3%)	0.101
Disease duration, years	17.7 ± 9.1	17.2 ± 10.1	16.9 ± 8.5	16.6 ± 8.9	0.731
Retinopathy	58 (66.3%)	37 (67.3%)	60 (60.3%)	63 (67.5%)	0.498
Cataract	34 (80.2%)	22 (80.5%)	24 (84.1%)	41 (78.9%)	0.666
Neuropathy	63 (63.4%)	35 (69%)	52 (65.6%)	66 (66%)	0.807
Nephropathy	69 (59.9%)	49 (56.6%)	59 (60.9%)	76 (60.8%)	0.888
Cerebrovascular disorder	18 (89.5%)	9 (92%)	14 (90.7%)	15 (92.3%)	0.803
Myocardial infarction and angina	29 (83.1%)	18 (84.1%)	23 (84.8%)	44 (77.3%)	0.249
Arteriosclerosis obliterans	19 (89%)	8 (92.9%)	11 (92.7%)	22 (88.7%)	0.412
Hypertension	90 (47.7%)	71 (37.2%)	86 (43%)	116 (40.2%)	0.304
Dyslipidemia	97 (43.6%)	73 (35.4%)	105 (30.5%)	126 (35.1%)	0.095
Fatty liver	46 (73.3%)	45 (60.2%)	44 (70.9%)	71 (63.4%)	0.055
Medication information
Dosage of sitagliptin
25 mg/day	36 (20.9%)	29 (25.7%)	24 (15.9%)	27 (13.9%)	0.226
50 mg/day	135 (78.5%)	83 (73.5%)	126 (83.4%)	166 (85.6%)
100 mg/day	1 (0.6%)	1 (0.9%)	1 (0.7%)	1 (0.5%)
Classification of insulin
Three times or more (no long-acting type)	39 (22.7%)	23 (20.4%)	27 (17.9%)	49 (25.3%)	0.410
Three times or more (including a long-acting type)	60 (34.9%)	51 (45.1%)	57 (37.7%)	59 (30.4%)
Twice, mixed type	30 (17.4%)	14 (12.4%)	28 (18.5%)	37 (19.1%)
Administered once, long-acting type	28 (16.3%)	21 (18.6%)	30 (19.9%)	37 (19.1%)
Others	15 (8.7%)	4 (3.5%)	9 (6%)	12 (6.2%)
Number of insulin administrations	2.7 ± 1.1	2.9 ± 1.1	2.7 ± 1.1	2.6 ± 1.0	0.197
Total amount of insulin administered, U/day	30.2 ± 23.0	33.3 ± 22.2	33.8 ± 21.5	32.1 ± 21.7	0.473
Previous treatment with insulin, years	6.9 ± 6.1	7.3 ± 6.9	6.7 ± 4.8	6.0 ± 4.9	0.341
Concomitant medications
Sulfonylurea	25 (85.5%)	16 (85.8%)	38 (74.8%)	41 (78.9%)	0.041**
Biguanide	59 (65.7%)	40 (64.6%)	67 (55.6%)	81 (58.2%)	0.200
α-Glucosidase inhibitors	38 (77.9%)	17 (85%)	25 (83.4%)	49 (74.7%)	0.091
Thiazolidine	12 (93%)	6 (94.7%)	15 (90.1%)	10 (94.8%)	0.313
Laboratory data at the start of sitagliptin
HbA1c, %	8.53 ± 1.24	8.56 ± 1.25	8.70 ± 1.31	8.73 ± 1.32	0.404
Fasting blood glucose, mg/dL	202.3 ± 67.2	169.4 ± 50.6	178.1 ± 77.7	194.4 ± 73.5	0.098
Casual blood glucose, mg/dL	195.9 ± 86.8	195.1 ± 94.8	194.7 ± 71.8	207.4 ± 84.7	0.516
BMI, kg/m²	24.19 ± 3.82	25.40 ± 4.94	26.05 ± 4.31	25.75 ± 4.66	< 0.001*
SBP, mm Hg	131.6 ± 13.2	128.4 ± 14.2	130.7 ± 15.8	131.1 ± 17.2	0.396
DBP, mm Hg	74.2 ± 9.3	72.0 ± 10.2	75.4 ± 12.0	76.2 ± 10.9	0.011*
eGFR, mL/min/1.73 m²	77.1 ± 21.8	76.1 ± 23.6	75.5 ± 21.8	75.9 ± 24.3	0.957
LDL-C, mg/dL	110.7 ± 25.1	109.6 ± 29.6	108.1 ± 30.3	106.3 ± 29.6	0.623
HDL-C, mg/dL	60.6 ± 15.0	54.2 ± 18.2	53.5 ± 14.9	54.3 ± 14.6	< 0.001*
TG, mg/dL	151.1 ± 127.2	163.9 ± 132.8	173.5 ± 96.2	176.7 ± 117.7	0.246
GOT, U/L	25.2 ± 15.7	24.2 ± 18.0	25.0 ± 12.1	24.5 ± 15.6	0.960
GPT, U/L	26.3 ± 20.9	27.5 ± 21.1	30.6 ± 22.0	27.1 ± 19.0	0.383
γ-GTP, U/L	46.8 ± 80.5	45.4 ± 44.6	45.4 ± 40.0	43.7 ± 54.8	0.978
BUN, mg/dL	18.3 ± 5.5	15.4 ± 4.4	16.3 ± 5.1	15.5 ± 4.9	0.002*
Uric acid, mg/dL	4.9 ± 1.3	5.1 ± 1.3	5.2 ± 1.5	5.0 ± 1.4	0.711

Table 1. Patient Characteristics

Item

Group 1

Group 2

Group 3

Group 4

Data are presented as number (%) or mean ± SD. BMI: body mass index; SBP: systolic blood pressure; DBP: diastolic blood pressure; eGFR: estimated glomerular filtration rate; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; TG: triglyceride; GOT: glutamate oxaloacetate transaminase; GPT: glutamate pyruvate transaminase; γ-GTP: γ-glutamyl transpeptidase; BUN: blood urea nitrogen; HbA1c: hemoglobin A1c; SD: standard deviation. *P < 0.05 ANOVA; **P < 0.05 Chi-squared test.

172

113

151

194

Age, years

67.1 ± 10.4

64.4 ± 10.0

63.4 ± 12.1

63.0 ± 12.8

0.003*

Men/women

92 (53.5%)/80 (46.5%)

51 (45.1%)/62 (54.9%)

73 (48.3%)/78 (51.7%)

79 (40.7%)/115 (59.3%)

0.101

Disease duration, years

17.7 ± 9.1

17.2 ± 10.1

16.9 ± 8.5

16.6 ± 8.9

0.731

Retinopathy

58 (66.3%)

37 (67.3%)

60 (60.3%)

63 (67.5%)

0.498

Cataract

34 (80.2%)

22 (80.5%)

24 (84.1%)

41 (78.9%)

0.666

Neuropathy

63 (63.4%)

35 (69%)

52 (65.6%)

66 (66%)

0.807

Nephropathy

69 (59.9%)

49 (56.6%)

59 (60.9%)

76 (60.8%)

0.888

Cerebrovascular disorder

18 (89.5%)

9 (92%)

14 (90.7%)

15 (92.3%)

0.803

Myocardial infarction and angina

29 (83.1%)

18 (84.1%)

23 (84.8%)

44 (77.3%)

0.249

Arteriosclerosis obliterans

19 (89%)

8 (92.9%)

11 (92.7%)

22 (88.7%)

0.412

Hypertension

90 (47.7%)

71 (37.2%)

86 (43%)

116 (40.2%)

0.304

Dyslipidemia

97 (43.6%)

73 (35.4%)

105 (30.5%)

126 (35.1%)

0.095

Fatty liver

46 (73.3%)

45 (60.2%)

44 (70.9%)

71 (63.4%)

0.055

Medication information

Dosage of sitagliptin

25 mg/day

36 (20.9%)

29 (25.7%)

24 (15.9%)

27 (13.9%)

0.226

50 mg/day

135 (78.5%)

83 (73.5%)

126 (83.4%)

166 (85.6%)

100 mg/day

1 (0.6%)

1 (0.9%)

1 (0.7%)

1 (0.5%)

Classification of insulin

Three times or more (no long-acting type)

39 (22.7%)

23 (20.4%)

27 (17.9%)

49 (25.3%)

0.410

Three times or more (including a long-acting type)

60 (34.9%)

51 (45.1%)

57 (37.7%)

59 (30.4%)

Twice, mixed type

30 (17.4%)

14 (12.4%)

28 (18.5%)

37 (19.1%)

Administered once, long-acting type

28 (16.3%)

21 (18.6%)

30 (19.9%)

37 (19.1%)

Others

15 (8.7%)

4 (3.5%)

9 (6%)

12 (6.2%)

Number of insulin administrations

2.7 ± 1.1

2.9 ± 1.1

2.7 ± 1.1

2.6 ± 1.0

0.197

Total amount of insulin administered, U/day

30.2 ± 23.0

33.3 ± 22.2

33.8 ± 21.5

32.1 ± 21.7

0.473

Previous treatment with insulin, years

6.9 ± 6.1

7.3 ± 6.9

6.7 ± 4.8

6.0 ± 4.9

0.341

Concomitant medications

Sulfonylurea

25 (85.5%)

16 (85.8%)

38 (74.8%)

41 (78.9%)

0.041**

Biguanide

59 (65.7%)

40 (64.6%)

67 (55.6%)

81 (58.2%)

0.200

α-Glucosidase inhibitors

38 (77.9%)

17 (85%)

25 (83.4%)

49 (74.7%)

0.091

Thiazolidine

12 (93%)

6 (94.7%)

15 (90.1%)

10 (94.8%)

0.313

Laboratory data at the start of sitagliptin

HbA1c, %

8.53 ± 1.24

8.56 ± 1.25

8.70 ± 1.31

8.73 ± 1.32

0.404

Fasting blood glucose, mg/dL

202.3 ± 67.2

169.4 ± 50.6

178.1 ± 77.7

194.4 ± 73.5

0.098

Casual blood glucose, mg/dL

195.9 ± 86.8

195.1 ± 94.8

194.7 ± 71.8

207.4 ± 84.7

0.516

BMI, kg/m²

24.19 ± 3.82

25.40 ± 4.94

26.05 ± 4.31

25.75 ± 4.66

< 0.001*

SBP, mm Hg

131.6 ± 13.2

128.4 ± 14.2

130.7 ± 15.8

131.1 ± 17.2

0.396

DBP, mm Hg

74.2 ± 9.3

72.0 ± 10.2

75.4 ± 12.0

76.2 ± 10.9

0.011*

eGFR, mL/min/1.73 m²

77.1 ± 21.8

76.1 ± 23.6

75.5 ± 21.8

75.9 ± 24.3

0.957

LDL-C, mg/dL

110.7 ± 25.1

109.6 ± 29.6

108.1 ± 30.3

106.3 ± 29.6

0.623

HDL-C, mg/dL

60.6 ± 15.0

54.2 ± 18.2

53.5 ± 14.9

54.3 ± 14.6

< 0.001*

TG, mg/dL

151.1 ± 127.2

163.9 ± 132.8

173.5 ± 96.2

176.7 ± 117.7

0.246

GOT, U/L

25.2 ± 15.7

24.2 ± 18.0

25.0 ± 12.1

24.5 ± 15.6

0.960

GPT, U/L

26.3 ± 20.9

27.5 ± 21.1

30.6 ± 22.0

27.1 ± 19.0

0.383

γ-GTP, U/L

46.8 ± 80.5

45.4 ± 44.6

45.4 ± 40.0

43.7 ± 54.8

0.978

BUN, mg/dL

18.3 ± 5.5

15.4 ± 4.4

16.3 ± 5.1

15.5 ± 4.9

0.002*

Uric acid, mg/dL

4.9 ± 1.3

5.1 ± 1.3

5.2 ± 1.5

5.0 ± 1.4

0.711

**Table 2.** Number of Patients Who Developed Hypoglycemia
	n	0 - 3 months	4 - 6 months	7 - 9 months	10 - 12 months	By 12 months from baseline
Data are n (%). N.S. Chi-squared test. N.S.: no significance.
Group 1	172	17 (9.9%)	8 (4.7%)	9 (5.2%)	8 (4.7%)	25 (14.5%)
Group 2	113	10 (8.8%)	5 (4.4%)	6 (5.3%)	4 (3.5%)	16 (14.2%)
Group 3	151	4 (2.6%)	0 (0%)	3 (2.0%)	6 (4.0%)	12 (7.9%)
Group 4	194	13 (6.7%)	10 (5.2%)	8 (4.1%)	11 (5.7%)	23 (11.9%)
P		0.094	0.054	0.444	0.818	0.275

Table 2. Number of Patients Who Developed Hypoglycemia

0 - 3 months

4 - 6 months

7 - 9 months

10 - 12 months

By 12 months from baseline

Data are n (%). N.S. Chi-squared test. N.S.: no significance.

Group 1

172

17 (9.9%)

8 (4.7%)

9 (5.2%)

8 (4.7%)

25 (14.5%)

Group 2

113

10 (8.8%)

5 (4.4%)

6 (5.3%)

4 (3.5%)

16 (14.2%)

Group 3

151

4 (2.6%)

0 (0%)

3 (2.0%)

6 (4.0%)

12 (7.9%)

Group 4

194

13 (6.7%)

10 (5.2%)

8 (4.1%)

11 (5.7%)

23 (11.9%)

0.094

0.054

0.444

0.818

0.275