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 8, Number 11, November 2016, pages 805-814

Comparison of Combined Tofogliflozin and Glargine, Tofogliflozin Added to Insulin, and Insulin Dose-Increase Therapy in Uncontrolled Type 2 Diabetes

Figure 1. Adjusted mean changes over 24 weeks in HbA1c (%). Data are adjusted mean ± standard deviation (SD) at baseline and adjusted mean ± SD on treatment. *P < 0.05 vs. baseline; **P < 0.01 vs. baseline; ***P < 0.001 vs. baseline by paired t-test. Above P values were derived using Mann-Whitney analysis to examine between-group differences.

Figure 2. Adjusted mean changes over 24 weeks in fasting plasma glucose (FPG, mg/dL). Data are adjusted mean ± standard deviation (SD) at baseline and adjusted means ± SD on treatment. *P < 0.05 vs. baseline; **P < 0.01 vs. baseline; ***P < 0.001 vs. baseline by paired t-test.

Figure 3. Adjusted mean changes over 24 weeks in total insulin dose (U). Data are adjusted mean ± standard deviation (SD) at baseline and adjusted mean ± SD on treatment. *P < 0.05 vs. baseline; **P < 0.01 vs. baseline; ***P < 0.001 vs. baseline by paired t-test. Above P values were derived using Mann-Whitney analysis to examine between-group differences.

Figure 4. Adjusted mean changes over 24 weeks in weight (kg). Data are adjusted mean ± standard deviation (SD) at baseline and adjusted mean ± SD on treatment. *P < 0.05 vs. baseline; **P < 0.01 vs. baseline; ***P < 0.001 vs. baseline by paired t-test. Above P values were derived using Mann-Whitney analysis to examine between-group differences.

Figure 5. Adjusted mean changes over 24 weeks in systolic blood pressure (mm Hg). Data are adjusted mean ± standard deviation (SD) at baseline and adjusted mean ± SD on treatment. *P < 0.05 vs. baseline; **P < 0.01 vs. baseline; ***P < 0.001 vs. baseline by paired t-test analysis.

Figure 6. Adjusted mean changes over 24 weeks in diastolic blood pressure (mm Hg). Data are adjusted mean ± standard deviation (SD) at baseline and adjusted mean ± SD on treatment. *P < 0.05 vs. baseline; **P < 0.01 vs. baseline; ***P < 0.001 vs. baseline by paired t-test analysis.

**Table 1.** Insulin Dose Algorithm
Mean pre-breakfast glucose value and/or mean pre-dinner glucose value (mg/dL)	Adjustment of basal insulin or mixed insulin dose (units)
Bolus insulin dose adjusted at discretion of treating physician only if no episodes of severe hypoglycemia. Outpatient visits every 2 weeks for first few months in the insulin + tofogliflozin group and glargine + tofogliflozin group.
≤ 56	-4
56 - 80	-2
81 - 110	No adjustment
111 - 126	1
127 - 144	2
145 - 162	3
≥ 163	≥ 4

Table 1. Insulin Dose Algorithm

Mean pre-breakfast glucose value and/or mean pre-dinner glucose value (mg/dL)

Adjustment of basal insulin or mixed insulin dose (units)

Bolus insulin dose adjusted at discretion of treating physician only if no episodes of severe hypoglycemia. Outpatient visits every 2 weeks for first few months in the insulin + tofogliflozin group and glargine + tofogliflozin group.

≤ 56

-4

56 - 80

-2

81 - 110

No adjustment

111 - 126

127 - 144

145 - 162

≥ 163

≥ 4

**Table 2.** Demographic and Baseline Patient Characteristics
	Insulin (n = 15)	Insulin + tofogliflozin (n = 19)	Glargine + tofogliflozin (n = 19)
n: number of patients in the full analysis set. BMI: body mass index; OAD: oral antidiabetic drug; SD: standard deviation; SBP: systolic blood pressure; DBP: diastolic blood pressure. All characteristics were balanced across the randomized groups at baseline.
Mean age (SD), years	62.0 (10.1)	54.1 (11.5)	56.6 (12.5)
Male, n (%)	10 (66.6)	10 (52.6)	8 (42.1)
Mean weight (SD), kg	69.8 (15.6)	83.6 (20.5)	79.2 (22.1)
Mean BMI (SD), kg/m²	26.2 (3.9)	30.2 (5.1)	29.2 (7.0)
Mean duration of type 2 diabetes (SD), years	17.2 (8.3)	12.7 (4.2)	15.3 (5.9)
Mean duration of insulin treatment (SD), years	7.1 (3.3)	6.8 (2.8)	6.9 (4.8)
Insulin regimen, n (%)
Basal	1 (6.6)	2 (10.5)	0 (0.0)
Mix	13 (86.6)	11 (57.9)	12 (63.1)
Bolus + basal	1 (6.6)	6 (31.6)	7 (36.8)
Mean total insulin dose (SD), U	35.9 (16.0)	42.2 (23.1)	39.9 (12.1)
Background OAD, n (%)
Sulphonylurea	2 (13.3)	5 (26.3)	4 (21.0)
DPP4 inhibitor	7 (46.6)	8 (42.1)	10 (52.6)
Metformin	10 (66.6)	11 (57.9)	15 (78.9)
Others	1 (6.7)	0 (0.0)	0 (0.0)
Mean HbA1c (SD), %	8.1 (0.3)	9.0 (1.2)	8.8 (0.9)
Mean fasting plasma glucose (SD), mg/dL	165.0 (16.6)	185.5 (24.6)	171.9 (24.1)
Concomitant medications, n (%)
Antihypertensive agents	11 (73.3)	10 (52.6)	15 (78.9)
Lipid-lowering agents	9 (60.0)	13 (68.4)	13 (68.4)
Acetylsalicylic acid	1 (6.6)	1 (5.2)	0 (0.0)
Mean eGFR (SD), mL/min/1.73 m²	85.3 (23.1)	89.4 (34.6)	91.7 (29.3)
Mean SBP (SD), mm Hg	126.4 (9.5)	127.5 (13.7)	130.5 (5.9)
Mean DBP (SD), mm Hg	74.3 (12.9)	76.4 (13.3)	74.6 (10.3)
Mean total cholesterol (SD), mg/dL	173.3 (20.0)	179.1 (25.3)	180.6 (26.8)
Mean triglycerides (SD), mg/dL	147.8 (72.2)	166.6 (114.4)	152.9 (55.8)
Mean LDL cholesterol (SD), mg/dL	102.2 (19.2)	103.2 (17.3)	108.6 (24.2)
Mean HDL cholesterol (SD), mg/dL	54.5 (12.5)	54.0 (12.5)	54.5 (10.1)

Table 2. Demographic and Baseline Patient Characteristics

Insulin (n = 15)

Insulin + tofogliflozin (n = 19)

Glargine + tofogliflozin (n = 19)

n: number of patients in the full analysis set. BMI: body mass index; OAD: oral antidiabetic drug; SD: standard deviation; SBP: systolic blood pressure; DBP: diastolic blood pressure. All characteristics were balanced across the randomized groups at baseline.

Mean age (SD), years

62.0 (10.1)

54.1 (11.5)

56.6 (12.5)

Male, n (%)

10 (66.6)

10 (52.6)

8 (42.1)

Mean weight (SD), kg

69.8 (15.6)

83.6 (20.5)

79.2 (22.1)

Mean BMI (SD), kg/m²

26.2 (3.9)

30.2 (5.1)

29.2 (7.0)

Mean duration of type 2 diabetes (SD), years

17.2 (8.3)

12.7 (4.2)

15.3 (5.9)

Mean duration of insulin treatment (SD), years

7.1 (3.3)

6.8 (2.8)

6.9 (4.8)

Insulin regimen, n (%)

Basal

1 (6.6)

2 (10.5)

0 (0.0)

Mix

13 (86.6)

11 (57.9)

12 (63.1)

Bolus + basal

1 (6.6)

6 (31.6)

7 (36.8)

Mean total insulin dose (SD), U

35.9 (16.0)

42.2 (23.1)

39.9 (12.1)

Background OAD, n (%)

Sulphonylurea

2 (13.3)

5 (26.3)

4 (21.0)

DPP4 inhibitor

7 (46.6)

8 (42.1)

10 (52.6)

Metformin

10 (66.6)

11 (57.9)

15 (78.9)

Others

1 (6.7)

0 (0.0)

Mean HbA1c (SD), %

8.1 (0.3)

9.0 (1.2)

8.8 (0.9)

Mean fasting plasma glucose (SD), mg/dL

165.0 (16.6)

185.5 (24.6)

171.9 (24.1)

Concomitant medications, n (%)

Antihypertensive agents

11 (73.3)

10 (52.6)

15 (78.9)

Lipid-lowering agents

9 (60.0)

13 (68.4)

Acetylsalicylic acid

1 (6.6)

1 (5.2)

0 (0.0)

Mean eGFR (SD), mL/min/1.73 m²

85.3 (23.1)

89.4 (34.6)

91.7 (29.3)

Mean SBP (SD), mm Hg

126.4 (9.5)

127.5 (13.7)

130.5 (5.9)

Mean DBP (SD), mm Hg

74.3 (12.9)

76.4 (13.3)

74.6 (10.3)

Mean total cholesterol (SD), mg/dL

173.3 (20.0)

179.1 (25.3)

180.6 (26.8)

Mean triglycerides (SD), mg/dL

147.8 (72.2)

166.6 (114.4)

152.9 (55.8)

Mean LDL cholesterol (SD), mg/dL

102.2 (19.2)

103.2 (17.3)

108.6 (24.2)

Mean HDL cholesterol (SD), mg/dL

54.5 (12.5)

54.0 (12.5)

54.5 (10.1)

**Table 3.** Efficacy at 24 weeks
	Insulin (n = 15)	Insulin + tofogliflozin (n = 19)	Glargine + tofogliflozin (n = 19)
n: number of patients in the full analysis set. BMI: body mass index; OAD: oral antidiabetic drug; SD: standard deviation; SBP: systolic blood pressure; DBP: diastolic blood pressure.
HbA1c, %
Baseline (SD)	8.1 (0.3)	9.0 (1.2)	8.8 (0.9)
Adjusted mean change from baseline (95% CI; P-value)	-0.3 (-0.60 to 0.02; 0.062)	-1.0 (-1.49 to -0.59; 0.0001)	-0.8 (-1.28 to -0.22; 0.008)
Fasting plasma glucose, mg/dL
Baseline (SD)	165.0 (16.6)	185.5 (24.6)	171.9 (24.1)
Adjusted mean change from baseline (95% CI; P-value)	-10.9 (-20.9 to -0.87; 0.0359)	-61.3 (-81.86 to -39.76; < 0.0001)	-33.1 (-46.41 to -19.73; 0.0001)
Total weight, kg
Baseline (SD)	69.8 (15.6)	83.6 (20.5)	79.2 (22.1)
Adjusted mean change from baseline (95% CI; P-value)	0.6 (-0.28 to 1.39; 0.1772)	-2.9 (-4.46 to -1.27; 0.0014)	-3.4 (-4.87 to -1.91; 0.0002)
Mean daily insulin dose, U
Baseline (SD)	35.9 (16.0)	42.2 (23.1)	39.9 (12.1)
Adjusted mean change from baseline (95% CI; P-value)	5.1 (3.10 to 7.02; < 0.0001)	-2.6 (-5.57 to 0.45; 0.091)	-12.7 (-15.2 to -10.2; < 0.0001)
Systolic blood pressure, mm Hg
Baseline (SD)	126.4 (9.5)	127.5 (13.7)	130.5 (5.9)
Adjusted mean change from baseline (95% CI; P-value)	1.1 (-5.83 to 7.97; 0.7341)	-4.2 (-10.66 to 2.33; 0.1937)	-7.8 (-15.27 to -0.26; 0.0435)
Diastolic blood pressure, mm Hg
Baseline (SD)	74.3 (12.9)	76.4 (13.3)	74.6 (10.3)
Adjusted mean change from baseline (95% CI; P-value)	0.5 (-5.60 to 6.67; 0.8548)	-5.6 (-13.71 to 2.49; 0.1623)	-3.3 (-8.68 to 2.06; 0.2083)
HDL cholesterol, mg/dL
Baseline (SD)	54.5 (12.5)	54.0 (12.5)	54.5 (10.1)
Adjusted mean change from baseline (95% CI; P-value)	2.3 (-4.15 to 8.93; 0.4429)	1.8 (-1.01 to 4.68; 0.1925)	-1.57 (3.61 to 0.46; 0.1191)
Triglycerides, mg/dL
Baseline (SD)	147.8 (72.2)	166.6 (114.4)	152.9 (55.8)
Adjusted mean change from baseline (95% CI; P-value)	-0.85 (-22.40 to 20.71; 0.9333)	-13.1 (-59.31 to 33.09; 0.5572)	-25.6 (-44.39 to -6.89; 0.0112)
LDL cholesterol, mg/dL
Baseline (SD)	102.2 (19.2)	103.2 (17.3)	108.6 (24.2)
Adjusted mean change from baseline (95% CI; P-value)	2.0 (-5.00 to 9.00; 0.5455)	2.2 (-4.28 to 8.73; 0.4807)	2.2 (-4.28 to 8.72; 0.4807)
Total cholesterol, mg/dL
Baseline (SD)	102.2 (19.2)	103.2 (17.3)	108.6 (24.2)
Adjusted mean change from baseline (95% CI; P-value)	2.0 (-5.00 to 9.00; 0.5455)	2.2 (-4.28 to 8.73; 0.4807)	2.2 (-4.28 to 8.72; 0.4807)
eGFR, mL/min/1.73 m²
Baseline (SD)	85.3 (23.1)	89.4 (34.6)	91.7 (29.3)
Adjusted mean change from baseline (95% CI; P-value)	-10.9 (-20.73 to -1.00; 0.0332)	-8.8 (-14.28 to -3.28; 0.0037)	-3.2 (-11.56 to 5.14; 0.4282)

Table 3. Efficacy at 24 weeks

Insulin (n = 15)

Insulin + tofogliflozin (n = 19)

Glargine + tofogliflozin (n = 19)

n: number of patients in the full analysis set. BMI: body mass index; OAD: oral antidiabetic drug; SD: standard deviation; SBP: systolic blood pressure; DBP: diastolic blood pressure.

HbA1c, %

Baseline (SD)

8.1 (0.3)

9.0 (1.2)

8.8 (0.9)

Adjusted mean change from baseline (95% CI; P-value)

-0.3 (-0.60 to 0.02; 0.062)

-1.0 (-1.49 to -0.59; 0.0001)

-0.8 (-1.28 to -0.22; 0.008)

Fasting plasma glucose, mg/dL

Baseline (SD)

165.0 (16.6)

185.5 (24.6)

171.9 (24.1)

Adjusted mean change from baseline (95% CI; P-value)

-10.9 (-20.9 to -0.87; 0.0359)

-61.3 (-81.86 to -39.76; < 0.0001)

-33.1 (-46.41 to -19.73; 0.0001)

Total weight, kg

Baseline (SD)

69.8 (15.6)

83.6 (20.5)

79.2 (22.1)

Adjusted mean change from baseline (95% CI; P-value)

0.6 (-0.28 to 1.39; 0.1772)

-2.9 (-4.46 to -1.27; 0.0014)

-3.4 (-4.87 to -1.91; 0.0002)

Mean daily insulin dose, U

Baseline (SD)

35.9 (16.0)

42.2 (23.1)

39.9 (12.1)

Adjusted mean change from baseline (95% CI; P-value)

5.1 (3.10 to 7.02; < 0.0001)

-2.6 (-5.57 to 0.45; 0.091)

-12.7 (-15.2 to -10.2; < 0.0001)

Systolic blood pressure, mm Hg

Baseline (SD)

126.4 (9.5)

127.5 (13.7)

130.5 (5.9)

Adjusted mean change from baseline (95% CI; P-value)

1.1 (-5.83 to 7.97; 0.7341)

-4.2 (-10.66 to 2.33; 0.1937)

-7.8 (-15.27 to -0.26; 0.0435)

Diastolic blood pressure, mm Hg

Baseline (SD)

74.3 (12.9)

76.4 (13.3)

74.6 (10.3)

Adjusted mean change from baseline (95% CI; P-value)

0.5 (-5.60 to 6.67; 0.8548)

-5.6 (-13.71 to 2.49; 0.1623)

-3.3 (-8.68 to 2.06; 0.2083)

HDL cholesterol, mg/dL

Baseline (SD)

54.5 (12.5)

54.0 (12.5)

54.5 (10.1)

Adjusted mean change from baseline (95% CI; P-value)

2.3 (-4.15 to 8.93; 0.4429)

1.8 (-1.01 to 4.68; 0.1925)

-1.57 (3.61 to 0.46; 0.1191)

Triglycerides, mg/dL

Baseline (SD)

147.8 (72.2)

166.6 (114.4)

152.9 (55.8)

Adjusted mean change from baseline (95% CI; P-value)

-0.85 (-22.40 to 20.71; 0.9333)

-13.1 (-59.31 to 33.09; 0.5572)

-25.6 (-44.39 to -6.89; 0.0112)

LDL cholesterol, mg/dL

Baseline (SD)

102.2 (19.2)

103.2 (17.3)

108.6 (24.2)

Adjusted mean change from baseline (95% CI; P-value)

2.0 (-5.00 to 9.00; 0.5455)

2.2 (-4.28 to 8.73; 0.4807)

2.2 (-4.28 to 8.72; 0.4807)

Total cholesterol, mg/dL

Baseline (SD)

102.2 (19.2)

103.2 (17.3)

108.6 (24.2)

Adjusted mean change from baseline (95% CI; P-value)

2.0 (-5.00 to 9.00; 0.5455)

2.2 (-4.28 to 8.73; 0.4807)

2.2 (-4.28 to 8.72; 0.4807)

eGFR, mL/min/1.73 m²

Baseline (SD)

85.3 (23.1)

89.4 (34.6)

91.7 (29.3)

Adjusted mean change from baseline (95% CI; P-value)

-10.9 (-20.73 to -1.00; 0.0332)

-8.8 (-14.28 to -3.28; 0.0037)

-3.2 (-11.56 to 5.14; 0.4282)

**Table 4.** Treatment-Emergent Adverse Events
	Insulin (n = 15)	Insulin + tofogliflozin (n = 19)	Glargine + tofogliflozin (n = 19)
*Patient self-reporting only. Number of patients with hypoglycemia during the follow-up period. There were no significant differences among the groups.
Hypoglycemia (n)	4	5	4

Table 4. Treatment-Emergent Adverse Events

Insulin (n = 15)

Insulin + tofogliflozin (n = 19)

Glargine + tofogliflozin (n = 19)

*Patient self-reporting only. Number of patients with hypoglycemia during the follow-up period. There were no significant differences among the groups.

Hypoglycemia (n)