Patients
Between June 2016 and 2018, 69 patients with type 2 diabetes agreed to participate in this study. A total of 63 patients were randomized at a one-to-one ratio to either the empagliflozin or glimepiride group. Ultimately, 30 patients in the empagliflozin group and 28 patients in the glimepiride group were analyzed (Fig. 2). The baseline clinical and biochemical characteristics in the two treatment groups were statistically similar (Table 1). Patients received the following drugs in the empagliflozin vs. glimepiride groups prior to enrollment in the study: metformin (23.3% vs. 14.3%), DPP-4 inhibitor (30.0% vs. 28.6%), SGLT2-inhibitor (3.7% vs. 3.6%), sulfonylurea (13.3% vs. 14.3%), α-glucosidase inhibitor (3.3% vs. 7.1%), glinide (0% vs 3.6%), insulin (6.7% vs. 7.1%), and a GLP-1 analogue (0% vs 3.6%).
Table 1 Baseline characteristics of patients
|
Empagliflozin group
(± SD)
|
Glimepiride group
(± SD)
|
P-value
|
Age [years]
|
58.6 ± 8.5
|
54.3 ± 12.2
|
0.13
|
Sex (male/female)
|
18 / 12
|
18 / 10
|
0.74
|
Estimated duration of diabetes [years]
|
6.1 ± 7.2
|
4.9 ± 4.9
|
0.44
|
Recently diagnosed diabetes [%]
|
36.7
|
39.3
|
0.84
|
Current smoker [%]
|
20.0
|
39.3
|
0.11
|
FMD [%]
|
5.49 ± 2.05
|
5.46 ± 2.2
|
0.96
|
HbA1c [%]
|
6.9 ± 1.1
|
6.6 ± 0.7
|
1.0
|
FPG [mg/dL]
|
136.9 ± 65.2
|
127.1 ± 52.6
|
0.37
|
GA [%]
|
17.0 ± 3.7
|
16.3 ± 3.4
|
0.48
|
Body weight [kg]
|
70.0 ± 11.3
|
69.6 ± 17.1
|
0.92
|
BMI [kg/m2]
|
26.1 ± 3.7
|
25.9 ± 5.4
|
0.9
|
Cr [mg/dL]
|
0.76 ± 0.16
|
0.73 ± 0.16
|
0.54
|
eGFR [mL min−1 1.73 m−2]
|
74.9 ± 12.9
|
81.9 ± 19.7
|
0.11
|
UA [mg/dL]
|
5.5 ± 1.2
|
5.4 ± 1.5
|
0.96
|
LDL-C [mg/dL]
|
94.0 ± 26.7
|
89.2 ± 28.1
|
0.51
|
HDL-C [mg/dL]
|
54.7 ± 16.0
|
57.4 ± 16.4
|
0.52
|
TG [mg/dL]
|
197.7 ± 101.1
|
176.0 ± 131.5
|
0.2
|
sBP [mmHg]
|
129.6 ± 14.9
|
130.1 ± 20.5
|
0.9
|
dBP [mmHg]
|
80.8±10.0
|
78.0 ± 9.3
|
0.28
|
HR [bpm]
|
79.4 ± 14.8
|
77.5 ± 14.3
|
0.64
|
Metformin [mg]
|
883.3 ± 375.6
|
991.1 ± 473.8
|
0.34
|
Glargine [U/kg]
|
0.14 ± 0.07
|
0.16 ± 0.11
|
0.23
|
Values are shown as the means ± standard deviations (SDs). Paired Student’s t–tests were used to compare values between different groups.
FMD, flow-mediated dilation; HbA1c, glycated hemoglobin; FPG, fasting plasma glucose; GA, glycated albumin; BMI, body mass index; Cr, serum creatinine; eGFR, estimated glomerular filtration rate
Endothelial function
The average baseline FMD values before and after 12-week treatment with empagliflozin and glimepiride are presented in Table 2. No significant difference was observed in the changes in FMD in empagliflozin vs. glimepiride groups.
Table 2 FMD (% ± SD) with treatment
|
Empagliflozin
|
Glimepiride
|
P-value
|
FMD (0)
|
5.49 ± 2.05
|
5.46 ± 2.2
|
P = 0.96
|
FMD (12)
|
5.3 ± 2.28
|
5.09 ± 1.86
|
P = 0.71
|
|
P = 0.66
|
P = 0.49
|
|
ΔFMD (12) − (0)
|
−0.19 ± 2.34
|
−0.37 ± 2.77
|
P = 0.79
|
Values are shown as the means ± standard deviations (SDs).
FMD, flow-mediated dilation
FMD (0) means the baseline FMD value at 0 week. FMD (12) means the FMD value at 12 weeks after additional treatment.
Δ indicates the change in the FMD value between 0 and 12 weeks.
P-values in each row refer to a comparison of FMD values at the baseline and at week 12. P-values in each line refer to a comparison of changes in FMD values for both groups.
Metabolic markers
The fasting plasma glucose remained unchanged in both groups, with no significant difference evident between the two groups following treatment (P = 0.69; Table 3). HbA1c and glycated albumin (GA) levels significantly decreased in both groups (P ≤ 0.05). However, the changes in these metabolic markers were not significantly different between the two groups (ΔHbA1c, P = 0.75 and ΔGA, P = 0.42) Uric acid (UA) was significantly decreased in the empagliflozin group (P < 0.001) and significantly increased in the glimepiride group (P = 0.01). A significant difference between the two groups was also noted in the ΔUA (P < 0.001). Systolic (P = 0.59) and diastolic (P = 0.74) blood pressure along with the heart rate (P = 0.81) did not change significantly between the two groups. Empagliflozin treatment significantly increased low-density lipoprotein-C (LDL-C; P < 0.001), whereas triglycerides (TGs; P = 0.31) and high-density lipoprotein-C (HDL-C; P = 0.37) did not change significantly between the two groups. Glimepiride treatment led to a significant increase in body weight (P < 0.05) after treatment. In addition, a significant difference was observed in the change in body weight between the two groups (P = 0.02). However, in the subgroup of patients for whom a decrease in body weight was observed, ΔFMD was not significantly different between the two groups (P = 0.62; Table 4). Glimepiride also led to a significant increase in waist circumference after treatment (P = 0.004). Moreover, a significant difference was observed in the change in waist circumference between the two groups (P = 0.008). With regard to body composition, glimepiride led to a significant increase in total fat mass (P = 0.02). In comparison, empagliflozin significantly decreased body fluid volume (P = 0.03).
Table 3 Changes in metabolic markers
|
Empagliflozin
|
Glimepiride
|
|
Fasting plasma glucose (mg/dL) [mean ± SD]
|
Week 12
|
124.5 ± 52.1
|
119.9 ± 49.1
|
|
|
P = 0.11
|
P = 0.47
|
|
ΔFPG
|
−12.4 ± 44.4
|
−7.3 ± 52.0
|
P = 0.69
|
HbA1c (%) [mean ± SD]
|
Week 12
|
6.7 ± 1.1
|
6.4 ± 0.78
|
|
|
P = 0.001
|
P = 0.01
|
|
ΔHbA1c
|
−0.22 ± 0.36
|
−0.26 ± 0.5
|
P = 0.75
|
GA (%) [mean ± SD]
|
Week 12
|
16.0 ± 3.2
|
15.7 ± 3.1
|
|
|
P < 0.001
|
P = 0.05
|
|
ΔGA
|
−0.97 ± 1.3
|
−0.65 ± 1.6
|
P = 0.42
|
Renal function, Cr (mg/dL) [mean ± SD]
|
Week 12
|
0.79 ± 0.15
|
0.74 ± 0.16
|
|
|
P = 0.03
|
P = 0.8
|
|
eGFR (mL min−1 1.73 m−2) [mean ± SD]
|
Week 12
|
72.1 ± 11.7
|
81.5 ± 20.2
|
|
|
P = 0.02
|
P = 0.8
|
|
UA (mg/dL) [mean ± SD]
|
Week 12
|
4.8 ± 1.2
|
5.7 ± 1.4
|
|
|
P < 0.001
|
P = 0.01
|
|
ΔUA
|
−0.64 ± 0.9
|
0.26 ± 0.5
|
P < 0.001
|
Body weight (kg) [mean ± SD]
|
Week 12
|
69.4 ± 12.0
|
70.8 ± 18.2
|
|
|
P = 0.22
|
P < 0.05
|
|
ΔBody weight
|
−0.59 ± 2.5
|
1.2 ± 3.0
|
P = 0.02
|
Waist circumference (cm) [mean ± SD]
|
Baseline
|
91.6 ± 9.2
|
91.2 ± 15.7
|
P = 0.27
|
Week 12
|
90.9 ± 8.9
|
92.3 ± 15.3
|
|
|
P = 0.07
|
P = 0.004
|
|
ΔWaist circumference
|
−0.64 ± 1.8
|
1.1 ± 2.8
|
P = 0.008
|
Blood pressure (mmHg) [mean ± SD]
|
sBP
|
Week 12
|
130.2 ± 14.2
|
128.9 ± 19.3
|
|
|
P = 0.79
|
P = 0.62
|
|
ΔsBP
|
0.69 ± 13.7
|
−1.3 ± 13.5
|
P = 0.59
|
dBP
|
|
|
|
Week 12
|
80.6 ± 7.6
|
78.6 ± 12.0
|
|
|
P = 0.91
|
P = 0.72
|
|
ΔdBP
|
−0.24 ± 10.8
|
0.64 ± 9.3
|
P = 0.74
|
Heart rate
|
Week 12
|
80.1 ± 15.4
|
79.0 ± 12.8
|
|
|
P = 0.76
|
P = 0.55
|
|
ΔHeart rate
|
0.68±11.2
|
1.5±11.6
|
P = 0.81
|
Lipids (TG, HDL–C, LDL–C) (mg/dL) [mean ± SD]
|
LDL-C
|
Week 12
|
107.5 ± 33.0
|
93.9 ± 29.6
|
|
|
P < 0.001
|
P = 0.33
|
|
ΔLDL-C
|
13.5 ± 19.3
|
4.7 ± 25.2
|
P = 0.14
|
HDL-C
|
|
|
|
Week 12
|
56.0 ± 12.5
|
56.4 ± 13.1
|
|
|
P = 0.43
|
P = 0.61
|
|
ΔHDL-C
|
1.4 ± 9.4
|
−1.1 ± 10.9
|
P = 0.37
|
TG
|
|
|
|
Week 12
|
177.1 ± 86.9
|
185.7 ± 123.7
|
|
|
P = 0.29
|
P = 0.8
|
|
ΔTG
|
−20.6 ± 103.8
|
9.6 ± 121.5
|
P = 0.31
|
Body fluid volume (L) [mean ± SD]
|
Baseline
|
35.8 ± 6.8
|
36.6 ± 8.6
|
P = 0.69
|
Week 12
|
35.4 ± 6.9
|
36.3 ± 8.7
|
|
|
P = 0.03
|
P = 0.32
|
|
ΔBody fluid volume
|
−0.33 ± 0.72
|
−0.35 ± 1.8
|
P = 0.94
|
Total fat mass (kg) [mean ± SD]
|
Baseline
|
21.1 ± 6.8
|
20.5 ± 11.0
|
P = 0.8
|
Week 12
|
20.6 ± 6.8
|
21.7 ± 11.6
|
|
|
P = 0.16
|
P = 0.02
|
|
ΔTotal fat mass
|
−0.58 ± 2.1
|
1.2 ± 2.3
|
P = 0.006
|
Adverse events (%)
|
|
rash on both arms (3.3%)
|
hypoglycemia (3.6%)
|
|
Glargine (U) [mean ± SD]
|
Baseline
|
9.4 ± 4.6
|
11.7 ± 9.0
|
P = 0.6
|
Week 12
|
8.4 ± 5.1
|
9.6 ± 8.9
|
|
|
P = 0.02
|
P < 0.001
|
|
ΔGlargine
|
−1.0 ± 2.4
|
−2.1 ± 3.5
|
P = 0.16
|
|
|
|
|
|
Values are shown as the means ± standard deviations (SDs).
Δ indicates the changes in the FMD values between 0 and 12 weeks.
P-values in each row refers to the comparison of FMD values at the baseline and at week 12. The P-value in each line refers to the comparison of changes in FMD values for both the groups.
FMD, flow-mediated dilation; HbA1c, glycated hemoglobin; GA, glycated albumin; Cr, serum creatinine; eGFR, estimated glomerular filtration rate; CysC, cystatin C; eGFRcys, estimated glomerular filtration rate by cystatin C; UA, uric acid; sBP, systolic blood pressure; dBP, diastolic blood pressure; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride
Table 4 Change in FMD (% ± SD) with treatment in the subgroup of patients with decreased body weight during the observation period
|
Empagliflozin (n = 17)
|
Glimepiride (n = 8)
|
|
ΔFMD (12) − (0)
|
0.41 ± 2.55
|
0.94 ± 2.16
|
P = 0.62
|
FMD, flow-mediated dilation
Δ indicates the change in FMD value between 0 and 12 weeks.
The P-value refers to a comparison of changes in FMD values between both the groups.
The fasting C-peptide immunoreactivity (CPR; P = 0.55), homeostasis model assessment 2 steady state beta cell (%B) function (P = 0.2), homeostasis model assessment 2 insulin sensitivity (%S) (P = 0.09), and homeostasis model assessment 2 insulin resistance (P = 0.22) were not significantly different between the two groups (Additional file 1, Table A1). In this study, empagliflozin and glimepiride did not affect insulin secretion, insulin sensitivity, pancreatic β-cell function, or insulin resistance. The associations between arterial sclerosis markers and ΔFMD, ΔHbA1c, the change in body weight, ΔHDL-C, and ΔTG were related to ΔFMD. Additionally, the ΔFMD might have been greater if the baseline FMD was lower (Additional file 1, Table A2).