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 to an empagliflozin or glimepiride group. Ultimately, 30 patients in the empagliflozin group and 28 patients in the glimepiride group were analyzed (Fig. 2). Baseline clinical and biochemical characteristics were all statistically similar (Table 1).
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
|
Gender (male/female)
|
18 / 12
|
18 / 10
|
0.74
|
Estimated duration of diabetes [years]
|
6.1±7.2
|
4.9±4.9
|
0.44
|
Past smoker [%]
|
60.0
|
60.7
|
0.96
|
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
|
Body fluid volume [L]
|
35.8±6.8
|
36.6±8.6
|
0.69
|
Skeletal muscle mass [kg]
|
26.7±5.7
|
27.1±7.1
|
0.81
|
Total fat mass [kg]
|
21.1±6.8
|
20.5±11.0
|
0.8
|
Waist circumference [cm]
|
91.6±9.2
|
91.2±15.7
|
0.27
|
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
|
CysC [mg/L]
|
0.8±0.12
|
0.79±0.16
|
0.78
|
eGFRcys [mL min−1 1.73 m−2]
|
96.4±20.1
|
99.3±21.6
|
0.59
|
F–CPR [ng/mL]
|
3.1±1.7
|
2.5±1.9
|
0.23
|
Log U–Alb
|
2.9±1.7
|
2.5±1.6
|
0.34
|
Log L–FABP
|
0.96±0.85
|
0.6±0.85
|
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
|
CRP [mg/dL]
|
0.17±0.11
|
0.23±0.39
|
0.54
|
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
|
HOMA2%B
|
217.8±92.3
|
205.4±105.1
|
0.63
|
HOMA2%S
|
21.5±28.5
|
25.5±16.2
|
0.07
|
HOMA2IR
|
8.8±8.9
|
6.5±6.1
|
0.07
|
Metformin [mg]
|
883.3±375.6
|
991.1±473.8
|
0.34
|
Glargine [U]
|
9.4±4.6
|
11.7±9.0
|
0.6
|
ARB/ACE–I [%]
|
23.3
|
32.1
|
0.46
|
Statin [%]
|
40.0
|
53.6
|
0.31
|
Values are shown as the means ± standard deviation (SD). 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; CysC, cystatin C; eGFRcys, estimated glomerular filtration rate by cystatin C; F–CPR, fasting C–peptide immunoreactivity; U–Alb, urine albumin; L–FABP, liver–type fatty acid binding protein; UA, uric acid; LDL, low–density lipoprotein; HDL, high–density lipoprotein; TG, triglycerides; CRP, C–reactive protein; sBP, systolic blood pressure; dBP, diastolic blood pressure; HR, heart rate; HOMA2%B, Homeostasis Model Assessment 2 steady-state beta cell (%B) function; HOMA2%S, Homeostasis Model Assessment 2 insulin sensitivity (%S); HOMA2IR, Homeostasis Model Assessment 2 insulin resistance (IR); ARB/ACE–I, angiotensin type II receptor blocker/angiotensin converting enzyme–I
Endothelial function
Average baseline FMD values were 5.49 ± 2.05% and 5.46 ± 2.2% for empagliflozin and glimepiride groups, respectively (Tables 1 & 2). FMD values following treatment with empagliflozin and glimepiride were 5.3 ± 2.28% and 5.09 ± 1.86%, respectively (Table 2). Changes in FMD were –0.19 ± 2.34% and −0.37 ± 2.77% for empagliflozin and glimepiride groups, respectively, without a significant difference (P = 0.79).
Table 2 FMD (%±SD) with treatment
|
Empagliflozin
|
Glimepiride
|
|
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 deviation (SD).
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 week.
P values in each row show the comparison of FMD values at the baseline and at week 12. P value in each line shows the comparison of changes in FMD values for both the groups.
Metabolic markers
Fasting plasma glucose remained unchanged, with no significant difference evident between the two groups following treatment (P = 0.69) (Table 3). However, HbA1c and glycated albumin (GA) levels significantly decreased per group following treatment (P ≤ 0.05), with the ΔHbA1c (P = 0.75) and ΔGA (P = 0.42) showing no significant difference between the two groups. Uric acid (UA) significantly decreased in the empagliflozin group (P < 0.001), but 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 pressures along with the heart rate (P =0.81) did not changed significantly between the two groups. Empagliflozin treatment significantly increased low-density lipoprotein- C (LDL–C) (P < 0.001), whereas triglycerides (TG) (P = 0.31) and high-density lipoprotein- C (HDL–C) (P = 0.37) did not significantly changed between the two groups. Glimepiride treatment led to a significant increase of body weight (P < 0.05) after treatment, with a significant difference observed in the Δbody weight between the two groups (P = 0.02). However, for the subgroup showing decreased body weight, ΔFMD was not significantly different between the two groups (P = 0.62) (Table 4). Glimepiride also led to a significant increase of waist circumference after treatment (P = 0.004). A significant difference was also observed in the Δwaist circumference between the two groups (P = 0.008). With regard to body composition, glimepiride led to a significant increase of total fat mass (P = 0.02). In comparison, empagliflozin significant 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
|
Postprandial plasma glucose (mg/dL) [mean ± SD]
|
|
|
|
|
Week 12
|
169.6±87.0
|
165.1±61.1
|
|
|
P = 0.07
|
P = 0.26
|
|
ΔPPG
|
−16.5±43.9
|
−9.5±27.6
|
P = 0.63
|
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
|
|
CysC (mg/dL) [mean ± SD]
|
|
|
|
|
Week 12
|
0.84±0.13
|
0.82±0.17
|
|
|
P < 0.001
|
P = 0.03
|
|
eGFRcys (mL min−1 1.73 m−2) [mean ± SD]
|
|
|
|
|
Week 12
|
89.4±17.3
|
95.9±20.4
|
|
|
P = 0.01
|
P = 0.04
|
|
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]
|
|
|
|
|
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]
|
|
|
|
|
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
|
Skeletal muscle mass (kg) [mean ± SD]
|
|
|
|
|
Week 12
|
26.4±5.7
|
27.1±7.2
|
|
|
P = 0.08
|
P = 0.72
|
|
ΔSkeletal muscle mass
|
−0.21±0.6
|
0.05±0.7
|
P = 0.15
|
Total fat mass (kg) [mean ± SD]
|
|
|
|
|
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]
|
|
|
|
|
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 deviation (SD).
Δ indicates the changes in the FMD values between 0 and 12 week.
P values in each row show the comparison of FMD values at the baseline and at week 12. P value in each line shows the comparison of changes in FMD values for both the groups.
FMD, flow–mediated dilation; HbA1c, glycated hemoglobin; GA, glycated albumin; Cr, serum creatinine; eGRF, 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, triglycerides
Table 4 Change of FMD (%±SD) with treatment with subgroup of decreasing body weight for 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 week.
P value in each line shows the comparison of changes in FMD values of both the groups.
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 changed between the two groups (Table S1). In this study, empagliflozin and glimepiride did not affect insulin secretion, insulin sensitivity, pancreatic β-cell function, or insulin resistance. Table 5 showed associations between arterial sclerosis markers and ΔFMD. ΔHbA1c, Δbody weight, ΔHDL–C, and ΔTG were related to the ΔFMD. Additionally, the ΔFMD may have been greater if the baseline FMD was lower.
Table 5 Associations between arterial sclerosis markers and ΔFMD in all patients (n = 58)
|
Rawβ
|
Stdβ
|
P value
|
Age
|
0.01
|
0.05
|
0.7
|
Gender
|
−0.02
|
−0.004
|
0.98
|
Duration
|
0.02
|
0.06
|
0.67
|
FMD (0)
|
−0.74
|
−0.61
|
0.0001***
|
HbA1c (0)
|
−0.47
|
−0.18
|
0.18
|
FPG (0)
|
−0.005
|
−0.11
|
0.4
|
GA (0)
|
−0.17
|
−0.24
|
0.07
|
BW (0)
|
0.03
|
0.18
|
0.18
|
BMI (0)
|
0.12
|
0.2
|
0.15
|
UA (0)
|
0.31
|
0.16
|
0.22
|
LDL (0)
|
−0.02
|
−0.23
|
0.09
|
HDL (0)
|
−0.04
|
−0.26
|
0.05
|
TG (0)
|
0.004
|
0.2
|
0.11
|
Past smoker
|
−0.79
|
−0.15
|
0.25
|
sBP (0)
|
−0.03
|
−0.18
|
0.17
|
dBP (0)
|
−0.06
|
−0.21
|
0.11
|
ΔHbA1c
|
−1.85
|
−0.31
|
0.02*
|
ΔGA
|
−0.16
|
−0.1
|
0.48
|
ΔFPG
|
−0.005
|
−0.09
|
0.49
|
ΔBW
|
−0.33
|
−0.38
|
0.003**
|
ΔLDL-C
|
0.01
|
0.11
|
0.43
|
ΔHDL-C
|
0.08
|
0.31
|
0.02*
|
ΔTG
|
−0.009
|
−0.38
|
0.003**
|
ΔsBP
|
0.01
|
0.06
|
0.63
|
ΔdBP
|
0.05
|
0.18
|
0.18
|
ARB/ACE-I
|
0.41
|
0.07
|
0.59
|
Statin
|
0.34
|
0.07
|
0.62
|
Values are shown as the means. *P < 0.05, ** P < 0.01, and ***P < 0.001 indicate a significant association between arterial sclerosis markers and ΔFMD.
(0), baseline; FMD, flow-mediated dilation; HbA1c, glycated hemoglobin; FPG, fasting plasma glucose; GA, glycated albumin; BW, body weight; BMI, body mass index; UA, uric acid; LDL, low-density lipoprotein; HDL, high-density lipoprotein; TG, triglycerides; sBP, systolic blood pressure; dBP, diastolic blood pressure; LDL-C, LDL cholesterol; HDL-C, HDL cholesterol; ARB, angiotensin receptor blocker; ACE-I, angiotensin converting enzyme inhibitor