Background
Methods
Study design and patients
Glycemic parameter measurements and definition of visit-to-visit glycemic variability
Brachial flow-mediated dilation measurement
Nitric oxide measurement
Endothelin-1 measurement
Evaluation of estimated glomerular filtration rate
Evaluation of urinary albumin excretion
Clinical laboratory measurements
Statistical methods
Results
Baseline demographic and clinical characteristics
Classified by tertile of SD of HbA1c | Classified by tertile of SD of FPG | |||||||
---|---|---|---|---|---|---|---|---|
First tertile group (n = 79) | Second tertile group (n = 80) | Third tertile group (n = 80) | P value | First tertile group (n = 79) | Second tertile group (n = 80) | Third tertile group (n = 80) | P value | |
Age (year)a | 65.97 ± 5.52 | 64.36 ± 7.30 | 64.88 ± 5.74 | 0.253 | 65.27 ± 6.09 | 64.71 ± 6.08 | 65.23 ± 6.62 | 0.825 |
Sex, female (%)b | 36 (45.57) | 42 (52.50) | 47 (58.75) | 0.252 | 41 (50.00) | 47 (59.49) | 37 (47.44) | 0.279 |
BMI (kg/m2)a | 24.43 ± 2.94 | 23.58 ± 2.71 | 23.79 ± 2.81 | 0.147 | 23.89 ± 2.89 | 23.44 ± 2.75 | 24.46 ± 2.79 | 0.074 |
SBP (mm Hg)a | 152.92 ± 11.85 | 153.01 ± 8.71 | 156.02 ± 8.99 | 0.083 | 152.35 ± 8.16 | 153.56 ± 9.70 | 156.03 ± 11.61 | 0.061 |
DBP (mm Hg)a | 83.68 ± 9.54 | 80.81 ± 7.73 | 82.92 ± 7.08 | 0.073 | 83.06 ± 8.34 | 82.38 ± 7.35 | 81.96 ± 8.99 | 0.701 |
Heart rate (bpm)a | 74.82 ± 9.65 | 76.01 ± 9.09 | 74.34 ± 8.89 | 0.498 | 74.65 ± 10.78 | 75.30 ± 7.30 | 75.23 ± 9.31 | 0.888 |
Duration of diabetes (years)c | 3.00 (2.85, 3.25) | 3.00 (2.85, 3.27) | 3.00 (2.82, 3.33) | 0.905 | 3.00 (2.90, 3.35) | 3.00 (2.69, 3.13) | 3.00 (2.93, 3.19) | 0.342 |
Current smoking, n (%)b | 8 (10.13) | 9 (11.25) | 7 (8.75) | 0.871 | 8 (9.76) | 8 (10.13) | 8 (10.26) | 0.994 |
Current drinking, n (%)b | 5 (6.33) | 6 (7.50) | 5 (6.25) | 0.940 | 7 (8.54) | 3 (3.80) | 6 (7.69) | 0.442 |
Hypertension history, n (%)b | 62 (78.48) | 60 (75.00) | 65 (81.25) | 0.631 | 64 (78.05) | 61 (77.22) | 62 (79.49) | 0.941 |
FPG (mmol/L)a | 9.80 ± 1.50 | 9.80 ± 1.57 | 10.14 ± 1.54 | 0.269 | 9.97 ± 1.43 | 9.99 ± 1.46 | 9.78 ± 1.72 | 0.625 |
HbA1c (%)a | 10.01 ± 2.00 | 10.17 ± 1.53 | 10.62 ± 1.34 | 0.061 | 10.21 ± 1.44 | 10.19 ± 1.76 | 10.40 ± 1.77 | 0.684 |
TCHO (mmol/L)a | 5.10 ± 0.99 | 5.36 ± 0.96 | 5.39 ± 1.00 | 0.127 | 5.41 ± 0.91 | 5.27 ± 0.96 | 5.18 ± 1.08 | 0.332 |
TG (mmol/L)a | 1.89 ± 1.11 | 1.61 ± 0.84 | 1.73 ± 1.01 | 0.200 | 1.65 ± 0.88 | 1.65 ± 0.88 | 1.92 ± 1.18 | 0.139 |
HDL-c (mmol/L)a | 1.37 ± 0.45 | 1.41 ± 0.48 | 1.38 ± 0.50 | 0.893 | 1.38 ± 0.50 | 1.36 ± 0.41 | 1.42 ± 0.52 | 0.768 |
LDL-c (mmol/L)a | 3.35 ± 1.15 | 3.63 ± 1.11 | 3.67 ± 1.21 | 0.167 | 3.70 ± 1.08 | 3.58 ± 1.03 | 3.38 ± 1.33 | 0.215 |
Hypoglycemic agents, n (%)b | ||||||||
Metformin | 73 (92.41) | 72 (90.00) | 75 (93.75) | 0.675 | 74 (90.24) | 74 (93.67) | 72 (92.31) | 0.720 |
Gliclazide | 39 (49.37) | 34 (42.50) | 35 (43.75) | 0.653 | 37 (45.12) | 36 (45.57) | 35 (44.87) | 0.996 |
Other sulfonylurea | 24 (30.38) | 21 (26.25) | 22 (27.50) | 0.839 | 22 (26.83) | 18 (22.78) | 27 (34.62) | 0.245 |
Thiazolidinedione | 7 (8.86) | 5 (6.25) | 8 (10.00) | 0.681 | 11 (13.41) | 4 (5.06) | 5 (6.41) | 0.120 |
Acarbose | 15 (18.99) | 15 (18.75) | 11 (13.75) | 0.613 | 19 (23.17) | 12 (15.19) | 10 (12.82) | 0.189 |
Glinide | 4 (5.06) | 4 (5.00) | 3 (3.75) | 0.905 | 5 (6.10) | 4 (5.06) | 2 (2.56) | 0.551 |
Insulin | 9 (11.39) | 7 (8.75) | 7 (8.75) | 0.809 | 8 (9.76) | 8 (10.13) | 7 (8.97) | 0.969 |
Other drugs, n (%)b | ||||||||
Antihypertension drug | 57 (72.15) | 56 (70.00) | 63 (79.63) | 0.425 | 58 (70.73) | 58 (73.42) | 60 (76.92) | 0.673 |
Aspirin | 56 (70.89) | 49 (61.25) | 43 (53.75) | 0.084 | 51 (62.20) | 47 (59.49) | 50 (64.10) | 0.836 |
Statins | 11 (13.92) | 13 (16.25) | 11 (13.75) | 0.883 | 12 (14.63) | 12 (15.19) | 11 (14.10) | 0.982 |
Baseline variables of renal and vascular endothelial function
Classified by tertile of SD of HbA1c | Classified by tertile of SD of FPG | |||||||
---|---|---|---|---|---|---|---|---|
First tertile group (n = 79) | Second tertile group (n = 80) | Third tertile group (n = 80) | P value | First tertile group (n = 79) | Second tertile group (n = 80) | Third tertile group (n = 80) | P value | |
ACR (mg/mmol)a | 1.60 (1.40, 2.25) | 1.57 (1.10, 2.72) | 1.78 (1.20, 2.52) | 0.792 | 1.60 (1.30, 2.14) | 1.58 (1.21, 2.50) | 1.80 (1.30, 2.80) | 0.306 |
Creatintine (mg/dl)b | 0.73 ± 0.13 | 0.74 ± 0.13 | 0.76 ± 0.13 | 0.429 | 0.72 ± 0.12 | 0.74 ± 0.13 | 0.77 ± 0.14 | 0.097 |
Cystatin C (mg/L)b | 0.78 ± 0.16 | 0.83 ± 0.16 | 0.82 ± 0.16 | 0.118 | 0.77 ± 0.16 | 0.82 ± 0.15 | 0.83 ± 0.17 | 0.053 |
eGFR-Cr (ml · min−1 · 1.73 m−2)b | 104.39 ± 26.40 | 99.89 ± 20.56 | 96.33 ± 22.21 | 0.091 | 102.85 ± 21.48 | 98.54 ± 22.95 | 99.19 ± 25.37 | 0.456 |
eGFR-Cys C (ml · min−1 · 1.73 m−2)b | 102.53 ± 18.30 | 96.57 ± 19.84 | 97.28 ± 19.84 | 0.102 | 103.26 ± 19.23 | 97.17 ± 18.16 | 95.97 ± 19.53* | 0.036 |
FMD (%)b | 8.27 ± 3.77 | 7.56 ± 3.47 | 8.08 ± 3.83 | 0.455 | 8.07 ± 3.57 | 8.30 ± 3.87 | 7.54 ± 3.62 | 0.413 |
NO (μmol/L)b | 61.62 ± 8.90 | 59.59 ± 9.61 | 61.47 ± 9.83 | 0.322 | 61.09 ± 9.07 | 62.55 ± 9.60 | 59.04 ± 9.49 | 0.061 |
ET-1 (pg/ml)b | 40.56 ± 6.63 | 40.44 ± 7.47 | 42.84 ± 6.99*,** | 0.055 | 40.78 ± 6.77 | 41.46 ± 6.89 | 41.60 ± 7.66 | 0.739 |
HbA1c and FPG profiles and severe hypoglycemic episodes during follow-up period
Classified by tertile of SD of HbA1c | Classified by tertile of SD of FPG | |||||||
---|---|---|---|---|---|---|---|---|
First tertile group (n = 79) | Second tertile group (n = 80) | Third tertile group (n = 80) | P value | First tertile group (n = 79) | Second tertile group (n = 80) | Third tertile group (n = 80) | P value | |
Mean HbA1c (%) | 8.22 ± 1.00 | 8.33 ± 0.79 | 8.11 ± 0.56 | 0.213 | 8.07 ± 0.65 | 8.23 ± 0.72 | 8.35 ± 0.99 | 0.093 |
SD of HbA1c (%) | 1.41 ± 0.50 | 2.68 ± 0.36* | 3.52 ± 0.47*,** | <0.001 | 2.05 ± 0.92 | 2.64 ± 0.81* | 2.93 ± 0.99* | <0.001 |
CV of HbA1c (%) | 17.66 ± 4.59 | 32.48 ± 3.68* | 43.89 ± 4.49*,** | <0.001 | 26.31 ± 9.60 | 32.21 ± 9.26* | 32.75 ± 10.63* | <0.001 |
Mean FPG (mmol/L) | 6.98 ± 0.97 | 6.92 ± 0.86 | 6.70 ± 0.55 | 0.075 | 6.76 ± 0.64 | 6.83 ± 0.74 | 7.02 ± 0.98 | 0.106 |
SD of FPG (mmol/L) | 3.49 ± 1.27 | 3.70 ± 0.91 | 4.26 ± 1.24*,** | <0.001 | 2.69 ± 0.48 | 3.68 ± 0.28* | 5.09 ± 0.95*, ** | <0.001 |
CV of FPG (%) | 50.10 ± 8.62 | 53.68 ± 7.80* | 63.87 ± 8.27*,** | <0.001 | 39.81 ± 5.34 | 53.87 ± 6.29* | 72.52 ± 8.56*, ** | <0.001 |
Severe hypoglycemic episodes (times) | 0.70 ± 0.64 | 1.09 ± 0.79* | 1.94 ± 1.63*,** | <0.001 | 1.02 ± 1.08 | 1.32 ± 1.22 | 1.40 ± 1.33 | 0.112 |
Vascular parameters and glycemic variability throughout follow-up period
Total (n = 239) | Classified by tertile of SD of HbA1c | Classified by tertile of SD of FPG | |||||||
---|---|---|---|---|---|---|---|---|---|
First tertile group (n = 79) | Second tertile group (n = 80) | Third tertile group (n = 80) | P value | First tertile group (n = 79) | Second tertile group (n = 80) | Third tertile group (n = 80) | P value | ||
Change percentage of FMD (%)a | 0.93 (−3.10, 4.92) | 4.18 (1.62, 6.14) | −0.20 (−2.94, 4.18)* | −2.34 (−4.96, 1.58)*,** | <0.001 | 2.37 (−1.46, 5.69) | 0.69 (−3.05, 5.50) | −1.43 (−4.26, 3.27)*,** | 0.001 |
Change percentage of NO (%)a | 1.20 (−6.40, 8.80) | 7.61 (2.60, 12.18) | −0.94 (−6.10, 6.08)* | −5.45 (−10.00, 2.93)*,** | <0.001 | 4.29 (−5.05, 11.58) | 3.00 (−6.85, 8.80)* | −2.01 (−7.45, 5.28)* | 0.002 |
Change percentage of ET-1 (%)b | −0.85 ± 5.16 | −3.03 ± 4.61 | −0.75 ± 5.17* | 1.23 ± 4.82*,** | <0.001 | −2.06 ± 4.65 | −0.97 ± 5.41 | 0.49 ± 5.16* | 0.006 |
Change percentage of ACR (%)a | −2.09 (−6.11,2.55) | −6.43 (−8.91, −2.53) | −2.09 (−4.78, 0.24)* | 3.10 (−1.36, 6.28)*,** | <0.001 | −3.48 (−7.52, −0.50) | −2.09 (−6.06, 2.35)* | −0.02 (−3.83, 5.83)*,** | <0.001 |
Change percentage of eGFR-Cr (%)b | 2.73 ± 6.43 | 7.49 ± 5.94 | 1.94 ± 5.35* | −1.24 ± 4.65*,** | <0.001 | 3.74 ± 5.90 | 2.83 ± 6.24 | 1.61 ± 7.00 | 0.101 |
Change percentage of eGFR-Cys C (%)b | 2.35 ± 5.84 | 6.64 ± 5.37 | 1.66 ± 4.89* | −1.25 ± 4.24*,** | <0.001 | 3.26 ± 5.34 | 2.47 ± 5.66 | 1.32 ± 6.36 | 0.097 |
Renal function and glycemic variability throughout follow-up period
Correlations of change percentage of brachial FMD, NO, ET-1, ACR, eGFR-Cr, and eGFR-Cys C throughout follow-up period with SD of HbA1c, CV of HbA1c, SD of FPG, and CV of FPG in all patients
Change percentage of ACR, eGFR-Cr, and eGFR-Cys C correlate with change percentage of brachial FMD, NO, and ET-1 in total patients
Multiple regression analysis
Change percentage of FMD (%) | Change percentage of NO (%) | Change percentage of ET-1 (%) | Change percentage of ACR (%) | Change percentage of eGFR-Cr (%) | Change percentage of eGFR-Cys C (%) | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Weight coefficient (95 % CI) | P value | Weight coefficient (95 % CI) | P value | Weight coefficient (95 % CI) | P value | Weight coefficient (95 % CI) | P value | Weight coefficient (95 % CI) | P value | Weight coefficient (95 % CI) | P value | |
5A. SDs of HbA1c and FPG are included in independent variables in models | ||||||||||||
SD of HbA1c | −0.158 (−0.211, −0.105) | <0.001 | −0.336 (−0.439, −0.234) | <0.001 | 0.125 (0.059, 0.190) | <0.001 | 0.312 (0.242, 0.382) | <0.001 | −0.334 (−0.394, −0.274) | <0.001 | −0.369 (−0.435, −0.303) | <0.001 |
SD of FPG | −0.137 (−0.201, −0.072) | <0.001 | −0.200 (−0.323, −0.077) | 0.002 | 0.132 (0.053, 0.211) | 0.001 | 0.090 (0.004, 0.176) | 0.039 | −0.356 (−0.658, −0.054) | 0.002 | −0.453 (−0.832, −0.074) | <0.001 |
Mean HbA1c | −0.298 (−0.580, −0.016) | <0.001 | -- | -- | -- | -- | 0.789 (0.006, 1.572) | 0.002 | -- | -- | −0.925 (−1.672, −0.178) | 0.022 |
Mean FPG | -- | -- | −2.306 (−4.294, −0.318) | 0.005 | -- | -- | 1.524 (0.497, 2.551) | 0.009 | -- | -- | −1.188 (−2.369, −0.007) | 0.049 |
Baseline SBP | −0.141 (−0.270, −0.012) | 0.006 | -- | -- | -- | -- | -- | -- | −0.269 (−0.516, −0.022) | 0.013 | -- | -- |
Smoking | −0.795 (−1.548, −0.042) | 0.025 | -- | -- | 0.636 (−0.422, 1.694) | 0.047 | 0.971 (0.009, 1.933) | 0.031 | −0.466 (−1.755, −0.823) | 0.038 | −1.335 (−2.248, −0.422) | 0.004 |
Baseline TCHO | -- | -- | -- | -- | 0.591 (−0.074, 1.256) | 0.041 | -- | -- | -- | -- | −1.925 (−3.572, −0.278) | 0.022 |
Baseline LDL-c | −0.434 (−0.867, −0.001) | 0.049 | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- |
5B. CVs of HbA1c and FPG are included in independent variables in models | ||||||||||||
CV of HbA1c | −0.165 (−0.219, −0.111) | <0.001 | −0.363 (−0.470, −0.256) | <0.001 | 0.114 (0.048, 0.179) | 0.001 | 0.306 (0.273, 0.376) | <0.001 | −0.373 (−0.439, −0.306) | <0.001 | −0.339 (−0.400, −0.279) | <0.001 |
CV of FPG | −0.141 (−0.206, −0.076) | <0.001 | −0.162 (−0.293, −0.030) | 0.016 | 0.140 (0.061, 0.219) | 0.001 | 0.092 (0.007, 0.176) | 0.034 | −0.118 (−0.225, −0.012) | 0.029 | −0.416 (−0.847, 0.015) | 0.041 |
Mean HbA1c | -- | -- | -- | -- | -- | -- | -- | -- | -- | -- | −0.873 (−1.716, −0.030) | 0.034 |
Mean FPG | -- | -- | −1.045 (−1.902, −0.178) | 0.015 | -- | -- | 1.530 (0.711, 2.348) | <0.001 | −0.530 (−1.012, −0.048) | 0.034 | −0.966 (−1.257, −0.675) | 0.026 |
Baseline SBP | −0.065 (−0.127, −0.003) | 0.040 | -- | -- | -- | -- | 0.121 (0.022, 0.219) | 0.017 | -- | -- | -- | -- |
Baseline TCHO | −0.511 (−1.019, −0.002) | 0.049 | -- | -- | 0.676 (0.045, 1.306) | 0.036 | -- | -- | -- | -- | -- | -- |
Baseline HDL-c | -- | -- | -- | -- | −1.139 (−2.229, −0.049) | 0.043 | -- | -- | -- | -- | -- | -- |