Background
Methods
Study population and design
Baseline investigations
Other baseline measurements
Follow-up and study end-points
Statistical analyses
Results
CVD event | No CVD event | p value | Patients dead at follow-up n = 83 | Patients alive at follow-up n = 254 | p value | |
---|---|---|---|---|---|---|
n = 86 | n = 251 | |||||
Age (years) | 44.5 (9.0) | 40.4 (9.6) | 0.001 | 45.3 (10.0) | 40.2 (9.2) | <0.001 |
Sex: male/female (%) | 62/38 | 60/40 | 0.81 | 69/31 | 58/42 | 0.081 |
Duration of diabetes (years) | 30.7 (8.7) | 26.7 (7.5) | <0.001 | 30.2 (9.9) | 26.9 (7.1) | 0.006 |
HbA1c (%) | 9.5 (1.5) | 8.9 (1.4) | <0.001 | 9.6 (1.5) | 8.8 (1.4) | <0.001 |
HbA1c (mmol/mol) | 80.5 (16.3) | 73.4 (15.0) | <0.001 | 81.6 (16.5) | 73.1 (14.8) | <0.001 |
Nephropathy (%) | 76 | 42 | <0.001 | 78 | 41 | <0.001 |
Retinopathy (no/simplex/proliferative) (%) | 8/37/55 | 20/45/35 | 0.002 | 6/37/57 | 21/45/34 | <0.001 |
BMI (kg/m2) | 23.9 (3.3) | 23.9 (2.8) | 0.919 | 23.7 (3.2) | 23.9 (2.8) | 0.513 |
LDL (mmol/l) | 3.64 (1.01) | 3.00 (0.95) | <0.001 | 3.60 (0.98) | 3.02 (0.97) | <0.001 |
HDL (mmol/l) | 1.43 (0.41) | 1.54 (0.51) | 0.082 | 1.53 (0.48) | 1.51 (0.50) | 0.791 |
Triglycerides (mmol/l) | 1.25 [0.93–1.70] | 0.81[0.63–1.19] | <0.001 | 1.29 [0.90–1.69] | 0.81 [0.64–1.18] | <0.001 |
Serum creatinine (µmol/l) | 92.1 [67–135] | 70 [62–81] | <0.001 | 94.0 [68–132] | 69 [62–81] | <0.001 |
eGFR (ml/min/1.73 m2) | 76.0 (31.6) | 101 (21.5) | <0.001 | 76.2 (30.9) | 100.7 (22.2) | <0.001 |
Urinary albumin excretion (mg/24 h) | 658 [34–1983] | 17 [7–532] | <0.001 | 761 [96–2040] | 17 [7–479] | <0.001 |
Systolic blood pressure (mmHg) | 157 (24) | 136 (20) | <0.001 | 159 (24) | 136 (19) | <0.001 |
Diastolic blood pressure (mmHg) | 85 (13) | 80 (12) | 0.001 | 87 (14) | 79 (11) | <0.001 |
Mean arterial pressure (mmHg) | 109 (15) | 98 (13) | <0.001 | 111 (15) | 98 (13) | <0.001 |
RAAS-inhibitors (%) | 52 | 21 | <0.001 | 52 | 22 | <0.001 |
Other antihypertensive medication (%) | 64 | 29 | <0.001 | 69 | 28 | <0.001 |
Smoking (never/former/current) (%) | 28/19/53 | 38/17/45 | 0.234 | 25/17/58 | 39/18/43 | 0.05 |
MMP-1 (ng/ml) | 4.58 [2.78–7.17] | 2.70 [1.67–4.71] | <0.001 | 5.00 [2.74–7.03] | 2.73 [1.68–4.68] | <0.001 |
MMP-2 (ng/ml) | 229 [201–273] | 185 [162–225] | <0.001 | 231 [201–281] | 185 [161–225] | <0.001 |
MMP-3 (ng/ml) | 21.3 [13.0–28.3] | 12.8 [8.6–21.3] | <0.001 | 23.9 [16.6–29.6] | 12.6 [8.5–20.2] | <0.001 |
MMP-9 (ng/ml) | 32.5 [20.4–65.3] | 21.7 [14.5–36.9] | <0.001 | 31.2 [20.7–63.6] | 21.8 [14.3–37.0] | <0.001 |
MMP-10 (pg/ml) | 764 [618–1227] | 640 [467–930] | 0.002 | 809 [627–1235] | 640 [463–916] | <0.001 |
TIMP-1 (ng/ml) | 210 [178–265] | 161 [137–204] | <0.001 | 221 [182–277] | 159 [136–204] | <0.001 |
sVCAM-1 (ng/ml) | 1003 [842–1174] | 905 [789–1105] | 0.03 | 1038 [936–1239] | 891 [789–1096] | <0.001 |
sICAM-1 (ng/ml) | 735 [628–835] | 671 [572–814] | 0.076 | 751 [632–882] | 670 [569–797] | 0.003 |
Endothelial dysfunction z-score | 0.23 (0.92) | −0.08 (1.02) | 0.012 | 0.41 (0.98) | −0.13 (0.97) | <0.001 |
CRP (mg/l) | 1.63 [0.64–3.24] | 1.00 [0.42–2.15] | 0.008 | 1.45 [0.60–3.30] | 1.03 [0.45–2.18] | 0.02 |
IL-6 (pg/ml) | 2.18 [1.53–3.43] | 1.52 [0.99–2.34] | <0.001 | 2.41 [1.78–3.88] | 1.45 [1.00–2.22] | <0.001 |
sPLA2 (µg/ml) | 4.40 [2.80–7.00] | 4.00 [2.70–6.40] | 0.421 | 4.00 [2.80–6.50] | 4.05 [2.70–6.60] | 0.821 |
Low-grade inflammation z-score | 0.32 (0.86) | −0.11 (1.02) | <0.001 | 0.3 (0.96) | −0.11 (0.99) | <0.001 |
Associations of MMPs and TIMP-1 with incident CVD
Model | MMP-1 | MMP-2 | MMP-3 | MMP-9 | MMP-10 | TIMP-1 | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
HR | 95% CI | p value | HR | 95% CI | p value | HR | 95% CI | p value | HR | 95% CI | p value | HR | 95% CI | p value | HR | 95% CI | p value | |
1 | 1.51 | 1.20; 1.91 | <0.001 | 1.65 | 1.28; 2.13 | <0.001 | 1.47 | 1.13; 1.92 | 0.004 | 1.44 | 1.17; 1.78 | 0.001 | 1.20 | 0.97; 1.50 | 0.101 | 1.87 | 1.40; 2.49 | <0.001 |
2 | 1.26 | 1.00; 1.60 | 0.054 | 1.49 | 1.11; 1.99 | 0.007 | 1.16 | 0.88; 1.53 | 0.308 | 1.24 | 0.99; 1.55 | 0.058 | 1.03 | 0.82; 1.29 | 0.801 | 1.33 | 0.95; 1.87 | 0.100 |
3 | 1.23 | 0.96; 1.59 | 0.103 | 1.34 | 0.96; 1.85 | 0.085 | 0.99 | 0.73; 1.34 | 0.991 | 1.21 | 0.96; 1.52 | 0.112 | 0.91 | 0.71; 1.16 | 0.440 | 1.03 | 0.72; 1.49 | 0.858 |
4 | 1.23 | 0.97; 1.55 | 0.094 | 1.47 | 1.11; 1.96 | 0.008 | 1.15 | 0.87; 1.52 | 0.321 | 1.18 | 0.93; 1.48 | 0.173 | 1.02 | 0.81; 1.28 | 0.890 | 1.23 | 0.87; 1.75 | 0.243 |
5 | 1.28 | 1.01; 1.63 | 0.043 | 1.48 | 1.11; 1.98 | 0.008 | 1.16 | 0.88; 1.54 | 0.284 | 1.24 | 1.00; 1.55 | 0.055 | 1.03 | 0.82; 1.29 | 0.799 | 1.32 | 0.94; 1.87 | 0.111 |
Associations of MMPs and TIMP-1 with all-cause mortality
Model | MMP-1 | MMP-2 | MMP-3 | MMP-9 | MMP-10 | TIMP-1 | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
HR | 95% CI | p va ue | HR | 95% CI | p value | HR | 95% CI | p value | HR | 95% CI | p value | HR | 95% CI | p value | HR | 95% CI | p value | |
1 | 1.62 | 1.28; 2.06 | <0.001 | 1.93 | 1.48; 2.51 | <0.001 | 1.82 | 1.38; 2.41 | <0.001 | 1.39 | 1.14; 1.69 | 0.001 | 1.33 | 1.06; 1.67 | 0.015 | 2.10 | 1.55; 2.85 | <0.001 |
2 | 1.38 | 1.07; 1.78 | 0.012 | 1.60 | 1.19; 2.15 | 0.002 | 1.39 | 1.05; 1.85 | 0.021 | 1.18 | 0.95; 1.46 | 0.133 | 1.13 | 0.90; 1.41 | 0.313 | 1.39 | 0.97; 1.98 | 0.070 |
3 | 1.45 | 1.10; 1.92 | 0.008 | 1.50 | 1.07; 2.09 | 0.017 | 1.32 | 0.95; 1.83 | 0.100 | 1.17 | 0.93; 1.46 | 0.179 | 1.01 | 0.78; 1.30 | 0.943 | 1.15 | 0.75; 1.74 | 0.529 |
4 | 1.34 | 1.04; 1.73 | 0.026 | 1.57 | 1.17; 2.10 | 0.002 | 1.40 | 1.06; 1.86 | 0.019 | 1.12 | 0.90; 1.40 | 0.314 | 1.12 | 0.90; 1.41 | 0.316 | 1.29 | 0.89; 1.87 | 0.173 |
5 | 1.47 | 1.13; 1.92 | 0.004 | 1.58 | 1.17; 2.12 | 0.002 | 1.41 | 1.07; 1.87 | 0.015 | 1.18 | 0.95; 1.45 | 0.132 | 1.13 | 0.90; 1.41 | 0.307 | 1.33 | 0.93; 1.92 | 0.118 |
Associations of MMPs and TIMP-1 with eGFR, lnUAE, LGI and ED
Model | eGFR | Ln-UAE | LGI | ED | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
β | 95% CI | p value | β | 95% CI | p value | β | 95% CI | p value | β | 95% CI | p value | |
MMP-1 | ||||||||||||
1 | −4.15 | −6.58; −1.73 | 0.001 | −0.01 | −0.13; 0.11 | 0.912 | 0.14 | 0.02; 0.25 | 0.017 | −0.07 | −0.18; 0.05 | 0.249 |
2 | −2.90 | −5.22; −0.57 | 0.015 | −0.03 | −0.14; 0.08 | 0.588 | 0.11 | 0.00; 0.22 | 0.045 | −0.12 | −0.23; −0.01 | 0.031 |
MMP-2 | ||||||||||||
1 | −11.9 | −14.27; −9.56 | <0.001 | 0.29 | 0.16; 0.41 | <0.001 | −0.02 | −0.14; 0.10 | 0.770 | 0.06 | −0.06; 0.18 | 0.333 |
2 | −10.1 | −12.48; −7.64 | <0.001 | 0.19 | 0.07; 0.32 | 0.002 | 0.02 | −0.11; 0.15 | 0.759 | 0.07 | −0.06; 0.19 | 0.318 |
MMP-3 | ||||||||||||
1 | −12.6 | −15.37; −9.92 | <0.001 | 0.28 | 0.13; 0.42 | <0.001 | 0.02 | −0.12; 0.16 | 0.779 | 0.02 | −0.12; 0.16 | 0.792 |
2 | −10.3 | −13.05; −7.64 | <0.001 | 0.16 | 0.02; 0.30 | 0.022 | 0.05 | −0.09; 0.19 | 0.513 | 0.02 | −0.12; 0.16 | 0.818 |
MMP-9 | ||||||||||||
1 | −0.72 | −3.13; 1.70 | 0.559 | 0.02 | −0.09; 0.14 | 0.708 | 0.28 | 0.18; 0.39 | <0.001 | 0.05 | −0.06; 0.16 | 0.347 |
2 | −0.14 | −2.56; 2.29 | 0.912 | 0.02 | −0.10; 0.13 | 0.781 | 0.22 | 0.11; 0.33 | <0.001 | −0.03 | −0.15; 0.08 | 0.580 |
MMP-10 | ||||||||||||
1 | −6.45 | −8.70; −4.19 | <0.001 | 0.08 | −0.03; 0.20 | 0.146 | 0.14 | 0.03; 0.25 | 0.010 | 0.13 | 0.03; 0.24 | 0.015 |
2 | −6.18 | −8.32; −4.03 | <0.001 | 0.11 | 0.00; 0.21 | 0.045 | 0.09 | −0.02; 0.19 | 0.104 | 0.09 | −0.02; 0.19 | 0.110 |
TIMP-1 | ||||||||||||
1 | −10.2 | −12.65; −7.82 | <0.001 | 0.26 | 0.14; 0.39 | <0.001 | 0.30 | 0.19; 0.42 | <0.001 | 0.23 | 0.11; 0.35 | <0.001 |
2 | −8.13 | −10.58; −5.68 | <0.001 | 0.17 | 0.05; 0.29 | 0.005 | 0.33 | 0.21; 0.45 | <0.001 | 0.22 | 0.10; 0.34 | <0.001 |