Table 1. Characteristics of the study participants by baseline serum alkaline phosphatase (ALP) quartiles*
Variables
|
Serum ALP, IU/L
|
P value†
|
Q1 (<79)
|
Q2 (79-<96)
|
Q3 (96-<116)
|
Q4 (≥116)
|
N
|
3486
|
3623
|
3577
|
3707
|
|
Age, yr
|
58.3±8.1
|
59.7±7.5
|
60.7±7.1
|
61.3±6.6
|
< 0.001
|
Male, No. (%)
|
1773 (50.9)
|
1609 (44.4)
|
1377 (38.5)
|
1059 (28.6)
|
< 0.001
|
Body mass index, kg/m2
|
25.4±3.6
|
25.1±3.6
|
24.8±3.6
|
24.4±3.7
|
< 0.001
|
Current smoking, No. (%)
|
963 (27.6)
|
938 (25.9)
|
810 (22.6)
|
664 (17.9)
|
< 0.001
|
Current drinking, No. (%)
|
1143 (32.8)
|
949 (26.2)
|
778 (21.8)
|
567 (15.3)
|
< 0.001
|
Family history of diabetes, No. (%)
|
151 (4.3)
|
145 (4.0)
|
125 (3.5)
|
116 (3.1)
|
0.036
|
Enalapril group, No. (%)
|
1727 (49.5)
|
1838 (50.7)
|
1800 (50.3)
|
1850 (49.9)
|
0.769
|
BP, mmHg
|
|
|
|
|
|
SBP at baseline
|
165.6±20.5
|
167.2±20.4
|
167.5±20.5
|
168.2±20.3
|
< 0.001
|
DBP at baseline
|
95.4±11.9
|
94.5±11.9
|
94.3±11.8
|
93.3±11.7
|
< 0.001
|
Time-averaged SBP
|
138.4±10.6
|
139.1±10.3
|
138.8±10.6
|
139±10.6
|
0.022
|
Time-averaged DBP
|
84.1±7.2
|
83.3±7.2
|
82.6±7.0
|
81.7±7.3
|
< 0.001
|
Laboratory results, mmol/L
|
|
|
|
|
|
Total cholesterol
|
5.6±1.1
|
5.6±1.1
|
5.5±1.1
|
5.3±1.1
|
< 0.001
|
Triglycerides
|
1.6±1.9
|
1.6±0.9
|
1.6±0.9
|
1.7±0.9
|
< 0.001
|
HDL cholesterol
|
1.3±0.4
|
1.3±0.4
|
1.4±0.4
|
1.4±0.4
|
< 0.001
|
Fasting glucose
|
5.5±0.7
|
5.4±0.7
|
5.4±0.7
|
5.3±0.7
|
< 0.001
|
eGFR, mL/min1.73/m2
|
93.7±13.1
|
93.8±12.8
|
93.3±12.1
|
93.6±12.2
|
0.455
|
Folate, ng/mL
|
7.8±3.3
|
8.2±3.8
|
8.5±3.8
|
9.3±4.4
|
< 0.001
|
Total homocysteine, μmol/L
|
14.9±9.9
|
14.5±8.8
|
14.5±8.0
|
14.1±6.9
|
< 0.001
|
Alkaline phosphatase, IU/L
|
66.1±10.4
|
87.1±4.8
|
104.9±5.8
|
140.0±24.1
|
< 0.001
|
Aspartate transaminase, IU/L
|
21.4(18.0,26.0)
|
22.7(19.2,27.8)
|
24.0(20.1,29.5)
|
26.7(21.9,33.1)
|
< 0.001
|
Alanine transaminase, IU/L
|
11.0(8.0,14.1)
|
12.0(9.0,16.0)
|
12.8(10.0,17.0)
|
14.0(11.0,19.0)
|
< 0.001
|
Gamma glutamyl transpeptidase, IU/L
|
19.1(14.3,27.6)
|
19.3(14.6,27.5)
|
19.3(14.6,28.1)
|
19.9(14.9,28.7)
|
0.005
|
Medication use, No. (%)
|
|
|
|
|
|
Antihypertensive drugs
|
1794 (51.5)
|
1708 (47.1)
|
1621 (45.3)
|
1531 (41.3)
|
< 0.001
|
Lipid lowering drugs
|
37 (1.1)
|
26 (0.7)
|
19 (0.5)
|
25 (0.7)
|
0.065
|
Antiplatelet drugs
|
161 (4.6)
|
109 (3.0)
|
102 (2.9)
|
71 (1.9)
|
< 0.001
|
*Continuous variables are presented as Mean ± SD or IQR (25th, 75th), categorical variables are presented as n (%)
†Difference between any two groups.
Abbreviations: ALP, serum alkaline phosphatase; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; SBP, systolic blood pressure
Table 2. Concomitant medication usage during the treatment period by baseline serum alkaline phosphatase quartiles*
Variables
|
Baseline serum alkaline phosphatase quartiles, IU/L
|
P value†
|
Q1 (<79)
|
Q2 (79-<96)
|
Q3 (96-<116)
|
Q4 (≥116)
|
N
|
3486
|
3623
|
3577
|
3707
|
|
Antihypertensive drugs
|
|
|
|
|
|
Calcium channel blockers
|
2804 (80.4)
|
2954 (81.5)
|
2958 (82.7)
|
3110 (83.9)
|
<0.001
|
Diuretics
|
2011 (57.7)
|
2028 (56.0)
|
1901 (53.1)
|
1750 (47.2)
|
<0.001
|
Lipid-lowering drugs
|
5 (0.1)
|
3 (0.1)
|
6 (0.2)
|
5 (0.1)
|
0.790
|
Antiplatelet drugs
|
33 (0.9)
|
35 (1.0)
|
26 (0.7)
|
17 (0.5)
|
0.045
|
*Regular concomitant medication usage was defined as 180 or more cumulative days of taking the drug of interest.
†Difference between any two groups.
Table 3. The association between baseline serum alkaline phosphatase (ALP) and study outcomes
ALP, IU/L
|
N
|
No. of
Events (%)
|
Crude Model
|
Adjusted Model*
|
OR (95%CI)
|
P value‡
|
OR (95%CI)
|
P value‡
|
New-onset diabetes
|
|
|
|
|
|
|
Continuous, per SD (30.5 IU/L) increment
|
14393
|
1549 (10.8)
|
1.07 (1.02,1.13)
|
0.007
|
1.07 (1.01,1.14)
|
0.027
|
Quartiles
|
|
|
|
|
|
|
Q1 (<79)
|
3486
|
343 (9.8)
|
1.00 (ref.)
|
|
1.00 (ref.)
|
|
Q2 (79-<96)
|
3623
|
381 (10.5)
|
1.08 (0.92,1.26)
|
0.346
|
1.09 (0.93,1.28)
|
0.291
|
Q3 (96-<116)
|
3577
|
390 (10.9)
|
1.12 (0.96,1.31)
|
0.143
|
1.14 (0.96,1.34)
|
0.130
|
Q4 (≥116)
|
3707
|
435 (11.7)
|
1.22 (1.05,1.42)
|
0.010
|
1.24 (1.05,1.48)
|
0.013
|
P for trend
|
|
|
0.009
|
|
0.013
|
|
Categories
|
|
|
|
|
|
|
Q1-2 (<96)
|
7109
|
724 (10.2)
|
1.00 (ref.)
|
|
1.00 (ref.)
|
|
Q3-4 (≥96)
|
7284
|
825 (11.3)
|
1.13 (1.01,1.25)
|
0.027
|
1.13 (1.00,1.27)
|
0.046
|
New-onset IFG†
|
|
|
|
|
|
|
Continuous, per SD (30.8 IU/L) increment
|
11062
|
1876 (17.0)
|
1.04 (0.99,1.09)
|
0.105
|
1.07 (1.02,1.14)
|
0.012
|
Quartiles
|
|
|
|
|
|
|
Q1 (<79)
|
2629
|
446 (17.0)
|
1.00 (ref.)
|
|
1.00 (ref.)
|
|
Q2 (79-<96)
|
2788
|
446 (16.0)
|
0.93 (0.81,1.08)
|
0.337
|
0.94 (0.81,1.09)
|
0.415
|
Q3 (96-<117)
|
2825
|
487 (17.2)
|
1.02 (0.89,1.17)
|
0.788
|
1.06 (0.91,1.23)
|
0.431
|
Q4 (≥117)
|
2820
|
497 (17.6)
|
1.05 (0.91,1.21)
|
0.520
|
1.14 (0.97,1.34)
|
0.101
|
P for trend
|
|
|
0.302
|
|
0.042
|
|
Categories
|
|
|
|
|
|
|
Q1-2 (<96)
|
5417
|
892(16.5)
|
1.00 (ref.)
|
|
1.00 (ref.)
|
|
Q3-4 (≥96)
|
5645
|
984 (17.4)
|
1.07 (0.97,1.18)
|
0.177
|
1.13 (1.02,1.27)
|
0.024
|
*Adjusted for age, sex, study center, treatment group, body mass index (BMI), smoking, alcohol drinking, family history of diabetes, SBP, fasting glucose (FG), total cholesterol (TC), triglycerides (TG), eGFR, folate, total homocysteine and the use of antihypertensive drugs at baseline, as well as time-averaged SBP during the treatment period.
†Subjects with baseline FG <6.1 mmol/L and without new-onset diabetes during follow-up were included in the analysis.
‡ In comparison with the first quartile.
Abbreviations: ALP, serum alkaline phosphatase; CI, confidence interval; eGFR, estimated glomerular filtration rate; IFG, impaired fasting glucose; OR, odds ratio; SD, standard deviations; SBP, systolic blood pressure
Table 4. Estimating the association between baseline serum alkaline phosphatase (ALP) and new-onset diabetes evaluated with risk ratio (RR)
ALP, IU/L
|
N
|
No. of
Events (%)
|
Crude Model
|
Adjusted Model*
|
RR (95%CI)
|
P value†
|
RR (95%CI)
|
P value†
|
New-onset diabetes
|
|
|
|
|
|
|
Continuous, per SD (30.5 IU/L) increment
|
14393
|
1549 (10.8)
|
1.06 (1.01,1.12)
|
0.011
|
1.06 (1.00,1.12)
|
0.034
|
Quartiles
|
|
|
|
|
|
|
Q1 (<79)
|
3486
|
343 (9.8)
|
1.00 (ref.)
|
|
1.00 (ref.)
|
|
Q2 (79-<96)
|
3623
|
381 (10.5)
|
1.07 (0.93,1.24)
|
0.372
|
1.09 (0.94,1.26)
|
0.274
|
Q3 (96-<116)
|
3577
|
390 (10.9)
|
1.12 (0.97,1.29)
|
0.166
|
1.12 (0.96,1.30)
|
0.143
|
Q4 (≥116)
|
3707
|
435 (11.7)
|
1.19 (1.04,1.38)
|
0.015
|
1.21 (1.03,1.41)
|
0.018
|
P for trend
|
|
|
0.013
|
|
0.019
|
|
*Adjusted for age, sex, study center, treatment group, body mass index (BMI), smoking, alcohol drinking, family history of diabetes, SBP, fasting glucose (FG), total cholesterol (TC), triglycerides (TG), eGFR, folate, total homocysteine and the use of antihypertensive drugs at baseline, as well as time-averaged SBP during the treatment period.
†In comparison with the first quartile.
Abbreviations: ALP, serum alkaline phosphatase; CI, confidence interval; eGFR, estimated glomerular filtration rate; RR, risk ratio; SD, standard deviations; SBP, systolic blood pressure
Table 5. The association between baseline serum alkaline phosphatase (ALP) and new-onset diabetes, with further adjustment for the use of calcium channel blockers, diuretics and antiplatelet drugs during the treatment period
ALP, IU/L
|
N
|
No. of
Events (%)
|
Crude Model
|
Adjusted Model*
|
OR (95%CI)
|
P value†
|
OR (95%CI)
|
P value†
|
Continuous, per SD increment
|
14393
|
1549 (10.8)
|
1.07 (1.02,1.13)
|
0.007
|
1.07 (1.01,1.14)
|
0.026
|
Quartiles
|
|
|
|
|
|
|
Q1 (<79)
|
3486
|
343 (9.8)
|
1.00 (ref.)
|
|
1.00 (ref.)
|
|
Q2 (79-<96)
|
3623
|
381 (10.5)
|
1.08 (0.92,1.26)
|
0.346
|
1.09 (0.93,1.28)
|
0.290
|
Q3 (96-<116)
|
3577
|
390 (10.9)
|
1.12 (0.96,1.31)
|
0.143
|
1.14 (0.96,1.34)
|
0.127
|
Q4 (≥116)
|
3707
|
435 (11.7)
|
1.22 (1.05,1.42)
|
0.010
|
1.24 (1.05,1.48)
|
0.013
|
P for trend
|
|
|
0.009
|
|
0.013
|
|
*Adjusted for age, sex, study center, treatment group, body mass index (BMI), smoking, alcohol drinking, family history of diabetes, SBP, fasting glucose (FG), total cholesterol (TC), triglycerides (TG), eGFR, folate, total homocysteine and the use of antihypertensive drugs at baseline, as well as time-averaged SBP, the use of calcium channel blockers, diuretics and antiplatelet drugs during the treatment period.
†In comparison with the first quartile.
Abbreviations: ALP, serum alkaline phosphatase; CI, confidence interval; eGFR, estimated glomerular filtration rate; OR, odds ratio; SD, standard deviations; SBP, systolic blood pressure
Table 6. The association between baseline serum alkaline phosphatase (ALP) and new-onset diabetes, with further adjustment for AST, ALT and GGT
ALP, IU/L
|
N
|
No. of
Events (%)
|
Crude Model
|
Adjusted Model*
|
OR (95%CI)
|
P value†
|
OR (95%CI)
|
P value†
|
Continuous, per SD increment
|
14393
|
1549 (10.8)
|
1.07 (1.02,1.13)
|
0.007
|
1.06 (1.00,1.13)
|
0.045
|
Quartiles
|
|
|
|
|
|
|
Q1 (<79)
|
3486
|
343 (9.8)
|
1.00 (ref.)
|
|
1.00 (ref.)
|
|
Q2 (79-<96)
|
3623
|
381 (10.5)
|
1.08 (0.92,1.26)
|
0.346
|
1.08 (0.92,1.28)
|
0.327
|
Q3 (96-<116)
|
3577
|
390 (10.9)
|
1.12 (0.96,1.31)
|
0.143
|
1.13 (0.96,1.33)
|
0.148
|
Q4 (≥116)
|
3707
|
435 (11.7)
|
1.22 (1.05,1.42)
|
0.010
|
1.23 (1.03,1.46)
|
0.020
|
P for trend
|
|
|
0.009
|
|
0.019
|
|
*Adjusted for age, sex, study center, treatment group, body mass index (BMI), smoking, alcohol drinking, family history of diabetes, SBP, fasting glucose (FG), total cholesterol (TC), triglycerides (TG), eGFR, folate, total homocysteine and the use of antihypertensive drugs, AST, ALT, GGT at baseline, as well as time-averaged SBP during the treatment period.
†In comparison with the first quartile.
Abbreviations: ALP, serum alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; eGFR, estimated glomerular filtration rate; GGT, gamma glutamyl transpeptidase; OR, odds ratio; SD, standard deviations; SBP, systolic blood pressure
Table 7. The association between change in serum alkaline phosphatase (ALP) and new-onset diabetes
ALP, IU/L
|
N
|
No. of
Events (%)
|
Crude Model
|
Adjusted Model*
|
OR (95%CI)
|
P value‡
|
OR (95%CI)
|
P value‡
|
Persistently low levels†
|
6087
|
549 (9.0)
|
1.00 (ref.)
|
|
1.00 (ref.)
|
|
Decreased levels
|
2744
|
237 (8.6)
|
0.95 (0.81,1.12)
|
0.559
|
0.96 (0.81,1.14)
|
0.653
|
Increased levels
|
993
|
162 (16.3)
|
1.97 (1.63,2.38)
|
<0.001
|
1.97 (1.61,2.42)
|
<0.001
|
Persistently high levels
|
4511
|
569 (12.6)
|
1.46 (1.29,1.65)
|
<0.001
|
1.57 (1.36,1.81)
|
<0.001
|
*Adjusted for age, sex, study center, treatment group, body mass index (BMI), smoking, alcohol drinking, family history of diabetes, SBP, fasting glucose (FG), total cholesterol (TC), triglycerides (TG), eGFR, folate, total homocysteine and the use of antihypertensive drugs at baseline, as well as time-averaged SBP during the treatment period.
†We categorized the participants into four groups according to median of baseline serum ALP (96 IU/L): persistently low ALP levels (<96 IU/L at both baseline and exit visit), persistently high ALP levels (≥96 IU/L at both baseline and exit visit), decreased ALP levels (≥96 IU/L at baseline and <96 IU/L at exit visit), and increased ALP levels (<96 IU/L at baseline and ≥96 IU/L at exit visit).
‡In comparison with persistently low ALP levels.
Abbreviations: ALP, serum alkaline phosphatase; CI, confidence interval; eGFR, estimated glomerular filtration rate; GGT, gamma glutamyl transpeptidase; OR, odds ratio; SBP, systolic blood pressure