Study participants and baseline characteristics
In this study, a total of 14,393 participants with complete major data and without diabetes and liver disease at baseline, were included in the final analyses (Additional file 1: Figure S1).
Baseline characteristics of participants by baseline ALP quartiles are presented in Table 1. The mean and median serum ALP levels were 100 IU/L (SD, 30.5) and 96 IU/L, respectively. Participants with higher ALP levels were older and more likely to be female; had higher SBP, TG, high-density lipoprotein (HDL) cholesterol, FG, folate levels at baseline and time-averaged on-treatment SBP during the treatment period; lower BMI, DBP, TC, tHcy levels at baseline and time-averaged on-treatment DBP during the treatment period; and lower frequency in use of antihypertensive drugs and antiplatelet drugs at baseline, as wells as lower frequency of current smoking, alcohol drinking and family history of diabetes (Table 1).
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 (%) |
In addition, during the treatment period, participants with higher ALP levels had higher frequency in use of calcium channel blockers; lower frequency in use of diuretics and antiplatelet drugs. (Additional file 1: Table S1)
Association Between Baseline Serum Alp And Study Outcomes
During median follow-up of 4.5 years (IQR, 4.2–4.7 years), 1,549 (10.8%) participants developed new-onset diabetes.
Overall, there was a positive relation of serum ALP and the risk of new-onset diabetes (per SD increment, adjusted OR, 1.07; 95%CI: 1.01, 1.14) (Fig. 1A) and new-onset IFG (per SD increment, adjusted OR, 1.07; 95%CI: 1.02, 1.14) (Fig. 1B). Consistently, compared with participants with serum ALP < 96 IU/L (median), significantly higher risks of new-onset diabetes (adjusted OR, 1.13; 95%CI: 1.00, 1.27) and new-onset IFG (adjusted OR, 1.13; 95%CI: 1.02, 1.27) were found in those with serum ALP ≥ 96 IU/L (Table 2).
Table 2
The association between baseline 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
|
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. |
Similar results were also found in participants with a normal range of baseline serum ALP (20–140 IU/L) [18] levels (per SD increment; adjusted OR, 1.07; 95%CI: 1.01, 1.14) (Additional file 1: Figure S2). More importantly, further adjustment for use of calcium channel blockers, diuretics and antiplatelet drugs during the treatment period (per SD increment; adjusted OR, 1.07; 95%CI: 1.01, 1.14) (Additional file 1: Table S2), or other liver enzymes, including GGT, ALT, AST (per SD increment; adjusted OR, 1.06; 95% CI: 1.00, 1.13) (Additional file 1: Table S3) did not substantially change the results.
Stratified Analyses
In the stratified analyses, a stronger positive association between baseline ALP with new-onset diabetes was found in participants with tHcy < 10 µmol/L (per SD increment; adjusted OR, 1.24; 95%CI: 1.10, 1.40 vs. ≥10 µmol/L: adjusted OR, 1.03; 95%CI: 0.96, 1.10; P-interaction = 0.007) and FG ≥ 5.9 mmol/L (quartile 3) (per SD increment; adjusted OR, 1.16; 95%CI: 1.07, 1.27 vs. <5.9 mmol/L: adjusted OR, 1.00; 95%CI: 0.93, 1.08; P-interaction = 0.009) (Fig. 2).
However, other variables, including sex, age, BMI, treatment group, current smoking, current alcohol drinking, SBP, TC levels at baseline, as well as time-averaged SBP, calcium channel blockers usage and diuretics usage over the trial period, did not significantly modified the association between baseline serum ALP and new-onset diabetes (all P-interactions > 0.05) (Fig. 2).