Study participants and baseline characteristics
As shown in the flow chart (Figure S1), a total of 5129 hypertensive male subjects were included in the current study. The mean age of our study participants was 63.92 ± 9.62 years, the mean serum total bilirubin was 15.67 (7.76) μmol/L, 194 subjects (3.78%) had PAD, and 828 (16.14%) had diabetes.
The baseline characteristics of the study participants stratified by quartiles of LgTBiL levels are summarized in Table 1. Participants with higher levels of LgTBiL tended to be a current alcohol drinker and had higher rates of diabetes mellitus; higher values of DBP, pulse, FBG, BMI, WC, HC, TC, HDL, AST, ALT, eGFR, and albumin; lower rates of PAD, CKD and smoking; and lower values for age (all P < 0.01). There were no statistically significant differences among the four groups in terms of SBP, Hcy, TG, stroke, CHD, antihypertensive drugs, glucose-lowering drugs, or lipid-lowering drugs (all P > 0.05).
Table 1 Baseline characteristics of study participants by quartiles of baseline LgTBiL levels
Characteristics
|
Total
|
LgTBiL, μmol/L
|
P value
|
Q1 (<1.04)
|
Q2 (1.04-1.15)
|
Q3 (1.15-1.27)
|
Q4 (≥1.27)
|
N
|
5129
|
1281
|
1272
|
1293
|
1283
|
|
Age,year
|
63.92 ± 9.62
|
64.37 ± 9.23
|
64.23 ± 9.44
|
63.60 ± 9.86
|
63.50 ± 9.91
|
0.043
|
BMI,kg/m2
|
23.36 ± 4.01
|
22.98 ± 3.44
|
23.43 ± 3.60
|
23.44 ± 3.46
|
23.58 ± 5.23
|
0.001
|
WC, cm
|
83.85 ± 9.69
|
82.79 ± 9.88
|
84.14 ± 9.72
|
84.08 ± 9.36
|
84.40 ± 9.71
|
<0.001
|
HC, cm
|
91.83 ± 6.82
|
91.31 ± 6.79
|
92.02 ± 7.20
|
92.03 ± 6.71
|
91.98 ± 6.53
|
0.016
|
Smoking status, N (%)
|
|
|
|
|
|
<0.001
|
Never
|
1070 (20.86%)
|
213 (16.63%)
|
241 (18.95%)
|
292 (22.58%)
|
324 (25.25%)
|
|
Former
|
1516 (29.56%)
|
358 (27.95%)
|
358 (28.14%)
|
395 (30.55%)
|
405 (31.57%)
|
|
Current
|
2543 (49.58%)
|
710 (55.43%)
|
673 (52.91%)
|
606 (46.87%)
|
554 (43.18%)
|
|
Drinking status, N (%)
|
|
|
|
|
|
<0.001
|
Never
|
1906 (37.17%)
|
546 (42.62%)
|
470 (36.98%)
|
461 (35.65%)
|
429 (33.44%)
|
|
Former
|
1090 (21.26%)
|
289 (22.56%)
|
294 (23.13%)
|
290 (22.43%)
|
217 (16.91%)
|
|
Current
|
2132 (41.58%)
|
446 (34.82%)
|
507 (39.89%)
|
542 (41.92%)
|
637 (49.65%)
|
|
SBP, mmHg
|
146.63 ± 17.96
|
147.16 ± 18.60
|
146.68 ± 17.37
|
146.04 ± 17.32
|
146.65 ± 18.52
|
0.475
|
DBP, mmHg
|
90.35 ± 11.06
|
89.30 ± 11.22
|
90.06 ± 10.93
|
90.48 ± 11.12
|
91.55 ± 10.85
|
<0.001
|
heart rate (HR), bpm
|
74.41 ± 14.06
|
73.28 ± 13.84
|
73.73 ± 13.11
|
74.57 ± 13.53
|
76.06 ± 15.51
|
<0.001
|
Laboratory data
|
|
|
|
|
|
|
Hcy,μmol/L
|
20.50 ± 13.64
|
20.17 ± 12.99
|
19.94 ± 12.67
|
21.13 ± 15.31
|
20.77 ± 13.42
|
0.103
|
FBG, mmol/L
|
6.07 ± 1.50
|
5.94 ± 1.40
|
6.01 ± 1.47
|
6.12 ± 1.52
|
6.19 ± 1.59
|
<0.001
|
TC, mmol/L
|
4.93 ± 1.06
|
4.83 ± 1.09
|
4.93 ± 1.06
|
4.97 ± 1.05
|
4.99 ± 1.05
|
<0.001
|
TG, mmol/L
|
1.65 ± 1.26
|
1.67 ± 1.54
|
1.61 ± 1.09
|
1.65 ± 1.15
|
1.68 ± 1.20
|
0.570
|
HDL-C, mmol/L
|
1.55 ± 0.44
|
1.47 ± 0.41
|
1.53 ± 0.43
|
1.57 ± 0.43
|
1.63 ± 0.49
|
<0.001
|
AST, U/L
|
27.98 ± 21.81
|
26.26 ± 16.53
|
26.73 ± 11.58
|
27.44 ± 10.84
|
31.48 ± 36.91
|
<0.001
|
ALT, U/L
|
22.25 ± 20.96
|
20.79 ± 15.60
|
21.27 ± 13.95
|
22.36 ± 15.21
|
24.55 ± 32.85
|
<0.001
|
Albumin, g/L
|
46.49 ± 4.16
|
45.26 ± 4.13
|
46.29 ± 3.90
|
47.06 ± 4.09
|
47.35 ± 4.20
|
<0.001
|
TBiL, μmol/L
|
15.67 ± 7.76
|
8.87 ± 1.51
|
12.51 ± 0.90
|
16.08 ± 1.27
|
25.17 ± 9.47
|
<0.001
|
eGFR, mL/min/1.73 m2
|
86.18 ± 20.46
|
82.96 ± 23.79
|
86.68 ± 19.40
|
86.48 ± 19.98
|
88.61 ± 17.83
|
<0.001
|
Comorbidities, N (%)
|
|
|
|
|
|
|
Stroke
|
403 (7.86%)
|
107 (8.35%)
|
102 (8.02%)
|
106 (8.20%)
|
88 (6.86%)
|
0.484
|
CHD#
|
273 (5.32%)
|
55 (4.29%)
|
72 (5.66%)
|
68 (5.26%)
|
78 (6.08%)
|
0.217
|
Diabetes mellitus$
|
828 (16.14%)
|
188 (14.68%)
|
184 (14.47%)
|
219 (16.94%)
|
237 (18.47%)
|
0.015
|
CKD
|
781 (15.23%)
|
263 (20.53%)
|
191 (15.02%)
|
182 (14.08%)
|
145 (11.30%)
|
<0.001
|
PAD
|
194 (3.78%)
|
64 (5.00%)
|
33 (2.59%)
|
45 (3.48%)
|
52 (4.05%)
|
0.013
|
Medication use, N (%)
|
|
|
|
|
|
|
Antihypertensive drugs
|
3362 (65.55%)
|
844 (65.89%)
|
829 (65.17%)
|
849 (65.66%)
|
840 (65.47%)
|
0.985
|
Glucose-lowering drugs
|
232 (4.52%)
|
58 (4.53%)
|
55 (4.32%)
|
55 (4.25%)
|
64 (4.99%)
|
0.807
|
Lipid-lowering drugs
|
177 (3.45%)
|
40 (3.12%)
|
45 (3.54%)
|
48 (3.71%)
|
44 (3.43%)
|
0.871
|
Abbreviation: PAD, peripheral arterial disease; BMI, body mass index; WC, waist circumference; HC, hip circumference; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; CHD, coronary heart disease; CKD, chronic kidney disease; FBG: fasting blood glucose; Hcy, homocysteine; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; TC, total cholesterol; TG, Triglycerides; TBiL, total bilirubin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; eGFR, estimated glomerular filtration rate.
$diabetes mellitus was defined as self-reported physician diagnosis of diabetes or FBG concentration ≥7.0 mmol/L or use of glucose-lowering drugs.
#CKD was defined as eGFR < 60mL/min/1.73 m2 or a self-reported physician diagnosis of CKD.
Associations between LgTBiL and PAD
A multivariate logistic regression model was performed to evaluate the associations between LgTBiL and the prevalence of PAD. The effect values (ORs) and 95% confidence intervals (CIs) for full adjustment are listed in Table 2. Every 1 unit increase in LgTBiL was associated with 56% increased odds of PAD (OR 1.56 [95% CI 0.64 to 3.81]), but the results did not reach statistical significance. For sensitivity analysis, we also handled LgTBiL as quartiles and as a categorical variable. Compared with participants in Q2, a higher odds of PAD was found in participants in Q1 (OR, 1.89; 95% CI: 1.20-2.96), Q3 (OR, 1.58; 95% CI: 0.98-2.53) and Q4 (OR, 2.16; 95% CI: 1.35-3.45). Table 2 shows that among participants in Q3, the odds of increased PAD were not significant; therefore, Q3 and Q2 populations were combined as a control group. The results showed that in comparison with participants in Q2-Q3 of LgTBiL, there was a significantly increased odds ratio of PAD for participants in both Q1 (OR, 1.49; 95% CI: 1.04-2.14) and Q4 (OR, 1.70; 95% CI: 1.16-2.48). The results suggested that the relationship between LgTBiL and the prevalence of PAD was not merely linear.
Table 2 ORs and 95% CI of PAD incidence according to TBiL levels (μmol/L)
LgTBiL
|
N
|
Events (%)
|
PAD OR (95%CI), P value
|
Crude model
|
Model 1
|
Model 2
|
Continuous
|
5129
|
194 (3.78%)
|
0.74 (0.33, 1.68) 0.473
|
1.12 (0.48, 2.63) 0.789
|
1.56 (0.64, 3.81) 0.332
|
Quartiles
|
|
|
|
|
|
Q1 (<1.04)
|
1281
|
64 (5.00%)
|
1.97 (1.29, 3.03) 0.002
|
1.94 (1.25, 3.02) 0.003
|
1.89 (1.20, 2.96) 0.006
|
Q2 (1.04-1.15)
|
1272
|
33 (2.59%)
|
1.00
|
1.00
|
1.00
|
Q3 (1.15-1.27)
|
1293
|
45 (3.48%)
|
1.35 (0.86, 2.14) 0.193
|
1.54 (0.96, 2.46) 0.071
|
1.58 (0.98, 2.53) 0.059
|
Q4 (≥1.27)
|
1283
|
52 (4.05%)
|
1.59 (1.02, 2.47) 0.041
|
1.93 (1.22, 3.06) 0.005
|
2.16 (1.35, 3.45) 0.001
|
Categories
|
|
|
|
|
|
Q1 (<1.04)
|
1281
|
64 (5.00%)
|
1.68 (1.20, 2.35) 0.003
|
1.55 (1.09, 2.20) 0.015
|
1.49 (1.04, 2.14) 0.031
|
Q2-Q3 (1.04-1.27)
|
2565
|
78 (3.04%)
|
1.00
|
1.00
|
1.00
|
Q4 (≥1.27)
|
1283
|
52 (4.05%)
|
1.35 (0.94, 1.93) 0.103
|
1.53 (1.06, 2.23) 0.024
|
1.70 (1.16, 2.48) 0.007
|
Crude model was adjusted for none.
Model 1 was adjusted for age, BMI, WC, HC, SBP, DBP, pulse, smoking status, drinking status.
Model 2 was adjusted for all variables in Model 1 plus adjusted for FBG, TC, TG, Hcy, HDL-C, AST, ALT, eGFR, CHD, antihypertensive drugs, glucose-lowering drugs, lipid-lowering drugs.
Threshold effect analysis of LgTBiL on PAD
To find the nonlinear relationship between LgTBiL and the prevalence of PAD, we used a generalized additive model and penalized spline method (Figure 1). The smoothing curve showed that a U-shaped curve association existed between LgTBiL and the prevalence of PAD in Chinese male adults with hypertension (after adjusting for age, BMI, WC, HC, SBP, DBP, pulse, smoking status, alcohol consumption, FBG, TC, TG, Hcy, HDL-C, AST, ALT, eGFR, CHD, antihypertensive drugs, glucose-lowering drugs, and lipid-lowering drugs). We further fitted the relationship between LgTBiL and the prevalence of PAD using the two-piecewise logistic regression model (Table 3) and calculated that the inflection point was 1.08 (LgTBiL = 1.08, TBiL = 12.02 μmol/L). Among the participants whose LgTBiL <1.08 μmol/L (TBiL <12.02 μmol/L), there was a significant trend toward decreasing odds of PAD development with increasing LgTBiL (OR, 0.11; 95% CI: 0.02- 0.83). However, the odds of PAD development significantly increased with increasing levels of LgTBiL (OR, 5.26; 95% CI: 59-17.38) in participants with LgTBiL ≥ 1.08 (TBiL ≥ 12.02 μmol/L).
Table 3 Threshold effect analysis of TBil on PAD using two piecewise logistic regression model
LgTBiL
|
N
|
Events (%)
|
PAD OR (95%CI)†, P value
|
Crude model
|
Model 1
|
Model 2
|
Continuous
|
5129
|
194 (3.78%)
|
0.74 (0.33, 1.68) 0.473
|
1.12 (0.48, 2.63) 0.789
|
1.56 (0.64, 3.81) 0.332
|
Inflection point
|
|
|
|
|
|
≤ 1.08
|
1739
|
72 (4.14%)
|
0.07 (0.01, 0.44) 0.004
|
0.10 (0.01, 0.73) 0.023
|
0.11 (0.02, 0.83) 0.032
|
>1.08
|
3390
|
122 (3.59%)
|
2.40 (0.77, 7.51) 0.131
|
3.45 (1.08, 11.05) 0.037
|
5.26 (1.59, 17.38) 0.007
|
P for log likelihood ratio test
|
|
|
0.009
|
0.012
|
0.007
|
Crude model was adjusted for none.
Model 1 was adjusted for age, BMI, WC, HC, SBP, DBP, pulse, smoking status, drinking status.
Model 2 was adjusted for all variables in Model 1 plus adjusted for FBG, TC, TG, Hcy, HDL-C, AST, ALT, eGFR, CHD, antihypertensive drugs, glucose-lowering drugs, lipid-lowering drugs.
Subgroup analyses
We performed exploratory subgroup analyses to assess the association between LgTBiL and the prevalence of PAD in two groups of participants separated by the turning point of LgTBiL (1.08) (Figure 2). The effect of LgTBiL on PAD showed no significant difference in the following subgroups: age (<65 vs. ≥65 years), BMI (< 24 vs. ≥24 kg/m2), smoking status (never vs. former vs. current), AST/ALT (<1 vs. ≥1), diabetes mellitus (no vs. yes), and CKD (no vs. yes) in both groups (all P for interactions >0.05) after adjustment for age, BMI, WC, HC, SBP, DBP, pulse, smoking status, alcohol consumption, FBG, TC, TG, Hcy, HDL-C, AST, ALT, eGFR, CHD, antihypertensive drugs, glucose-lowering drugs, and lipid-lowering drugs, except for the stratifying variable.