Baseline characteristics of included patients and risk factors associated with HCC occurrence in the T2D-FLD cohort
We identified 212,443 patients with coexisting FLD and T2D (the FLD-T2D cohort). (Fig. 1)
Baseline characteristics of the cohort are shown in Table S1. The mean age (± standard deviation) was 54.5 years (± 12.54), and 123,539 (58.6%) male patients were included. Univariate and multivariate Cox regression analyses were performed to identify independent risk factors for the included patients. (Table 1)
Table 1. Univariate and Multivariate Cox regression analysis to identify risk factors associated with HCC occurrence in the FLD-T2D cohort (N=212,443)
|
Univariate
|
Multivariate
|
Variables
|
HR
|
95% CI
|
P value
|
HR
|
95% CI
|
P value
|
Age, year
|
1.06
|
1.05-1.06
|
<0.001
|
1.07
|
1.06-1.08
|
<0.001
|
Sex, female
|
2.53
|
2.07- 3.08
|
<0.001
|
2.72
|
2.21-3.34
|
<0.001
|
Charlson Comorbidity Index, 0
|
1
|
|
|
1
|
|
|
1
|
0.98
|
0.65-1.49
|
0.937
|
0.99
|
0.65-1.51
|
0.971
|
2
|
1.39
|
0.96-2.03
|
0.083
|
1.23
|
0.83-1.81
|
0.302
|
≥3
|
1.54
|
1.07-2.20
|
0.190
|
1.06
|
0.72-1.57
|
0.762
|
Comorbidities
|
|
|
|
|
|
|
Hypertension
|
1.50
|
1.27-1.77
|
<0.001
|
1.00
|
0.76-1.31
|
0.977
|
Dyslipidemia
|
0.66
|
0.55-0.78
|
<0.001
|
0.66
|
0.52-0.82
|
<0.001
|
Heart failure
|
1.57
|
0.98-2.50
|
0.062
|
1.04
|
0.64-1.71
|
0.867
|
Cerebrovascular disease
|
0.87
|
0.51-1.48
|
0.606
|
|
|
|
Coronary artery disease
|
0.97
|
0.56-1.69
|
0.920
|
|
|
|
Peripheral vascular disease
|
0.91
|
0.66-1.25
|
0.560
|
|
|
|
Hypothyroidism
|
0.78
|
0.46-1.30
|
0.339
|
|
|
|
End stage renal disease
|
1.29
|
0.48-3.45
|
0.610
|
|
|
|
Chronic viral hepatitis
|
10.18
|
8.23-12.59
|
<0.001
|
4.06
|
2.02-8.19
|
<0.001
|
Alcoholic liver disease
|
4.68
|
3.61-6.06
|
<0.001
|
3.25
|
2.48-4.26
|
<0.001
|
Chronic viral hepatitis B
|
10.38
|
8.15-13.22
|
<0.001
|
1.64
|
0.80-3.36
|
0.177
|
Chronic viral hepatitis C
|
11.18
|
7.42-16.83
|
<0.001
|
1.52
|
0.71-3.26
|
0.282
|
Liver cirrhosis
|
32.6
|
25.0-42.5
|
<0.001
|
8.34
|
6.10-11.40
|
<0.001
|
Chronic pulmonary disease
|
2.43
|
1.46-4.07
|
<0.001
|
1.36
|
0.81-2.29
|
0.251
|
Co-medications
|
|
|
|
|
|
|
Statin
|
0.58
|
0.49-0.71
|
<0.001
|
0.67
|
0.52-0.86
|
0.002
|
Ezetimibe
|
0.37
|
0.20-0.67
|
0.001
|
0.54
|
0.29-1.00
|
0.049
|
Fibrate
|
0.40
|
0.22-0.73
|
0.002
|
0.47
|
0.26-0.86
|
0.015
|
ACEi
|
1.00
|
0.45-2.24
|
0.994
|
|
|
|
Angiotensin II Receptor Blocker
|
1.37
|
1.15-1.62
|
<0.001
|
1.13
|
0.88-1.44
|
0.343
|
Calcium channel blocker
|
1.65
|
1.37-1.97
|
<0.001
|
1.31
|
1.04-1.65
|
0.020
|
Beta-blocker
|
1.41
|
1.10-1.80
|
0.007
|
1.04
|
0.79-1.37
|
0.765
|
Aspirin
|
1.34
|
1.07-1.67
|
0.009
|
1.02
|
0.81-1.30
|
0.849
|
Clopidogrel
|
0.91
|
0.59-1.41
|
0.666
|
|
|
|
Level of antidiabetic treatment, Level 1
|
1
|
|
|
|
|
|
Level 2
|
1.09
|
0.76-1.57
|
0.637
|
1.10
|
0.76-1.59
|
0.605
|
Level 3
|
1.51
|
1.12-2.04
|
0.007
|
1.36
|
1.01-1.85
|
0.045
|
Concordance index = 0.824 (standard error = 0.013)
HCC, hepatocellular carcinoma; FLD, fatty liver disease; T2D, type 2 diabetes mellitus ; HR, hazard ratio; CI, confidence interval; ACEi, angiotensine converting enzyme inhibitor.
In the univariate analysis, older age, male sex, and several comorbidities including hypertension, dyslipidemia, chronic obstructive pulmonary disease, chronic viral hepatitis, alcoholic liver disease, chronic viral hepatitis B, chronic viral hepatitis C, and liver cirrhosis were significantly associated with HCC occurrence with several co-medication use. Statin, ezetimibe, and fibrate use was associated with lower HCC occurrence, whereas ARB, CCB, beta-blockers, and aspirin use was associated with a higher risk of HCC. In addition, level 3 antidiabetic treatment, i.e., insulin use with OHA after cohort entry, was also a significant variable in the univariate analysis. Furthermore, we performed a multi-variate analysis to identify independent variables associated with HCC occurrence after adjusting for the included variables. Variables with P value ≤ 0.1 in univariate analysis were entered into the multivariate analysis. Finally, we identified that older age (HR = 1.07, 95% CI = 1.06-1.08, P <0.001 ), male sex (HR = 2.72, 95% CI =2.21-3.34, P <0.001 ), dyslipidemia (HR = 0.66, 95% CI = 0.52-0.82, P <0.001 ), chronic viral hepatitis (HR = 4.06, 95% CI = 2.02-8.19, P <0.001 ), alcoholic liver disease (HR = 3.25, 95% CI = 2.48-4.26, P <0.001 ), liver cirrhosis (HR = 8.34, 95% CI = 6.10-11.40, P <0.001 ), and level 3 antidiabetic treatment (HR = 1.36, 95% CI = 1.01-1.85, P = 0.045), were independent risk factors for HCC in this cohort. In terms of co-medications, the use of statins (HR = 0.67, 95% CI = 0.52-0.86, P = 0.002 ), ezetimibe (HR = 0.54, 95% CI = 0.29-1.00, P = 0.049), and fibrates (HR = 0.47, 95% CI = 0.26-0.86, P <0.001 ) was associated with a lower risk of HCC occurrence, whereas the use of CCB (HR = 1.31, 95% CI = 1.04-1.65, P = 0.020) was associated with a higher risk of HCC.
Impact of statin, fibrate, ezetimibe, and CCB on HCC occurrence in the PS-matched cohort
To ensure an accurate analysis of the impact of each drug, we divided the cohort based on the use of statins, fibrates, ezetimibe, and CCBs. (Fig. 1) To control for confounding variables, PS matching was applied to ensure an aSMD of <0.1 between the drug user and non-user groups. Tables 2, 3, 4 and 5 show the comprehensive baseline characteristics of the drug user and non-user groups in each cohort pre- and post-PS matching.
Table 2. Baseline characteristics of pre- and post-PS matched cohort divided according to statin use
|
Pre-PS matched cohort (N=212,443)
|
Post-PS matched cohort (N=72,714)
|
characteristics
|
Statin users
(N= 86,976)
|
Statin non-users
(N= 125,467)
|
aSMD
|
Statin users
(N=36,357)
|
Statin non-users (N=36,357)
|
aSMD
|
Age, years (mean ± SD)
|
58.81 (10.77)
|
51.52 (12.80)
|
0.617
|
55.16 (10.85)
|
54.95 (11.72)
|
0.019
|
Sex, male, n (%)
|
44,372 (51.0)
|
80,167 (63.9)
|
0. 263
|
20953 (57.6)
|
20840 (57.3)
|
0.006
|
Index year
|
|
|
|
|
|
|
2015
|
9900 (11.4)
|
18563 (14.8)
|
0.154
|
4778 (13.1)
|
4753 (13.1)
|
0.015
|
2016
|
12458 (14.3)
|
21079 (16.8)
|
|
5806 (16.0)
|
5897 (16.2)
|
|
2017
|
13952 (16.0)
|
20792 (16.6)
|
|
6013 (16.5)
|
5949 (16.4)
|
|
2018
|
14865 (17.1)
|
20953 (16.7)
|
|
6119 (16.8)
|
6068 (16.7)
|
|
2019
|
17280 (19.9)
|
22425 (17.9)
|
|
6919 (19.0)
|
6811 (18.7)
|
|
2020
|
18521 (21.3)
|
21655 (17.3)
|
|
6722 (18.5)
|
6879 (18.9)
|
|
Charlson Comorbidity Index
|
|
|
|
|
|
|
0
|
988 (1.1)
|
15879 (12.7)
|
0.651
|
489 (1.3)
|
477 (1.3)
|
0.011
|
1
|
9940 (11.4)
|
26411 (21.1)
|
|
4344 (11.9)
|
4420 (12.2)
|
|
2
|
22501 (25.9)
|
37402 (29.8)
|
|
10958 (30.1)
|
11073 (30.5)
|
|
<=3
|
53547 (61.6)
|
45775 (36.5)
|
|
20566 (56.6)
|
20387 (56.1)
|
|
Comorbidities
|
|
|
|
|
|
|
Hypertension
|
58451 (67.2)
|
39382 (31.4)
|
0.767
|
18921 (52.0)
|
18564 (51.1)
|
0.02
|
Dyslipidemia
|
85805 (98.7)
|
41067 (32.7)
|
1.929
|
35295 (97.1)
|
35380 (97.3)
|
0.014
|
Heart failure
|
3792 (4.4)
|
1315 (1.0)
|
0.205
|
844 (2.3)
|
726 (2.0)
|
0.022
|
Cerebrovascular disease
|
4335 (5.0)
|
1929 (1.5)
|
0.195
|
1073 (3.0)
|
990 (2.7)
|
0.014
|
Coronary artery disease
|
4239 (4.9)
|
852 (0.7)
|
0.257
|
690 (1.9)
|
561 (1.5)
|
0.027
|
Peripheral vascular disease
|
11378 (13.1)
|
6969 (5.6)
|
0.261
|
3557 (9.8)
|
3359 (9.2)
|
0.019
|
Hypothyroidism
|
4911 (5.6)
|
2959 (2.4)
|
0.168
|
1793 (4.9)
|
1771 (4.9)
|
0.003
|
Obesity or overweight
|
230 (0.3)
|
286 (0.2)
|
0.007
|
106 (0.3)
|
111 (0.3)
|
0.003
|
Chronic kidney disease
|
994 (1.1)
|
358 (0.3)
|
0.102
|
251 (0.7)
|
232 (0.6)
|
0.006
|
End stage renal disease
|
992 (1.1)
|
358 (0.3)
|
0.102
|
251 (0.7)
|
232 (0.6)
|
0.006
|
Chronic viral hepatitis
|
2123 (2.4)
|
2813 (2.2)
|
0.013
|
1109 (3.1)
|
1129 (3.1)
|
0.003
|
Alcoholic liver disease
|
2837 (3.3)
|
3312 (2.6)
|
0.037
|
1523 (4.2)
|
1495 (4.1)
|
0.004
|
Primary biliary cholangitis
|
61 (0.1)
|
38 (0.0)
|
0.018
|
25 (0.1)
|
15 (0.0)
|
0.012
|
Chronic viral hepatitis B
|
1417 (1.6)
|
1987 (1.6)
|
0.004
|
782 (2.2)
|
746 (2.1)
|
0.007
|
Chronic viral hepatitis C
|
347 (0.4)
|
487 (0.4)
|
0.002
|
161 (0.4)
|
212 (0.6)
|
0.02
|
Liver cirrhosis
|
321 (0.4)
|
677 (0.5)
|
0.025
|
197 (0.5)
|
200 (0.6)
|
0.001
|
Chronic respiratory disease
|
1329 (1.5)
|
1053 (0.8)
|
0.064
|
423 (1.2)
|
466 (1.3)
|
0.011
|
Co-medications,
|
|
|
|
|
|
|
Aspirin
|
19719 (22.7)
|
6899 (5.5)
|
0.509
|
4008 (11.0)
|
3528 (9.7)
|
0.043
|
Clopidogrel
|
8191 (9.4)
|
1310 (1.0)
|
0.383
|
1068 (2.9)
|
775 (2.1)
|
0.051
|
Antiplatelet, others
|
6019 (6.9)
|
2286 (1.8)
|
0.251
|
1378 (3.8)
|
1178 (3.2)
|
0.03
|
Ezetimibe
|
16218 (18.6)
|
115 (0.1)
|
0.672
|
294 (0.8)
|
115 (0.3)
|
0.066
|
Fibrates
|
7537 (8.7)
|
5224 (4.2)
|
0.185
|
4291 (11.8)
|
4292 (11.8)
|
<0.001
|
Omega3
|
581 (0.7)
|
115 (0.1)
|
0.094
|
272 (0.7)
|
104 (0.3)
|
0.064
|
ACEi
|
1582 (1.8)
|
490 (0.4)
|
0.137
|
284 (0.8)
|
244 (0.7)
|
0.013
|
ARB
|
42654 (49.0)
|
26206 (20.9)
|
0.618
|
12987 (35.7)
|
12530 (34.5)
|
0.026
|
Calcium channel blocker
|
28620 (32.9)
|
19502 (15.5)
|
0.414
|
9124 (25.1)
|
8866 (24.4)
|
0.016
|
Beta blocker
|
13648 (15.7)
|
7108 (5.7)
|
0.329
|
3513 (9.7)
|
3293 (9.1)
|
0.021
|
Level of antidiabetic treatment
|
|
|
|
|
|
|
Level I
|
78055 (89.7)
|
106339 (84.8)
|
0.159
|
32383 (89.1)
|
32380 (89.1)
|
0.003
|
Level II
|
3302 (3.8)
|
8544 (6.8)
|
|
1649 (4.5)
|
1635 (4.5)
|
|
Level III
|
5619 (6.5)
|
10584 (8.4)
|
|
2325 (6.4)
|
2342 (6.4)
|
|
PS, propensity score; aSMD, absolute standardized mean difference; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.
Table 3. Baseline characteristics of pre- and post-PS matched cohort divided according to fibrate use
|
Pre-PS matched cohort (N=212,443)
|
Post-PS matched cohort (N=25,518)
|
characteristics
|
Fibrate users
(N= 12,761)
|
Fibrate non-users (N= 199,682)
|
aSMD
|
Fibrate users
(N= 12,759)
|
Fibrate non-users (N= 12,759)
|
aSMD
|
Age, years (mean +/- SD)
|
54.48 (10.90)
|
54.50 (12.63)
|
0.002
|
54.49 (10.90)
|
54.27 (12.54)
|
0.019
|
Sex, male, n (%)
|
8728 (68.4)
|
115811 (58.0)
|
0.217
|
8726 (68.4)
|
8572 (67.2)
|
0.026
|
Index year
|
|
|
|
|
|
|
2015
|
823 (6.4)
|
27640 (13.8)
|
0.319
|
823 (6.5)
|
883 (6.9)
|
0.022
|
2016
|
1515 (11.9)
|
32022 (16.0)
|
|
1515 (11.9)
|
1491 (11.7)
|
|
2017
|
2006 (15.7)
|
32738 (16.4)
|
|
2006 (15.7)
|
1979 (15.5)
|
|
2018
|
2294 (18.0)
|
33524 (16.8)
|
|
2294 (18.0)
|
2247 (17.6)
|
|
2019
|
2787 (21.8)
|
36918 (18.5)
|
|
2787 (21.8)
|
2808 (22.0)
|
|
2020
|
3336 (26.1)
|
36840 (18.4)
|
|
3334 (26.1)
|
3351 (26.3)
|
|
Charlson Comorbidity Index
|
|
|
|
|
|
|
0
|
169 (1.3)
|
16698 (8.4)
|
0.379
|
169 (1.3)
|
165 (1.3)
|
0.013
|
1
|
1599 (12.5)
|
34752 (17.4)
|
|
1599 (12.5)
|
1626 (12.7)
|
|
2
|
3825 (30.0)
|
56078 (28.1)
|
|
3823 (30.0)
|
3877 (30.4)
|
|
≥3
|
7168 (56.2)
|
92154 (46.2)
|
|
7168 (56.2)
|
7091 (55.6)
|
|
Comorbidities
|
|
|
|
|
|
|
Hypertension
|
8312 (65.1)
|
89521 (44.8)
|
0.417
|
8310 (65.1)
|
8346 (65.4)
|
0.006
|
Dyslipidemia
|
12662 (99.2)
|
114210 (57.2)
|
1.183
|
12660 (99.2)
|
12660 (99.2)
|
<0.001
|
Heart failure
|
391 (3.1)
|
4716 (2.4)
|
0.043
|
391 (3.1)
|
452 (3.5)
|
0.027
|
Cerebrovascular disease
|
413 (3.2)
|
5851 (2.9)
|
0.018
|
413 (3.2)
|
473 (3.7)
|
0.026
|
Coronary artery disease
|
307 (2.4)
|
4784 (2.4)
|
0.001
|
307 (2.4)
|
479 (3.8)
|
0.078
|
Peripheral vascular disease
|
1472 (11.5)
|
16875 (8.5)
|
0.103
|
1472 (11.5)
|
1406 (11.0)
|
0.016
|
Hypothyroidism
|
628 (4.9)
|
7242 (3.6)
|
0.064
|
628 (4.9)
|
610 (4.8)
|
0.007
|
Obesity or overweight
|
31 (0.2)
|
485 (0.2)
|
<0.001
|
31 (0.2)
|
44 (0.3)
|
0.019
|
Chronic kidney disease
|
151 (1.2)
|
1201 (0.6)
|
0.062
|
151 (1.2)
|
165 (1.3)
|
0.01
|
End stage renal disease
|
150 (1.2)
|
1200 (0.6)
|
0.061
|
150 (1.2)
|
165 (1.3)
|
0.011
|
Chronic viral hepatitis
|
284 (2.2)
|
4652 (2.3)
|
0.007
|
284 (2.2)
|
313 (2.5)
|
0.015
|
Alcoholic liver disease
|
708 (5.5)
|
5441 (2.7)
|
0.142
|
707 (5.5)
|
698 (5.5)
|
0.003
|
Primary biliary cholangitis
|
14 (0.1)
|
85 (0.0)
|
0.024
|
14 (0.1)
|
11 (0.1)
|
0.008
|
Chronic viral hepatitis B
|
178 (1.4)
|
3226 (1.6)
|
0.018
|
178 (1.4)
|
216 (1.7)
|
0.024
|
Chronic viral hepatitis C
|
42 (0.3)
|
792 (0.4)
|
0.011
|
42 (0.3)
|
48 (0.4)
|
0.008
|
Liver cirrhosis
|
57 (0.4)
|
941 (0.5)
|
0.004
|
57 (0.4)
|
64 (0.5)
|
0.008
|
Chronic respiratory disease
|
148 (1.2)
|
2234 (1.1)
|
0.004
|
148 (1.2)
|
172 (1.3)
|
0.017
|
Co-medications,
|
|
|
|
|
|
|
Aspirin
|
2173 (17.0)
|
24445 (12.2)
|
0.136
|
2173 (17.0)
|
2150 (16.9)
|
0.005
|
Clopidogrel
|
685 (5.4)
|
8816 (4.4)
|
0.044
|
685 (5.4)
|
836 (6.6)
|
0.05
|
Antiplatelet, others
|
680 (5.3)
|
7625 (3.8)
|
0.072
|
680 (5.3)
|
666 (5.2)
|
0.005
|
Ezetimibe
|
1563 (12.2)
|
14770 (7.4)
|
0.164
|
1563 (12.3)
|
1540 (12.1)
|
0.006
|
Statin
|
7537 (59.1)
|
79439 (39.8)
|
0.393
|
7537 (59.1)
|
7492 (58.7)
|
0.007
|
Omega3
|
117 (0.9)
|
579 (0.3)
|
0.081
|
117 (0.9)
|
86 (0.7)
|
0.027
|
ACEi
|
153 (1.2)
|
1919 (1.0)
|
0.023
|
153 (1.2)
|
148 (1.2)
|
0.004
|
ARB
|
6631 (52.0)
|
62229 (31.2)
|
0.432
|
6629 (52.0)
|
6616 (51.9)
|
0.002
|
Calcium channel blocker
|
4494 (35.2)
|
43628 (21.8)
|
0.299
|
4492 (35.2)
|
4459 (34.9)
|
0.005
|
Beta blocker
|
1866 (14.6)
|
18890 (9.5)
|
0.159
|
1865 (14.6)
|
1890 (14.8)
|
0.006
|
Level of antidiabetic treatment
|
|
|
|
|
|
|
Level I
|
11399 (89.3)
|
172995 (86.6)
|
0.083
|
11397 (89.3)
|
11368 (89.1)
|
0.008
|
Level II
|
558 (4.4)
|
11288 (5.7)
|
|
558 (4.4)
|
577 (4.5)
|
|
Level III
|
804 (6.3)
|
15399 (7.7)
|
|
804 (6.3)
|
814 (6.4)
|
|
PS, propensity score; aSMD, absolute standardized mean difference; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.
Table 4. Baseline characteristics of pre- and post-PS matched cohorts divided according to ezetimibe use
|
Pre-PS matched cohort (N=212,443)
|
Post-PS matched cohort (N=32,656)
|
characteristics
|
Ezetimibe users
(N= 16,333)
|
Ezetimibe non-users (N= 196,110)
|
aSMD
|
Ezetimibe users
(N= 16,328)
|
Ezetimibe non-users (N= 16,328)
|
aSMD
|
Age, years (mean +/- SD)
|
57.32 (10.84)
|
54.27 (12.64)
|
0.259
|
57.33 (10.83)
|
57.31 (11.22)
|
0.002
|
Sex, male, n (%)
|
8756 (53.6)
|
115783 (59.0)
|
0.11
|
8753 (53.6)
|
8704 (53.3)
|
0.006
|
Index year
|
|
|
|
|
|
|
2015
|
662 (4.1)
|
27801 (14.2)
|
0.553
|
662 (4.1)
|
713 (4.4)
|
0.017
|
2016
|
1170 (7.2)
|
32367 (16.5)
|
|
1170 (7.2)
|
1175 (7.2)
|
|
2017
|
2301 (14.1)
|
32443 (16.5)
|
|
2301 (14.1)
|
2261 (13.8)
|
|
2018
|
3002 (18.4)
|
32816 (16.7)
|
|
3002 (18.4)
|
2991 (18.3)
|
|
2019
|
4182 (25.6)
|
35523 (18.1)
|
|
4182 (25.6)
|
4201 (25.7)
|
|
2020
|
5016 (30.7)
|
35160 (17.9)
|
|
5011 (30.7)
|
4987 (30.5)
|
|
Charlson Comorbidity Index
|
|
|
|
|
|
|
0
|
203 (1.2)
|
16664 (8.5)
|
0.444
|
203 (1.2)
|
215 (1.3)
|
0.011
|
1
|
1774 (10.9)
|
34577 (17.6)
|
|
1772 (10.9)
|
1807 (11.1)
|
|
2
|
4341 (26.6)
|
55562 (28.3)
|
|
4340 (26.6)
|
4361 (26.7)
|
|
≥3
|
10015 (61.3)
|
89307 (45.5)
|
|
10013 (61.3)
|
9945 (60.9)
|
|
Comorbidities
|
|
|
|
|
|
|
Hypertension
|
10274 (62.9)
|
87559 (44.6)
|
0.372
|
10273 (62.9)
|
10290 (63.0)
|
0.002
|
Dyslipidemia
|
16131 (98.8)
|
110741 (56.5)
|
1.178
|
16126 (98.8)
|
16124 (98.8)
|
0.001
|
Heart failure
|
719 (4.4)
|
4388 (2.2)
|
0.121
|
719 (4.4)
|
705 (4.3)
|
0.004
|
Cerebrovascular disease
|
834 (5.1)
|
5430 (2.8)
|
0.12
|
834 (5.1)
|
857 (5.2)
|
0.006
|
Coronary artery disease
|
877 (5.4)
|
4214 (2.1)
|
0.17
|
876 (5.4)
|
848 (5.2)
|
0.008
|
Peripheral vascular disease
|
2135 (13.1)
|
16212 (8.3)
|
0.156
|
2135 (13.1)
|
2103 (12.9)
|
0.006
|
Hypothyroidism
|
994 (6.1)
|
6876 (3.5)
|
0.121
|
993 (6.1)
|
990 (6.1)
|
0.001
|
Obesity or overweight
|
54 (0.3)
|
462 (0.2)
|
0.018
|
54 (0.3)
|
41 (0.3)
|
0.015
|
Chronic kidney disease
|
218 (1.3)
|
1134 (0.6)
|
0.078
|
217 (1.3)
|
209 (1.3)
|
0.004
|
End stage renal disease
|
217 (1.3)
|
1133 (0.6)
|
0.077
|
216 (1.3)
|
209 (1.3)
|
0.004
|
Chronic viral hepatitis
|
421 (2.6)
|
4515 (2.3)
|
0.018
|
421 (2.6)
|
431 (2.6)
|
0.004
|
Alcoholic liver disease
|
616 (3.8)
|
5533 (2.8)
|
0.053
|
614 (3.8)
|
638 (3.9)
|
0.008
|
Primary biliary cholangitis
|
18 (0.1)
|
81 (0.0)
|
0.025
|
18 (0.1)
|
19 (0.1)
|
0.002
|
Chronic viral hepatitis B
|
267 (1.6)
|
3137 (1.6)
|
0.003
|
267 (1.6)
|
309 (1.9)
|
0.02
|
Chronic viral hepatitis C
|
63 (0.4)
|
771 (0.4)
|
0.001
|
63 (0.4)
|
57 (0.3)
|
0.006
|
Liver cirrhosis
|
61 (0.4)
|
937 (0.5)
|
0.016
|
61 (0.4)
|
51 (0.3)
|
0.01
|
Chronic respiratory disease
|
234 (1.4)
|
2148 (1.1)
|
0.03
|
234 (1.4)
|
216 (1.3)
|
0.009
|
Co-medications,
|
|
|
|
|
|
|
Aspirin
|
3263 (20.0)
|
23355 (11.9)
|
0.222
|
3262 (20.0)
|
3198 (19.6)
|
0.01
|
Clopidogrel
|
1773 (10.9)
|
7728 (3.9)
|
0.267
|
1771 (10.8)
|
1705 (10.4)
|
0.013
|
Antiplatelet, others
|
1117 (6.8)
|
7188 (3.7)
|
0.143
|
1117 (6.8)
|
1141 (7.0)
|
0.006
|
Statin
|
16218 (99.3)
|
70758 (36.1)
|
1.834
|
16213 (99.3)
|
16213 (99.3)
|
<0.001
|
Fibrate
|
1563 (9.6)
|
11198 (5.7)
|
0.146
|
1562 (9.6)
|
1522 (9.3)
|
0.008
|
Omega3
|
108 (0.7)
|
588 (0.3)
|
0.052
|
107 (0.7)
|
172 (1.1)
|
0.043
|
ACEi
|
277 (1.7)
|
1795 (0.9)
|
0.069
|
277 (1.7)
|
287 (1.8)
|
0.005
|
ARB
|
7947 (48.7)
|
60913 (31.1)
|
0.365
|
7943 (48.6)
|
7935 (48.6)
|
0.001
|
Calcium channel blocker
|
5406 (33.1)
|
42716 (21.8)
|
0.256
|
5402 (33.1)
|
5404 (33.1)
|
<0.001
|
Beta blocker
|
2611 (16.0)
|
18145 (9.3)
|
0.204
|
2611 (16.0)
|
2539 (15.5)
|
0.012
|
Level of antidiabetic treatment
|
|
|
|
|
|
|
Level I
|
14601 (89.4)
|
169793 (86.6)
|
0.097
|
14596 (89.4)
|
14588 (89.3)
|
0.003
|
Level II
|
632 (3.9)
|
11214 (5.7)
|
|
632 (3.9)
|
629 (3.9)
|
|
Level III
|
1100 (6.7)
|
15103 (7.7)
|
|
1100 (6.7)
|
1111 (6.8)
|
|
PS, propensity score; aSMD, absolute standardized mean difference; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker.
Table 5. Baseline characteristics of pre- and post-PS matched cohorts divided according to CCB use
|
Pre-PS matched cohort (N=212,443)
|
Post-PS matched cohort (N=83,084)
|
characteristics
|
CCB users
(N= 48,122)
|
CCB non-users (N=164,321)
|
aSMD
|
CCB users
(N= 41,542)
|
CCB non-users (N= 41,542)
|
aSMD
|
Age, years (mean +/- SD)
|
59.17 (11.05)
|
53.14 (12.62)
|
0.509
|
59.15 (11.12)
|
59.21 (10.86)
|
0.005
|
Sex, male, n (%)
|
27597 (57.3)
|
96942 (59.0)
|
0.033
|
23030 (55.4)
|
22474 (54.1)
|
0.027
|
Index year
|
|
|
|
|
|
|
2015
|
5699 (11.8)
|
22764 (13.9)
|
0.097
|
5236 (12.6)
|
5455 (13.1)
|
0.026
|
2016
|
7080 (14.7)
|
26457 (16.1)
|
|
6283 (15.1)
|
6501 (15.6)
|
|
2017
|
7586 (15.8)
|
27158 (16.5)
|
|
6660 (16.0)
|
6711 (16.2)
|
|
2018
|
8240 (17.1)
|
27578 (16.8)
|
|
6980 (16.8)
|
6876 (16.6)
|
|
2019
|
9365 (19.5)
|
30340 (18.5)
|
|
7979 (19.2)
|
7839 (18.9)
|
|
2020
|
10152 (21.1)
|
30024 (18.3)
|
|
8404 (20.2)
|
8160 (19.6)
|
|
Charlson Comorbidity Index
|
|
|
|
|
|
|
0
|
1361 (2.8)
|
15506 (9.4)
|
0.359
|
1074 (2.6)
|
949 (2.3)
|
0.022
|
1
|
6328 (13.1)
|
30023 (18.3)
|
|
5280 (12.7)
|
5220 (12.6)
|
|
2
|
12935 (26.9)
|
46968 (28.6)
|
|
10840 (26.1)
|
10728 (25.8)
|
|
≥3
|
27498 (57.1)
|
71824 (43.7)
|
|
24348 (58.6)
|
24645 (59.3)
|
|
Comorbidities
|
|
|
|
|
|
|
Hypertension
|
47862 (99.5)
|
49971 (30.4)
|
2.096
|
41282 (99.4)
|
41282 (99.4)
|
<0.001
|
Dyslipidemia
|
37125 (77.1)
|
89747 (54.6)
|
0.489
|
32497 (78.2)
|
32708 (78.7)
|
0.012
|
Heart failure
|
1719 (3.6)
|
3388 (2.1)
|
0.091
|
1678 (4.0)
|
1681 (4.0)
|
<0.001
|
Cerebrovascular disease
|
2473 (5.1)
|
3791 (2.3)
|
0.15
|
2129 (5.1)
|
2030 (4.9)
|
0.011
|
Coronary artery disease
|
1709 (3.6)
|
3382 (2.1)
|
0.091
|
1649 (4.0)
|
1671 (4.0)
|
0.003
|
Peripheral vascular disease
|
6991 (14.5)
|
11356 (6.9)
|
0.248
|
5827 (14.0)
|
5689 (13.7)
|
0.01
|
Hypothyroidism
|
2073 (4.3)
|
5797 (3.5)
|
0.04
|
1909 (4.6)
|
1991 (4.8)
|
0.009
|
Obesity or overweight
|
133 (0.3)
|
383 (0.2)
|
0.009
|
118 (0.3)
|
111 (0.3)
|
0.003
|
Chronic kidney disease
|
538 (1.1)
|
814 (0.5)
|
0.07
|
491 (1.2)
|
505 (1.2)
|
0.003
|
End stage renal disease
|
537 (1.1)
|
813 (0.5)
|
0.07
|
490 (1.2)
|
504 (1.2)
|
0.003
|
Chronic viral hepatitis
|
1282 (2.7)
|
3654 (2.2)
|
0.029
|
1120 (2.7)
|
1126 (2.7)
|
0.001
|
Alcoholic liver disease
|
1856 (3.9)
|
4293 (2.6)
|
0.07
|
1544 (3.7)
|
1506 (3.6)
|
0.005
|
Primary biliary cholangitis
|
26 (0.1)
|
73 (0.0)
|
0.004
|
25 (0.1)
|
23 (0.1)
|
0.002
|
Chronic viral hepatitis B
|
833 (1.7)
|
2571 (1.6)
|
0.013
|
718 (1.7)
|
735 (1.8)
|
0.003
|
Chronic viral hepatitis C
|
262 (0.5)
|
572 (0.3)
|
0.029
|
236 (0.6)
|
211 (0.5)
|
0.008
|
Liver cirrhosis
|
242 (0.5)
|
756 (0.5)
|
0.006
|
223 (0.5)
|
227 (0.5)
|
0.001
|
Chronic respiratory disease
|
740 (1.5)
|
1642 (1.0)
|
0.048
|
661 (1.6)
|
681 (1.6)
|
0.004
|
Co-medications,
|
|
|
|
|
|
|
Aspirin
|
11672 (24.3)
|
14946 (9.1)
|
0.415
|
9894 (23.8)
|
9696 (23.3)
|
0.011
|
Clopidogrel
|
3690 (7.7)
|
5811 (3.5)
|
0.18
|
3318 (8.0)
|
3260 (7.8)
|
0.005
|
Antiplatelet, others
|
3132 (6.5)
|
5173 (3.1)
|
0.157
|
2714 (6.5)
|
2750 (6.6)
|
0.003
|
Statin
|
28620 (59.5)
|
58356 (35.5)
|
0.494
|
24973 (60.1)
|
25301 (60.9)
|
0.016
|
Ezetimibe
|
5406 (11.2)
|
10927 (6.6)
|
0.161
|
4482 (10.8)
|
4340 (10.4)
|
0.011
|
Fibrate
|
4494 (9.3)
|
8267 (5.0)
|
0.167
|
3611 (8.7)
|
3498 (8.4)
|
0.01
|
Omega3
|
269 (0.6)
|
427 (0.3)
|
0.047
|
219 (0.5)
|
183 (0.4)
|
0.012
|
ACEi
|
599 (1.2)
|
1473 (0.9)
|
0.034
|
594 (1.4)
|
540 (1.3)
|
0.011
|
ARB
|
37535 (78.0)
|
31325 (19.1)
|
1.46
|
30959 (74.5)
|
30675 (73.8)
|
0.016
|
Beta blocker
|
8487 (17.6)
|
12269 (7.5)
|
0.311
|
7423 (17.9)
|
7452 (17.9)
|
0.002
|
Level of antidiabetic treatment
|
|
|
|
|
|
|
Level I
|
42708 (88.7)
|
141686 (86.2)
|
0.082
|
36852 (88.7)
|
36916 (88.9)
|
0.007
|
Level II
|
2109 (4.4)
|
9737 (5.9)
|
|
1786 (4.3)
|
1731 (4.2)
|
|
Level III
|
3305 (6.9)
|
12898 (7.8)
|
|
2904 (7.0)
|
2895 (7.0)
|
|
PS, propensity score; aSMD, absolute standardized mean difference; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker.
Before PS matching, notable disparities were observed between the groups in each cohort, whereas the PS-matched cohort had normalized mean differences, achieving an aSMD <0.1 for all variables, indicative of an exceptional equilibrium among covariates. This outcome highlighted the effectiveness of the matching procedure in ensuring group comparability for further analysis. Table S2, S3, S4, and S5 and Fig S1 demonstrate the successful adjustment of covariate differences between the groups following PS matching in each subgroup.
Fig. 2 shows a comparison of the Kaplan–Meier curves between subgroups divided according to specific drug usage in the post PS-matched cohorts.
As a result, we identified that patients who were used statins (HR = 0.58, 95% CI= 0.42-0.80, P < 0.001) and fibrates (HR = 0.46, 95% CI= 0.22-0.93, P = 0.031) had lower risks of HCC compared to non-users, whereas CCB users (HR = 1.35, 95% CI= 1.05-1.72, P = 0.019) showed a higher risk of HCC compared to non-users in each post-PS matched cohort. However, the ezetimibe users and non-users did not show any statistical differences (HR = 0.58, 95% CI= 0.14-2.44, P = 0.46).