A total of 13 078 patients treated with and without pioglitazone were matched in a 1:1 ratio. The demographic characteristics of the two cohorts were almost similar (Table 1). Most patients were aged <65 years and 50% were males. Approximately 4%, 10%, and 10% of the patients in both cohorts had HF, arrhythmia, and CKD, respectively. Additionally, approximately 74% and 76% of patients in the two groups had HTN and hyperlipidemia, respectively. Forty-four percent of the patients had one CV risk factor, whereas 56% had had two CV risk factors. The number of patients treated with angiotensin-converting-enzyme inhibitor (ACEI), angiotensin receptor blockers (ARB), α-blocker, β-blocker, calcium channel blockers (CCB), diuretics, and other anti-hypertensive agents was similar between the two groups. Approximately 28%, 20%, and 51% of patients were treated with ≤1, 2, and ≥3 anti-hypertensive agents, respectively. Approximately 56% of the patients were treated with statin and less than 1% of the patients in both groups used high-intensity statin. More patients in the pioglitazone cohort used moderate-intensity statin (pioglitazone cohort: 58.76%, non-pioglitazone cohort: 52.84%; p < 0.01), whereas, more patients in the non-pioglitazone cohort used low-intensity statin (pioglitazone cohort: 46.81%, non-pioglitazone cohort: 40.88%; p < 0.01). Approximately 35% of the patients used fibrate, 36% of whom were also treated with other cholesterol-lowering agents. Approximately 57% of the patients in both groups used aspirin. Less than 1%, 2%, and 8% of the patients in both groups used warfarin, clopidogrel, and other anti-platelet agents, respectively. More patients in the non-pioglitazone cohort used sulfonylureas (SU) (pioglitazone cohort: 92.92%, non-pioglitazone cohort: 94.13%; p = 0.01) and more patients in the pioglitazone cohort used α-glucosidase inhibitor (pioglitazone cohort: 25.77%, non-pioglitazone cohort: 23.17%; p < 0.01) and glinide (pioglitazone cohort: 15.81%, non-pioglitazone cohort: 14.15%; p = 0.01). However, the number of patients who used metformin and dipeptidyl peptidase 4 (DPP4) inhibitors was similar between the two groups. Approximately 13% of the patients used no more than one glucose-lowering agents and 7% of the patients in both groups used more than four glucose- lowering agents. More patients in the non-pioglitazone cohort used two glucose-lowering agents (pioglitazone cohort: 51.38%, non-pioglitazone cohort: 54.46%; p < 0.01), whereas more patients in the pioglitazone cohort used three glucose-lowering agents (pioglitazone cohort: 27.65%, non-pioglitazone cohort: 23.98%; p < 0.01). The mean follow-up duration was ~4 years in both cohorts, but it was longer in the pioglitazone cohort than in the non-pioglitazone cohort (4.45 ± 2.39 years vs. 4.19 ± 2.64 years; p < 0.01).
Table 1. Baseline demographic characteristics of patients with DM treated with and without pioglitazone
|
Before PS matching
|
After PS matching
|
|
non-pioglitazone user
|
pioglitazone user
|
|
non-pioglitazone user
|
pioglitazone user
|
|
|
n = 32 337
|
n = 7574
|
|
n = 6539
|
n = 6539
|
|
Characteristics
|
N
|
%
|
n
|
%
|
p-value
|
N
|
%
|
n
|
%
|
p-value
|
Age, years
|
|
|
|
|
|
|
<55
|
12160
|
37.60
|
2810
|
37.10
|
0.42
|
2302
|
35.2
|
2338
|
35.75
|
0.51
|
55–65
|
8960
|
27.71
|
2463
|
32.52
|
<0.0001
|
2085
|
31.89
|
2126
|
32.51
|
0.44
|
≥65
|
11217
|
34.69
|
2301
|
30.38
|
<0.0001
|
2152
|
32.91
|
2075
|
31.73
|
0.15
|
Mean ± SD
|
59.48 ± 13.36
|
59.09 ± 11.31
|
0.001
|
59.74 ± 12.32
|
59.52 ± 11.51
|
0.29
|
Gender
|
|
|
|
|
|
|
|
|
|
|
Female
|
17068
|
52.78
|
3801
|
50.18
|
<0.0001
|
3250
|
49.70
|
3242
|
49.58
|
0.89
|
Male
|
15269
|
47.22
|
3773
|
49.82
|
<0.0001
|
3289
|
50.30
|
3297
|
50.42
|
0.89
|
Comorbidity
|
|
|
|
|
|
|
|
|
|
|
Heart failure
|
1920
|
5.94
|
326
|
4.30
|
<0.0001
|
306
|
4.68
|
296
|
4.53
|
0.68
|
Arrhythmia
|
4686
|
14.49
|
768
|
10.14
|
<0.0001
|
690
|
10.55
|
695
|
10.63
|
0.89
|
Chronic kidney disease
|
3621
|
11.20
|
788
|
10.40
|
0.05
|
665
|
10.17
|
681
|
10.41
|
0.65
|
Vascular risk factor
|
|
|
|
|
|
|
|
|
|
|
Hypertension
|
21589
|
66.76
|
5677
|
74.95
|
<0.0001
|
4863
|
74.37
|
4843
|
74.06
|
0.69
|
Hyperlipidemia
|
21387
|
66.14
|
5956
|
78.64
|
<0.0001
|
5003
|
76.51
|
5022
|
76.80
|
0.69
|
Number of risk factors
|
|
|
|
|
|
|
|
|
|
|
1
|
18750
|
57.98
|
3136
|
41.40
|
<0.0001
|
2899
|
44.33
|
2848
|
43.55
|
0.36
|
2
|
13587
|
42.02
|
4438
|
58.60
|
<0.0001
|
3640
|
55.67
|
3691
|
56.45
|
0.36
|
Drug use
|
|
|
|
|
|
|
|
|
|
|
Hypertensive agents
|
|
|
|
|
|
|
|
|
|
|
ACEI
|
13087
|
40.47
|
40.16
|
53.02
|
<0.0001
|
3382
|
51.72
|
3386
|
51.78
|
0.94
|
ARB
|
7213
|
22.31
|
2727
|
36.00
|
<0.0001
|
2257
|
34.52
|
2263
|
34.61
|
0.91
|
α-Blocker
|
6744
|
20.86
|
1616
|
21.34
|
0.35
|
1418
|
21.69
|
1418
|
21.69
|
1.00
|
β-Blocker
|
19379
|
59.93
|
4498
|
59.39
|
0.39
|
3873
|
59.23
|
3893
|
59.54
|
0.72
|
CCB
|
13766
|
42.57
|
3569
|
47.48
|
<0.0001
|
3154
|
48.23
|
3087
|
47.21
|
0.24
|
Diuretics
|
12474
|
38.58
|
3045
|
40.20
|
0.009
|
2702
|
41.32
|
2656
|
40.62
|
0.41
|
Others
|
2736
|
8.46
|
538
|
7.10
|
0.0001
|
463
|
7.08
|
475
|
7.26
|
0.68
|
Number of hypertensive agents
|
|
|
|
|
|
|
|
|
|
|
≤1
|
10911
|
33.74
|
2096
|
27.67
|
<0.0001
|
1809
|
27.66
|
1834
|
28.05
|
0.62
|
2
|
7432
|
22.98
|
1561
|
20.61
|
<0.0001
|
1356
|
20.74
|
13.42
|
20.52
|
0.76
|
≥3
|
13994
|
43.28
|
3917
|
51.72
|
<0.0001
|
3374
|
51.6
|
3363
|
51.43
|
0.84
|
Hypolipidemic agents
|
|
|
|
|
|
|
|
|
|
|
Statin
|
10366
|
32.06
|
4506
|
59.49
|
<0.0001
|
3664
|
56.03
|
3664
|
56.03
|
1.00
|
Initial Statin therapy
|
|
|
|
|
|
|
|
|
|
|
High intensity
|
32
|
0.31
|
16
|
0.36
|
0.01
|
13
|
0.35
|
13
|
0.35
|
1.00
|
Moderate intensity
|
5418
|
52.27
|
2677
|
59.41
|
<0.0001
|
1936
|
52.84
|
2153
|
58.76
|
<0.0001
|
Low intensity
|
4916
|
47.42
|
1813
|
40.24
|
<0.0001
|
1715
|
46.81
|
1498
|
40.88
|
<0.0001
|
Fibrate
|
6984
|
21.6
|
2805
|
37.03
|
<0.0001
|
2304
|
35.23
|
2282
|
34.90
|
0.69
|
Others
|
7621
|
23.57
|
2881
|
38.04
|
<0.0001
|
2397
|
36.66
|
2383
|
36.44
|
0.80
|
Anti-platelet agents
|
|
|
|
|
|
|
|
|
|
|
Aspirin
|
17438
|
53.93
|
4354
|
57.49
|
<0.0001
|
3735
|
57.12
|
3723
|
56.94
|
0.83
|
Warfarin
|
320
|
0.99
|
50
|
0.66
|
0.007
|
44
|
0.67
|
47
|
0.72
|
0.75
|
Clopidogrel
|
575
|
1.78
|
178
|
2.35
|
0.001
|
149
|
2.28
|
159
|
2.43
|
0.56
|
Others
|
2644
|
8.18
|
636
|
8.40
|
0.52
|
538
|
8.23
|
551
|
8.43
|
0.68
|
Oral antidiabetic agents
|
|
|
|
|
|
|
|
|
|
|
Metformin
|
10103
|
31.24
|
6588
|
86.98
|
<0.0001
|
5610
|
85.79
|
5557
|
84.98
|
0.19
|
Sulfonylureas
|
12478
|
38.59
|
7111
|
93.89
|
<0.0001
|
6155
|
94.13
|
6076
|
92.92
|
0.01
|
DPP4 inhibitors
|
569
|
1.76
|
672
|
8.87
|
0.001
|
465
|
7.11
|
499
|
7.63
|
0.26
|
Alpha-glucosidase inhibitor
|
1977
|
6.11
|
2521
|
33.28
|
<0.0001
|
1515
|
23.17
|
1685
|
25.77
|
0.001
|
Glinide
|
1338
|
4.14
|
1430
|
18.88
|
<0.0001
|
925
|
14.15
|
1034
|
15.81
|
0.01
|
Number of oral antidiabetic agents
|
|
|
|
|
|
|
|
|
|
|
≤1
|
23544
|
72.81
|
893
|
11.79
|
<0.0001
|
896
|
13.70
|
893
|
13.66
|
0.94
|
2
|
6553
|
20.26
|
3418
|
45.13
|
<0.0001
|
3561
|
54.46
|
3360
|
51.38
|
0.0004
|
3
|
1723
|
5.33
|
2411
|
31.83
|
<0.0001
|
1568
|
23.98
|
1808
|
27.65
|
<0.0001
|
≥4
|
517
|
1.60
|
852
|
11.25
|
<0.0001
|
514
|
7.86
|
478
|
7.31
|
0.23
|
Follow-up duration, year
|
5.25 ± 3.19
|
4.36 ± 2.36
|
<0.0001
|
4.19 ± 2.64
|
4.45 ± 2.39
|
<0.0001
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Data are presented as n (%) or mean ± SD.
PS: propensity score
ACEI, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blockers; CCB, calcium channel blockers;
Number of oral glucose-lowering agents used including metformin, sulfonylureas, DPP4 inhibitors, alpha-glucosidase inhibitor, and glinide
*High-intensity statins: atorvastatin ≧40 mg/day, or rosuvastatin ≧20 mg/day
**Moderate-intensity statins: 10 mg/day ≦ atorvastatin <40 mg/day, 5 mg/day ≦ rosuvastatin<20 mg/day, 20 mg/day ≦ simvastatin, pravastatin ≧ 40 mg/day, lovastatin ≧40 mg/day and fluvastatin ≧80 mg/day
***Low-intensity statins: atorvastatin <10 mg/day, rosuvastatin <5 mg/day, simvastatin <20 mg/day, pravastatin <40 mg/day, lovastatin <40 mg/day, and fluvastatin <80 mg/day
As shown in Table 2, the overall incidence of ischemic stroke was 29 268 per 1000 person-years in the pioglitazone cohort, a value lower than that found in the non-pioglitazone cohort (27 682 per 1000 person-years), with an adjusted hazard ratio (aHR) of 0.78 (95% CI = 0.62–0.95, p = 0.03).
Table 2. Hazard ratios and 95% confidence intervals of ischemic stroke owing to pioglitazone use
Variables
|
ischemic stroke (n = 306)
|
crude HR (95% CI)
|
p-value
|
Adjusted HR (95% CI)
|
p-value
|
Event
|
PY
|
IR
|
Pioglitazone
|
|
|
|
|
|
|
|
No
|
170
|
27682
|
6.14
|
1 (reference)
|
|
1 (reference)
|
|
Yes
|
136
|
29268
|
4.65
|
0.75 (0.60–0.90)**
|
0.009
|
0.78 (0.62–0.95)*
|
0.03
|
|
*p < 0.05, **p < 0.01, ***p < 0.001
PY, person-years; IR, incidence rate, per 1000 person-years; HR, hazard ratio; CI, confidence interval;PY, person-year; IR, incidence rate, per 1000 person-years; HR, hazard ratio; CI, confidence interval;
HR adjusted for age, sex, heart failure, arrhythmia, chronic kidney disease, hypertension, hyperlipidemia, hypertensive agents, lipid-lowering agents, anti-platelet agents, and oral glucose-lowering agents
The subgroup analyses defined by the different baseline features did not disclose any significant alterations in the observed effect of pioglitazone (Table 3; all p-values for interaction >0.05).
Table 3. Hazard ratios and 95% confidence intervals of ischemic stroke stratified by age, sex, and comorbidities between the pioglitazone and non-pioglitazone groups
|
non-pioglitazone user (n = 6539)
|
pioglitazone user (n = 6539)
|
Crude HR (95% CI)
|
Adjusted HR (95% CI)
|
p for interaction
|
Variables
|
Event
|
PY
|
IR
|
Event
|
PY
|
IR
|
All
|
170
|
27682
|
6.14
|
136
|
29268
|
4.65
|
0.75 (0.60–0.90)**
|
0.78 (0.62–0.95)*
|
|
Age group (years)
|
|
|
|
|
|
|
|
|
0.11
|
<45
|
46
|
10445
|
4.40
|
23
|
10857
|
2.12
|
0.48 (0.29–0.79)**
|
0.50 (0.30–0.82)**
|
|
45–64
|
52
|
8663
|
6.00
|
45
|
9659
|
4.66
|
0.77 (0.52–1.16)
|
0.76 (0.51–1.14)
|
|
≥65
|
72
|
8573
|
8.40
|
68
|
8752
|
7.77
|
0.90 (0.65–1.29)
|
0.89 (0.64–1.25)
|
|
Gender
|
|
|
|
|
|
|
|
|
0.58
|
Female
|
73
|
14124
|
5.17
|
63
|
14981
|
4.21
|
0.81 (0.57–1.13)
|
0.85 (0.30–1.20)
|
|
Male
|
97
|
13557
|
7.15
|
73
|
14287
|
5.11
|
0.71 (0.52–0.96)*
|
0.68 (0.20–0.92)*
|
|
Comorbidity
|
|
|
|
|
|
|
|
|
|
Heart failure
|
|
|
|
|
|
|
|
|
0.16
|
No
|
156
|
26555
|
5.87
|
130
|
28034
|
4.64
|
0.78 (0.62–0.99)*
|
0.79 (0.2–1.01)
|
|
Yes
|
14
|
1126
|
12.43
|
6
|
1234
|
4.86
|
0.38 (0.15–0.96)*
|
0.38 (0.14–1.03)
|
|
Arrhythmia
|
|
|
|
|
|
|
|
|
0.63
|
No
|
152
|
24900
|
6.10
|
124
|
26350
|
4.71
|
0.76 (0.60–0.95)*
|
0.76 (0.60–0.97)*
|
|
Yes
|
18
|
2781
|
6.47
|
12
|
2918
|
4.11
|
0.67 (0.32–1.41)
|
0.89 (0.41–1.95)
|
|
Chronic kidney disease
|
|
|
|
|
|
|
|
|
0.57
|
No
|
154
|
24998
|
6.16
|
126
|
26500
|
4.75
|
0.76 (0.61–0.97)*
|
0.77 (0.61–0.98)*
|
|
Yes
|
16
|
2683
|
5.96
|
10
|
2768
|
3.61
|
0.60 (0.27–1.32)
|
0.51 (0.22–1.21)
|
|
Hypertension
|
|
|
|
|
|
|
|
|
0.59
|
No
|
28
|
7737
|
3.62
|
25
|
8027
|
3.11
|
0.87 (0.51–1.51)
|
0.87 (0.50–1.52)
|
|
Yes
|
142
|
19944
|
7.12
|
111
|
21241
|
5.23
|
0.72 (0.57–0.93)*
|
0.74 (0.57–0.95)*
|
|
Hyperlipidemia
|
|
|
|
|
|
|
|
|
0.54
|
No
|
56
|
7518
|
7.45
|
46
|
7388
|
6.23
|
0.83 (0.56–1.24)
|
0.83 (0.55–1.24)
|
|
Yes
|
114
|
20163
|
5.65
|
90
|
21880
|
4.11
|
0.71 (0.54–0.94)**
|
0.72 (0.54–0.96)*
|
|
Number of risk factor
|
|
|
|
|
|
|
|
|
0.36
|
1
|
72
|
13348
|
5.39
|
61
|
13391
|
4.56
|
0.84 (0.60–1.19)
|
0.85 (0.60–1.20)
|
|
2
|
98
|
14333
|
6.84
|
75
|
15877
|
4.72
|
0.68 (0.50–0.92)*
|
0.70 (0.52–0.95)*
|
|
Number of hypertensive agents
|
|
|
|
|
|
|
|
|
0.23
|
≤1
|
44
|
8820
|
4.99
|
39
|
9002
|
4.33
|
0.87 (0.57–1.35)
|
0.86 (0.55–1.35)
|
|
2
|
36
|
6058
|
5.94
|
35
|
6131
|
5.71
|
0.95 (0.59–1.51)
|
0.93 (0.57–1.50)
|
|
≥3
|
90
|
12802
|
7.03
|
62
|
14134
|
4.39
|
0.61 (0.44–0.85)**
|
0.64 (0.46–0.89)**
|
|
Number of oral antidiabetic agents
|
|
|
|
|
|
|
|
|
0.14
|
≤1
|
39
|
4666
|
8.36
|
17
|
4563
|
3.73
|
0.44 (0.25–0.79)**
|
0.41 (0.23–0.75)**
|
|
2
|
84
|
15397
|
5.46
|
74
|
15125
|
4.89
|
0.46 (0.89–1.21)
|
0.91 (0.66–1.25)
|
|
3
|
33
|
6052
|
5.45
|
37
|
7873
|
4.70
|
0.84 (0.52–1.25)
|
0.89 (0.55–1.42)
|
|
≥4
|
14
|
1566
|
8.94
|
8
|
1706
|
4.69
|
0.52 (0.22–1.24)
|
0.56 (0.22–1.43)
|
|
|
HR adjusted for age, sex, heart failure, arrhythmia, chronic kidney disease, hypertension, hyperlipidemia, hypertensive agents, lipid-lowering agents, anti-platelet agents, and oral glucose-lowering agents
Compared with non-pioglitazone users, individuals exposed to low-, intermediate-, or high-dose pioglitazone did demonstrate an association, with a 0.79-fold (adjusted HR 0.79, 95% CI = 0.58–1.06), 0.74-fold (adjusted HR 0.74, 95% CI = 0.53–0.98), and 0.66-fold (adjusted HR 0.66, 95% CI = 0.46–0.87) decrease in the risk of ischemic stroke, respectively (Table 4). Moreover, there was a significant decreasing trend of ischemic stroke risk with the increase in pioglitazone dose (p-value for trend = 0.04).
Table 4. Hazard ratios and 95% confidence intervals of ischemic stroke associated with the defined daily doses of pioglitazone
Variables
|
ischemic stroke (n = 306)
|
crude HR (95% CI)
|
adjust HR (95% CI)
|
Event
|
PY
|
IR
|
Pioglitazone, DDD (per year)
|
|
|
|
|
|
0
|
170
|
27682
|
6.14
|
1 (reference)
|
1 (reference)
|
<100
|
58
|
12093
|
4.80
|
0.77 (0.57–1.03)
|
0.79 (0.58–1.06)
|
100-250
|
41
|
8935
|
4.59
|
0.74 (0.52–0.95)*
|
0.74 (0.53–0.98)*
|
>250
|
37
|
8239
|
4.49
|
0.63 (0.45–0.84)**
|
0.66 (0.46–0.87)*
|
p for trend
|
|
|
|
0.02
|
0.04
|
|
HR adjusted for age, sex, heart failure, arrhythmia, chronic kidney disease, hypertension, hyperlipidemia, hypertensive agents, lipid-lowering agents, anti-platelet agents, and oral glucose-lowering agents
As shown in Figure 2, the cumulative incidence of ischemic stroke was significantly lower in the pioglitazone cohort than in the non-pioglitazone cohort (log-rank test, p = 0.01).