Supplementary Table 1. Propensity Score Model Results of Probability of Occurrence
of Hypoglycemia
95% CI
Parameter
Estimate Odds Ratios Lower Upper P value
0.027
1.027
1.026
1.029
<.0001
Age, per year
Year of Index Date
1
2000
0.1071
1.113
0.967
1.281
0.1355
2001
-0.1762
0.838
0.734
0.957
0.0093
2002
-0.2256
0.798
0.7
0.91
0.0007
2003
0.0299
1.03
0.908
1.17
0.6436
2004
-0.3661
0.693
0.612
0.786
<.0001
2005
-0.6884
0.502
0.444
0.569
<.0001
2006
-0.8734
0.418
0.369
0.472
<.0001
2007
-0.8055
0.447
0.396
0.505
<.0001
2008
-1.0709
0.343
0.304
0.387
<.0001
2009
-1.3696
0.254
0.225
0.287
<.0001
2010
Month of Index Date
1
January
-0.3043
0.738
0.679
0.801
<.0001
February
-0.3625
0.696
0.642
0.755
<.0001
March
-0.054
0.947
0.872
1.029
0.2002
April
-0.1863
0.83
0.764
0.901
<.0001
May
-0.0868
0.917
0.842
0.998
0.0444
June
-0.2903
0.748
0.689
0.813
<.0001
July
-0.2382
0.788
0.727
0.854
<.0001
August
0.0647
1.067
0.984
1.157
0.1185
September
-0.3223
0.724
0.668
0.786
<.0001
October
-0.3213
0.725
0.668
0.787
<.0001
November
-0.2795
0.756
0.697
0.821
<.0001
December
-0.1752
0.839
0.81
0.869
<.0001
Male
0.0117
1.012
1.011
1.012
<.0001
The duration of diabetes mellitus
Monthly income
1
Dependent
0.1021
1.107
1.058
1.159
<.0001
NT 0–19,100
-0.0886
0.915
0.879
0.953
<.0001
NT 19,100–42,000
-0.7264
0.484
0.432
0.541
<.0001
>NT 42,000
a
Urbanization level
1
1
0.164
1.178
1.135
1.223
<.0001
2
0.2328
1.262
1.169
1.363
<.0001
3
0.3347
1.398
1.197
1.632
<.0001
4
Outpatient Visits of Metabolism
&Endocrinology, in the past one
year
05 visits
610 visits
1115 visits
>15 visits
Outpatient Visits of Nephrologist, in
the past one year
05 visits
610 visits
1115 visits
>15 visits
Charlson comorbidity index scoreb
1
2
3
4
Adapted Diabetes Complications
Severity Indexscorec (SD)
Anti-diabetic drugs
Acarbose inhibits enzymes
Sulfonylurea
Insulin
Metformin
Thiazolidinediones
Glinide
Dipeptidyl peptidase-4 inhibitor
Anti-hypertensive drug
Alpha-blocker
Beta-blocker
Calcium channel blocker
Diuretics
ACE inhibitors or ARB
Other anti-hypertensive drug
Other concomitant medications
Antiplatelet agentd
Steroid
Nitrate
NSAID
PPI
Statin
SSRI
0.0841
-0.1094
0.06
1
1.088
0.896
1.062
1.026
0.815
0.934
1.153
0.986
1.207
0.0048
0.0248
0.3572
0.2034
-0.0328
0.0569
1
1.226
0.968
1.059
1.159
0.843
0.899
1.296
1.111
1.246
<.0001
0.642
0.4946
0.0853
0.2186
0.4518
1
1.089
1.244
1.571
1.01
1.154
1.453
1.174
1.341
1.699
0.0267
<.0001
<.0001
0.2556
1.291
1.276
1.306
<.0001
0.2734
0.5888
1.9072
0.7082
0.4978
0.6379
0.2168
1.314
1.802
6.734
2.03
1.645
1.893
1.242
1.222
1.731
6.312
1.953
1.538
1.745
1.067
1.414
1.876
7.184
2.111
1.76
2.052
1.446
<.0001
<.0001
<.0001
<.0001
<.0001
<.0001
0.0052
0.0743
0.0173
-0.0294
0.3313
0.1208
0.3479
1.077
1.017
0.971
1.393
1.128
1.416
0.982
0.971
0.933
1.33
1.083
1.264
1.181
1.067
1.011
1.459
1.175
1.587
0.1144
0.4724
0.1484
<.0001
<.0001
<.0001
-0.0203
0.3182
0.1065
0.3363
0.7351
-0.1938
0.3909
0.98
1.375
1.112
1.4
2.086
0.824
1.478
0.938
1.296
1.037
1.344
1.922
0.784
1.315
1.024
1.458
1.194
1.458
2.264
0.866
1.662
0.3675
<.0001
0.0031
<.0001
<.0001
<.0001
<.0001
Comorbidities
-0.3218
0.725
0.696
0.755
<.0001
Coronary artery disease
0.0321
1.033
0.985
1.083
0.1874
Hypertension
-0.2236
0.8
0.759
0.842
<.0001
Heart failure
-0.2019
0.817
0.765
0.873
<.0001
Peripheral vascular disease
-0.0132
0.987
0.95
1.025
0.4984
Peptic ulcer disease
-0.0726
0.93
0.895
0.966
0.0002
Liver disease
-0.0145
0.986
0.916
1.061
0.6994
Atrial fibrillation
-0.2445
0.783
0.755
0.813
<.0001
Dyslipidemia
0.0477
1.049
1.003
1.097
0.0361
Cerebrovascular disease
-0.0367
0.964
0.911
1.02
0.2005
Valvular heart disease
-0.00013
1
0.951
1.051
0.9958
Cancer
-0.1604
0.852
0.78
0.93
0.0003
Autoimmune disease
Abbreviations: CI, confidence interval; NT$, new Taiwan dollars;
ACE,angiotensin-converting-enzyme; ARB,Angiotensin II receptor blockers; NSAIDs,
Non-steroidal anti-inflammatory drugs; PPI, proton pump inhibitors; SSRI, Selective serotonin
re-uptake inhibitors.
aUrbanization levels in Taiwan are divided into four strata according to the Taiwan National
Health Research Institute publications. Level 1 designates the most urbanized areas, and level 4
designates the least urbanized areas.
bCharlson Comorbidity Index (CCI) score is used to determine overall systemic health. With
each increased level of CCI score, there are stepwise increases in the cumulative mortality.
cAdapted Diabetes Complications Severity Index is a 13-point scale from 7 complication
categories: retinopathy, nephropathy, neuropathy, cerebrovascular, cardiovascular, peripheral
vascular disease, and metabolic, ranging from each complication. Each complication produced a
numeric score ranging from 0 to 2 (0 = no abnormality, 1 = some abnormality, 2 = severe
abnormality).
d
Including aspirin, clopidogrel, ticlopidine and cilostazol
Supplementary Table 2. Baseline Characteristics of Diabetes Patients Before Propensity
Score-Matching
Before Propensity Score-Matching
Hypoglycemic
Non-hypoglycemic
p
Characteristics
cohort
cohort
Value
15,049
889,673
Patient (no.)
42.6 (34.8)
30.0 (28.7)
<0.001
Mean age (SD), year
7,121 (47.3)
465,143 (52.3)
<0.001
Male, n(%)
<0.001
Monthly income, NT$, n(%)
5,224 (34.7)
237,809 (26.7)
Dependent
3,675 (24.4)
182,844 (20.6)
<19,100
5,797 (38.5)
385,664 (43.3)
19,10041,999
353 (2.3)
83,356 (9.4)
42,000
a
<0.001
Urbanization , n(%)
4,553 (30.3)
325,522 (36.6)
Level 1
9,457 (62.8)
515,926 (58.0)
Level 2
855 (5.7)
40,579 (4.6)
Level 3
184 (1.2)
7,646 (0.9)
Level 4 (rural area)
Outpatient Visits of Metabolism &Endocrinology, in
<0.001
the past one year, n(%)
12,869 (85.5)
789,925 (88.8)
05 visits,
1,402 (9.3)
69,968 (7.9)
610 visits
498 (3.3)
21,791 (2.4)
1115 visits
280 (1.9)
7,989 (0.9)
>15 visits
Adapted Diabetes Complications Severity Index
3 (1-5)
1 (0-2)
<0.001
scored (IQR)
<0.001
Charlson Comorbidity Index Scorec, n(%)
1,191 (7.9)
172,665 (19.4)
1
1,854 (12.3)
209,933 (23.6)
2
2,439 (16.2)
189,960 (21.4)
3
9,565 (63.6)
317,115 (35.6)
4
Duration of diagnosis of diabetes, months, median
(IQR)
Anti-diabetic drugs, n(%)
<0.001
959 (6.4)
24,147 (2.7)
Acarbose inhibits enzymes
<0.001
4,721 (31.4)
130,153 (14.6)
Sulfonylurea
<0.001
1,504 (10.0)
9,489 (1.1)
Insulin
<0.001
6,939 (46.1)
225,681 (25.4)
Metformin
<0.001
1,178 (7.8)
24,055 (2.7)
Thiazolidinediones
<0.001
769 (5.1)
15,359 (1.7)
Glinide
<0.001
210 (1.4)
6,023 (0.7)
Dipeptidyl peptidase-4 inhibitor
Anti-hypertensive drug, n(%)
<0.001
551 (3.7)
15,861 (1.8)
Alpha-blocker
<0.001
2,491 (16.6)
109,179 (12.3)
Beta-blocker
<0.001
4,838 (32.1)
184,001 (20.7)
Calcium channel blocker
<0.001
2,920 (19.4)
68,355 (7.7)
Diuretics
<0.001
4,969 (33.0)
163,674 (18.4)
ACE inhibitors or ARB
<0.001
345 (2.3)
9,615 (1.1)
Other anti-hypertensive drug
Other concomitant medications, n(%)
<0.001
3,804 (25.3)
112,776 (12.7)
Antiplatelet agent d
<0.001
1,448 (9.6)
44,983 (5.1)
Steroid
<0.001
1,116 (7.4)
24,257 (2.7)
Nitrate
<0.001
3,543 (23.5)
142,673 (16.0)
NSAID
<0.001
755 (5.0)
16,354 (1.8)
PPI
<0.001
1,713 (11.4)
91,224 (10.3)
Statin
<0.001
330 (2.2)
10,325 (1.2)
SSRI
Comorbidities, n(%)
<0.001
6,799 (45.2)
270,102 (30.4)
Coronary artery disease
<0.001
11,789 (78.3)
540,035 (60.7)
Hypertension
<0.001
3,038 (20.2)
72,452 (8.1)
Heart failure
<0.001
1,198 (8.0)
36,777 (4.1)
Peripheral vascular disease
<0.001
8,016 (53.3)
383,523 (43.1)
Peptic ulcer disease
<0.001
5,332 (35.4)
322,579 (36.3)
Liver disease
<0.001
1,001 (6.7)
21,044 (2.4)
Atrial fibrillation
<0.001
8,014 (53.3)
494,887 (55.6)
Dyslipidemia
<0.001
6,400 (42.5)
170,851 (19.2)
Cerebrovascular disease
<0.001
1,758 (11.7)
69,282 (7.8)
Valvular heart disease
<0.001
2,210 (14.7)
90,350 (10.2)
Cancer
0.067
574 (3.8)
31,455 (3.5)
Autoimmune disease
0.08 (0.02-0.09)
0.01 (0.003-0.016) <0.001
Propensity score, median (IQR)
* All data were descripted as number (%), except mean age and propensity score.
Abbreviations: SD, standard deviation; NT$, new Taiwan dollars; ACE,angiotensin-converting-enzyme;
ARB,Angiotensin II receptor blockers; NSAIDs, Non-steroidal anti-inflammatory drugs; PPI, proton pump
inhibitors; SSRI, Selective serotonin re-uptake inhibitors.
aUrbanization levels in Taiwan are divided into four strata according to the Taiwan National Health Research
Institute publications. Level 1 designates the most urbanized areas, and level 4 designates the least urbanized
areas.
bCharlson Comorbidity Index (CCI) score is used to determine overall systemic health. With each increased
level of CCI score, there are stepwise increases in the cumulative mortality.
c
Adapted Diabetes Complications Severity Index is a 13-point scale from 7 complication categories:
retinopathy, nephropathy, neuropathy, cerebrovascular, cardiovascular, peripheral vascular disease, and
metabolic, ranging from each complication. Each complication produced a numeric score ranging from 0 to 2
(0 = no abnormality, 1 = some abnormality, 2 = severe abnormality).
d Including aspirin, clopidogrel, ticlopidine and cilostazol
Supplementary Table 3. Incidence and Risk of Chronic Kidney Disease Among Diabetes Patients With
HypoglycemiaBefore Propensity Score Matching.
Crude
No. of
Incidence
Hazard Ratio
Haz
Person-years
PValue
Event
rate*
(95% CI)
(9
30,424
3,860,042
7.88
As Reference
Non-hypoglycemic cohort
1,499
57,308
26.14
3.34 (3.17-3.51)
<0.001 2.09
Hypoglycemic cohort
3
* per 10 person-years.
aAdjusted for propensity score
Abbreviations: CI, confidence interval.
Supplementary Table 4. Association Between HypoglycemiaEpisode and Risk of Chronic Kidney Diseas
Diagnosed Diabetes Patients Without Chronic Kidney Disease Between 2000 and 2010
Crude
No. of
Incidence
Hazard Ratio
Haz
Person-years
P Value
Event
rate*
(95% CI)
(9
48,358
6,913,265
7.00
As Reference
Non-hypoglycemic
b
Hypoglycemic episode
3,126
78,671
39.74
4.92 (4.74-5.11)
<0.001 3.27
3
* per 10 person-years.
a
Adjusted for all-covariate listed in Table 1.
b
All hypoglycemic episodes occurred between 2000 and 2011 were identified and were calculated as time-de
Abbreviations: CI, confidence interval.