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Risk and Preventive Medication of Acute Pancreatitis in Patients with Type 2 Diabetes Mellitus in Taiwan: A
Population-based Cohort Study
Journal: American Journal of Gastroenterology Manuscript ID: AJG-10-2337
Manuscript Type: Original Contributions Keywords: Pancreas, Diabetes Manuscript Section: Pancreatic
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• Type of manuscript:Original clinical study
• Manuscript title: Risk and Preventive Medication of Acute Pancreatitis in Patients with Type 2 Diabetes Mellitus in Taiwan: A Population-based Cohort Study
Shih-Wei Lai, M.D.1; Chih-Hsin Muo, MS2; Kuan-Fu Liao, M.D.3; Fung-Chang Sung, Ph.D., MPH2; Pei-Chun Chen, Ph.D., MSPH2;
Running head:Acute pancreatitis and Type 2 diabetes mellitus
Current Author Addresses:
1Department of Family Medicine, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung city, 404, Taiwan
2Department of Public Health and Management Office for Health Data, China Medical University, No. 91, Hsueh-Shih Road, Taichung city, 404, Taiwan
3Department of Internal Medicine, Taichung Tzu Chi General Hospital, No.66, Sec. 1, Fongsing Rd., Tanzih Township, Taichung County, 427, Taiwan
Corresponding author:
Pei-Chun Chen, Ph.D., MSPH Assistant Professor
Department of Public Health
China Medical University College of Public Health No.91, Hsueh-Shih Road, Taichung city, 404, Taiwan Phone: 886-4-2205-3366 ext 2119; fax: 886-4-2205-4070 E-mail: peichun@mail.cmu.edu.tw
Word count: 249 in abstract, 2163 in text, 4 tables, 1 figure and 19 references
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Study Highlights
Type 2 DM increases the risk of acute pancreatitis. Anti-diabetic drugs can reduce the risk.
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Abstract
Objectives. To assess the risk and preventive medication of acute pancreatitis for
patients with Type 2 diabetes mellitus (DM).
Methods. From the claims data of one million randomly sampled from 23 million enrollees of
the Taiwan National Health Insurance, we identified 19,518 adult patients with newly diagnosed
Type 2 DM in 2000–2005. We also identified 78,072 patients without the disease, frequency
matched with sex and age during the same period as controls. Both groups were followed up until
the end of 2008 to measure the incidences of acute pancreatitis and the effectiveness of
anti-diabetes medication in reducing the risk.
Results. Both cohorts were similar in sex and age distributions. Patients with Type 2
DM had an incidence rate of acute pancreatitis 1.95-fold greater than non-diabetics
(27.7 vs. 14.2 per 10,000 person-years). Results of the multivariable Cox model
analysis showed a slightly decreased hazard ratio (HR) of 1.89 (95% confidence
interval (CI) = 1.65–2.18). Alcoholism (HR = 6.92, 95% CI = 3.28–14.6), gallstones
(HR = 2.52, 95% CI = 1.35–4.72), and hepatitis C infection (HR = 3.35, 95% CI =
1.72–6.52) were also significant factors predicting acute pancreatitis. Patients taking
biguanides, sulfonylureas, thiazolidinediones, or alpha-glucosidase inhibitors were
benefited with 37% to 56% of risk reduction of the disease.
Conclusions. There is a higher risk of acute pancreatitis in patients with Type 2 DM
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in Taiwan. Alcoholism, gallstones, and hepatitis C infection are the other risk factors
for the disease. Anti-diabetic drugs can reduce the risk.
Key words: acute pancreatitis; alcoholism; gallstones; Type 2 diabetes mellitus
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Introduction
Acute pancreatitis is a condition of pancreatic inflammation with varied incidence
among populations. In a systematic review, Yadav et al. [1] found that the annual
incidence of acute pancreatitis ranged 4.2–45.3 per 100,000 in Europeans from
1966–2005. The annual incidence in California increased from 33.2 per 100,000 in
1994 to 43.8 per 100,000 in 2001 [2]. Fagenholz et al. [3] found that the
hospitalization rate for acute pancreatitis in the US increased from 40 per 100,000 in
1988 to 70 per 100,000 in 2003. Clinically, acute pancreatitis is often associated with
significant co-morbidity and substantial mortality rates. The overall fatality of the
disease ranges approximately from 2%–5% [3–5].
The etiology of acute pancreatitis is undoubtedly multifactorial. Extant
epidemiological studies have shown that gallstones, hypertriglyceridemia, obesity,
viral hepatitis, and lifestyle are significant factors associated with acute pancreatitis
[6–9]. Two large cohort studies have demonstrated that patients with Type 2 diabetes
mellitus (DM) are at a higher risk for acute pancreatitis [9,10]. The retrospective
cohort analysis of the US claims data found a 2.83-fold greater risk of acute
pancreatitis for Type 2 DM patients than non-DM persons [10]. The analysis of the
UK General Practice Research Database also showed a 1.49-fold increased risk for
Type 2 DM patients [9]; however, both cohort studies were limited to Western
populations and had no data on preventive measures.
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The prevalence of DM in Taiwan was approximately 8.2%–11.4% in 1986–2002
[11–13]. Since 2009, the disease has become the fifth leading cause of death [14]. No
cohort study has explored the association between acute pancreatitis and Type 2 DM
in Asian populations. Assessment of this association requires a large population size.
We took the advantage of a large dataset available from the National Health Insurance
(NHI) program in Taiwan to conduct a follow-up assessment of this association. We
estimated the incidence of acute pancreatitis among patients with Type 2 DM relative
to a population without diabetes. We also characterized other risk factors associated
with acute pancreatitis, and investigated whether anti-diabetic drugs are beneficial in
reducing risk.
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Materials and Methods
Data sources
The NHI program was reformed from 13 insurance-related systems of Taiwan in
March 1995. By the end of 2008, this insurance program covered more than 99% of
the entire population of Taiwan (23 million) [15]. We obtained a dataset of
reimbursement claims from the National Health Research Institutes (NHRI), which
manages the NHI databank. The dataset represented the registry of a randomly
sampled cohort of one million people enrolled in the NHI system with claims from
1996–2008. This dataset included information on ambulatory cares, in-patient care,
dental services, prescription drugs, medical institutions, physicians, and registration
entries, with individual personal identification coded for public access. Limited data
on personal socio-demographic status, such as sex, birth date, affiliation to insured
occupational group, income level for insurance fee estimate, and residential area, were
also available.
Criteria and definition
The criteria of diseases were defined according to the International Classification of
Diseases 9th Revision, Clinical Modification (ICD-9-CM). We used a retrospective
cohort design to identify patients aged 20 and older newly diagnosed with Type 2 DM
(ICD-9 codes 250 x 0 or 250 x 2) and currently using anti-diabetic drugs in
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2000–2005. The anti-diabetes drugs included biguanides, sulfonylureas,
thiazolidinediones, alpha-glucosidase inhibitors, D-phenylalanine derivatives,
dipeptidyl peptidase 4 inhibitors, incretin mimetic agents, and insulin. For each DM
case, we randomly selected four persons without medical claims for diabetes
frequency matching with age (every five-year span) and sex in the same time period.
Patients with known history of pancreatic cancer, chronic pancreatitis, Type 1 DM,
and gestational diabetes were excluded from this study. To measure the incidence of
acute pancreatitis (ICD-9 codes 577.0), both Type 2 diabetic and non-diabetic cohorts
were followed up until the end of 2008, or were censored because of death or
withdrawal from the insurance program. The entry study index date for a study
subject was defined by the date the individual was identified from the claims data.
Statistical analysis
We estimated the incidence rate as the number of acute pancreatitis identified and
divided by the total follow-up person-years for each cohort by sex, specific age, and
follow-up years. Cox proportional hazard analysis was used to estimate the hazard
ratio (HR) of acute pancreatitis and 95% confidence intervals (CI) for patients with
Type 2 DM compared with non-DM people. Univariate and multivariate models were
used to assess the risk levels associated with demographic factors and co-morbidities
identified in the baseline. The potential co-morbidities included obesity,
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hypertriglyceridemia, alcoholism, gallstones, hepatitis B infection, and hepatitis C
infection. Data analyses also compared the risk of acute pancreatitis associated with
anti-diabetes medication. The statistical significance level was set at two-sided
probability value of < 0.05. All analyses used the SAS software version 9.1 (SAS
Institute Inc., Cary, North Carolina).
Ethical considerations
All individual personal data in the insurance reimbursement claims data were
scrambled to secure patient privacy for public access. This study was exempted from
a full review by the Institution Review Board.
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Results
Baseline characteristics of the study population
Eligible study subjects consisted of 19,518 patients in Type 2 diabetic cohort and
78,072 persons in non-diabetic cohort, with similar sex and age distributions and
mean ages of 56.7 years (Table 1). The Type 2 diabetic cohort had higher prevalence
of obesity, hypertriglyceridemia, alcoholism, gallstones, hepatitis B, and hepatitis C
infections at the baseline (P < 0.0001).
During the follow-up period, the incidence of acute pancreatitis was 1.95-fold greater
in Type 2 diabetic cohort than in non-diabetic cohort (27.7 vs. 14.2 per 10,000
person-years), with the adjusted HR decreased slightly to 1.89 (Table 2). The
sex-specific hazard ratio (HR) shows that men were at higher risk than women. The
age-specific HR was higher in Type 2 diabetic subjects aged 20–39 years (HR = 5.48,
95% CI = 3.64–8.25), followed by aged 40–64 (HR = 2.02, 95% CI = 1.66–2.45), and
aged 65 years and older (HR = 1.34, 95% CI = 1.05–1.71), compared with
non-diabetic age-matched group. The risk of acute pancreatitis was higher in patients
with a diabetic duration of more than five years (HR = 2.40, 95% CI = 1.78–3.25).
The cumulative incidence of acute pancreatitis was twofold higher in diabetic patients
than the non-diabetic group during the entire follow-up period, and the difference
increased with follow-up time (Figure 1).
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Co-morbidity and acute pancreatitis by univariate and multivariate Cox
proportional hazard analysis
Adjusted hazard ratios and 95% confidence intervals of acute pancreatitis associated
with Type 2 DM and co-morbidities are shown in Table 3. The age- and sex-adjusted
HR of acute pancreatitis for patients with Type 2 DM was reduced slightly to 1.89
(95% CI = 1.65–2.18). Hyperlipidemia, alcoholism, gallstones and hepatitis C
infection were identified as co-morbidities independently associated with acute
pancreatitis. The risk increased further for the diabetic patients with alcoholism (HR =
6.92, 95% CI = 3.28–14.6) and hepatitis C infection (HR = 3.35, 95% CI = 1.72–6.52),
but not hyperlipidemia and gallstones.
Influence of anti-diabetic drugs on the risk of acute pancreatitis
Table 4 shows the effectiveness of taking anti-diabetic drugs in reducing the risk of
acute pancreatitis. Controlling for sex, age, and co-morbidities, the results show that
HR of developing acute pancreatitis were 0.46 (95% CI = 0.35–0.61) for those taking
biguanides, 0.63 (95% CI = 0.47–0.83) for sulfonylureas, 0.63 (95% CI = 0.46–0.87)
for thiazolidinediones, and 0.44 (95% CI = 0.31–0.62) for alpha-glucosidase
inhibitors. The beneficial effect of using insulin was not statistically significant (HR =
0.81, 95% CI = 0.64–1.02).
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Discussion
Though not utterly novel, to the best of our knowledge, this is the first
population-based cohort study that simultaneously determines the risk of developing
acute pancreatitis and the effectiveness of anti-diabetic medication in reducing the
risk for diabetic patients in Taiwan. In the present study, the incidence of acute
pancreatitis in Type 2 diabetic cohort was approximately two-fold greater than that in
non-diabetic cohort, a moderate risk consistent with previous studies [9-10]. The
incidence of acute pancreatitis measured by sex and age was consistently higher in
patients with Type 2 DM. The age-specific incidence also showed that Type 2
diabetic patients 20–39 years of age had the highest incidence rate ratio compared to
non-diabetics, which was consistent with the finding of Noel et al. [10]. This indicates
that the risk of acute pancreatitis is relatively great for young patients of DM.
The risk of developing acute pancreatitis in patients with Type 2 DM varied
moderately among studies. The multivariate Cox model analysis in this study
measured an adjusted HR slightly higher than the finding of 1.49-fold in the UK
General Practice Research Database (GPRD) study [9]; however, it was lower than
the HR of 2.83 in the study using a US insurance claims database [10]. Although the
biological mechanism between Type 2 DM and acute pancreatitis could not be proven
from this observational study, these cohort studies suggest that patients with Type 2
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We also found that patients with both DM and hepatitis C infection were at higher
risk to develop acute pancreatitis. A previous study has reported that patients with
acute hepatitis A, B, and E infections are at higher risk of acute pancreatitis [8],
without mentioning the risk for hepatitis C. Some case reports have shown that
interferon therapy in patients with chronic hepatitis C infection can induce acute
pancreatitis [16, 17]. In this study, 50 patients with chronic hepatitis C infection
received interferon therapy; however, no patient developed acute pancreatitis during
the follow-up period (data not shown). Because there was no data of hepatitis C RNA
in this dataset, we cannot posit a plausible biological explanation for why patients
with hepatitis C infection are at an elevated risk of acute pancreatitis. However, our
data show that patients having both hepatitis C and Type 2 diabetes at a higher risk of
acute pancreatitis.
Epidemiological studies have consistently reported the association between acute
pancreatitis with other co-morbidities, particularly gallstones and alcohol
consumption [6, 7]. Our study also demonstrates the evidence of a slight additional
effect from diabetes to those with co-morbidity of alcoholism, with an HR increase
from 6.05 to 6.92. This indicates that alcoholism has a greater influence than Type 2
diabetes in the risk of developing acute pancreatitis. No such additional effects were
evident in patients with both gallstones and diabetes.
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In further analysis, we found that patients using biguanides, sulfonylureas,
thiazolidinediones, or alpha-glucosidase inhibitors had 37%–56% reduction of acute
pancreatitis risk. Using insulin decreased risk of developing acute pancreatitis;
however, the association was not statistically significant. Gonzalez-Perez et al. found
that diabetic patients had decreased risks of developing acute pancreatitis using
insulin [odds ratio (OR) = 0.34, 95% CI = 0.13–0.91] or long-term (more than 3 years)
use of metformin (OR = 0.5, 95% CI = 0.28–0.91) [18]. In contrast, Gonzalez-Perez
et al. also found patients taking sulfonylureas for more than 3 years were at higher
risk (OR) = 1.66, 95% CI = 1.01–2.74) [18]. Because of lack of prospective studies,
we cannot posit any further explanation regarding the relation of anti-diabetic drugs to
the risk of acute pancreatitis. Further studies are required to explore the implication of
anti-diabetic drugs on acute pancreatitis.
Our study has several strengths. This study was based on a Taiwan
population-based study with a large sample size and with an increased statistical
power testing significant. The representative large sample size increased the validity
of identifying rare diseases such as acute pancreatitis for this study.
The limitations in the present study should be noted. A number of suspected risk
factors of acute pancreatitis, such as cigarette smoke, were not available. This was due
to the inherent limitation of insurance dataset. However, women in Taiwan rarely
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smoke, and account for less than 5% of the smokers [19]. Smoking is not likely an
important risk factor associated with acute pancreatitis because the risk difference
between men and women in this study is small.
Conclusion
Patients with Type 2 diabetes mellitus are at an elevated risk of acute pancreatitis,
and the risk is relatively greater for young patients. Patients infected with hepatitis C
and who suffer from alcoholism may be at additional risk. In contrast, we have also
found that anti-diabetic drugs demonstrate an effective mechanism of reducing the
risk of acute pancreatitis, particularly for those taking biguanides, sulfonylureas,
thiazolidinediones, or alpha-glucosidase inhibitors.
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Funding
This study was supported in part by grants of the Department of Health, Taiwan
(DOH 97-HP-1101, 2008-2010), Clinical Trial and Research Center of Excellence
(DOH99-TD-B-111-004) and Cancer Research Center of Excellence
(DOH99-TD-C-111-005), the National Science Council (NSC 98-2621-M-039 -001)
and the China Medical University Hospital (1MS1). The funding agencies had no role
in the study design, data collection and analysis, decision to publish, or preparation of
the manuscript.
Acknowledgement
The authors thank the National Health Research Institute in Taiwan for providing us
the insurance claims data.
Conflict of Interest Statement
The authors disclose no conflicts of interest.
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References
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3. Fagenholz PJ, Castillo CF, Harris NS, Pelletier AJ, Camargo CA Jr.
Increasing United States hospital admissions for acute pancreatitis, 1988-2003.
Ann Epidemiol. 2007;17(7):491-7.
4. Lowenfels AB, Maisonneuve P, Sullivan T. The changing character of acute pancreatitis: epidemiology, etiology, and prognosis. Curr Gastroenterol Rep.
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12. Chou P, Chen HH, Hsiao KJ. Community-based epidemiological study on diabetes in Pu-Li, Taiwan. Diabetes Care 1992;15:81-9.
13. Lai SW, Ng KC. Descriptive Analysis of Diabetes Mellitus in Patients Receiving Health Checkups—A Hospital-based Study. Changhua J Med.
2004;9(Suppl ):267-71.
14. Department of Health, Taiwan: Main Causes of Death in 2009 [cited 2010
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September 1]. Available from URL:
http://www.doh.gov.tw/CHT2006/DM/DM2_2.aspx?now_fod_list_no=11122&c lass_no=440&level_no=3
15. Bureau of National Health Insurance, Department of Health, Taiwan. [cited 2010 September]
http://www.nhi.gov.tw/webdata/AttachFiles/Attach_14258_2_97-ch.pdf
16. Eland IA, Rasch MC, Sturkenboom MJ, Bekkering FC, Brouwer JT, Delwaide J, Belaiche J, Houbiers G, Stricker BH. Acute pancreatitis attributed to the use of interferon alfa-2b. Gastroenterology. 2000;119(1):230-3.
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Acute pancreatitis associated with interferon and ribavirin therapy in patients with chronic hepatitis C. Dig Dis Sci. 2004;49(6):1000-6.
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1
Table 1. Baseline characteristics between Type 2 diabetic cohort and non-diabetic cohort identified in 2000–2005
Type 2 diabetes No
N=78,072
Yes N=19,518
N % n % P value*
Sex 1.00
Women 35,092 (45.0) 8,773 (45.0) Men 42,980 (55.0) 10,745 (55.0)
Age group (years) 1.00
20–39 7,772 (10.0) 1,943 (10.0) 40–64 48,012 (61.4) 12,003 (61.4)
≥65 22,288 (28.6) 5,572 (28.6)
Mean (SD) (years) 56.7 (13.7) 56.8 (13.3) 0.80 Baseline co-morbidity
Obesity 402 (0.5) 505 (2.6) <0.0001 Hypertriglyceridemia 441 (0.6) 421 (2.2) <0.0001 Alcoholism 404 (0.5) 158 (0.8) <0.0001 Gallstones 1,525 (2.0) 511 (2.6) <0.0001 Hepatitis B 1,509 (1.9) 508 (2.6) <0.0001 Hepatitis C 859 (1.1) 328 (1.7) <0.0001
*Chi-square test comparing patients with and without Type 2 diabetes.
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Table 2. Incidence density of acute pancreatitis estimated by sex, age, and follow-up years for Type 2 diabetic and non-diabetic cohorts identified in 2000–2005
Non-diabetes Type 2 diabetes N Cases Person-
years
Incidence† N Cases Person- years
Incidence † HR (95% CI)
All 78,072 621 436,653 14.2 19,518 295 106,512 27.7 1.95 (1.70–2.24) Sex
Women 35,092 258 198,319 13.0 8,773 121 48,534 24.9 1.92 (1.54–2.38) Men 42,980 363 238,334 15.2 10,745 174 57,978 30.0 1.97 (1.65–2.36) Age, years
20–39 7,772 40 44,678 8.95 1,943 54 10,996 49.1 5.48 (3.64–8.25) 40–64 48,012 314 276,147 11.4 12,003 155 67,605 22.9 2.02 (1.66–2.45)
≥ 65 22,288 267 115,827 23.1 5,572 86 27,911 30.8 1.34 (1.05–1.71) Follow-up
<1 years 78,072 104 77,332 13.5 19,518 46 19,205 24.0 1.78 (1.26–2.52) 1 76,607 113 75,890 14.9 18,931 54 18,685 28.9 1.94 (1.40–2.68) 2 75,202 98 74,490 13.2 18,464 47 18,261 25.7 1.96 (1.38–2.77) 3 73,744 100 66,893 15.0 18,031 43 16,295 26.4 1.77 (1.24–2.52) 4 60,304 89 53,131 16.8 14,645 38 12,884 29.5 1.76 (1.20–2.57)
≥ 5 46,381 117 88,916 13.2 11,212 67 21,182 31.6 2.40 (1.78–3.25)
† Incidence rate: per 10,000 person-years.
HR (hazard ratio): Type 2 diabetes vs. non-diabetes (95% CI) Cases of outpatient services for acute pancreatitis.
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Table 3. Interaction effect on acute pancreatitis between diabetes and co-morbidities
Non-diabetes Type 2 diabetes
Cases Incidence† HR (95% CI) Cases Incidence† Adjusted HR
(95% CI)
All 621 14.2 1.00 (reference) 295 27.7 1.89 (1.65–2.18)
Hypertriglyceridemia
No 612 14.1 1.00 (reference) 290 27.8 1.93 (1.68–2.22)
Yes 9 39.0 2.39 (1.24–4.62) 5 22.1 1.45 (0.60–3.49)
Alcoholism
No 606 13.9 1.00 (reference) 288 27.2 1.92 (1.67–2.21)
Yes 15 80.5 6.05 (3.62–10.1) 7 96.0 6.92 (3.28–14.6)
Gallstones
No 577 13.4 1.00 (reference) 285 27.4 2.01 (1.74–2.32)
Yes 44 58.2 3.78 (2.77–5.15) 10 40.2 2.52 (1.35–4.72)
Hepatitis C
No 607 14.0 1.00 (reference) 286 27.2 1.90 (1.65–2.19)
Yes 14 34.7 2.03 (1.18–3.47) 9 59.3 3.35 (1.72–6.52)
† Incidence: per 10,000 person-years.
HR: adjusted for age, sex and co-morbidities.
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Table 4. Cox model measured hazard ratios and 95% confidence intervals of acute pancreatitis associated with anti-diabetic drugs identified in 2000–2005
N Case Person-year Incidence† Crude HR
(95% CI) Adjusted HR
(95% CI)
Insulin
Non-use 7,892 124 39,770 31.2 1.00 (reference) 1.00 (reference) Use 11,626 171 66,741 25.6 0.81 (0.64–1.02) 0.81 (0.64–1.02) Biguanide
Non-use 3,161 73 14,488 50.4 1.00 (reference) 1.00 (reference) Use 16,357 222 92,023 24.1 0.47 (0.36–0.62) 0.46 (0.35–0.61) Sulfonylurea
Non-use 3,348 62 15,403 33.8 1.00 (reference) 1.00 (reference) Use 16,170 233 91,109 25.6 0.62 (0.47–0.83) 0.63 (0.47–0.83) Thiazolidinedione
Non-use 15,721 250 83,143 30.1 1.00 (reference) 1.00 (reference) Use 3,797 45 23,368 19.3 0.63 (0.46–0.87) 0.63 (0.46–0.87) Alpha-glucosidase
inhibitor
Non-use 15,098 257 80,072 32.1 1.00 (reference) 1.00 (reference) Use 4,420 38 26,440 14.4 0.44 (0.32–0.62) 0.44 (0.31–0.62) Adjusted HR: adjusted for age, sex, and co-morbidities.
† Incidence: per 10,000 person-years.