Risk of esophagus cancer in diabetes mellitus: A population-based case-control study in Taiwan

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 Type of manuscript: Original study

Old Title: Esophagus cancer and diabetes mellitus: A population-based case- control study in Taiwan (Revision 2)

New Title: Risk of esophagus cancer in diabetes mellitus: A population-based case-control study in Taiwan

Running head: Esophagus cancer and diabetes mellitus

Kao-Chi Cheng, MD and MPH

; Yu-Lung Chen, MD and MPH

; Shih-Wei Lai, MD

; Pang-Yao Tsai, MSPH

; Fung-Chang Sung, PhD and MPH

1

Department of Family Medicine and

Management Office for Health Data, China Medical University Hospital, Taichung 404, Taiwan

2

School of Medicine and

Department of Public Health, China Medical University, Taichung 404, Taiwan

Corresponding author:

Fung-Chang Sung, PhD, MPH Professor

China Medical University College of Public Health 91 Hsueh-Shih Road, Taichung 404, Taiwan Phone: 886-4-2206-2295; fax: 886-4-2201-9901 e-mail: fcsung1008@yahoo.com

Word counts: 196 in abstract, 2120 in text; 4 tables and 49 references

ABSTRACT

Background: Diabetes mellitus (DM) has been associated with the cancer risk. This study investigated relationship between DM and esophageal cancer using Taiwan’s

insurance data.

Methods: We identified 549 patients with esophageal cancer newly diagnosed in 2000-2009 and randomly selected 2196 controls without any cancer, frequency matched by sex, age and diagnosis year of cases. Logistic regression model estimated odds ratios (ORs) and 95% confidence intervals (CI) of esophageal cancer associated

with DM, sex, age. co-morbidities and medications.

Results: Cases were more prevalent than controls for alcoholism and esophageal disorders and using nonsteroidal anti-inflammatory drugs (NSAIDs) and

cyclooxygenase-2 inhibitors but not DM. Esophageal cancer had no association with DM (OR 0.99, 95% CI 0.71-1.37), but significantly associated with alcoholism (OR 14.1, 95% CI 7.87-25.4), esophageal ulcer (OR 10.1, 95% CI 5.70-17.9), esophageal reflux (OR 3.47, 95% CI 2.14-5.26) and uses of NSAIDs (OR 2.73, 95% CI 1.80- 4.13). An elevated risk of esophageal cancer appeared in DM patients taking insulin

(OR 2.57, 95% CI 1.08-6.15) or sulfonyurea (OR 3.80, 95% CI 1.16-12.5).

Conclusions: Patients with DM are not at higher risk for esophagus cancer. However,

esophageal disorders and anti-diabetic drugs are associated with the risk of the

disease.

Keywords: case-control study, diabetes, esophagus cancer, insulin.

INTRODUCTION

Glucose metabolism disorders (GMDs) such as diabetes mellitus (DM), impaired fasting glucose regulation (IFG), impaired glucose intolerance (IGT), and

hypoglycemia are systemic diseases that have been associated with many other diseases including malignancy [1]. The estimated prevalence of diabetes for all ages worldwide may increase from 2.8% in 2000 to 4.4% in 2030 [2]. DM is also a

prevalent public health problem in Taiwan. According to statistics, the mortality rates

from DM have almost doubled over the past 10 years in Taiwan. The prevalence of DM in Taiwan has been higher than 5% since 1985 [3]. Studies have associated DM with increased risk of cancers, such as esophageal cancer, hepatocellular carcinoma, bladder cancer, kidney cancer, breast cancer, and endometrial cancer [4-11]. The risk of esophageal cancer linking with DM has been controversy. A meta-analysis,

including 6 case-control studies and 11 cohort studies, found a summary relative risk of 2.72 (95% confidence interval (CI) 1.01-4.46) for esophageal cancer linking with

DM [8].

Esophagus cancer incidence has been rising rapidly in many countries [12-16]..The

incidence of esophageal adenocarcinoma rose approximately sixfold in the United

States from 1975 to 2001 [15]. The 5-year mortality rates may exceed 80% for

patients with the cancer [17]. Histological data have shown that populations with esophageal cancer in the Western countries suffer mainly from the adenocarcinoma [12-17]. Population in Taiwan has exactly the other type of esophageal cancer;

approximately 95% patients have the squamous cell carcinoma [18]. The association between squamous cell carcinoma and DM in the Taiwan population may be different from that between adenocarcinoma and DM in the Western populations. This study

was designed to use the Taiwan National Health Insurance claims data to evaluate

whether the squamous cell carcinoma of the esophagus is associated with DM.

Materials and methods

Data sources

This case-control study used data available from the National Health Insurance (NHI) program in Taiwan. The insurance program was integrated from all public insurance programs in 1995 as a single payment program [19-22]. The National Health Research Institutes are responsible to management the claims data and

converted the data into various data sets for research. This study used the claims data

of inpatient and out-patients of 1-million insured people randomly selected from all

23-million population. Data files can be linked with scrambled identification to

protect individual privacy. Information on anthropometry, laboratory tests and

lifestyle was not available.

Study subjects

This study identified 549 patients aged 20 years and above newly diagnosed with esophageal cancer (ICD-9 150.X and V10.03) during the period of 2000-2009. The index date for each case was the date of diagnosis of esophageal cancer. For each esophageal cancer case, four controls were randomly selected from the same data set frequency matched by sex, age, and then the year the case being selected when controls having a health care visit in the same year. Subjects with esophageal cancer

and any other cancer (ICD-9 140-208 and A-code A08x-A14x) identified by the index year were excluded. We retrospectively screened to 1997 for the medical diagnosis of DM (ICD-9 250.xx and A-code A181) with prescription of DM medication for each selected subject. Similar process was performed to screen for co-morbidities that may

associate with the development of esophageal cancer. They were alcoholism (ICD-9

codes 303, 305.00, 305.01, 305.02, 305.03, and V11.3 and A-code A215), tobacco use

disorders (ICD-9 codes 305.1X), periodontal disease (523.8 and 523.9X), HPV

infection (079.4), hyperlipidemia (272.0, 272.1, 272.2, 272.3 and 272.4), Barrett's

esophagus (530.85), esophageal ulcer (530.2), esophageal reflux (530.81, 530.11) and

esophageal burn (947.2). Other factors examined were the use of nonsteroidal anti-

inflammatory drugs (NSAIDs) like aspirin, cyclooxygenase-2 inhibitors (COX-2

inhibitors) and anti-diabetic drugs identified from the prescription files. The anti-

diabetic drugs included metformin, sulfonylureas, thiazolidinediones, alpha- glucosidase inhibitors, D-phenylalanine derivatives, dipeptidyl peptidase 4 inhibitors,

incretin mimetic agents and insulins.

Statistical analysis

We compared the distributions in sex, age, co-morbidities and medications between esophageal cancer cases and controls and tested differences using the Chi-square test.

The significant variables were further included in the multivariate logistic regression analysis to measure odds ratio (OR) and 95% CI for esophageal cancer, with diabetes status forced in the analysis. Further analyses explored whether the risk of esophageal cancer was associated with the duration of diabetes (< 2 vs. > 2 years) and using anti- diabetic drugs. The association with anti-diabetic drug was estimated individually.

The statistical significance level was set at probability value of < 0.05 (SAS software

version 9.1, SAS Institute Inc., Cary, North Carolina, USA).

Ethical considerations

This study used surrogate identification for each study subject to link study files to secure patient privacy. The present study was exempted from a full ethical review.

RESULTS

Baseline characteristics

Table 1 compares the demographic characteristics and co-morbidities between esophageal cancer cases and controls. Both groups were predominantly men (92.9%) with the mean age of 60.9 (standard deviations 3.03 vs. 12.9) years. There were no significant differences between cases and controls in the prevalence of DM (10.4% vs.

10.1%, p = 0.85) and hyperlipidemia. Cases were more prevalent with co-morbidities of alcoholism, esophageal ulcer, esophageal reflux, and COX-2 inhibitors except use of other NSAIDs .

Risk measures

Table 2 shows that esophageal cancer was not related to DM in both univariate and multivariate logistic regression analyses (OR 0.99, 95% CI 0.71-1.37). Among co- morbidities, esophageal cancer had the strongest association with alcoholism (OR 14.1, 95% CI 7.87-25.4), followed by esophagus ulcer (OR 10.1, 95% 5.70-17.9), esophagus reflux (OR 3.47, 95% CI 2.14-5.62) and use of other NSAIDs (OR 2.73, 95% CI 1.80-4.13). Table 2 also shows a protective association between periodontal

disease and esophageal cancer (OR 0.20, 95% CI 0.02-0.88).

Table 3 shows patients with DM for longer than 2 years were at higher risk of the cancer than patients with shorter DM history with an OR of 2.28 (95% CI 0.85-6.08) after controlling for sex, age, alcoholism, periodontal disease, esophagus ulcer, esophagus reflux, COX-2 inhibitors and other NSAIDs.

Influence of anti-diabetic drugs

Data analysis showed that patients taking anti-diabetic drugs were at higher risk of esophageal cancer (Table 4). The associations were significant for insulin (OR 2.58, 95%1.08-6.15) and sulfonylureas (OR 3.80, 95% 1.16-12.5), and moderately

significant for metformin.

DISCUSSION

Studies investigating the relationship between malignancy and DM have revealed conflicting results on the association between DM and esophagus cancer, and other cancers [8, 23-27, 34-39]. Based on histology, the distribution of squamous cell

carcinoma and adenocarcinoma varies among different geographic areas. Most of studies on esophageal cancer have been conducted on adenocarcinoma of the esophagus for the populations in Western countries [8, 23-27, 37-39]. The positive association between the risk of esophagesl cancer and DM in the meta-analysis conducted by Huang et al consisted of 15 studies from Western countries and two studies from Asian countries [8]. More than 80% of esophagus cancer cases in the

Asian are squamous cell carcinoma [40,42]. Whether the risk of squamous cell carcinoma of esophagus has a relationship with DM has not been well explored. Our study makes up for the gap because the previous study found that the squamous cell carcinoma is the major type of esophageal cancer in Taiwan, accounting as high as

95% of patients with the disease [18].

The present population-based case-control study failed to find a significant association between DM and esophagus cancer in Taiwan. Regardless no association was found between DM and esophageal cancer, this study shows several co-

morbidities were much more prevalent in cases than in controls. Consistent with other

studies [26,27,37-39], we also found heavy alcohol drinking is the strongest risk factor associated with esophageal cancer. A Korean study found a relative risk of 5.62 for mortality from esophageal cancer [26]. Japanese have an OR of 15 for esophageal caner among high alcohol consumers [27]. The risk may increase further to

approximately 70-fold higher for those with alcohol flushing response, indicating individuals with difficulty to metabolite alcohol are at a much higher risk for the cancer. The exact mechanism of how alcoholic beverage is associated with esophagus cancer risk is not clear. Although ethanol has not been shown as carcinogenic in laboratory animals, it may act through its major metabolite, acetaldehyde, a carcinogen in animal models [27, 38, 43-45]. The dose-response relationship with alcohol strongly indicates it as an independent risk factor, particularly for esophagus

squamous–cell cancer [26, 37,39].

Esophageal cancer is significantly associated with esophageal ulcer and esophageal reflux, and medications in this study. Both esophageal ulcer and

esophageal reflux are likely the earlier signals for the subsequent development of the

cancer of esophagus due to esophageal stricture formation, such as acid peptic and

medication-induced. Peptic strictures account for most of esophageal strictures [46-

49]. Purdy et al. found esophageal mucosa injury is associated with sloughing

esophagitis, chronic debilitation and medications [46]. García Rodríguez et al. have

also reported that l ong te rm pharmacological gastric acid suppression is associated with the risk of oesophageal and gastric adenocarcinoma [47]. In this study, anti-

diabetes drugs and other NSAIDs are significantly associated with the disease.

LIMITATIONS

This study was conducted using insurance claims data, a few limitations should

be considered. First, smoking is an important factor associated with esophageal

cancer. But, this information is not available in the insurance claims. However, we are

able to identify patients with the diagnosis of alcoholism. There is strong relationship

between drinking and smoking. And we did find alcoholism is an indicator that may

well predict the cancer. Second, this case-control study enrolled study subjects with

and without esophageal cancer identified from 2000 to 2009. The frequency matched

study design fails to observe age difference between cases and controls. However, we

have also conducted an unmatched analysis by randomly sampling controls, which

revealed a mean age of 15.4 years younger in the controls. This analysis also showed

that DM is not a factor associated with esophageal cancer. Therefore, the frequency

matched samples are representative of the insured population. Finally, the insurance

registry does not provide the information on histological type and genotype of the

cancer. We were unable to differentiate whether the associated risk factors different

between squamous cell carcinoma and adenocarcinoma among study subjects. It is

likely that the small portion of adenocarcinoma may not change the association

between DM and the risk of esophageal cancer in the present study.

CONCLUSIONS

In conclusion, the results of our study fail to show a significant association between DM and the risk of esophagus cancer. Instead, alcoholism, esophageal ulcer and

esophageal reflux are significant predictors for the cancer. Patients of heavy drink, with esophageal ulcer, esophageal reflux and peptic strictures are at high risk of developing the disease.

Specific author contributions:

Kao-Chi Cheng: (1) substantial contributions to the conception of this article; (2) planned and conducted the study; (3) initiated the draft of the article and critically revised it;

Shih-Wei Lai: (1) substantial contributions to the conception of this article; (2) planned and conducted the study; (3) initiated the draft of the article and critically revised it;

Yu-Lung Chen: (1) substantial contributions to the conception of this article; (2) initiated the draft of the article and critically revised it;

Pang-Yao Tsai: (1) conducted data analyses; (2) critically revised the article;

Fung-Chang Sung: (1) substantial contributions to the study concept and design; (2) conducted data analysis and data interpretation; (3) critically revised the article.

Funding

This study was supported in part by grants from Taiwan Department of Health

Clinical Trial and Research Center of Excellence (DOH101-TD-B-111-004), the

Cancer Research Center of Excellence (DOH 100-TD-C-111-005), the National

Science Council (NSC 100-2621-M-039-001), and China Medical University Hospital

analysis, decision to publish, or preparation of the manuscript.

Acknowledgements

The authors (Guarantor’s Name : Fung-Chang Sung) thank the National Health Research Institute in Taiwan for providing the insurance claims data.

Conflict of Interest Statement

The authors disclose no conflicts of interest.

REFERENCES

46. Purdy JK, Appelman HD, McKenna BJ. Sloughing esophagitis is associated with chronic debilitation and medications that injure the esophageal mucosa. Mod Pathol 2012 Jan 27. doi: 10.1038/modpathol.2011.204. [Epub ahead of print]

47. García Rodríguez LA, Lagergren J, Lindblad M. Gastric acid suppression and risk of oesophageal and gastric adenocarcinoma: a nested case control study in the UK. Gut 2006, 55(11):1538-44. Epub 2006 Jun 19.

48. Ljung R, Martin L, Lagergren J. Oral disease and risk of oesophageal and gastric cancer in a nationwide nested case-control study in Sweden. Eur J Cancer 2011, 47(14):2128-2132.

49. Uno K, Iijima K, Hatta W, Koike T, Abe Y, Asano N, Kusaka G, Shimosegawa T. Direct measurement of gastroesophageal reflux episodes in patients with squamous cell carcinoma by 24-h pH-impedance monitoring. Am J

Gastroenterol 2011,106(11):1923-1929.

Table 1. Comparisons in socio-demographic status, co-morbidity and medication between esophageal cancer cases and controls frequency matched by sex, age and index year

Esophageal cancer No

N=2196

Yes N=549

N % n % P value

Age, mean (SD), years 60.9 (3.03) 60.9 (12.9) 0.24

20-39 56 2.55 14 2.55 1.00

40-64 1,328 60.5 332 60.5

≥65 812 37.0 203 37.0

Sex 1.00

Women 156 7.10 39 7.10

Men 2,040 92.9 510 92.9

Comorbidity

Diabetes mellitus 222 10.1 57 10.4 0.85

Alcoholism 16 0.73 53 9.65 <0.0001

Obesity 4 0.18 1 0.18 1.00

Tobacco use disorder 7 0.32 5 0.91 0.07

Periodontal disease 33 1.50 2 0.36 0.03

HPV infection -- -- -- -- --

Hyperlipidemia 324 14.8 65 11.8 0.08

Barrett's esophagus -- -- -- -- --

Esophageal reflux 39 1.78 43 7.83 <0.0001 Medication

Use of aspirin 305 13.9 83 15.1 0.46

Use of COX-2 inhibitors 495 22.5 159 29.0 0.002

Use of other NSAIDs 1,877 85.5 522 95.1 <0.0001

Data are presented as the number of subjects in each group, with percentages given in parentheses

Chi-square test and

Fisher’s exact test comparing patients with and without

esophageal cancer

Table 2. Crude and adjusted odds ratios and 95% confidence intervals of esophageal cancer associated with diabetes and covariates

Crude Adjusted

Variable OR (95%CI) OR (95%CI)

Diabetes mellitus

No 1.00 1.00

Yes 1.03 (0.76-1.40) 0.99 (0.71-1.37)

Alcoholism

No 1.00 1.00

Yes 14.6 (8.25-25.7) 14.1 (7.87-25.4)

Periodontal disease

No 1.00 1.00

Yes 0.24 (0.06-1.00) 0.20 (0.04-0.88)

Esophageal ulcer

No 1.00 1.00

Yes 12.1 (7.01-21.0) 10.1 (5.70-17.9)

Esophageal reflux

No 1.00 1.00

Yes 4.70 (3.02-7.33) 3.47 (2.14-5.62)

COX-2 inhibitors

Never use 1.00 1.00

Ever use 1.40 (1.14-1.73) 1.06 (0.83-1.34)

Other NSAIDs

Never use 1.00 1.00

Ever use 3.28 (2.19-4.92) 2.73 (1.80-4.13)

Adjusted for sex, age, DM, alcoholism, periodontal disease, esophagus ulcer,

esophagus reflux, other NSAIDs and COX-2 inhibitors

Table 3. Adjusted odds ratios for esophageal cancer in relation to duration of diabetes mellitus

Duration of diabetes(years)

Case Control Odds ratio (95% CI)

Number (%) Model 1 Model 2

0-2 6 44 1.00 1.00

≥2 51 178 2.10 (0.85-5.31) 2.28 (0.85-6.08)

Model 1 was adjusted for age and sex

Model 2 was additionally adjusted for sex, age, alcoholism, periodontal disease,

esophagus ulcer, esophagus reflux, other NSAIDs and COX-2 inhibitors

Table 4. Odds ratios of esophageal cancer in relation to use of anti-diabetic drugs Use of anti-diabetic drugs Case Control Odds ratio (95% CI)

Number (%) Model 1 Model 2

Insulins

never use 7(12.3) 69(31.1) 1.00 1.00

ever use 50(87.7) 153(68.9) 3.27(1.40-

7.60)

2.58(1.08-6.15) Metformin

never use 5(8.77) 43(19.4) 1.00 1.00

ever use 52(91.2) 179(80.6) 2.34(0.87-

6.24)

2.84(0.99-8.18) Sulfonylureas

never use 4(7.02) 38(17.1) 1.00 1.00

ever use 53(92.9) 184(82.9) 2.75(0.94-

8.10)

3.80(1.16-12.5) Thiazolidinediones

never use 49(86.0) 180(81.1) 1.00 1.00

ever use 8(14.0) 42(18.9) 0.65(0.28-

1.49)

1.11(0.46-2.65) Alpha-glucosidase inhibitors

never use 48(84.2) 188(84.7) 1.00 1.00

ever use 9(15.8) 34(15.3) 1.00(0.44-

2.24) Model 1 was adjusted for age and sex

Model 2 was additionally adjusted for sex, age, alcoholism, periodontal disease,

esophagus ulcer, esophagus reflux, other NSAIDs and COX-2 inhibitors