Alimentary Pharmacology and Therapeutics
Long-term metformin use reduces gastric cancer risk in type 2 diabetics without insulin treatment: a nationwide cohort study Y.-I. Kim*, S. Y. Kim†, S.-J. Cho*, J.-H. Park†, I. J. Choi*, Y. J. Lee‡, E. K. Lee‡, M.-C. Kook*, C. G. Kim*, K. W. Ryu* & Y.-W. Kim*
*Center for Gastric Cancer, National Cancer Center, Goyang, Korea. † National Cancer Control Institute, National Cancer Center, Goyang, Korea. ‡ Center for Thyroid Cancer, National Cancer Center, Goyang, Korea.
Correspondence to: Dr Soo-Jeong Cho, Center for Gastric Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410–769, Korea. E-mail: [email protected] Jong-Hyock Park, National Cancer Control Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410–769, Korea. E-mail: [email protected] Young-Il Kim and So Young Kim contributed equally to this work.
Publication data Submitted 29 October 2013 First decision 22 November 2013 Resubmitted 24 January 2014 Accepted 24 January 2014 EV Pub Online 20 February 2014 This article was accepted for publication after full peer-review.
SUMMARY Background Metformin use has been associated with a decreased incidence and mortality of various cancers. Aim To evaluate the association between metformin use and gastric cancer. Methods We randomly selected 100 000 type 2 diabetic patients from the 2004 Korean National Health Insurance claim database, and assessed gastric cancer incidence among 39 989 patients (aged 30–97 years) who were regularly treated with anti-diabetic drugs and followed-up from 2004 to 2010. In total, 26 690 patients had used metformin out of 32 978 diabetics who had not regularly used insulin (insulin non-users), and 5855 patients had used metformin out of 7011 regular insulin users. Results Patients who used metformin showed a lower incidence of gastric cancer than those who did not use metformin, in insulin non-users (P = 0.047, log-rank test). However, in patients on regular insulin, there was no difference of gastric cancer incidence according to metformin use. In insulin non-users, the adjusted hazard ratio (AHR) for metformin use was 0.73 (95% confidential interval [CI], 0.53–1.01) with borderline statistical significance (P = 0.059). Duration of metformin use was associated with the reduction in gastric cancer risk (AHR, 0.88; 95% CI 0.81–0.96, P = 0.003), especially in patients who used metformin for more than 3 years (AHR, 0.57; 95% CI, 0.37–0.87; P = 0.009). Conclusion Metformin use >3 years in type 2 diabetics who do not use insulin is associated with a significantly reduced gastric cancer risk. Aliment Pharmacol Ther 2014; 39: 854–863
854
ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12660
Metformin reduces gastric cancer risk INTRODUCTION Patients with diabetes mellitus have a significantly increased risk of developing various cancer types, vs. nondiabetics.1, 2 This increased risk has been explained by insulin resistance and resultant hyperinsulinemia.1, 3 In vitro experiments demonstrated that insulin promotes tumour cell proliferation and motility in colon, breast, prostate and bladder cancer cells cultured under hyperglycaemic conditions.4 In addition, several in vitro and in vivo studies showed that insulin and insulin-like growth factor (IGF) signalling enhances tumour cell proliferation.5 Diabetes and hyperglycaemia are also associated with increased gastric cancer incidence6, 7 and gastric cancer-related mortality.8, 9 Helicobacter pylori infection, one of the most important risk factors of gastric cancer,10 may be associated with higher gastric cancer risk in diabetic patients.11, 12 H. pylori infection increases glucose-mediated insulin release resulting in hyperinsulinemia,11 and independently promotes insulin resistance;12 together, these effects might facilitate hyperinsulinemia-mediated gastric mucosal carcinogenesis. The anti-diabetic drug metformin is reported to have anti-cancer activity in laboratory and epidemiological studies. In vitro, metformin inhibits proliferation of various cancer cell types including prostate, breast and colon,13–15 and also tumour growth in mouse prostate and breast cancer xenograft models.13, 16 In epidemiological studies, metformin therapy is associated with a decreased risk of various cancers.17–23 However, a recent population-based Taiwanese study reported that metformin did not reduce gastric cancer risk.20 In the present study, we hypothesised that metformin use reduces gastric cancer risk. To test this hypothesis, we analysed data of type 2 diabetes patients from the Korean National Health Insurance (KNHI) claim database, and compared gastric cancer incidences between metformin users and non-users. MATERIALS AND METHODS Database The KNHI programme managed by the KNHI Corporation is a mandatory social insurance that provides universal coverage to virtually all Koreans except for Medicaid beneficiaries in the lowest income bracket (approximately 3% of Koreans). The claim database is based on all payments claimed for a specific disease code and also contains all data necessary for reimbursement, Aliment Pharmacol Ther 2014; 39: 854-863 ª 2014 John Wiley & Sons Ltd
including patient socio-demographic information such as sex, age, residential area, comorbid diseases, a detailed list of diagnostic tests, procedures and prescriptions provided and outcomes (deaths). This database is extensively used for epidemiological24, 25 and health policy studies.26 The International Classification of Diseases 10th Revision codes27 were used to identify type 2 diabetes (E11) and gastric cancer (C16). This study was approved by the Institutional Review Board of the National Cancer Center, Korea (NCCRE-11-003). Informed consent requirements were waived because the study was based on routinely collected administrative data, and patient data were kept anonymous.
Study population Overall, 1 314 168 patients had claimed payments for a diagnosis of type 2 diabetes from January to December 2004. According to the personal information protection policy, the KNHI Corporation provided the data of randomly sampled 100 000 patients from the KNHI claim database at 2004 using SAS version 9.2 software (SAS Institute, Inc., Cary, NC, USA). This claim database might include the data from patients whose actual diagnosis was not type 2 diabetes due to disease code input errors or upcoding. Therefore, to identify exact patients who had a diagnosis of type 2 diabetes, only patients who had claimed payments for oral anti-diabetic drugs [including metformin, thiazolidinediones (TZDs), or sulphonylurea] or insulin were considered for inclusion in this study. Patients who had never claimed payments for any oral anti-diabetic drugs and insulin were excluded, because their diagnosis of type 2 diabetes might be falsely coded or upcoding. Among remaining patients, we further excluded patients who had claimed payments for any oral anti-diabetic drugs and insulin for less than six consecutive months, because they were likely to be irregular drug users or be in an early period of diabetes. Finally, only patients who had claimed for those drugs for at least six consecutive months were included in the final cohort. All included patients were divided into regular insulin users and insulin non-users, to exclude a potential cumulative effect of insulin use on gastric cancer incidence. We defined a regular insulin user as a patient who had claimed payments for insulin for at least 6 consecutive months, and insulin non-user as a patient who had never claimed or had claimed payments for insulin for less than six consecutive months. Patients in regular insulin users or non-users were also further classified into the regular metformin users (payment claims for metformin ≥six consecutive months) or non-users (pay855
Y.-I. Kim et al. ments claims for metformin 3.0 years 6568 (24.6) Mean 2.13 Standard deviation 1.56 145 (0.5) Occurrence of gastric cancer, n (%)
Regular metformin Metformin users (n = 5855) non-users (n = 1156)
P
63 55–70
Long-term metformin use reduces gastric cancer risk in type 2 diabetics without insulin treatment: a nationwide cohort study Y.-I. Kim*, S. Y. Kim†, S.-J. Cho*, J.-H. Park†, I. J. Choi*, Y. J. Lee‡, E. K. Lee‡, M.-C. Kook*, C. G. Kim*, K. W. Ryu* & Y.-W. Kim*
*Center for Gastric Cancer, National Cancer Center, Goyang, Korea. † National Cancer Control Institute, National Cancer Center, Goyang, Korea. ‡ Center for Thyroid Cancer, National Cancer Center, Goyang, Korea.
Correspondence to: Dr Soo-Jeong Cho, Center for Gastric Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410–769, Korea. E-mail: [email protected] Jong-Hyock Park, National Cancer Control Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 410–769, Korea. E-mail: [email protected] Young-Il Kim and So Young Kim contributed equally to this work.
Publication data Submitted 29 October 2013 First decision 22 November 2013 Resubmitted 24 January 2014 Accepted 24 January 2014 EV Pub Online 20 February 2014 This article was accepted for publication after full peer-review.
SUMMARY Background Metformin use has been associated with a decreased incidence and mortality of various cancers. Aim To evaluate the association between metformin use and gastric cancer. Methods We randomly selected 100 000 type 2 diabetic patients from the 2004 Korean National Health Insurance claim database, and assessed gastric cancer incidence among 39 989 patients (aged 30–97 years) who were regularly treated with anti-diabetic drugs and followed-up from 2004 to 2010. In total, 26 690 patients had used metformin out of 32 978 diabetics who had not regularly used insulin (insulin non-users), and 5855 patients had used metformin out of 7011 regular insulin users. Results Patients who used metformin showed a lower incidence of gastric cancer than those who did not use metformin, in insulin non-users (P = 0.047, log-rank test). However, in patients on regular insulin, there was no difference of gastric cancer incidence according to metformin use. In insulin non-users, the adjusted hazard ratio (AHR) for metformin use was 0.73 (95% confidential interval [CI], 0.53–1.01) with borderline statistical significance (P = 0.059). Duration of metformin use was associated with the reduction in gastric cancer risk (AHR, 0.88; 95% CI 0.81–0.96, P = 0.003), especially in patients who used metformin for more than 3 years (AHR, 0.57; 95% CI, 0.37–0.87; P = 0.009). Conclusion Metformin use >3 years in type 2 diabetics who do not use insulin is associated with a significantly reduced gastric cancer risk. Aliment Pharmacol Ther 2014; 39: 854–863
854
ª 2014 John Wiley & Sons Ltd doi:10.1111/apt.12660
Metformin reduces gastric cancer risk INTRODUCTION Patients with diabetes mellitus have a significantly increased risk of developing various cancer types, vs. nondiabetics.1, 2 This increased risk has been explained by insulin resistance and resultant hyperinsulinemia.1, 3 In vitro experiments demonstrated that insulin promotes tumour cell proliferation and motility in colon, breast, prostate and bladder cancer cells cultured under hyperglycaemic conditions.4 In addition, several in vitro and in vivo studies showed that insulin and insulin-like growth factor (IGF) signalling enhances tumour cell proliferation.5 Diabetes and hyperglycaemia are also associated with increased gastric cancer incidence6, 7 and gastric cancer-related mortality.8, 9 Helicobacter pylori infection, one of the most important risk factors of gastric cancer,10 may be associated with higher gastric cancer risk in diabetic patients.11, 12 H. pylori infection increases glucose-mediated insulin release resulting in hyperinsulinemia,11 and independently promotes insulin resistance;12 together, these effects might facilitate hyperinsulinemia-mediated gastric mucosal carcinogenesis. The anti-diabetic drug metformin is reported to have anti-cancer activity in laboratory and epidemiological studies. In vitro, metformin inhibits proliferation of various cancer cell types including prostate, breast and colon,13–15 and also tumour growth in mouse prostate and breast cancer xenograft models.13, 16 In epidemiological studies, metformin therapy is associated with a decreased risk of various cancers.17–23 However, a recent population-based Taiwanese study reported that metformin did not reduce gastric cancer risk.20 In the present study, we hypothesised that metformin use reduces gastric cancer risk. To test this hypothesis, we analysed data of type 2 diabetes patients from the Korean National Health Insurance (KNHI) claim database, and compared gastric cancer incidences between metformin users and non-users. MATERIALS AND METHODS Database The KNHI programme managed by the KNHI Corporation is a mandatory social insurance that provides universal coverage to virtually all Koreans except for Medicaid beneficiaries in the lowest income bracket (approximately 3% of Koreans). The claim database is based on all payments claimed for a specific disease code and also contains all data necessary for reimbursement, Aliment Pharmacol Ther 2014; 39: 854-863 ª 2014 John Wiley & Sons Ltd
including patient socio-demographic information such as sex, age, residential area, comorbid diseases, a detailed list of diagnostic tests, procedures and prescriptions provided and outcomes (deaths). This database is extensively used for epidemiological24, 25 and health policy studies.26 The International Classification of Diseases 10th Revision codes27 were used to identify type 2 diabetes (E11) and gastric cancer (C16). This study was approved by the Institutional Review Board of the National Cancer Center, Korea (NCCRE-11-003). Informed consent requirements were waived because the study was based on routinely collected administrative data, and patient data were kept anonymous.
Study population Overall, 1 314 168 patients had claimed payments for a diagnosis of type 2 diabetes from January to December 2004. According to the personal information protection policy, the KNHI Corporation provided the data of randomly sampled 100 000 patients from the KNHI claim database at 2004 using SAS version 9.2 software (SAS Institute, Inc., Cary, NC, USA). This claim database might include the data from patients whose actual diagnosis was not type 2 diabetes due to disease code input errors or upcoding. Therefore, to identify exact patients who had a diagnosis of type 2 diabetes, only patients who had claimed payments for oral anti-diabetic drugs [including metformin, thiazolidinediones (TZDs), or sulphonylurea] or insulin were considered for inclusion in this study. Patients who had never claimed payments for any oral anti-diabetic drugs and insulin were excluded, because their diagnosis of type 2 diabetes might be falsely coded or upcoding. Among remaining patients, we further excluded patients who had claimed payments for any oral anti-diabetic drugs and insulin for less than six consecutive months, because they were likely to be irregular drug users or be in an early period of diabetes. Finally, only patients who had claimed for those drugs for at least six consecutive months were included in the final cohort. All included patients were divided into regular insulin users and insulin non-users, to exclude a potential cumulative effect of insulin use on gastric cancer incidence. We defined a regular insulin user as a patient who had claimed payments for insulin for at least 6 consecutive months, and insulin non-user as a patient who had never claimed or had claimed payments for insulin for less than six consecutive months. Patients in regular insulin users or non-users were also further classified into the regular metformin users (payment claims for metformin ≥six consecutive months) or non-users (pay855
Y.-I. Kim et al. ments claims for metformin 3.0 years 6568 (24.6) Mean 2.13 Standard deviation 1.56 145 (0.5) Occurrence of gastric cancer, n (%)
Regular metformin Metformin users (n = 5855) non-users (n = 1156)
P
63 55–70
