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Decreased risk of cholangiocarcinoma in diabetic patients treated with metformin


1 TWS Medical Center, Bangkok, Thailand
2 Department of Community Medicine, Dr. D. Y. Patil University, Pune, Maharashtra, India; Department of Medical Science, Faculty of Medicine, University of Nis, Nis, Serbia

Correspondence Address:
Pathum Sookaromdee,
TWS Medical Center, Bangkok
Thailand
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_368_18

 > Abstract 


Background: Cholangiocarcinoma is an important biliary tract cancer. The high incidence of this cancer is observed in tropical Asia. Several underlying factors are mentioned for this cancer including to diabetes mellitus. The use of the antidiabetic drug, metformin, is mentioned for possibility for decreasing risk for cholangiocarcinoma.
Methods: The work is aimed to estimate the change in risk of local people in the endemic area of cholangiocarcinoma in scenario that diabetic patients are treated with metformin in the highly endemic area of cancer in Thailand.
Results: In this study, the authors estimated the change in risk of local people in the endemic area of cholangiocarcinoma in scenario that diabetic patients are treated with metformin.
Conclusion: The results show a slight decreased risk of cholangiocarcinoma in that scenario.

Keywords: Cholangiocarcinoma, diabetes, metformin



How to cite this URL:
Sookaromdee P, Wiwanitkit V. Decreased risk of cholangiocarcinoma in diabetic patients treated with metformin. J Can Res Ther [Epub ahead of print] [cited 2019 Oct 19]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=263624




 > Introduction Top


Cholangiocarcinoma is an important biliary tract cancer. The high incidence of this cancer is seen in tropical Asia. The disease is usually late detected, and the high mortality rate is reported. In endemic area, the main clinical presentation of this cancer is the severe obstructive jaundice.[1] Several underlying factors are mentioned for this cancer including to diabetes mellitus.[2] The use of the antidiabetic drug, metformin, is mentioned for the possibility for decreasing risk for cholangiocarcinoma.[3] In this study, the authors estimated the change in risk of local people in the endemic area of cholangiocarcinoma in scenario that diabetic patients are treated with metformin. The results show a slightly decreased risk of cholangiocarcinoma in that scenario.


 > Materials and Methods Top


The work is aimed to estimate the change in risk of local people in the endemic area of cholangiocarcinoma in scenario that diabetic patients are treated with metformin in the highly endemic area of cancer in Thailand.[4] The available nationwide data of cholangioma in Thailand is used as a primary source for simulation in this study.[5] For simulation of the assigned scenario, diabetic patients treated with metformin, the previous referencing data on metformin use in cholangiocarcinoma patient with underlying diabetes mellitus is referred to (the rates of metformin use in cholangiocarcinoma with diabetes and general control with diabetes are equal to 24.76% and 64.71%, respectively).[6] The odds ratio in general case and in the case with the assigned scenario, diabetic patients treated with metformin, are calculated and compared.


 > Results Top


According to the available nationwide data of cholangioma in Thailand [Table 1], the odd ratio concerning risk of diabetes for cholangiocarcinoma is equal to 2.31 (95% confidence interval [CI] = 2.24–2.38). After the simulation study, the odd ratio concerning the risk of diabetes for cholangiocarcinoma is equal to 2.27 (95% CI = 2.14–2.41). There is a slight decrease in odds ratio [Table 2].
Table 1: Nationwide data of cholangiocarcinoma showing the risk of diabetes mellitu

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Table 2: The risk for cholangiocarcinoma in simulation with assigned scenario, diabetic patients treated with metformin

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 > Discussion Top


Apart from the well-known risk, opisthorchiasis, there are several little-mentioned risk factors for cholangiocarcinoma including to “inflammatory bowel disease, hepatitis C virus, hepatitis B virus, cirrhosis, diabetes, obesity, alcohol drinking, tobacco smoking, and host genetic polymorphisms.”[7] The diabetes mellitus is an interesting mentioned risk factor since this metabolic problem is very common in general clinical practice. Basically, diabetes mellitus is widely mentioned for its relationship to cholangiocarcinoma.[8] In poorly controlled diabetes, the high blood glucose can enhance progression of cholangiocarcinoma cells through STAT3 activation.[9] In Thailand, the country with world highest incidence of cholangiocarcinoma, the diabetes is proven to associate with fatty liver that may facilitate the cholangiocarcinogenesis and noted as an important risk factor to be managed.[10] In the epidemiological study from other settings with high incidence of cholangiocarcinoma such as Taiwan, diabetes is also identified as an important risk.[11]

For management of diabetes, the control by both dietary modification and antidiabetic drug is widely practiced. The effect of using metformin on the risk of cholangiocarcinoma is an interesting topic in clinical oncology. Metformin is mentioned for possible advantage in cholangiocarcinoma Trinh et al. reported that metformin could help inhibit migration and invasion of cholangiocarcinoma [12] and promote apoptosis of cancerous cells.[13] It is proposed that the use of metformin in diabetic patients might help decrease risk of cholangiocarcinoma.[6] Nevertheless, Yang et al. mentioned that there was no improved survival in cholangiocarcinoma patient with underlying diabetes and treated with metformin.[14]

In this report, the authors try to assess the change in risk of local people in the endemic area of cholangiocarcinoma in scenario that diabetic patients are treated with metformin. Of interest, there is a slight reduction in odds ratio, but there is still a high risk. In our setting, diabetes patient, regardless treatment with metformin, has a high risk for cholangiocarcinoma. The general focus for primary prevention in our setting where the liver fluke is common is still the prevention of opisthorchiasis.[4]


 > Conclusion Top


Regardless of metformin therapy, diabetes mellitus can contribute to increased risk of cholangiocarcinoma.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Wiwanitkit V. Clinical findings among 62 Thais with cholangiocarcinoma. Trop Med Int Health 2003;8:228-30.  Back to cited text no. 1
    
2.
Saengboonmee C, Seubwai W, Wongkham C, Wongkham S. Diabetes mellitus: Possible risk and promoting factors of cholangiocarcinoma: Association of diabetes mellitus and cholangiocarcinoma. Cancer Epidemiol 2015;39:274-8.  Back to cited text no. 2
    
3.
Kaewpitoon SJ, Loyd RA, Rujirakul R, Panpimanmas S, Matrakool L, Tongtawee T, et al. Benefits of metformin use for cholangiocarcinoma. Asian Pac J Cancer Prev 2015;16:8079-83.  Back to cited text no. 3
    
4.
Hughes T, O'Connor T, Techasen A, Namwat N, Loilome W, Andrews RH, et al. Opisthorchiasis and cholangiocarcinoma in Southeast Asia: An unresolved problem. Int J Gen Med 2017;10:227-37.  Back to cited text no. 4
    
5.
Chaiteerakij R, Pan-Ngum W, Poovorawan K, Soonthornworasiri N, Treeprasertsuk S, Phaosawasdi K, et al. Characteristics and outcomes of cholangiocarcinoma by region in Thailand: A nationwide study. World J Gastroenterol 2017;23:7160-7.  Back to cited text no. 5
    
6.
Chaiteerakij R, Yang JD, Harmsen WS, Slettedahl SW, Mettler TA, Fredericksen ZS, et al. Risk factors for intrahepatic cholangiocarcinoma: Association between metformin use and reduced cancer risk. Hepatology 2013;57:648-55.  Back to cited text no. 6
    
7.
Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology 2011;54:173-84.  Back to cited text no. 7
    
8.
Tsilidis KK, Kasimis JC, Lopez DS, Ntzani EE, Ioannidis JP. Type 2 diabetes and cancer: Umbrella review of meta-analyses of observational studies. BMJ 2015;350:g7607.  Back to cited text no. 8
    
9.
Saengboonmee C, Seubwai W, Pairojkul C, Wongkham S. High glucose enhances progression of cholangiocarcinoma cells via STAT3 activation. Sci Rep 2016;6:18995.  Back to cited text no. 9
    
10.
Thinkhamrop K, Khuntikeo N, Phonjitt P, Chamadol N, Thinkhamrop B, Moore MA, et al. Association between diabetes mellitus and fatty liver based on ultrasonography screening in the world's highest cholangiocarcinoma incidence region, Northeast Thailand. Asian Pac J Cancer Prev 2015;16:3931-6.  Back to cited text no. 10
    
11.
Chang JS, Tsai CR, Chen LT. Medical risk factors associated with cholangiocarcinoma in Taiwan: A population-based case-control study. PLoS One 2013;8:e69981.  Back to cited text no. 11
    
12.
Trinh SX, Nguyen HT, Saimuang K, Prachayasittikul V, Chan On W. Metformin inhibits migration and invasion of cholangiocarcinoma cells Asian Pac J Cancer Prev 2017;18:473-7.  Back to cited text no. 12
    
13.
Tang D, Xu L, Zhang M, Dorfman RG, Pan Y, Zhou Q, et al. Metformin facilitates BG45-induced apoptosis via an anti - Warburg effect in cholangiocarcinoma cells. Oncol Rep 2018;39:1957-65.  Back to cited text no. 13
    
14.
Yang Z, Zhang X, Roberts RO, Roberts LR, Chaiteerakij R. Metformin does not improve survival of cholangiocarcinoma patients with diabetes. Hepatology 2016;63:667-8.  Back to cited text no. 14
    



 
 
    Tables

  [Table 1], [Table 2]



 

 
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