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Insulin therapy and risk of colorectal cancer: an updated meta-analysis of epidemiological studies ab

c

Ao Sun , Rui Liu & Guangshan Sun

b

a

Tianjin Medical University TianjinChina

b

Tianjin Junliangcheng Hospital TianjinChina

c

Tianjin Union Medicine Center TianjinChina Published online: 26 May 2015.

Click for updates To cite this article: Ao Sun, Rui Liu & Guangshan Sun (2014) Insulin therapy and risk of colorectal cancer: an updated metaanalysis of epidemiological studies, Current Medical Research and Opinion, 30:3, 423-430 To link to this article: http://dx.doi.org/10.1185/03007995.2013.858622

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Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2013.858622

Vol. 30, No. 3, 2014, 423–430

Article ST-0281.R2/858622 All rights reserved: reproduction in whole or part not permitted

py Un t rig au fo t ht di hor r S sp ize a la d le © y, u s 20 vi e o ew p r 14 r C o an h d p ibi om In rin ted m fo rm t a . Au e si th rc aU ng or i le is al K co ed D py us is Lim fo ers tr ite rp c i b a er n d so d ut na ow io l u nl n se oa d,

Ao Sun

Abstract

Tianjin Medical University, Tianjin, China Tianjin Junliangcheng Hospital, Tianjin, China

Rui Liu

Tianjin Union Medicine Center, Tianjin, China

Guangshan Sun

Objective: An increasing number of studies show that exogenous insulin therapy may promote colorectal carcinogenesis. However, the results of the association between insulin therapy and risk of colorectal cancer (CRC) among type 2 diabetes patients are inconsistent. The purpose of our study is to examine the effect of insulin therapy on CRC risk among patients with type 2 diabetes in an updated meta-analysis.

Tianjin Junliangcheng Hospital, Tianjin, China

Address for correspondence: Rui Liu MM, Department of Clinical Laboratory, Tianjin Union Medicine Center, 190 Jieyuan Street, Tianjin 300121, People’s Republic of China. Tel: +86 13752062169; Fax: +86 22 24913292; [email protected] Keywords: Colorectal adenoma – Colorectal cancer – Insulin therapy – Meta-analysis – Risk Accepted: 16 October 2013; published online: 6 November 2013 Citation: Curr Med Res Opin 2014; 30:423–30

No

Co

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Original article Insulin therapy and risk of colorectal cancer: an updated meta-analysis of epidemiological studies

Research design and methods: Medline and Embase were searched for the reference lists of pertinent articles published from January 1970 to April 2013. Two investigators independently extracted the data and reached consensus on the inclusion and exclusion criteria. Pooled relative risks and 95% confidence intervals were calculated with a randomeffects model. Results: Analysis of six studies, including 374,950 participants, showed that compared with non-insulin or metformin treatment, insulin treatment was associated with an increase of 37% in the risk of colorectal neoplasm among patients with type 2 diabetes, with moderate heterogeneity (I 2 ¼ 40%). The sensitivity analysis showed that exclusion of one small case–control study had no appreciable changes on the pooled results. Subgroup analyses suggested that there were significant positive associations between insulin therapy and risk of CRC in some subgroups, rather than all subgroups. Conclusions: Our meta-analysis supports a relationship between insulin therapy and increased risk of CRC in patients with type 2 diabetes. Because of bias and confounding of included studies, caution is needed when interpreting our results. Further investigations are needed.

Introduction Both colorectal cancer (CRC) and type 2 diabetes are serious public health threats to all nations. Worldwide, every year, more than 1 million individuals will develop CRC1, which is among the top three causes of cancer death in both men and women in the Western world2. Over the past three decades, the number of people with type 2 diabetes has more than doubled globally3. Obesity, sedentary lifestyle, and Western diet have been considered to be associated with an increased risk of CRC4,5, and they are also important risk factors for development of type 2 diabetes6. These similar risk factors suggest that there may be certain biological correlation between CRC and type 2 diabetes. The results of several previous meta-analyses supported that diabetes mellitus was associated ! 2014 Informa UK Ltd www.cmrojournal.com

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with an increased risk of CRC7–11. The hyperinsulinemia hypothesis independently proposed by McKeown-Eyssen12 and Giovannucci13, which postulated an etiological role on the increased levels of insulin in colorectal carcinogenesis, may be an explanation for the relationship between type 2 diabetes and risk of CRC. During the early stages of type 2 diabetes, increased levels of insulin are produced by b-pancreatic cells in response to poor insulin sensitivity or insulin resistance which is associated with hyperinsulinemia14. With the progression of type 2 diabetes, patients begin to require insulin therapy when there is significant decline in endogenous insulin production15. Hyperinsulinemia is actually augmented during this phase by exogenous insulin despite the inefficiency of endogenous insulin16–18. A previous observational study, which investigated a relationship between increased levels of circulating insulin and cancer, suggested that cancer growth may be influenced by the insulin–insulin-like-growth factor-1 (IGF-1) signaling axis19. Insulin directly promotes colorectal carcinogenesis by activating its own receptor, the receptors of IGF-1 (IGF1R), or hybrid insulin/IGF-1 receptors, all of which are expressed by colorectal epithelial and carcinoma cells20. High levels of insulin indirectly decrease the secretion of insulin-like growth factor-binding proteins (IGFBPs) that lead to increased bioavailability of IGF-121. Insulin or IGF-1 activating to IGF1R, its tyrosine kinase activity is active, and this stimulates signaling through two key intracellular networks (the PI3K-AKTTOR system and the RAF-MAPK systems) that enhance the proliferation and survival of colorectal epithelial and carcinoma cells22. As far as CRC is concerned, liver, pancreas, endometrium, postmenopausal breast and bladder cancer are commonly seen in type 2 diabetes potentially due to the same mechanism23. Meanwhile, the evidence of animal models supports the idea that exogenous insulin may promote colon carcinogenesis. An animal model showed that exogenous insulin also led to an increased number of rats with colonic tumors and the number of tumors per rat24. Another in vivo study25 indicated that insulin increased the growth of aberrant crypt focis (ACFs), with more crypts per ACFs, and more large ACFs per colon in insulin treated rats than in controls. ACFs are preneoplastic lesions and sequential quantification of their number and growth features (crypt multiplicity) in animal colons may provide further insight into the pathogenesis of colon cancer26. Furthermore, large doses of exogenous insulin increase food intake and body weight27. Overfeeding and weight gain may create a host environment rich in circulating excess nutrients and growth factors, all of which have been found to accelerate the growth of neoplastic cells28. This tumor-promoting humoral milieu is predicted to be exacerbated in obese patients because of the preexisting impairment in energy metabolism29. 424

Insulin therapy and risk of CRC Sun et al.

In the UKPDS (United Kingdom Prospective Diabetes Study), 53% of patients with type 2 diabetes required insulin therapy 6 years after their initial diagnosis, and almost 80% required insulin by 9 years30,31. It is necessary to evaluate the potential risk of insulin treatment, because numerous epidemiological studies15,32–35 have provided evidence that insulin therapy might have positive effects on increased risk of CRC among type 2 diabetes patients. Nonetheless, it is worth noticing that the results of epidemiological studies15,32–36 which investigated the association between insulin therapy and risk of CRC among type 2 diabetes patients are inconsistent. In an effort to bring more clarity to this important question, we carried out a meta-analysis of published epidemiological studies to independently assess the role of insulin therapy on CRC risk among patients with type 2 diabetes. In addition, sensitivity and subgroup analyses were performed to further demonstrate the stability of the pooled effect estimate and investigate the sources of heterogeneity in pooled relative risk.

Materials and methods Search strategy Studies were identified by searching the online databases (Medline and Embase) from January 1970 to April 2013. The overall search strategy included medical subject heading terms and/or text words: ‘insulin therapy’, ‘insulin use’, ‘insulin treatment’, ‘colorectal cancer’, ‘colorectal neoplasms’, ‘colorectal adenoma’, ‘colon cancer’, ‘colon neoplasms’, ‘colon adenoma’, ‘rectal cancer’, ‘rectal neoplasms’ and ‘rectal adenoma’. Because CRC develops through a multistep process characterized by precursor lesions37, we also include studies that assessed the association between insulin treatment and colorectal adenoma. Our search was restricted to studies published in the English language and conducted in humans. Titles and available abstracts were scanned for relevance, identifying papers requiring further consideration. Our systematic review was conducted according to the meta-analysis of observational studies in epidemiology (MOOSE) guidelines38.

Inclusion and exclusion criteria The inclusion criteria were as follows: (1) original article; (2) cohort or case–control study; (3) insulin therapy as the main independent variable compared with non-insulin or metformin treatment; (4) patients with type 2 diabetes; and (5) studies provided relative risk (RR), odds ratio (OR) or hazard ratio (HR) with their 95% confidence intervals (CIs). Studies were excluded if (1) no individual data on type of diabetes; (2) patients with type 1 diabetes; www.cmrojournal.com ! 2014 Informa UK Ltd

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(3) any insulin was used within both investigational and comparator groups; (4) subjects included hereditary CRC syndromes, history of CRC, chronic inflammatory bowel disease, or previous bowel resection; (5) reported estimate of effect without calculation of confidence interval; and (6) no age- and gender-adjusted estimate. When there were multiple publications from the same cohort, data from the most recent reports or the bigger studies were included.

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Data extraction and statistical analysis The full text of any article that was deemed potentially eligible was evaluated for the decision on inclusion or exclusion. Two investigators independently extracted the data and reached consensus on the predefined inclusion and exclusion criteria. Figure 1 shows the process of study selection. The data that we extracted included publication reference (the first author’s last name, year of publication, geographic origin, and follow-up period), study population (objects of study, number of participants, mean age, number of exposed and unexposed subjects), study type, adjusted risk estimates with their corresponding confidence intervals, and confounding adjustments. For each study, we extracted the risk estimates that reflected the greatest degree of control for potential confounders. Forest plots were used to compare results across studies. Pooled relative risk estimates with their corresponding Potential articles identified through literature searches (n=282)

Excluded after title review (n=239) Excluded after abstract review (n=10)

Potential articles included in this systematic review (n=33)

Excluded after full article review (n=13) Duplicate articles (n=3) Did not evaluate the risk of insulin therapy and CRC (n=2) Did not have individual data on type of diabetes (n=2) Reported type 1 diabetes and insulin analogue (n=6) Case-control study (n=1)

Articles indentified in overall search (n=6) •Studies on colorectal cancer (n=5) •Study on colorectal adenoma (n=1)

Figure 1. Flow diagram for study selection.

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95% confidence intervals (CIs) were derived by the method of DerSimonian and Laird39 using the assumptions of a random-effects model, which incorporates betweenstudy variability. In order to investigate the sources of heterogeneity in pooled relative risk, we did sensitivity and subgroup analyses. In the sensitivity analysis, we excluded one small case–control study32 that investigated the relationship between insulin use and risk of colorectal adenoma to examine its effect on the pooled effect estimate. And we conducted subgroup meta-analyses by study design, exposure comparison, and follow-up duration for cohort studies. In assessing heterogeneity among studies, we used the Cochran Q test and I2 statistic40. These were used to test whether the differences obtained between studies was due to chance. For the Cochran Q test, a P value 50.10 was considered statistically significant for heterogeneity; for I2 statistic, a value450% was considered a measure of severe heterogeneity. Publication bias was visually assessed by constructing a funnel plot41. Because funnel plots have several limitations and represent only an informal approach to detect publication bias, we further carried out formal testing using Begg’s adjusted rank correlation test and Egger’s regression asymmetry test42. All statistical analyses were performed using STATA version 12.0 (Stata Corporation, College Station, TX, USA). P values that were less than 0.05 were considered statistically significant. All statistical tests were two-sided.

Results Six relevant studies met the predefined inclusion criteria (Figure 1), including a total of 374,950 participants. Of these six studies, two were case–control studies15,32, one was a retrospective cohort study33, and three were prospective cohort studies34–36. Characteristics of the studies are presented in Table 1. Two studies were conducted in the UK15,33, one study in Korea32, one study in the United States36, and two studies in China34,35. Five studies investigated the relationship between insulin treatment and risk of CRC15,33–36, and only one study investigated the relationship for colorectal adenoma32. All six studies included only type 2 diabetes patients. A pooled estimate of RR and 95% CI of association between insulin therapy and risk of colorectal neoplasm on the six studies is shown in Figure 2. Compared with non-insulin or metformin treatment, insulin treatment was associated with an increased risk of colorectal neoplasm among patients with type 2 diabetes (pooled RR ¼ 1.37, 95% CI ¼ 1.01–1.73; P50.001), with moderate heterogeneity (Q ¼ 10.00, P ¼ 0.124; I2 ¼ 40%). There was no funnel plot asymmetry for the association between insulin treatment and risk of colorectal neoplasm (Figure 3). P values for Begg’s adjusted rank correlation Insulin therapy and risk of CRC Sun et al.

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A cohort of patients with type 2 diabetes underwent total colonoscopy at the Gastrointestinal Endoscopy Unit at Hallym University Sacred Heart Hospital (325 patients; mean age:66.8) Exposed group: 38 insulin users Comparison group: 162 non-insulin users

A cohort of people treated in UK general practices participating in The Health Information Network (THIN) (62,809 patients; mean age: 64.3) Exposed group: 10,067 insulin users Comparison group: 31,421 metformin users

A cohort of adult participants in the Cancer Prevention Study II (CPS-II) Nutrition (184,194 participants; age: 50–74) Exposed group: 7094 insulin users Unexposed group: 21,176 non-insulin users

A cohort of patients with type 2 diabetes in the Taiwan’s National Health Insurance (NHI) database (61,777 patients; mean age: 61.44) Exposed group: 751 insulin users Comparison group: 3963 metformin users

A cohort of Shanghai residents with type 2 diabetes from the Shanghai Diabetes Registry (SDR) (12,973 patients; mean age: 62.2) Exposed group: 3639 insulin users Comparison group: 5135 non-insulin users

Chung32 (2008, Korea) 2003–2006

Currie33 (2009, UK) 2000–2009

Campbell36 (2010, USA) 1992–2007

Hsieh34 (2012, Taiwan, China) 2000–2008

Gu35 (2013, China) 2001–2010

Prospective cohort study

Prospective cohort study

Prospective cohort study

Retrospective cohort study

Case–control study (26 cases; 74 controls)

Nested case–control study (125 cases; 1195 controls)

Study type

CRC (13): 1.25 (0.50–3.12)

CC þ RC (18): 2.135 (1.226–3.717)

CRC (85): M (59): 1.11 (0.82–1.51) F (26): 0.94 (0.60–1.48)

CRC (292): 1.69 (1.23–2.33)

Colorectal adenoma (26): 3 (1.1–8.9)

CRC (125): 2.1 (1.2–3.4)

Adjusted RR (95% CI)

Age, sex, macrovascular, smoking, concomitant oral glucose lowering agents, HbA1c, diabetes duration

Age, sex

Age, sex, BMI, physical activity, NSAID use, FHC, endoscopy history, alcohol use

Age, sex, smoking status, prior solid tumor

Age, sex, BMI, duration of diabetes, HbA1c, lipids, metformin, and aspirin

Age, sex

Confounding adjustments

RR ¼ relative risk; CI ¼ confidence interval; CRC ¼ colorectal cancer; CC ¼ colon cancer; RC ¼ rectal cancer; M ¼ male; F ¼ female; BMI ¼ body mass index; FHC ¼ family history of colorectal cancer; NSAID ¼ nonsteroidal anti-inflammatory drug. The RRs with 95% confidence intervals were derived by pooling the sex/subsite-specific RRs.

A cohort of patients with type 2 diabetes in the General Practice Research Database (GPRD) (52,872 patients; mean age:74.9) Exposed group: 3160 insulin users (1 year of insulin use) Unexposed group: 21,758 non-insulin users

Study population

Yang15 (2004, UK) 1987–2002

Source

Table 1. Characteristics of six studies of insulin therapy and risk of colorectal cancer.

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Study ID

RR (95% CI) 15

Study ID

RR (95% CI) 15

Yang 2004

2.10 (1.20, 3.40) 8.48

Yang 2004

2.10 (1.20, 3.40) 8.72

Chung 200832

3.00 (1.10, 8.90) 0.83

Currie 200933

1.69 (1.23, 2.33) 21.39

Currie 200933

3.00 (1.23, 2.33) 21.19

Campbell 201036 (M)

Campbell 201036 (M)

1.11 (0.82, 1.51) 30.40

Campbell 2010

Campbell 201036 (F)

0.94 (0.60, 1.48) 25.84

Hsieh 2012

2.13 (1.23, 3.72) 7.13

Hsieh 201234

2.13 (1.23, 3.72) 6.92

Gu 201335

1.25 (0.50, 3.12) 6.56

Gu 201335

1.25 (0.50, 3.12) 6.35

1.36 (0.99, 1.72) 100.00

Overall (I-squared = 40.0%, p = 0.124)

1.37 (1.01, 1.73) 100.00

Overall (I-squared = 45.8%, p = 0.100)

0 1.37

4

2

0

−2

−4 .5

1

1.5

2

s.e. of: logRR

Figure 3. Funnel plot of five studies evaluating the association between insulin therapy and risk of colorectal cancer. Begg’s regression asymmetry test (P ¼ 0.293).

test and Egger’s regression asymmetry test were 0.293 and 0.896, respectively, indicating a low probability of publication bias. In the sensitivity analysis, we excluded one small case– control study32 that investigated the relationship between insulin use and risk of colorectal adenoma. The rest included one nested case–control study15, one retrospective cohort study33, and three prospective cohort studies34–36. We found that the pooled estimate of RR and 95% CI (pooled RR ¼ 1.36, 95% CI ¼ 0.99–1.72; P50.001) was similar to the overall results, with moderate heterogeneity (Q ¼ 9.23, P ¼ 0.100; I2 ¼ 45.8%) (Figure 4). Therefore, exclusion of one small case–control study indicated the stability of the positive association between insulin treatment and risk of CRC. We conducted subgroup meta-analyses by study design, exposure comparison, and follow-up duration for cohort ! 2014 Informa UK Ltd www.cmrojournal.com

1.11 (0.82, 1.51) 30.29

(F)

0.94 (0.60, 1.48) 25.91

34

0

Begg’s funnel plot with pseudo 95% confidence limits

0

36

8.9

Figure 2. Association between insulin therapy and risk of colorectal neoplasm in six studies. RR, relative risk; CI, confidence interval; M, male; F, female; Squares, study-specific RR estimate (size of the square reflects the study specific statistical weight, i.e. the inverse of the variance); horizontal line 95% CI, diamond summary RR estimate and its corresponding 95% CI. All statistical tests were two-sided. Statistical heterogeneity between studies was assessed with the I 2 test.

logRR

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% Weight

March 2014

1.36

4

Figure 4. Association between insulin therapy and risk of colorectal cancer on five studies. RR, relative risk; CI, confidence interval; M, male; F, female; Squares, study-specific RR estimate (size of the square reflects the study specific statistical weight, i.e. the inverse of the variance); horizontal line 95% CI, diamond summary RR estimate and its corresponding 95% CI. All statistical tests were two-sided. Statistical heterogeneity between studies was assessed with the I 2 test.

studies (Table 2). Subgroup analyses indicated that there were significant positive associations between insulin therapy and risk of CRC in some subgroups, rather than all subgroups. For study design, the pooled estimate of RR for case–control studies (pooled RR ¼ 2.17, 95% CI ¼ 1.11– 3.23; P ¼ 0.663) was higher than for cohort studies (pooled RR ¼ 1.27, 95% CI ¼ 0.92–1.62; P ¼ 0.146); however, there was no heterogeneity among study types (P ¼ 0.114). By exposure comparison, the association was stronger in the insulin vs. metformin group (pooled RR ¼ 1.76, 95% CI ¼ 1.26–2.27; P ¼ 0.522) than in the insulin vs. non-insulin group (pooled RR ¼ 1.14, 95% CI ¼ 0.83–1.45; P ¼ 0.328), and there was significant heterogeneity (P ¼ 0.040). Finally, we found that the association between follow-up duration and risk of CRC was stronger in the 510 year group (pooled RR ¼ 1.71, 95% CI ¼ 0.81–2.62; P ¼ 0.337) than in the 10 year group (pooled RR ¼ 1.21, 95% CI ¼ 0.82–1.59; P ¼ 0.100), and there was no heterogeneity among follow-up duration for cohort studies (P ¼ 0.319).

Discussion We conducted a meta-analysis of case–control and cohort studies to assess the possible effect of insulin therapy on CRC risk among patients with type 2 diabetes. Findings from this meta-analysis indicated that compared with noninsulin or metformin treatment, insulin treatment was associated with an increase of 37% in the risk of colorectal neoplasm among patients with type 2 diabetes, with moderate heterogeneity. The sensitivity analysis showed that exclusion of one small case–control study had no appreciable changes on the pooled results. Subgroup analyses showed that there were significant positive associations Insulin therapy and risk of CRC Sun et al.

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Table 2. Pooled estimates of RR and 95% CI for case–control and cohort studies of the association between insulin therapy and risk of CRC by study design, exposure comparison, and follow-up duration for cohort studies.

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Subgroup

No. of studies

Pooled RR (95% CI)

Between studies

Between subgroups

Q

P

I

2

Q

P

Study design Case–control Cohort studies

2 4

2.17 (1.11–3.23) 1.27 (0.92–1.62)

0.19 6.82

0.663 0.146

0.0% 41.3%

2.50

0.114

Exposure comparison Insulin vs. metformin Insulin vs. non-insulin

2 4

1.76 (1.26–2.27) 1.14 (0.83–1.45)

0.41 4.63

0.522 0.328

0.0% 13.5%

4.21

0.040

Follow-up duration 510 years 10 years

2 2

1.71 (0.81–2.62) 1.21 (0.82–1.56)

0.92 4.60

0.337 0.100

0.0% 56.5%

0.99

0.319

between insulin therapy and risk of CRC in some subgroups, rather than all subgroups. Two previous meta-analyses43,44 assessed the association between insulin treatment and risk of overall and site-specific cancer. They found that insulin treatment was associated with an increased risk of CRC in type 2 diabetes or combined type 1 and type 2 diabetes patients, with statistically significant heterogeneity among studies. We conduct a more rigorous pooled estimate of the relationship between insulin therapy and risk of CRC among patients with type 2 diabetes. In order to reduce the interference of type 1 diabetes, our study just includes six epidemiological studies with type 2 diabetes patients and insulin therapy as the main independent variable. Thus, our updated meta-analysis effectively weakened the selection bias among studies. It is known that biases and unknown confounders cannot be adjusted for, and adjustments for known confounders can only be reduced but not fully eliminated. So caution is needed when interpreting our results. First, if patients with type 2 diabetes can’t reach the goal of glycemic control with oral anti-diabetic drugs (OADs), they may need to receive insulin treatment. It means that type 2 diabetes patients using insulin were less healthy, with older age, poor glucose control, longer diabetes duration and more comorbidities. The risk of developing CRC increases with advancing age45, and more than 90% of CRC cases occur in people aged 50 or older46. Older diabetic patients with CRC often had a poorer prognosis47. So increasing age could interfere as a potential confounder in the association between insulin therapy and CRC risk. Second, metformin treatment was confirmed to be associated with a significantly lower risk of CRC in patients with type 2 diabetes48. But the protective effect of metformin as comparison may overstate the relationship between insulin use and risk of CRC. It is reported that the use of sulfonylurea or statins was associated with a small reduction in the risk of colon cancer in patients with 428

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diabetes49,50. Moreover, long-term use of low-dose aspirin appeared to be associated with a lower incidence of CRC51. Thus, the true association between insulin therapy and CRC risk may be distorted by prescription bias. Third, the detail of most studies on the duration and dose of insulin use and risk of CRC was still incomplete. There also seemed to be significant sources of heterogeneity. It remains an open question as to whether, or to what extent, differences in circulating levels of insulin influence CRC progression in patients receiving treatment for diabetes33. Although colonoscopy screening may be a valuable tool for the prevention and diagnosis of colorectal cancer, the screenings are not performed in patients with diabetes for purposes of reducing CRC secondary to insulin therapy. The colonoscopy screenings for colorectal cancer are performed in patients, who happen to be using insulin, as part of regular routine medical care. Nagel and Goke suggested that recommendations for colorectal carcinoma screening should use recent epidemiologic evidence, and all patients with type 2 diabetes should be recommended to undergo colonoscopy before starting insulin therapy, and screening intervals should not exceed 5 years52. Finally, reasons for the gender differences in the association between insulin therapy and CRC risk are not clear. Moreover, the existing difference of geographic origin may contribute to the cause of heterogeneity in our meta-analysis. Though the funnel plot analysis and Begg’s test did not provide obvious evidence for publication bias, the possibility of publication bias cannot be ruled out. In summary, our meta-analysis supports a relationship between insulin therapy and increased risk of CRC in patients with type 2 diabetes. Further investigations are needed.

Transparency Declaration of funding This study wasn’t funded.

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Declaration of financial/other relationships A.S., R.L. and G.S. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

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Insulin therapy and risk of colorectal cancer: an updated meta-analysis of epidemiological studies.

An increasing number of studies show that exogenous insulin therapy may promote colorectal carcinogenesis. However, the results of the association bet...
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