Type 2 diabetes mellitus and risk of colorectal adenoma: a meta-analysis of observational studies
- Feifei Yu†1,
- Yibin Guo†2,
- Hao Wang†3,
- Jian Feng†2,
- Zhichao Jin2,
- Qi Chen2,
- Yu Liu4 and
- Jia He2Email author
© Yu et al. 2016
Received: 1 November 2014
Accepted: 5 August 2016
Published: 17 August 2016
To summarize the relationship between type 2 diabetes mellitus (T2DM) and risk of colorectal adenomas (CRA), we performed a meta-analysis of observational studies.
To find studies, we searched PubMed, Embase, the Cochrane Library, Web of Science and conference abstracts and related publications for American Society of Clinical Oncology and the European Society of Medical Oncology. Studies that reported relative risks (RRs) or odds ratios (ORs) with 95 % confidence intervals (CIs) for the association between T2DM and risk of CRA were included. The meta-analysis assessed the relationships between T2DM and risk of CRA. Sensitivity analyses were performed in two ways: (1) by omitting each study iteratively and (2) by keeping high-quality studies only. Publication bias was detected by Egger’s and Begg’s tests and corrected using the trim and fill method.
This meta-analysis included 17 studies with 28,999 participants and 6798 CRA cases. We found that T2DM was a risk factor for CRA (RR: 1.52; 95 % CI: 1.29–1.80), and also for the advanced adenoma (RR: 1.41; 95 % CI: 1.06–1.87). Patients with existing T2DM (RR: 1.56; 95 % CI: 1.16–2.08) or newly diagnosed T2DM (RR: 1.51; 95 % CI: 1.16–1.97) have a risk of CRA. Similar significant results were found in retrospective studies (RR: 1.57; 95 % CI: 1.30–1.89) and population based cross-sectional studies (RR: 1.46; 95 % CI: 1.21–1.89), but not in prospective studies (RR: 1.27; 95 % CI: 0.77–2.10).
Our results suggested that T2DM plays a risk role in the risk of developing CRA. Consequently, medical workers should increase the rate of CRA screening for T2DM patients so that they can benefit from behavioural interventions that can help prevent the development of colorectal cancer. Additional, large prospective cohort studies are needed to make a more convincing case for these associations.
KeywordsType 2 diabetes mellitus Colorectal adenoma Meta-analysis
Diabetes mellitus (DM) is the fourth or fifth leading cause of death in developed countries and one of the biggest threats to human health worldwide . More than 90 % of all DM is type 2 diabetes mellitus (T2DM) [2, 3]. Colorectal cancer (CRC) is the third most common cancer in the world. Colorectal adenoma (CRA) (also known as adenomatous polyp and always found by colonoscopy screen ) is a prevalent precancerous lesion that can lead to CRC through the adenoma–carcinoma sequence .
Research on risk factors for CRA has focused on several epidemiological factors, including smoking , alcohol consumption , body mass index , physical activity , and calcium intake . Recent research on patients with diabetes suggested that insulin therapy and diabetes itself may increase the risk of CRC [10–12]. However, the association between T2DM and the risk of CRA risk has not yet been fully established. Some researchers asserted that there were no overall associations between T2DM and CRA risk [13–16], while others reported a higher risk [17–20]. To further examine these findings and provide evidence of association between T2DM and risk of CRA risk, we performed a meta-analysis about T2DM on the risk of CRA.
Two investigators (FY and YG) independently conducted a systematic literature searches on January 10, 2016 in PubMed, Embase, the Cochrane Library and Web of Science without limiting the publication date range. The following search terms were used: (diabetes mellitus OR diabetes OR diabetic OR glucose) AND (colorectal OR colon OR rectal) AND (adenomas OR adenoma OR adenomatous OR polyp). No language restrictions and any other limitations were imposed. Conference abstracts on the websites of American Society of Clinical Oncology’s (ASCO) and the European Society for Medical Oncology’s (ESMO) annual meetings were also searched, along with the reference lists of the identified publications. Additional file 1 includes the complete searching process.
The titles and abstracts of all of the studies from the searches were screened independently by three reviewers (FY, YG and JF). To be included in this meta-analysis, studies had to be at least one of the following criteria: (1) retrospective or perspective observational study of the association between diabetes mellitus and CRA, or (2) a study reporting the relative risks (RRs) or odds ratios (ORs) for T2DM on CRA with 95 % confidence intervals (95 % CIs) adjusted for gender, age, or other factors. Studies reporting on the CRA recurrence were excluded.
Data extraction was performed by three reviewers (FY, YG and WH), and verified independently for accuracy by a forth reviewer (JH). The following information was collected for each study: title and author, publication year, population, location, sample size, proportion of males and covariates controlled for by matching or multivariate analysis. For studies that reported several multivariate adjusted ORs, the effect estimate that adjusted for the maximum potential confounders was selected. Two investigators (FY and ZJ) conducted a quality assessment using the 9-star Newcastle-Ottawa Scale (NOS) , which was verified by a third investigator (YG). We considered studies with a NOS score of seven or more to be high-quality studies. The study selection process was based on the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines  and is described in Additional file 2.
We examined the relationship between T2DM and CRA risk on the basis of the adjusted RRs and ORs and corresponding 95 % CI published in each study. A fixed effects model was used to estimate the pooled RR and OR with 95 % CIs if there was no evidence of heterogeneity; otherwise, a random effect model was used [23, 24]. Because the incidence of CRA is low, the ORs in retrospective studies approximate the RRs [25, 26]. Heterogeneity between the studies was evaluated by the chi-square test and I-squared (I2) statistic . Statistical heterogeneity was considered significant when p < 0.10 .
Several methods were used to test and adjust for potential publication bias. Visual inspection of funnel plots was performed, and the Egger’s regression test  and Begg’s test  were used. Where publication bias existed, we used the trim and fill method to correct it . Subgroups analyses by gender, adenoma subsite, and study type were performed to explore the potential heterogeneity among the included studies. Sensitivity analyses were performed in two ways: (1) by excluding each study iteratively from the meta-analysis and (2) by keeping high-quality studies only.
All statistical tests were two-sided and regarded as statistically significant at p < 0.05 Stata (Version 11.0; Stata Corp, College Station, TX) was used for all analyses.
Characteristic of studies included in the meta-analysis
Category of exposure (N)
Chiranjeev Dash 
age, educational status, body mass index (weight (kg)/height (m)2), physical activity, family history of colorectal cancer in a first-degree relative, menopausal status, smoking status, alcohol intake, total energy intake, red meat intake, fruit and vegetable intake, and regular aspirin use
Heike Ursula 
Colorectal neoplasia (389)
age and sex
Tomomi Marugame 
Newly diagnosed T2DM (41)
CRA (560), Proximal adenomas(254), Distal adenomas (306)
hospital, rank in the Self Defense Forces, alcohol use, and cigarette smoking
Hongha T Vu 
ethnicity, body mass index, smoking, and alcohol use
Rodney Eddi 
Adenomatous polyps (261)
Age, Sex, TG, LDL, HDL, Smoking, Family history of CRC, Aspirin, NSAID, Statins
Mehulkumar K. Kanadiya 
Joseph Carl Anderson 
Any Sessile Serrated Adenomas (90)
Bouwens, M 
Combined adenoma-serrated phenotype (139)
de Kort, S 
age, gender, BMI and other relevant risk factors
Jill E. Elwing 
All diabetics (100)
Any Adenoma (159)
age, race, hypertension, hypercholesterolemia, BMI, and NSAID status
Advanced adenoma (46)
Kazushige Kawai 
Suminori Kono 
sigmoid colon adenomas (821)
body mass index (wt [kg]/ht [m]2), cigarette smoking, alcohol use, rank of the Self Defense Forces, and hospital.
Takasei Nishii 
Age- and BMI
Sunghwan Suh 
sex, age, BMI, TC, HDL, TG, Fasting plasma glucose, HbA1c
Thomas R 
Advanced adenoma (243)
Wang, JH 
abdominal circumference, daily calories & fat intake, increased diastolic blood pressure, history of hypertension or fatty liver, family history of cancer in digestive system, LDL and hsCRP, while female and daily fiber intake
Misciagna, G 
Diabetes (34)/ Glucose (mg/100 ml)
Diabetes and risk of colorectal adenoma
Subgroup analyses for the effect of diabetes on risk of colorectal adenoma
RR (95 % CI)
Sub-site of adenoma
Type of diabetes
Newly diagnosed T2DM
Population based study
Studies with high quality
This study indicated that patients with diabetes, especially type 2, have about 50 % increased relative risk of developing CRA than non-diabetic individuals, regardless of their geographic location. Although sample size was small in the newly diagnosed T2DM subgroup, the heterogeneity was also small and a significant risk relationship between T2DM and CRA was still detected. A similar result was only found in the advanced adenoma subgroup, not in the proximal, distal, colon or multiple adenoma subgroups. When low-quality studies were excluded, the positive association still existed. These results suggested that T2DM patients should pay more attention to their risk of CRA.
The positive relationship between T2DM and CRA may be linked to insulin resistance or an increased insulin-like growth factor 1 (IGF-1) might take effect in the adenoma–carcinoma process. High insulin levels could promote tumor growth [31, 45, 46]. Also, diabetes may lead to slower bowel transit, which would increase the probability of exposure to potential carcinogens for colonic mucosa [47–49]. It is worth noting that there might be some confounding effects because of the similar risk factors for both T2DM and CRA, such as physical inactivity, obesity, and an unhealthy diet habit [12, 50]. For example, a case–control study reported that higher red meat intake could significantly increase the risk of colon adenoma . At the same time, obese people also tend to consume more red meats and have a higher risk of diabetes. Therefore, dietary habits might be a confounding factors. Finally, some researchers also report that obesity might be a confounder in the association between T2DM and colorectal disease .
Some studies reported a difference in risk between males and females [12, 39, 53–55]; however, the results of our subgroup analysis showed no difference. One possible explanation involves the redistribution of body fat that can occur when women experience menopause. The increase in visceral body mass fat could lead to hyperinsulinemia so that women, especially post-menopausal women, are more susceptible to colorectal diseases. However, the existence of menopause in some women cannot explain the different CRC risks for males and females [56–59]. Discrepancies among these studies and ours and the insignificant results by adenoma sub-site might be attributed to the limited sample sizes and insufficient statistical power. For the prospective studies, varied different follow-up procedures and mix of ethnicities different study populations might be the sources of heterogeneity.
Our analysis revealed that with T2DM have about a 5 % higher risk of CRA than newly diagnosed diabetes patients, revealing the duration of T2DM as a risk factor for CRA. A possible explanation is that known T2DM patients’ bowels are exposed to hyperinsulinemia or a hyperglycemic environment for a longer time, and such hormonal or metabolic abnormalities (according to former study ) could affect tumour growth. However, some studies reported that metformin use was a protective factor of CRA  and cancer . If this is true, diagnosed diabetes patients should have a lower risk of adenomas than new patients, which is counter to our results. On the other hand, the severity of T2DM, which was not confirmed in the included studies, may affect colorectal disease risk and contribute to the mixed results. In sum, there might be a dose–response relationship between insulin and CRA, and further studies should include this as an important potential confounding factor.
Several limitations of in this meta-analysis that should be taken into consideration. First, results for several subgroups, such as gender and adenoma sub-site subgroup, were based on a limited number of studies. Therefore, we cannot rule out the possibility that insufficient statistical power is present. Second, in the present analysis, some small studies with inverse associations between T2DM and risk of CRA risk seemed to be suppressed. The presence of possible publication bias could have led to an overestimation of the effect of T2DM on CRA risk. However, the adjusted result was comparable after trim and fill method corrections. Third, we could not account for all of the confounding factors in the meta-analysis, though most confounders were adjusted in the original RRs. Many factors might induce the adenomas, such as age, ethnicity, inactivity, regular aspirin use, obesity, and family history of CRA, and menopausal status. We could not control for these covariates because of lack of relevant data. Relevant studies with additional data on these other factors may be found by searching by searching beyond the sources used for this study. Furthermore, we could not determine whether using insulin as a therapy for T2DM is an important factor because CRA risk might be altered by hyperinsulinemia, thought to be an important promoter of carcinogenesis [62, 63]. At the same time, metformin may have a direct anti-proliferative effect . Finally, most of the existing studies did not discuss the influences of T2DM severity level on CRA risk. Thus, more cohort studies about these topics should be conducted.
In conclusion, the results of our meta-analysis indicated that patients with T2DM have higher risks for the development of CRA, which is an important inducement for colorectal cancer. Our study has important implications for clinical and public health. Because T2DM and CRA are prevalent in the developed and developing countries , medical workers should increase the rate of CRA screening for T2DM patients so that they can benefit from behavioural interventions that can help prevent CRA . Large prospective studies that investigate the interactions among environmental and behavioral factors, medications, and functional polymorphisms are also needed to further clarify the etiology of CRA.
This work was supported by National Natural Science Foundation (81001287), Natural Science Foundation of Shanghai (15ZR1412300), Leading Talents of Science in Shanghai 2010 (022), and the Fourth Round of Three-year Action Plan on Public Health Discipline and Talent Program of Shanghai: Evidence-based Public Health and Health Economics in Shanghai (15GWZK0901).
Availability of data and materials
The datasets supporting the conclusions of this article are included within the article and its additional files.
FY, ZJ and JH discussed and developed the question for this review. FY and YG carried out the searches. FY, YG, HW and JF assessed the eligibility of the studies for inclusion, extracted data and carried out all analysis. All authors were involved in interpreted and discussed results. FY wrote the first draft of this paper and it was reviewed by JH. FY and YG revised the paper and the English was improved by JF and JH. QC and YL completed the figures and tables of the analysis. All authors agreed on the final draft of this study. JH is the guarantor.
The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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