Endometrial cancer (EC) is the most common cancer of the female reproductive system. In 2011, the American Cancer Society reported that, in the United States, there were 46,470 new EC and more than 8000 deaths caused by EC, making it the fourth most common incident cancer among women and the second most common cause of gynecologic cancer death.1,2 Incidence of EC is on the rise, with a lifetime risk of approximately 3%. Most strikingly, 5-year survival of EC is currently significantly worse than that of 30 years ago (84% survival in 2006 vs 88% survival in 1975), making EC only one of 2 cancers with increased mortality.1 The increasing incidence is partly due to increased life expectancy, but changes in lifestyle factors are also likely to be important. Previous publications show that less parity, increasing body mass index, and low physical activity have been considered the most important risk factors for EC.3 Moreover, smoking and hypertension are also risk factors for EC development. However, many individuals who have been exposed to these risk factors never develop EC.
Coinciding with the increasing EC incidence, the prevalence of diabetes mellitus (DM) has been growing markedly over the past 2 decades in most countries. It is reported that approximately 366 million adults (age range, 20–79 years) were estimated to have diabetes in 2011 worldwide.4 Much evidence has been accumulating to suggest that diabetes is associated with an increased risk for several malignancies, such as colorectal,5 liver,6 kidney,7 and pancreatic8 cancer. Furthermore, diabetes may increase the risk of all-cause mortality among people with cancer.9 Several biologic mechanisms have been indicated to explain the potentially causal relationship between DM and risk of cancer. It is suggested that abnormal metabolic, immunologic, and hormonal characteristics of DM may promote cancer development. The hypothesized biologic mechanisms are related to the effect of insulin and insulin-like growth factors axis on cellular growth and proliferation. Insulin or insulin-like growth factors axis would trigger intracellular signaling cascades with mitogenic and antiapoptotic effects, which is involved in the development and progression of malignancies.10,11
A previous meta-analysis of 16 studies (3 cohort and 13 case-control studies) performed by Friberg et al12 was published in 2007, which showed that diabetes was significantly associated with an increased risk of EC [summary relative risk (SRR), 2.10; 95% confidence interval (CI), 1.75–2.53]. Since the meta-analysis was published, several large additional cohort studies on the association of DM and EC have been published.13–17 Here, we update the evidence published up to June 2012. This updated analysis will provide more precise risk estimates than the previous analysis. Furthermore, we also evaluated whether this association differs according to various study characteristics.
Literature Search Strategy
We conducted a computerized search of the PubMed (from January 1, 1966, to June 30, 2012) and EMBASE databases (from January 1, 1974, to June 30, 2012) with the following medical subject heading (MeSH) terms and/or keywords: diabetes or diabetes mellitus; cancer or tumor or neoplasm(s) or carcinoma(s); endometrial or endometrium or corpus uteri; epidemiologic studies or prospective studies or cohort studies or follow-up studies. To achieve maximum sensitivity, limits or filters were not placed on the searches. No language restrictions were imposed. We also reviewed the reference of relevant publications to identify additional relevant studies and reviewed publications on DM and risk of total and specific cancers to search for results on EC incidence or mortality. The search strategy was updated if a reference was omitted. The process was performed 3 times to ensure that all references were included.
Eligible Studies and Data Extraction
Studies were included into the meta-analysis if (1) they were original articles with full text—the review, comment, editorial, letter, or other articles not reporting primary data were not considered; (2) they had a prospective cohort design; (3) one of exposure of interests was DM; (4) EC as one of the following-up outcome; (5) relative risk, hazards ratio (HR), or standardized incidence/mortality rate (SIR/SMR) with their 95% CI were reported (or there were enough data to calculate them). If more than 1 study used the same cohort and objectives, the one with the most wide-ranging population were included.
Data were extracted independently by 2 investigators (Zhang and Su), and discrepancies were resolved by discussion with 2 other investigators (Hao and Sun). For each study, the following information was extracted: author (the first author’s last name), publication year, country, year of the study conducted, number of subjects, age, exposed group size, comparison group size, the follow-up period, ascertainment methods of DM, type of DM, ascertainment methods of EC, number of EC, International Classification of Diseases of EC, adjusted RRs and their 95% CIs, and controlled variables. When studies provided more than 1 RR according to the duration of diabetes before EC was diagnosed, we extracted the RR for individuals diagnosed with diabetes more than 1 year before the diagnosis of EC.
We divided epidemiological studies on the relationship between diabetes and EC risk into 2 types based on their design: cohort studies (incidence and/or mortality rate ratio) and cohort studies with an external comparison group (SIR and/or SMR). We conducted separate meta-analyses of EC incidence and mortality. The measure of effect of interest is the relative risk (RR). Studies reporting an estimate for type 1 diabetes were analyzed separately.
The presence of between-study heterogeneity was investigated using the χ2-based Cochran Q statistic test, and P < 0.1 was interpreted as significant heterogeneity. The I2 index stood for the percentage of the total variation across studies because of heterogeneity, and the value greater than 50% is considered a measure of severe heterogeneity. When there is significant heterogeneity among study results, the random-effects model (DerSimonian and Laird method)18 was used to calculate summary estimate. Otherwise, the summarized estimate was calculated based on the fixed effects model (the inverse variance method).
Stratified analysis was performed for geographical region (Europe, North America, Asia), study design (DM-free as controls, population as controls), year of publication (≤2007, >2007), diabetes ascertainment [self-reported (SR), medical records (MRs), diabetes registry (DR)], outcome ascertainment, type of DM, and by adjustments for some variables (age, physical activity). Only the studies based on rate ratio or HR were included for subgroup analysis.
A sensitivity analysis was also conducted, in which 1 study at a time was removed and the rest were analyzed to estimate whether the results could have been affected markedly by a single study. Several methods were used to evaluate the publication bias. Visual inspection of asymmetry in funnel plots was performed. The Egger test19 was also used to statistically assess publication bias (P < 0.10 was considered to be statistically significant publication bias). All statistical analyses were conducted using STATA 11.0 (STATA, College Station, Tex), and meta-analysis was performed using the “metan” command. All statistical tests were 2 sided.
Characteristics in Selected Studies
Using the predefined search strategy, we identified 21 eligible prospective cohort studies (Fig. 1), including 12,195 incident cases of EC and 575 deaths with a mean follow-up of 13.3 years.3,13–17,20 –33 Of the 21 studies, 11 studies used incidence and/or mortality rates as the measurement of RR,3,13–17,20–24 and 10 cohort studies used SIR/SMR as the measurement of RR.25 –33 The characteristics of the included studies are shown in Table 1 and Table 2. Agreement between the 2 reviewers for studies to be included was good (Cohen κ = 0.92).
In the 21 cohort studies, 6 studies assessed type 2 DM (T2D) only,14,15,20,22 ,31,33 12 studies assessed type 1 and type 2 DM (largely T2D),3,13,16,17,21,23–28 ,32 2 studies (1 article) assessed type 1 and type 2 DM separately,30 and 1 study reported type 1 DM (T1D) only.29 Of the 3 studies reported on T1D and EC, 2 studies provided SIR,29,30 and 1 study provided a standardized mortality ratio.30 The 21 cohorts were from 8 different countries: 7 studies from Sweden,3,16,21,26,27,29 ,31 5 from the United States,20,22,23,25 ,32 3 (2 articles) from the United Kingdom,14,30 2 from Denmark,17,28 and 1 each from Norway,13 Canada,15 Japan,24 and Italy33). Diabetes mellitus was determined on the following: MRs (n = 12),13,16,17,25 –33 self-report (n = 6),3,20–24 DR (n = 2),14,15 and medication use (n = 1).30
Diabetes Mellitus and EC Incidence
As shown in Figure 2, the summary RR with 95% CI was 1.81 (1.38–2.37) in a random-effects model for individuals with diabetes compared with individuals without diabetes or general population. Although there was significant heterogeneity among these studies (test for heterogeneity: Q = 280.96, P < 0.001, I2 = 95.4%). In a random-effects model, the summary RR were 1.93 (95% CI, 1.23–3.02) for cohorts with diabetes compared with those without DM, and 1.65 (1.47–1.86) for cohorts with T2D compared with general population.
We conducted subgroup meta-analyses by geographical region, study design, year of publication, diabetes ascertainment, type of DM, and adjustments for some variables. Table 3 shows the detailed results stratified by characteristics of study (only the T2D or largely T2D). Overall, the positive association between DM and risk of EC was consistently observed in each subgroup. The SRRs were similar for studies conducted in Europe (SRR, 1.88; 95% CI, 1.38–2.57; test for heterogeneity: Q = 264.27, P < 0.001, I2 = 96.2%) or in North America (SRR, 1.58; 95% CI, 1.33–1.89; test for heterogeneity; Q = 0.36, P = 0.834, I2 = 0%). The similar finding was in T2D diabetes (SRR, 1.76; 95% CI, 1.59–1.94) or largely T2D (SRR, 1.95; 95% CI, 1.33–2.87).
The association between DM and EC incidence was stronger in studies published after January 2008 (SRR, 2.04; 95% CI, 1.31–3.17) than in studies published before January 2008 (SRR, 1.62; 95% CI, 1.50–1.75), and diabetes ascertain through MR (SRR, 1.94; 95% CI, 1.39–2.71) than through DR (SRR, 1.60; 95% CI, 1.31–1.95) or SR (SRR, 1.62; 95% CI, 1.21–2.16).
We also investigated the impact of confounding factors on the estimates of RR. When we restricted the meta-analysis to those studies controlled for confounding factors including age, physical activity, more than 3 factors, and 3 factors or less, the positive association between diabetes and risk of EC remained.
Diabetes Mellitus and EC Mortality
We identified 6 cohort studies that reported results on diabetes and mortality from EC22–24,30 ,32,33 (Tables 1 and 2). Combining the results from these studies yielded a summary RR of 1.23 (95% CI, 0.80–1.90) for patients with diabetes compared with those without diabetes or general populations (Fig. 3). There was significant heterogeneity among studies (P = 0.035, I2 = 58.2%). Of the 3 cohort studies that reported EC mortality,22–24 1 reported a statistically significant positive association,22 and 2 did not observe a significant association.23,24 When the 3 studies were pooled, a positive, significant association between diabetes and mortality from EC was found (SRR, 1.47; 95% CI, 1.06–2.04; test for heterogeneity: Q = 1.64, P = 0.440, I2 = 38.7%). Other cohort studies30 ,32,33 reported SMR, and no association was observed between diabetes and EC mortality (SRR, 0.970; 95% CI, 0.52–1.81; test for heterogeneity: Q = 4.93, P = 0.085, I2 = 59.5%).
Type 1 Diabetes and EC Incidence
Two cohorts providing SIRs reported on the association between type 1 diabetes and EC.29,30 When the 2 studies were meta-analyzed, a statistically significant risk association between type 1 diabetes and EC incidence was found (SRR, 2.25; 95% CI, 1.32–3.82; test for heterogeneity: Q = 1.57, P = 0.211, I2 = 36.1%).
Sensitivity and Publication Bias Analyses
To explicit the stability of the positive association between DM and EC incidence, we conducted sensitivity analyses by removing 1 study at a time and calculated the pooled RR for the remaining studies. For example, when we excluded the study of Carstensen et al17 from the analysis (the study carried the most weight), the estimated pooled RR was similar as before (RR, 1.66; 95% CI, 1.51–1.83); the results indicated that no single study significantly influenced the pooled RR.
There was no funnel plot asymmetry for the association between DM and EC risk (Fig. 4). Egger test was used to provide statistical evidence of funnel plot symmetry; the P value for Egger regression asymmetry test was 0.173, suggesting a low probability of publication bias.
Cancers and DM is an important medical, social, and economic concern to the society, and the prevalence of DM is increasing in developed and many developing countries. The worldwide DM epidemic will continue to escalate as a result of the increasing proportion of older people, and thus, it will further contribute to the public health burden of cancer. Over the past 2 decades, many studies have been carried out on DM and EC after the early warning in the early 1990s.13 Some case-control34 and cohort studies15,16 carried out in the north Europe, United States, and Canada investigated the relationship between DM and the risk of EC. In general, these investigations yielded controversial results: findings from our meta-analysis of cohort studies indicated that compared with nondiabetic individuals or general populations, individuals with T2D may have more than 80% increased risk of EC and individuals with type 1 diabetes may have a 2-fold increased risk of EC. However, our analysis does not support the concept that diabetes is associated with increased risk of EC mortality.
This study demonstrate a slightly lower RR compared with a previous systematic review conducted by Friberg et al12 in which diabetic individuals had a 2-fold greater risk of EC compared with individuals without DM. However, their study included both case-control and cohort studies. Case-control studies are subject to several biases, recall and selection bias, which tend to overestimate positive links even when there are none. In this study, we included 14 cohort studies and excluded those case-controlled studies, which will at least partially increase the validity of the association between DM and EC risk. There are 2 mechanisms that could be plausible in the development of EC in diabetic women. Hyperinsulinemia is a mark of diabetes, and insulin has been shown to stimulate the growth of endometrial stromal cells.35 Hyperinsulinemia may also increase levels of free estrogens through inhibiting production of sex hormone–binding globulin, and estrogens have been shown to increase EC risk.36 Both our findings on the relationship between EC mortality and diabetes and our data on the risk of EC in type 1 diabetes are more limited by uncertainty because of the smaller number of studies and of studies including small numbers of cases.
Some potential limitations of this meta-analysis should be acknowledged. First, confounding might be present because DM and EC share several risk factors, such as age, body mass index, and physical activity. In the current analysis, adjustment for some potential confounders did not significantly change the relationship between DM and EC risk. Actually, cohort studies are less susceptible to bias because of the prospective design. However, confounding cannot be fully excluded because our analyses were based on observational studies. Second, diabetes status in some studies was based on self-report, which may lead to some misclassification. This underreporting may result in an underestimate of the magnitude of the association between DM and EC risk. However, earlier study has shown that SR responses for many common chronic diseases such as DM are reliable when compared with MRs.37 Third, it has been reported that type 1 diabetes may not be related to EC risk,30 and most of the studies did not distinguish between type 1 and T2D, which would tend to attenuate any true relation between DM and EC risk. It is likely that most of individuals with diabetes included in these studies had T2D because this disease is by far the most common form particularly in older individuals. Fourth, we extracted the risk estimates that reflected the greatest degree of the control potential confounders because it was hard to obtain raw data from each study to conduct standardized adjustments. Therefore, it is probable that the results based on the adjustment for different confounders were different from those based on standardized adjustments. Fifth, a number of researches have suggested that metformin (an antidiabetic drug) is a protective reagent against the development and progression of some cancers.38 Moreover, the use of insulin or insulin analog was recently indicated to be a contributor to the increased risk of some cancers.39 However, no studies included in this meta-analysis controlled for the effect of antidiabetic drugs, which may distort the true relationship between diabetes and risk of EC. Sixth, great heterogeneity exists for population demographics, study design, duration of follow-up, and adjustment for confounders. We could not account for these differences, despite the use of appropriate meta-analytic techniques with random-effect models. Nevertheless, multiple subgroup analyses found that the risk estimate was robust across various quality components. Finally, only published studies were included in our meta-analysis. Publication bias may have occurred; however, the results obtained from funnel plot analysis and formal statistical tests did not provide evidence for such bias.
In conclusion, there is a significant association between DM and increased risk of EC incidence, and the association probably is not due to confounding factors, despite the fact that these studies are observational. Regarding the current DM epidemic, these results reinforce the claim in favor of greater public awareness about healthy lifestyle to prevent these 2 major increasing public health problems.
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