Is diabetes mellitus associated with increased incidence and disease-specific mortality in endometrial cancer? A systematic review and meta-analysis of cohort studies

Abstract

Objective: To assess the association between diabetes mellitus (DM) and the incidence and disease-specific mortality of endometrial cancer (EC).

Methods: MEDLINE, EMBASE and conference abstracts of the 2011-2013 Annual Meetings of Society of Gynecological Oncology were searched for reports of original cohort studies that enrolled diabetic and non-diabetic women who were free of EC at baseline to compare the incidence and disease-specific mortality of EC by DM status. The included reports were examined for demographic characteristics of study populations, study design, effect measures and risk of bias. Statistical heterogeneity was evaluated with Chi-square test of the Cochrane Q statistics at the 0.05 significance level and I(2) statistic. Publication bias was assessed by visual examination of a funnel plot and the Egger's test for small-study effects.

Results: Twenty-nine cohort studies (17 prospective, 12 retrospective) were eligible for this review, 23 of which reported EC incidence, five reported disease-specific mortality and one reported both. For incidence of EC among women with versus without DM, the summary relative risk (RR) was 1.89 (95%CI, 1.46-2.45; p<0.001) and the summary incidence rate ratio was 1.61 (95%CI, 1.51-1.71; p<0.001). The pooled RR of disease-specific mortality was 1.32 (95%CI, 1.10-1.60; p=0.003), while results in the studies reporting standardized mortality ratios were inconsistent. There remains considerable amount of clinical and methodological heterogeneity among the included studies; moreover, the hazard ratios for incident EC showed significant statistical heterogeneity and therefore were not quantitatively synthesized.

Conclusions: There is consistent evidence for an independent association between DM and an increased risk of incident EC, while the association between DM and EC-specific mortality remains uncertain. Further studies with better considerations for selection bias, information bias and confounding will further facilitate causal inference involving DM and EC.

Keywords: Diabetes mellitus; Disease-specific mortality; Endometrial cancer; Incidence; Meta-analysis; Systematic review.

Fig. 1

Flowchart of study selection^1,2,3. 1. Searched on Feb 12th 2014. 2. The cohort studies by Weiderpass et al. and Adami et al. were derived from the same cohort and since the former study focused on endometrial cancer and breast cancer while the second one compared multiple cancer outcomes, only the study by Weiderpass et al. was retained. 3. SR: systematic review.

Fig. 2

Meta-analysis of the adjusted incidence measures of endometrial cancer^1–5. 1. Abbreviations: SIR: standardized incidence ratio; RR: relative risk; HR: hazard ratio; IRR: incidence rate ratio; OR: odds ratio; ES: effect size. 2. SIRs were derived from indirect standardization, where different reference groups were used. Therefore by definition, SIRs are not directly comparable and should not be quantitatively combined across studies. 3. HRs were not summarized due to the significant heterogeneity across studies. 4. The IRR from the study by Carstensen et al. being analyzed was imputed from the graphs, which compared cancer incidence among diabetic women using insulin to that among the non-diabetic women. 5. The percentage weight for each study was calculated as the proportion of weight it carries among all the studies regardless of the effect measures reported.

Fig. 3

Meta-analysis of the adjusted disease-specific mortality measures of endometrial cancer^1–3. 1. Abbreviations: RR: relative risk; SMR: standardized mortality ratio; ES: effect size. 2. SMRs were derived from indirect standardization, where different reference groups were used. Therefore by definition, SMRs are not directly comparable and should not be quantitatively combined across studies. 3. The percentage weight for each study was calculated as the proportion of weight it carries among all the studies regardless of the effect measures reported.

Fig. 4

Funnel plot for all included studies¹. 1. Abbreviations: RR: relative risk; HR: hazard ratio; IRR: incidence rate ratio; OR: odds ratio; SIR: standardized incidence ratio; SMR: standardized mortality ratio; Cl: confidence limit.