Diabetes as a Risk Factor for Hematologic Malignancy

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In a meta-analysis of current observational (both case-control and prospective cohort) studies evaluating the potential association between type 2 diabetes mellitus and the incidence of hematological malignancy, an increased risk for non-Hodgkin lymphoma and leukemia was demonstrated as well as a trend toward an increased risk for myeloma. Confounding factors such as age, obesity, smoking, and alcohol (risks for both diabetes and malignancy) could not be completely accounted for in such an analysis. However, certain potential mechanisms, such as increased inflammatory cytokines and over expression of insulin-like growth factor, known features of diabetes, may also be of importance in the development of certain hematological malignancies, and warrant investigation.

Source: Castillo JJ, et al. Increased incidence of non-Hodgkin lymphoma and myeloma in patients with diabetes mellitus type 2: A meta-analysis of observational studies. Blood 2012;119:4845-4850.

Although there have been prior reports of an association of certain hematological malignancies with diabetes mellitus, including a meta-analysis from this same group,1 a clear association has not been definitively established, particularly for certain types of hematologic malignancy. To address this, Castillo and colleagues conducted a second meta-analysis including additional studies published since their prior report. Articles were included in this analysis if they contained original data from epidemiologic observational studies (cohort or case-control) examining potential association between type 2 diabetes mellitus (DM2) and the incidence of lymphoma, leukemia, or myeloma over a minimum follow-up of 3 years. The quality of included studies was determined using the Newcastle-Ottawa Scale.2 There were 26 studies identified (13 case-control and 13 cohort studies) evaluating the association of DM2 with one or more hematological malignancy. The meta-analysis was performed using standard methodology3 with random-effect modeling4 with specific attention to account for publication bias.5

Outcome was calculated as odds ratio (OR) for a specific hematological malignancy occurring in patients with DM2. The OR for non-Hodgkin lymphoma (NHL) was increased at 1.22 (95% confidence interval [CI] 1.07-1.39; P < 0.01) but the OR for Hodgkin lymphoma was not. There was an increased OR for peripheral T-cell lymphoma (OR 2.42, 95% CI 1.24-4.72; P = 0.009) but not for other NHL subtypes. The OR for leukemia was 1.22 (95% CI 1.03-1.44; P = 0.02), and the OR for myeloma was 1.22 (95% CI 0.98-1.53; P = 0.08).

Commentary

Thus, this analysis demonstrated that patients with DM2 have a mild-to-moderate increased risk of developing NHL, particularly peripheral T-cell lypmphoma (PTCL), but, curiously, not Hodgkin lymphoma. Furthermore, the odds for developing leukemia were increased, but the power of the study was insufficient to identify whether the risk pertained to acute or chronic, or for that matter lymphoid or myeloid variants. Further, the risk for myeloma was apparent, but did not quite reach a level of statistical significance.

Epidemiologic studies are famous for identifying interesting and potentially important associations. Thus, it appears the presence of type 2 diabetes renders an increased risk for certain hematologic malignancies. The authors point to a joint consensus statement from the American Diabetes Association and the American Cancer Society6 in which several features of DM2 are mentioned as potential pathways to hematologic malignancy, including inflammation, hyperinsulinemia, increased insulin-like growth factor (IGF), and up-regulation of the IGF-1 receptor. To complicate things, there are a number of factors that are risks for both DM2 and neoplasia (including hematologic malignancy) such as advancing age, obesity, smoking, and alcohol.

Diabetes is very common, especially with advancing age, and with the shifting demographic in the United States and elsewhere, in-depth studies that identify the mechanisms of this association would be of great value, particularly if the causative factors can be modified and the risk for hematological malignancy thereby reduced.

References

1. Mitri J, et al. Diabetes and risk of Non-Hodgkin's lymphoma: A meta-analysis of observational studies. Diabetes Care 2008;31:2391-2397.

2. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603-605.

3. Stroup DF, et al. Meta-analysis of observational studies in epidemiology: A proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008-2012.

4. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539-1558.

5. Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000;56:455-463.

6. Giovannucci E, et al. Diabetes and cancer: A consensus report. CA Cancer J Clin 2010;60:207-221.