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Letters to the Editor
Patients with MGUS, MM, amyloidosis, HL, NHL, TCL, ALL, and CLL were more likely to have a preceding DM diagnosis compared to matched controls, whereas patients with WM and HCL were not. These results remained significant for MGUS, amyloidosis, ALL, and CLL when DM was diagnosed >6 months prior to the LPD (Table 1). Large Israeli and Canadian studies showed an attenuated long-term risk for MM, NHL, and leukemia >1 year after DM diagnosis, although the association remained significant.3,4 Our study had substantially more cases. Other studies that have not evaluated time-depen- dent risk showed an overall association of DM with MM, NHL, and CLL.5-7 Prior data suggesting that maternal DM increases childhood ALL risk in offspring indicate biolog- ic mechanisms behind this long-term increased risk of ALL associated with DM, thus warranting further study in adults.9
Diagnosis of DM >6 months prior was associated with decreased risk of development of WM (OR: 0.77; 95% CI: 0.65-0.91; P<0.05), which is unique compared to all other LPD and has not been reported before. This may be related to the protective effect of anti-diabetic drugs10 although no data is available on their effect in patients with WM. However, further research is needed to expand on this finding of the study.
Risk of MGUS and CLL remained increased after excluding DM diagnoses <6 months prior. These disor- ders are often asymptomatic, particularly MGUS, and their diagnosis might be associated with medical follow- up. In a sensitivity analysis controlling for the number of clinic visits, we found that MGUS was not increased in DM (OR: 0.99; 95% CI: 0.92-1.07; P=0.89), indicating that detection bias during medical follow-up likely explains the association we had initially observed in MGUS. CLL can present both as an asymptomatic or symptomatic disease, meaning that a similar analysis for CLL would be difficult to interpret. However, a large pro- portion of CLL patients are asymptomatic, so a similar detection bias in part may be reasonably conjectured in CLL.
Long-term risk of amyloidosis was also increased in DM (OR: 1.62; 95% CI: 1.44-1.83; P<0.001). DM is a chronic inflammatory disorder associated with amyloid deposition in pancreatic islets11 and kidneys.12 However, these sites are not routinely biopsied, so these findings are likely to be incidental and underrepresented by inter- national classification of diseases (ICD) codes. This sug- gests that the increased risk of AL may be related to DM. Light chain glycosylation is associated more frequently with AL than with other LPD13 and DM is associated with higher incidence of protein glycosylation,14 suggest- ing a possible mechanism for the role of DM in the devel- opment of AL.
Short-term risk of cancer diagnosis after DM diagnosis may result from detection bias, particularly because risk factors (aging, obesity, physical activity, diet, alcohol, and smoking) are common to both DM and cancer. In symp- tomatic conditions, patients may have DM diagnosed <6 months prior through clinical encounters for similar symptoms of fatigue and weight loss. In asymptomatic disorders such as MGUS and CLL, clinical encounters for DM may lead to increased rates of LPD diagnosis. Alternatively, a direct biological link via hyperinsulinemia (insulin like growth factor-1), chronic inflammation (cytokines), or hyperglycemia (epigenetic changes or pro- tein glycation/glycosylation) may lead to development or acceleration of early-stage cancer, particularly as patients may have prediabetes or undiagnosed DM for many years.15 Patients with DM for >6 months are likely to be
Table 2. Monoclonal gammopathy of undetermined significance pro- gression to more advanced disease by diabetes mellitus state.
n
Median age (years)
Age range (years)
male(%) 60 52
Diabetes mellitus
No diabetes mellitus
2,224 73 26-95
12,563 72 18-99
Diagnosed with DM after MGUS Progressed n (%)
MM
WM
Amyloidosis unspecified Other LPD
Cox models (no DM as reference) Progressed (overall)
MM
WM
Amyloidosis unspecified Other LPD
739 (33%) 220 (9.9%) 137 (6.2%)# 35 (1.6%) 14 (0.6%)# 35 (1.6%)
-
2,031 (16.2%) 1,115 (8.9%)# 380 (3.0%) 153 (1.2%)# 384 (3.1%)
0.89 (95% CI: 0.78-1.03); P=0.11 1.06 (95% CI: 0.88-1.26); P=0.54 0.72 (95% CI: 0.51-1.02); P=0.06 0.74 (95% CI: 0.43-1.29); P=0.29 0.70 (95% CI: 0.50-1.00); P=0.047
#These numbers include two individuals - one with diabetes mellitus (DM) with concomitant multiple myeloma (MM) and amyloidosis and one without DM with concomitant Waldenström macroglobulinemia (WM) and amyloidosis diagnosed on the same day. They have been counted once for each diagnosis. MGUS: mono- clonal gammopathy of undetermined significance; LPD: lymphoproliferative disor- der.
on anti-diabetic medications including metformin, which protects against MGUS progression,10 and insulin, which does not increase the risk for NHL and MM compared to untreated diabetics.6 Sensitivity analysis using a 12 month cut-off for time between DM and LPD diagnosis showed essentially the same results (data not shown).
Patients with DM are not more likely to progress from MGUS to MM, WM, amyloidosis, or other LPD (Table 2). However, we could not control for the use of anti-diabet- ic drugs that may lower rates of MGUS progression.10 Interestingly, we found decreased risk of progression from MGUS to WM of borderline significance (P=0.06) which is consistent with the findings of the main analysis showing an association of DM and decreased risk of WM.
The large sample size to detect differences in rare dis- eases is a major strength of this study. Limitations include lack of granular information related to DM (including DM subtypes), body mass index, LPD, and race/ethnicity, as well as a likely lack of racial/ethnic diversity in this population. Also, the diagnoses are based on ICD codes, relying on the correct registration by physicians.
This is the largest population-based study of preceding DM diagnosis on the time-dependent risk of individual LPD, showing there is an attenuated long-term risk with ALL, CLL, and amyloidosis. Furthermore, DM was not associated with MGUS progression.
Urvi A. Shah,1,* Sæmundur Rögnvaldsson,2,*
Andriy Derkach,3 Magnus Björkholm,4 Ingemar Turesson,5 Yael David,6 Malin Hultcrantz,1 Carlyn Tan,1 Hani Hassoun,1 Neha Korde,1 Alexander Lesokhin,1 Sham Mailankody,1 Sigurður Yngvi Kristinsson2,4,# and C. Ola Landgren7,#
1Department of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2Department of Medicine, University of Iceland, Reykjavík, Iceland; 3Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer
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