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LETTERS TO THE EDITOR
Diabetes mellitus and risk of plasma cell and lymphoproliferative disorders in 94,579 cases and 368,348 matched controls
The prevalence of co-occurring diabetes mellitus (DM) and cancer is increasing worldwide. Small studies have shown an association between overall plasma cell and lymphoproliferative disorders (LPD) and DM. We evalu- ated the association between DM and nine LPD as well as unspecified amyloidosis from a population-based matched case-control study in Sweden, including 94,579 cases and 368,348 controls. We found a significant increase of LPD diagnoses within 6 months of DM diag- nosis, but >6 months after DM diagnosis, DM remained associated with increased risk of acute lymphoblastic leukemia (ALL; odds ratio [OR]: 1.47; 95% confidence interval [CI]: 1.04-2.06), chronic lymphocytic leukemia (CLL; OR: 1.18; 95% CI: 1.1-1.25), and amyloidosis (OR: 1.62; 95% CI: 1.44-1.83), as well as decreased risk of Waldenström macroglobulinemia (WM; OR: 0.77; 95% CI: 0.65-0.91). DM was not associated with increased risk of monoclonal gammopathy of undetermined signif- icance (MGUS) after controlling for medical visits (OR: 0.99; 95% CI: 0.92-1.07) or with MGUS progression. Our findings show that DM association is time-dependent and suggest that some previously observed associations may be disease-specific or caused by detection bias. In contrast, our results suggest that there may be a biologi- cal mechanism for the association between DM and ALL.
Epidemiologic studies suggest patients with DM are at a higher risk for many cancers.1-3 Smaller epidemiologic studies and a meta-analysis have shown an association between DM and LPD, including plasma cell disorders, suggesting increased risk for multiple myeloma (MM), leukemia, and non-Hodgkin lymphoma (NHL).1,3-6 One study noted this risk only in CLL.7 However, an associa- tion with DM has not yet been studied in related disor- ders such as MGUS, amyloidosis (unspecified including AL amyloidosis [AL] and related amyloid disorders), WM, Hodgkin lymphoma (HL), hairy cell leukemia (HCL), ALL, and T-cell malignancies, including T-cell lymphoma and mycosis fungoides (TCL). To our knowledge, this is the largest population-based study to evaluate this risk of specific LPD in relation to prior DM diagnosis.
In the main analysis, we conducted a population-based
matched case-control study to evaluate the impact of pre- ceding DM on the development of LPD in adults. We included cases of MM, WM, HL, NHL, TCL, HCL, ALL, and CLL in the Swedish Cancer Registry and cases of amyloidosis (International Classification of Diseases [ICD] codes E85.8, E85.9) and CLL in the Swedish National Patient Registry from 1987 to 2013. Individuals with MGUS were acquired from a network of Swedish hematology and oncology centers and the Swedish National Patient Registry as previsouly described.8 For each case, up to four controls matched by age, sex, and county of residence were included from the general pop- ulation. Cases with no matching controls were excluded. DM diagnosis was acquired from the Swedish National Patient Registry (ICD E10, E11, E12, E13, E14).
We first assessed the risk of LPD at any time after DM diagnosis. Second, because DM may be diagnosed or reg- istered when patients seek care for the symptoms of LPD — which often have considerable diagnostic delay — we assessed the association of LPD diagnosis with DM diag- nosis ≤6 months or >6 months before the LPD diagnosis. We also included a sensitivity analysis with a cut-off at 12 months. Conditional logistic regression, conditioned on the matching variables, was performed to estimate odds ratios. A sensitivity analysis was performed for individu- als with MGUS. Because MGUS is asymptomatic, it is often diagnosed during medical visits for other disorders, and detection bias of MGUS and DM may result from DM or MGUS follow-up. We restricted the analysis to years with available outpatient visit data (≥2001); exclud- ed participants with no clinical encounters (visit or admission) <1 year before the matched MGUS case diag- nosis; and used logistic regression adjusting for number of visits in the year preceding inclusion, in addition to adjusting for sex, age, and year of inclusion.
In a secondary analysis, we assessed the risk of pro- gression from MGUS to MM, WM, amyloidosis, or other LPD. Participants were followed from the date of MGUS diagnosis until diagnosis of LPD. In order to avoid immortal time bias we included DM as a time-dependent covariate in a Cox-model adjusting for age, sex, and year of MGUS diagnosis.
All analyses were performed in R (v3.6.3; R Core Team, 2020) using the survival and survminer packages. The study was conducted in accordance with the principles of the Declaration of Helsinki.
Table 1. Prevalence of diabetes mellitus preceding the diagnosis of lymphoproliferative disorders compared to matched controls.
Diagnosis
LPD (n) DM diagnosed before LPD DM diagnosed ≤6 months before LPD DM diagnosed >6 months before LPD case control DM DM OR 95%CI DM DM OR 95%CI DM DM OR 95%CI
890 3,515 4,402 17,410 32,898 128,896
1.3% 0.4% 3.65 1.67-8.00**
0.9% 0.2% 5.81 3.59-9.4***
1.4% 0.4% 4.08 3.58-4.64***
1.3% 0.3% 3.72 2.07-6.66***
2.3% 0.4% 5.90 4.98-6.98***
2.5% 0.1% 19.19 7.97-46.22*** 4% 2.8% 1.47 1.04-2.06*
case control
case control
case control
HCL
HL
NHL
TCL 1,784 7,012 7% 5.3% 1.35 1.09-1.67**
5.1% 5% 1.03 0.73-1.44 4.2% 3% 1.46 1.23-1.74*** 7.2% 5.9% 1.23 1.17-1.29***
3.7% 4.6% 0.8 0.54-1.18 3.3% 2.8% 1.19 0.98-1.44 5.7% 5.6% 1.03 0.97-1.08 5.7% 4.9% 1.16 0.93-1.47 5.9% 6% 0.97 0.9-1.05
MM
ALL
WM
MGUS# 19,172 75,032 10% 6.8% 1.55 1.46-1.64*** CLL 18,422 71,796 9.3% 6.7% 1.44 1.36-1.53*** Amyloidosis 5,373 21,200 9.6% 5.4% 1.93 1.72-2.15***
15,275 59,695 1,198 4,738 3,380 13,260
8.1% 6.4% 1.30 1.22-1.39*** 6.5% 3% 2.35 1.75-3.15*** 7.6% 7.4% 1.03 0.89-1.19
2.2% 0.5% 4.04 2.91-5.6*** 1.8% 0.4% 4.37 3.74-5.11*** 2% 0.4% 4.82 4.14-5.61*** 1.8% 0.4% 5.33 3.93-7.21***
5.4% 6.8% 0.77 0.65-0.91* 8.2% 6.3% 1.33 1.25-1.41*** 7.3% 6.2% 1.18 1.1-1.25*** 7.8% 5% 1.62 1.44-1.83***
#Refer to text for MGUS adjustment per sensitivity analysis.*P<0.05; **P<0.01; ***P<0.001. DM: diabetes mellitus; LPD: ymphoproliferative disorders; HCL: hairy cell leukemia; HL: Hodgkin lymphoma; NHL: non-Hodgkin lymphoma; TCL: T-cell lymphoma; MM: multiple myeloma; ALL: acute lymphoblastic leukemia; WM: Waldenström macroglobulinemia; MGUS: monoclonal gammopathy of undetermined significance; CLL: chronic lymphocytic leukemia; OR: odds ratio; CI: confidence interval.
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