The Association of Dyslipidemia with the Development of Chronic Lymphocytic Leukemia: A Population-Based Study
Authors: Mozessohn Lee , Earle Craig , Spaner David , Cheng Stephanie Y. , Kumar Matthew , Buckstein Rena 
Published: November 2019

Abstract
Background: Metabolic syndrome (MetS) is a risk factor for the development of cancer. Pre-clinical data suggests that chronic lymphocytic leukemia (CLL) cells are dependent on adipocytes and fatty acids for growth and that aberrant lipid metabolism is an important pathogenic mechanism in CLL. Our objective was to determine whether patients with CLL have a higher incidence of MetS prior to their CLL diagnosis compared to those without CLL and to determine the impact of lipid-lowering medications including statins on survival.
Methods: We conducted a population-based retrospective cohort study in Ontario, Canada using administrative databases (i.e., Ontario Cancer Registry, Ontario Drug Benefit dataset, Aggregated Diagnostic Groups (ADGs), postal codes/income) of adults >66 years old to compare the prevalence of MetS and its components (diabetes, dyslipidemia, hypertension) in CLL patients that preceded their diagnosis. This was compared to age and sex-matched controls without CLL. Logistic regression was used to study the association between MetS and its components to CLL, adjusting for location (rural vs. urban), disease comorbidity burden (ADGs) and socioeconomic status. The Kaplan-Meier method was used to illustrate survival.
Results: We identified 2,124 persons with CLL and 7,935 controls from January 1, 2000 to December 31, 2005 with follow-up until death or March 31, 2014. The mean age was 75.6 and 42.1% were female. Overall, 14.1% had diabetes, 63.1% had hypertension and 28.0% had dyslipidemia. On univariable analysis, only dyslipidemia alone (OR 1.35; 95% CI 1.21 to 1.50) and the combination of diabetes and dyslipidemia (OR 1.18; 95% CI 1.00 to 1.39) were associated with the development of CLL, whereas MetS and diabetes alone were not. On multivariable analysis only dyslipidemia was independently significant (OR 1.30; 95% CI 1.16 to 1.47; see table). Notably, on univariable survival analysis the use of lipid-lowering agents comprised primarily of statins at any time (prior or subsequent to CLL diagnosis) was associated with a significantly improved median overall survival in patients with CLL (7.9 years, 95% CI 7.3 to 8.5 vs. 4.1 years, 95% CI 3.7 to 4.5 years; p < 0.0001; see figure 1).
Conclusions: We demonstrate a higher prevalence of dyslipidemia preceding a diagnosis of CLL compared to controls, supporting pre-clinical data. Also, the association of MetS and CLL appears to be driven primarily by dyslipidemia. Lipid-lowering medications and in particular statins appear to confer a survival advantage in CLL. Further multivariable survival analysis and ultimately prospective studies are needed to confirm these results and test their potential application to intervention strategies.
Table. Exposure Odds Ratio (CLL vs. Control) metabolic syndrome 1.10 (95% CI 0.92 to 1.32) diabetes + dyslipidemia 1.17 (95% CI 0.98 to 1.40) diabetes 1.03 (95% CI 0.90 to 1.17) dyslipidemia 1.30 (95% CI 1.16 to 1.47)
Figure 1. Figure 1.

Disclosures
Spaner: Roche: Honoraria; Lundbeck: Honoraria; Novartis: Research Funding; Janssen: Honoraria. Buckstein:Celgene: Honoraria, Other: Advisory Board.