Statin Use and Chronic Lymphocytic Leukemia Incidence: A Nested Case–Control Study in Manitoba, Canada

Abstract

Background: Recent studies have reported reduced risk of chronic lymphocytic leukemia (CLL) among statin users. However, the possibility that the effect of statins may differ by their chemical or pharmacodynamic properties has not been investigated. Methods: In this nested case-control study, all Manitobans ages !40 years when diagnosed with CLL (as a first cancer) from 1999 to 2014 (n ¼ 1,385) were matched (on gender, age, residence, and duration of insurance coverage) to cancer-free controls (n ¼ 6,841). Using conditional logistic regression, statin use was analyzed by individual statins and groups: hydrophilic, low-potency lipophilic (fluvastatin and lovastatin), and high-potency lipophilic statins. Results: Statin users constituted 27% and 28% of the CLL cases and controls, respectively. After adjusting for potential confounding by indication, patterns of healthcare utilization, and use of other drugs, CLL incidence was not associated with use of hydrophilic [odds ratio (OR) ¼ 1.08; 95% confidence interval (CI), 0.86-1.34] or high-potency lipophilic (OR ¼ 0.94; 95% CI, 0.79-1.11) statins. Low-potency lipophilic statins were associated with a lower risk of CLL (OR ¼ 0.64; 95% CI, 0.45-0.92), with stronger association (OR ¼ 0.44; 95% CI, 0.22-0.88) observed with more regular use (half to full standard dose on average). Conclusions: We found an association between lowpotency lipophilic statin use and reduced CLL risk, with a possible dose-response effect. Impact: Although requiring replication in future studies, our findings suggest that the effect of statins on CLL risk may depend on their specific chemical or pharmacodynamic properties.

Network-Based Drug Discovery Identifies Statins as a Repurposing Agent to Improve Activity of Current Therapies in Chronic Lymphocytic Leukemia.

“…Furthermore, the mevalonate pathway inhibition caused by simvastatin abrogates the protective effect of stromal cells in CLL cells [43]. Recently, an association between low-potency lipophilic statin (lovastatin and uvastatin) use and a reduced CLL risk, with a possible dose-response effect has been reported [44]. Our results emphasize on the fact that statins might play a role on the inhibition of the supportive microenvironment in CLL.…”

Targeting the Mevalonate Pathway in Cancer

“…Statins have drawn interest from oncologists based on epidemiological data [83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99] as well as numerous studies showing anticancer effects (a term we use here to encompass cytotoxic, cytostatic, and antimetastastic or differentiation-inducing effects) in cell lines and animal models with minimal toxicity to normal cells and tissues [47,[100][101][102][103][104][105][106][107][108][109]. However, the rigor of the epidemiological evidence has been challenged [110,111], and, as noted above, the concentrations of statins needed to suppress cancer cell survival in vitro are generally much higher than clinically achievable levels at prescribed doses in plasma and in tumors [22].…”

“…Epidemiological studies of statins in oncology often assume that all statins are equivalent [83][84][85][86][87][88][89][90][91][92][93][94][95][96][97][98][99].…”

Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia

“…It has also observed a high incidence of hypercholesterolemia in CLL patients supporting that cholesterol-lowering might impact the disease course 43 . Recently, an association between low-potency lipophilic statin (lovastatin and fluvastatin) use and a reduced CLL risk, with a possible dose-response effect has been reported 44 . Our results emphasize on the fact that statins might play a role on the inhibition of the supportive microenvironment in CLL.…”