Lipophilic Statin Use Research Articles

Statin use and risk of pancreatic cancer: a meta-analysis

Statins are commonly prescribed medications that potently reduce cholesterol levels and the risk of cardiovascular events. Preclinical studies suggested statins also possess cancer chemopreventive properties. However, the clinical studies provided contradictory results as to whether statins influence the risk of pancreatic cancer. Herein, we present this meta-analysis to assess the association between statin use and risk of pancreatic cancer. We conducted a comprehensive search up to August 2011 for the eligible studies. Pooled relative risk (RR) estimates and corresponding 95 % confidence intervals (CIs) were calculated using the inverse-variance-weighted random-effects model. Subgroup analyses were conducted where data were available. Heterogeneity was assessed by the Cochran's Q test and the I(2) statistic. We included 16 studies that involving 1,692,863 participants and 7,807 pancreatic cancer cases. Pooled results only indicated a non-significant decrease of pancreatic cancer risk among all statin users (RR 0.89; 95 % CIs, 0.74-1.07). Similar results were obtained in the subgroup analyses of the long-term (more than 4 years) follow-up (RR 0.94, 0.81-1.08) and statin use (RR 0.97, 0.76-1.23), and a null association was found between lipophilic statin use and pancreatic cancer risk (RR 1.03, 0.92-1.16). No evidence of publication bias was observed in the present meta-analysis. However, significant heterogeneity was detected among all studies (p < 0.00001, I(2) = 81 %). In conclusion, our results suggest that there is no association between statin use and pancreatic cancer risk, when statins are taken at daily doses for cardiovascular event prevention.

Abstract 4678: Post-diagnosis use of lipophilic statins and breast cancer recurrence: A Danish nationwide cohort study

Abstract Statins may affect non-cardiovascular endpoints, including cancer incidence and survival. These effects may depend on the solubility of the specific medicine. Our objective was to measure the association between post-diagnosis lipophilic and hydrophilic statin use and recurrence among non-metastatic breast cancer patients. We ascertained incident cases of stage I-III invasive breast cancer diagnosed in Denmark between 1996 and 2006 from the Danish Breast Cancer Cooperative Group registry, and linked these records to the Register of Medicinal Products (RMP), which automatically logs pharmacy transactions in Denmark. We determined statin prescriptions filled by cohort members by searching the RMP for appropriate ATC codes. Statins were classified by solubility (Table 1) and exposure status was updated yearly. Follow-up began upon completion of primary therapy and continued until the first of breast cancer recurrence, death from any cause, emigration from Denmark, or the end of 2006. Associations were estimated with time-dependent crude and multivariate Cox regression models. We enrolled 18,769 breast cancer patients, with a median follow-up of 6.2 years. Of the 3,282 women ever prescribed a statin after diagnosis, 2,518 were exclusively prescribed lipophilic statins and 210 were exclusively prescribed hydrophilic statins. Crude and multivariate models yielded similar estimates. Lipophilic (but not hydrophilic) statin use was associated with a reduced rate of breast cancer recurrence (compared with no statin use: multivariate HR for lipophilic statin use = 0.65, 95% CI: 0.55, 0.76; multivariate HR for hydrophilic statin use = 0.89, 95% CI: 0.61, 1.3). Associations were similar when estimated in the subset of women with no pre-diagnosis statin exposure. In this population-based prospective cohort study with complete information on prognostic and treatment variables, breast cancer patients who took lipophilic statins had a reduced rate of breast cancer recurrence. (a) Hazard ratios adjusted for age, menopausal status, tumor stage, ER status, adjuvant hormonal therapy, type of surgery, comorbidity, and co-prescription of aspirin. Estimates were similar in models further adjusted for chemotherapy, type of surgery, receipt of radiotherapy, and co-prescription of hormone replacement therapy, NSAIDs, anticoagulants and ACE inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4678. doi:10.1158/1538-7445.AM2011-4678

Lipophilic Statin Use and Risk of Breast Cancer Subtypes

Statins are widely used and of high interest as potential chemopreventive agents for cancer. Preclinical studies suggest that lipophilic statins have anticancer properties targeting hormone receptor (HR)-negative breast cancer. Few epidemiologic studies have investigated the relationship between lipophilic statin use and risk for breast cancer, stratified by HR status. We conducted a large case-control study within Kaiser Permanente of Northern California (KPNC) to determine whether chronic use of lipophilic statins is associated with decreased risk of HR-negative breast cancer or other breast cancer subtypes. We identified 22,488 breast cancer cases diagnosed from 1997 to 2007, and 224,860 controls matched to cases based upon birth year and duration of KPNC pharmacy coverage. Use of lipophilic statins was ascertained using the comprehensive electronic pharmacy records of KPNC. We found no association between lipophilic statin use (≥2 y versus never) and overall breast cancer risk (odds ratio(adj), 1.02; 95% CI, 0.97-1.08) in conditional logistic regression models adjusted for oral contraceptive and hormone therapy use. Women who used lipophilic statins did not have a decreased risk of HR-negative breast cancer (odds ratio(adj), 0.98; 95% CI, 0.84-1.14) nor altered risk of HR-positive disease (odds ratio(adj), 1.03; 95% CI, 0.97-1.10). Furthermore, lipophilic statin use was not associated with risk of any of the intrinsic subtypes, luminal A, luminal B, human epidermal growth factor receptor 2 positive/estrogen receptor negative, or triple negative. Our results do not support an association of lipophilic statin use with the risk for breast cancer in general or with risks of HR-negative or other breast cancer subtypes specifically. These findings do not confirm previous reports of a possible preventive association.

Abstract 1838: Lipophilic statin use and risk of breast cancer subtypes

Abstract Background: Preclinical studies suggest that lipophilic statins have anti-cancer properties and that hormone receptor (HR)-negative breast cancer is the most responsive subtype. Kumar et al. (2008) reported that patients with HR-negative cancers were less likely to have used lipophilic statins than patients with HR-positive disease. However, this study within Kaiser Permanente Northern California (KPNC) included only cases diagnosed in 2003 and, because of its case-only design, was unable to make risk inferences. We conducted a large case-control study spanning 11 years within KPNC to investigate whether lipophilic statin use is associated with: (1) decreased risk of HR-negative breast cancer, (2) increased risk of HR-positive breast cancer or (3) both. Furthermore, we investigated whether lipophilic statin use is associated with the risk of the intrinsic breast cancer subtypes and attempted to replicate Kumar et al.'s results. Methods: We identified 22,486 cases with invasive breast cancer of known HR-status diagnosed at KPNC from 1997 to 2007. Controls were individually matched to cases at a ratio of 10:1, based on year of birth and KPNC pharmacy coverage. Use of the lipophilic statins, oral contraceptives (OC) and menopausal hormones (HT) was ascertained via KPNC's electronic pharmacy records. Case-control odds ratios (OR) were adjusted for age, pharmacy coverage, OC and HT use; case-only ORs were additionally adjusted for race. We performed an external adjustment for the unmeasured confounders obesity and alcohol use. Results: We found no association between lipophilic statin use (≥ 2 years vs. never) and overall breast cancer risk (OR=1.02; 95% CI=0.97-1.08; p=0.42). Lipophilic statin users did not have a decreased risk of HR-negative breast cancer (OR=0.98; 95% CI=0.84 −1.14; p=0.74), or an increased risk of HR-positive disease (OR=1.03; 95% CI=0.97-1.10; p=0.31). Lipophilic statin use was not associated with risk of any of the intrinsic breast cancer subtypes, luminal A, luminal B, HER2+/ER- and triple negative. In case-only analysis including all 11 years, HR-negative cases had slightly lower odds of being lipophilic statins users (OR=0.91; 95% CI=0.78-1.05; p=0.18), however, this result was not statistically significant. We were able to replicate Kumar et al.'s findings for 2003, which was the only year in the 11-year study period with a statistically significantly lower proportion of HR-negative cases among statin users, and thus, likely a stochastic outlier. Conclusions: Our results do not support an association between lipophilic statin use and breast cancer risk in general or the risk of ER, PR and HER2-defined subtypes specifically. Any effect, if it exists at all, is likely much smaller than previous studies suggested. These findings should be considered in the interpretation of several ongoing breast cancer chemoprevention trials of lipophilic statins as well as in the planning of future interventional studies using statins. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1838.

Lipophilic but not hydrophilic statins selectively induce cell death in gynecological cancers expressing high levels of HMGCoA reductase.

Recent reports have suggested that statins induce cell death in certain epithelial cancers and that patients taking statins to reduce cholesterol levels possess lower cancer incidence. However, little is known about the mechanisms of action of different statins or the effects of these statins in gynaecological malignancies. The apoptotic potential of two lipophilic statins (lovastatin and simvastatin) and one hydrophilic statin (pravastatin) was assessed in cancer cell lines (ovarian, endometrial and cervical) and primary cultured cancerous and normal tissues. Cell viability was studied by MTS assays and apoptosis was confirmed by Western blotting of PARP and flow cytometry. The expressions of key apoptotic cascade proteins were analysed. Our results demonstrate that both lovastatin and simvastatin, but not pravastatin, selectively induced cell death in dose- and time-dependent manner in ovarian, endometrial and cervical cancers. Little or no toxicity was observed with any statin on normal cells. Lipophilic statins induced activation of caspase-8 and -9; BID cleavage, cytochrome C release and PARP cleavage. Statin-sensitive cancers expressed high levels of HMG-CoA reductase compared with resistant cultures. The effect of lipophilic statins was dependent on inhibition of enzymatic activity of HMG-CoA reductase since mevalonate pre-incubation almost completely abrogated the apoptotic effect. Moreover, the apoptotic effect involved the inhibition of synthesis of geranylgeranyl pyrophosphate rather than farnesyl pyrophosphate. In conclusion, lipophilic but not hydrophilic statins induce cell death through activation of extrinsic and intrinsic apoptotic cascades in cancerous cells from the human female genital tract, which express high levels of HMG-CoA reductase. These results promote further investigation in the use of lipophilic statins as anticancer agents in gynaecological malignancies.

Can lipophilic statins affect Her2/neu expression in breast cancer?

1521 Background: Growing evidence suggests the chemopreventive potential of statins against breast cancer, primarily based on preclinical studies. Lipophilic statins, particularly fluvastatin, have recently been shown in vitro to potentiate the cytotoxic effect of trastuzumab on Her2/neu positive breast cancer cells. However, no clinical studies have explored the relationship between lipophilic statin use and Her2/neu expression in breast cancer till date. We therefore performed a study to determine whether lipophilic statin use in breast cancer patients prior to diagnosis is related to the development of specific Her2/neu type (negative or positive) tumor compared to statin non- users. Methods: A retrospective cohort analysis of 363 female patients from the Albert Einstein Tumor Registry, presenting with breast cancer between January 1, 2004 and June 30, 2006 was done. The main outcome measured was the Her2/neu status of tumors in lipophilic statin users versus non-users, controlling for race, menopausal...

Statins and Cancer Risk

Objective Despite numerous randomized clinical trials and observational epidemiologic studies, evidence on the potential effectiveness of statins for prevention of cancer remains controversial. The objective of this study was to investigate the relation between lipophilic statin use and cancer occurrence. Methods We conducted a retrospective observational study based on a medical administrative database in the province of Quebec, Canada (1998-2004). Patients aged 45 years or more and discharged from the hospital alive after admission for acute myocardial infarction were included. High- and low-dose statin use were defined as a filled prescription, within 3 days after index discharge, at or above (below) the statin-specific target dose, for any of the 4 lipophilic statin medications: atorvastatin, simvastatin, lovastatin, or fluvastatin. Statin non-use was defined as non-use of any statins while simultaneously using major non-statin cardiac medications. A total of 30,076 patients, including high-dose statin users (n = 6015), low-dose statin users (n = 5323), and non-users (n = 18,738), were followed for up to 7 years. Multivariable Cox regression analyses were performed to estimate associations between statin dose category and the incidence of admission to hospital with a diagnosis of any type of cancer. Results The crude incidence rates of hospital admission with the diagnosis of any type of cancer were 13.9, 17.2, and 26.0 per 1000 person-years in statin high-dose users, low-dose users, and non-users, respectively. The estimated adjusted hazard ratios were 0.75 (95% confidence interval [CI], 0.60-0.95) for statin use at high dose and 0.89 (95% CI, 0.75-1.07) for statin use at low dose. No significant time-dependence of the effect of statins at either dose was detected. Conclusion The use of lipophilic statins at sufficiently high dose might be associated with a clinically important reduction in the incidence of cancer.

Statin use and risk of breast cancer

Findings that statins inhibited the proliferation of breast cancer cells in vitro and in rodents have raised interest in whether the use of statins might decrease a woman's risk of developing breast cancer. We analyzed data from a population-based case-control study to evaluate the association between the use of statins and breast cancer risk. Cases of incident invasive breast cancer in women 50 years of age or older and diagnosed from 1995-2001 were identified from population-based cancer registries in Wisconsin, Massachusetts, and New Hampshire. Controls were randomly selected, within each state, from lists of licensed drivers and Medicare beneficiaries. Information on the use of statins and other breast cancer risk factors was ascertained from structured telephone interviews. Overall, breast cancer cases were not more likely than controls to have ever used statins. Ever use of lipophilic statins as a group (simvastatin, lovastatin, and fluvastatin) and ever use of the hydrophilic statin pravastatin were also not associated with breast cancer risk. Ever use of fluvastatin was associated with a decreased risk of breast cancer (odds ratio [OR], 0.5; 95% confidence interval, 0.3-0.8) but the magnitude of the ORs did not vary across categories of duration of use. The use of statins overall was not associated with breast cancer risk.

Post-diagnosis statin use and breast recurrence sites in early stage breast cancer survivors

To the Editor, We read the article by Kwan et al. [1] in which they showed an inverse association between post-diagnosis, lipophilic statin use and risk of breast cancer recurrence in a prospective cohort study of early stage breast cancer survivors. However, information related to the specific recurrence sites were not discussed in their study. Evidence from animal models suggests that activation of osteoclastmediated bone resorption is an essential step in the process of bone metastasis [2]. Bisphosphonates are class of agents most frequently used to reduce skeletal-related events in patients with bone metastases by inhibiting osteoclast activity through inhibition of mevolanate pathway. Relationship between statins and nitrogen-containing bisphosphonates has been established. Both drugs interfere with the same metabolic pathway. Both exert their activity in the mevalonate pathway This pathway leads to cholesterol synthesis and to protein prenylation, adding a lipid chain to transpeptidases such as Ras and Ras-like transpeptidases in the osteoclast membrane which in turn leads to activation of osteoclasts [3]. Furthermore, some studies showed that bisphosphonates might reduce or prevent the incidence of bone metastases by inhibiting tumour-induced osteoclastic resorption of bone when they are used as an adjuvant treatment of breast cancer [4, 5]. Therefore, we suggest that post-diagnosis, lipophilic statin use may reduce bone metastases more than other recurrence sites in early stage breast cancer survivors.

Post-diagnosis statin use and breast cancer recurrence in a prospective cohort study of early stage breast cancer survivors

We examined the association between post-diagnosis statin use (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] inhibitors) and risk of breast cancer recurrence. The study included 1945 early stage breast cancer survivors participating in the Life After Cancer Epidemiology (LACE) Study. Women who were diagnosed from 1997 to 2000 and identified from the Kaiser Permanente Northern California (KPNC) Cancer Registry entered the cohort on average 2 years post-diagnosis. Information on statin use was obtained from the KPNC pharmacy database. A total of 210 breast cancer recurrences were reported and verified by medical record review. Cox proportional hazard models were used to estimate rate ratios (RR) and 95% confidence intervals (CI). The mean duration of statin use in the cohort among those who initiated use post-diagnosis was 1.96 years, and lipophilic statins were mainly used (97.8%). Starting statins after diagnosis was suggestive of a decreased risk of breast cancer recurrence (RR = 0.67; 95% CI: 0.39-1.13). Risk of recurrence decreased with increasing duration of statin use after diagnosis (p linear trend = 0.02). Our findings provide initial support for an inverse association between post-diagnosis, lipophilic statin use and risk of breast cancer recurrence.