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  Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 54  |  Issue : 2  |  Page : 470-477
 

Statins and risk of cancer: A meta-analysis of randomized, double-blind, placebo-controlled trials


1 Department of Cancer Control and Population Health; Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang, Republic of Korea
2 Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy; Cancer Epidemiology Branch, Division of Cancer Epidemiology and Prevention, Research Institute; Department of Family Medicine and Center for Cancer Prevention and Detection, National Cancer Center, Goyang, Republic of Korea
3 Department of Cancer Control and Population Health, National Cancer Center Graduate School of Cancer Science and Policy, Goyang, Republic of Korea

Date of Web Publication21-Feb-2018

Correspondence Address:
Prof. S K Myung
Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy; Cancer Epidemiology Branch, Division of Cancer Epidemiology and Prevention, Research Institute; Department of Family Medicine and Center for Cancer Prevention and Detection, National Cancer Center, Goyang
Republic of Korea
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_214_17

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 » Abstract 


PURPOSE: Several meta-analyses of randomized controlled trials (RCTs) reported no association between the use of statins and the risk of cancer. However, they included open-label RCTs, which did not use placebo as a control group. This study aimed to evaluate the effect of statins on cancer risk using a meta-analysis of randomized, double-blind, placebo-controlled trials (RDBPCTs). METHODS: We searched PubMed, EMBASE, and the Cochrane Library in March 2016. Two individual authors reviewed and selected RDBPCTs based on selection criteria. RESULTS: Out of 676 retrieved articles, a total of 21 RDBPCTs with 65,196 participants (32,618 in the statin group and 32,578 in the placebo group) were included in the meta-analysis. Overall, we found that there was no significant association between the use of statins and the risk of cancer (relative risk 0.97, 95% confidence interval 0.92–1.02, I2 = 0.0%) in a fixed-effect meta-analysis. In addition, in the subgroup meta-analyses, no beneficial effect of statins was observed when analyzed by statin type, country, follow-up period, methodological quality, underlying diseases/population, and type of cancer. CONCLUSIONS: The current meta-analysis of RDBPCTs found that there was no association between the use of statins and the risk of cancer.


Keywords: 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, cancer, meta-analysis, randomized controlled trials, statins


How to cite this article:
Kim M K, Myung S K, Tran B T, Park B. Statins and risk of cancer: A meta-analysis of randomized, double-blind, placebo-controlled trials. Indian J Cancer 2017;54:470-7

How to cite this URL:
Kim M K, Myung S K, Tran B T, Park B. Statins and risk of cancer: A meta-analysis of randomized, double-blind, placebo-controlled trials. Indian J Cancer [serial online] 2017 [cited 2019 Sep 19];54:470-7. Available from: http://www.indianjcancer.com/text.asp?2017/54/2/470/225791





 » Introduction Top


Statins, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, have become one of the most commonly prescribed drugs. In 2012, Crestor, a brand of rosuvastatin, was ranked third among the top 200 products by sales, and lovastatin, atorvastatin, simvastatin, and pravastatin were in the top 200 products by prescribed numbers.[1] Statins not only decrease the risk of coronary heart disease by lowering lipid levels but also stabilize plaque formation and reduce inflammation as well as thrombogenicity.[2],[3],[4]

Although several in vitro and animal studies reported statin-mediated carcinogenesis,[5],[6] many laboratory studies indicated antineoplastic properties of statins, such as reduction of tumor growth, inhibition of proliferation and metastasis, and induction of apoptosis.[7],[8],[9] However, observational epidemiological studies and randomized controlled trials (RCTs) reported inconsistent findings regarding the efficacy of statins in cancer prevention.[10],[11],[12],[13],[14],[15] Although three major large meta-analyses of RCTs [16],[17],[18] found no significant association between statins and cancer incidence, they included open-label RCTs, which did not use placebo as a control group. An open-label design is liable to performance bias such as differential behavior of study participants between the statin group and control groups or differential care by doctors or researchers.[19] Thus, this bias might affect the findings from an open-label RCTs.

The current study aimed to evaluate the effect of statins on the risk of cancer by using a meta-analysis of randomized, double-blind, placebo-controlled trials (RDBPCTs) according to various factors such as type of statin, country, follow-up period, methodological quality, underlying diseases/population, and cancer types.


 » Methods Top


Literature search

We searched PubMed, EMBASE, and the Cochrane Library in March 2016 with no date restrictions, using common keywords related to statins and cancer. The keywords were “statin,” “HMG-CoA reductase inhibitor,” “atorvastatin,” “fluvastatin,” “lovastatin,” “pitavastatin,” “pravastatin,” “rosuvastatin,” or “simvastatin” and “cancer,” “carcinoma,” or “malignant neoplasm.” In addition, we reviewed the relevant articles in their bibliographies.

Selection criteria

We included RDBPCTs that reported cancer incidence and used statins as a monotherapy and placebos as a control. If a study had multiple publications, the most recently published article was included.

Selection of relevant studies

Based on the prediscussed eligibility criteria, two of the authors (MK and BT) selected data independently from the databases and bibliographies. Disagreements between evaluators during the selection process were resolved by discussion or consulting a third author (SK).

Assessment of methodological quality

The Jadad score was used to assess the methodological quality of the trials.[20] The method of scoring is one of the most frequently used assessment tools. Scores ranged from 0 (lowest quality) to 5 (highest quality). The 5-full-point scale consists of points for randomization (1 point for description of randomization; additional 1 point for table of random numbers or computer-generated randomization), double-blinded (1 point for description of double-blinding 1 point; additional 1 point for use of masking), and follow-up (1 point for description of withdrawals and dropouts). Scores were calculated for each analyzed trial. Twenty-one analyzed trials were classified into two groups depending on the mean score of 3.85. Trials scored <3.85 were grouped together, and trials scored ≥3.85 were grouped together for subgroup analyses.

Overall and subgroup analyses

Among the final 21 trials, the association between statins and cancer incidence was investigated for the overall analysis. In addition, subgroup analyses were performed using various factors, including types of statins (lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin, or rosuvastatin), lipophilic or hydrophilic (lipophilic: atorvastatin, fluvastatin, lovastatin, or simvastatin; hydrophilic: pravastatin or rosuvastatin), sex (male only), age (>50 years), country by continents and country (North America: United States, Canada, and United States and Canada; Nordic countries; Finland; Europe: Netherlands, United Kingdom, Italy, Scotland, Germany, and UK and Ireland; Australia and New Zealand; and various countries), follow-up period (<3.87/≥years), methodological quality by the Jadad score, underlying diseases/population (hypercholesterolemia; diabetes; renal problem: renal transplant recipient who underwent maintenance hemodialysis; vascular disease; history of angioplasty; evidence of vascular disease and normal), and cancer types by organ system and specific site (genitourinary: prostate, prostate or testis, gynecological [cervical or endometrial]; gastrointestinal [GI]: colorectal, pancreas, liver, stomach, upper GI, or undefined GI; urinary tract: bladder, bladder or kidney, or undefined urinary tract; hematology: lymphoma or leukemia, lymphoma, lymphatic or hematopoietic, or undefined hematology; respiratory: lung or undefined respiratory; melanoma: melanoma or sarcoma; nonmelanoma; skin papilloma; carcinoma: breast and other cancers).

Statistical analyses

Based on an intention-to-treat analysis using 2 × 2 tables, we calculated relative risks (RRs) with 95% confidence intervals (CIs). Higgins I2 was used to test heterogeneity of trials, and the equation to analyze the variation across trials was as follows:[21]

I2 = 100% × (Q−df)/Q

In the equation, Q is Cochran's heterogeneity statistic, and df stands for the degrees of freedom, which is equal to a total number of studies minus one. I2 values range from 0% (no heterogeneity) to 100% (highest heterogeneity). I2 values >50% were considered to indicate substantial heterogeneity. To analyze pooled RRs and 95% CIs, a fixed-effect model was used for heterogeneity <50%, and a random-effect model was used for heterogeneity greater than 50%. Begg's funnel plot and Egger's test examined publication bias. Stata/IC version 12·0 software package (StataCorp, College Station, TX, USA) was used for all the statistical analyses.


 » Results Top


Identification of relevant studies

[Figure 1] presents a flow diagram for the identification of relevant trials. By searching PubMed, EMBASE, Cochrane Library, and bibliographies, 676 relevant articles were identified. One hundred fifty-eight duplicated articles were excluded, and two authors reviewed the articles independently to exclude articles that did not meet the predetermined selection criteria based on title and abstract of each article. We reviewed the full texts of 117 remaining articles after excluding the aforementioned articles. After the review, 97 articles were eliminated because they were identical to another trial sharing the same population (n = 10); were not relevant to the object of the study (n = 28); were not double-blinded (n = 5); were correspondence, summary, or review (n = 4); or had insufficient data (n = 50). We included 21 articles [22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42] in the final analysis.
Figure 1: Flow diagram of identification of relevant clinical trials

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General characteristics of the included trials

[Table 1] presents the general characteristics of the final 21 RDBPCTs. A total of 65,196 participants, with 32,618 participants receiving statins and 32,578 participants receiving placebo, were included in the analysis. Participant ages ranged from 18 to 80 years. The year of publication ranged between 1993 and 2011, spanning 18 years. The studies were conducted in North America (n = 5), Nordic countries (n = 2), Europe (n = 9), Australia and New Zealand (n = 1), and various other countries (n = 4). The follow-up periods ranged from 40 weeks to 13.2 years. The number of participants ranged from 250 to 17,802 participants. Among the 21 trials, different types of statins were usually given orally once a day, but few studies stated that statins were administered orally twice a day.
Table 1: General characteristics of the studies included in the final analysis (n=21)

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Methodological quality of trials

As shown in [Table 2], scores based on the Jadad scale ranged from 3 to 5, and the mean score was 3.85. Out of 21 RDBPCTs, 13 trials were considered as having high-quality (score ≥3.85), whereas eight trials were considered as having low-quality (score <3.85).
Table 2: Methodological quality of trials based on the Jadad Scale (n=21)

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Main analysis

In the fixed-effect meta-analysis of 21 RDBPCTs, the use of statins did not reduce the risk of cancer (RR = 0.97, 95% CI = 0.92–1.02, I2 = 0.0%) [Figure 2]. No publication bias was observed in the 21 RDBPCTs: The Begg's funnel plot exhibited a symmetrical shape, and Egger's P for bias was 0.67 [Figure 3].
Figure 2: The Association between the use of statins and the risk of cancer in a meta-analysis of randomized, double-blind, placebo-controlled trials (n = 21). *Fixed-effect model. RR=Relative risk; CI=Confidence interval

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Figure 3: Begg's funnel plots and Egger's test for identifying publication bias (n = 21). RR=Relative risk; SE=Standard error

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Subgroup meta-analyses

As shown in [Table 3], there was no significant association between the use of statin and the risk of cancer by type of statin, lipophilic versus hydrophilic, country, follow-up period, methodological quality, underlying disease/population. Furthermore, no association was observed in the subgroup meta-analyses by types of cancer [Table 4].
Table 3: The association between the use of statins and the risk of cancer in subgroup meta-analyses by various factors

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Table 4: The association between the use of statins and the risk of cancer in subgroup meta-analyses by type of cancer

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 » Discussion Top


In the present meta-analysis of RDBCTs, we found that there was no association between the use of statins and the risk of cancer. Furthermore, the use of statins was not associated with the risk of cancer in subgroup meta-analyses according to various factors such as type of statins, country, follow-up period, methodological quality, underlying diseases, population, and type of cancer.

Previously, it has been suggested that simvastatin could increase the risk of cancer through its angiogenesis-promoting activity in vitro, which is a primary driver in cancer propagation.[6] However, the majority findings from in vitro laboratory and animal studies support antitumor activities of statins in different cancer types.[8],[11],[13] There are possible mechanisms for the potential antitumor activities of statins even though they have not been fully elucidated. Statins could inhibit cell proliferation, induce apoptosis in cancer cells, and potentiate the anticancer activities of some cytokines and chemotherapeutics.[7] Specifically, statins have been shown to exert antiproliferative effects by synchronizing tumor cells through blocking the transition of G1-S in the cell cycle.[8] In addition, they could induce apoptosis predominantly through blocking geranylgeranylated proteins.[43]

Recent meta-analyses of observational epidemiological studies have also reported beneficial effects of statins against site-specific cancers. A meta-analysis of observational studies (10 case–control and four cohort studies) concluded that statin use was associated with a reduced risk of hematological malignancies such as leukemia and non-Hodgkin's lymphoma (summary RR = 0.86, 95% CI = 0.77–0.96).[44] Further, a meta-analysis of 20 case–control studies showed a reduced risk for any cancer (odds ratio [OR] = 0.71, 95% CI = 0.56–0.89).[10] However, statin use was not associated with the risk of kidney cancer in the meta-analysis of five case–control studies (OR = 0.74, 95% CI = 0.45–1.23) and five cohort studies (RR = 1.07, 95% CI = 0.96–1.90).[45] Similarly, no beneficial effect of statins against lung cancer was observed in the meta-analysis of seven case–control studies (OR = 0.81, 95% CI = 0.57–1.16) and seven cohort studies (RR = 0.94, 95% CI = 0.82–1.07).[46]

In the meantime, the previous meta-analyses of RCTs [19],[20],[21] consistently reported that there was no significant association between the use of statins and the risk of cancer. As mentioned before, those meta-analyses included an open-label design, which is liable to performance bias. Unlike the findings from preclinical studies such as in vitro laboratory studies and animal studies, our meta-analysis of RDBPCTs excluding open-label RCTs also showed the similar findings to the previous meta-analyses of RCTs including open-label RCTs. Preclinical studies may have limitations because murine models do not fully represent the human body or do not yield compatible results with human trials.[47] Furthermore, some researchers question the predictability of animal models for humans.[48] In addition, unlike RCTs, observational studies such as case–control studies and cohort studies have inherent methodological limitations such as bias and confounding that interfere with drawing reliable causal inferences even though they are adjusted in the analysis.

There are some potential limitations in the current study. First, cancer was not the primary endpoint in most of the included trials. Thus, the total cancer incidence in each trial might not reflect the real one. Second, regarding cancer latency, the mean follow-up period of the current analysis was relatively short, 3.87 years. Data with longer follow-up periods are necessary. In addition, although we used the Jadad scale to analyze the quality of trials, the validity of the scale might be controversial because the criterion does not measure allocation concealment.[49] Another scale, known as the Cochrane risk of bias, can be used to describe the quality of trials, but the inter-rater agreement varies across tools.[50]

To the best of our knowledge, this is the first meta-analysis that included only RDBPCTs on the association between the use of statin and the risk of cancer. In summary, we found no apparent evidence to support the use of statins to prevent cancer.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

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