|
 
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| ORIGINAL ARTICLE |
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| Year : 2023 | Volume
: 3
| Issue : 1 | Page : 14-31 |
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Statin use and risk of cancer: An umbrella meta-analysis
Ruby Kasana1, Christy Thomas1, Gaurav Das2, Munlima Hazarika3, Krishna Undela1
1 Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research Guwahati, Kamrup, Assam, India
2 Department of Surgical Oncology, Dr. Bhubaneswar Borooah Cancer Institute, Guwahati, Assam, India
3 Department of Medical Oncology, Dr. Bhubaneswar Borooah Cancer Institute, Guwahati, Assam, India
| Date of Submission | 26-Dec-2022 |
| Date of Decision | 10-Jan-2023 |
| Date of Acceptance | 11-Jan-2023 |
| Date of Web Publication | 16-May-2023 |
Correspondence Address:
Dr. Krishna Undela
Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, Kamrup, Guwahati - 781 101, Assam
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/aort.aort_34_22
BACKGROUND: The relationship between statin use and cancer risk has been debated for a long time. Physiologically plausible theories suggest that statins may lower the risk of cancer. We have updated the overview of meta-analyses to include up-to-date information, additional subgroup analyses, and site-specific cancer risk estimates.
MATERIALS AND METHODS: A systematic search was performed in the PubMed, Cochrane and Google scholar databases between June 2016 and December 2022. The search strategy included both statin- and cancer-related keywords. Meta-analyses examining the association between statin use and site-specific cancer risk were included. Two reviewers independently screened the literature, extracted data, and assessed the study quality using A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2) tool.
RESULTS: This up-to-date overview included 71 meta-analyses (33 new and 38 from the previous overview) of 14 site-specific cancers. Out of which, 29 (44%) meta-analyses had a “Critically low” and three reviews (5%) had a “High” quality of evidence with AMSTAR 2. The pooled results of meta-analyses showed that statins reduce the likelihood of biliary tract (33%), colorectal (9%), gastric (29%), gynecological (12%), hematological (19%), liver (42%), esophageal (19%), and pancreatic (18%) cancers. However, no association was identified between statin use and the risk of bladder, breast, kidney, lung, prostate, and skin cancers.
CONCLUSIONS: Statins may play a crucial role in cancer chemoprevention, reduce the risk of site-specific malignancies, and can be used as an adjuvant.
Keywords: Cancer, statin, umbrella meta-analysis
How to cite this article:
Kasana R, Thomas C, Das G, Hazarika M, Undela K. Statin use and risk of cancer: An umbrella meta-analysis. Ann Oncol Res Ther 2023;3:14-31 |
How to cite this URL:
Kasana R, Thomas C, Das G, Hazarika M, Undela K. Statin use and risk of cancer: An umbrella meta-analysis. Ann Oncol Res Ther [serial online] 2023 [cited 2023 May 31];3:14-31. Available from: http://www.aort.info/text.asp?2023/3/1/14/376898 |
| Introduction | |  |
Cancer is a leading cause of death worldwide. In 2020, there were 19.3 million new cancer cases and 10.0 million cancer-related deaths worldwide. By 2040, the number of new cancer cases per year is expected to rise to 29.5 million and the number of cancer-related deaths to 16.4 million.[1] Statins are hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors and may have anti-cancer effects through angiogenesis, cellular death, and proliferation changes.[2],[3] However, its impact on cancer remains unclear.[4]
Statins may lower the risk of cancer through various biologically reasonable strategies. However, there has been considerable debate regarding the possible link between statin use and increased cancer risk.[5] While there is some evidence of variable quality, postulate statins may be helpful in cancer chemoprevention and reduce the risk of some site-specific malignancies, but not all.[6] Therefore, we updated the previous overview of the meta-analysis conducted by our research group to generate extensive evidence on the association between statin use and the risk of developing site-specific cancers by pooling data from relevant meta-analyses.[7]
| Materials and Methods | | |
Search strategy and screening
This study is an update of the overview published by Undela et al. in 2017, which included meta-analyses published up to May 2016.[7] PubMed, Google Scholar, and the Cochrane Library databases were searched between June 2016 and December 2022 following a search strategy using keywords; “Hydroxymethylglutaryl-CoA Reductase Inhibitors” OR “Statin (s)” OR “HMG-CoA reductase inhibitor (s)” OR “lipid-lowering agent (s)” OR “Atorvastatin” OR “Fluvastatin” OR “Pravastatin” OR “Lovastatin” OR “Simvastatin” OR “Rosuvastatin” AND “Neoplasm” OR “Cancer” Two authors (RK and CT) performed the literature search. A third author resolved any concerns or uncertainties (KU).
Data synthesis
The study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses 2020 criteria.[8] The total number of studies identified, excluded, and included were recorded at each stage of the search and screening and presented in [Figure 1]. | Figure 1: Study flow diagram PRISMA 2020. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta Analyses
Click here to view |
Eligibility criteria
We included studies that focused on the association between statin use and risk of the specific site of cancer, studies that reported an estimated measure of impact size (relative risk [RR], hazard ratio [HR], or odds ratio [OR]) and its associated 95% confidence interval (CI), and studies that were published in the English language. Studies were excluded if current trials or their designs did not fit the inclusion criteria, systematic reviews that did not perform a meta-analysis, meta-analyses evaluating the influence of statin use on cancer management or prognosis and the risk of cancer recurrence, and those that included an experimental animal model.
Data abstraction
A standardized form was created in Microsoft Excel to extract the data from the included studies, which included the initial author's last name, publication year, the country of study, search databases of all studies with the date and number of studies detected, type of study designs, methods used to assess the quality of individual studies and identify heterogeneity and publication bias, number of subjects and cancer cases involved, quality of results, heterogeneity, and publication bias tests; pooled risk ratio estimates with 95% CIs for the primary outcome, secondary outcome, and subgroup analyses; and the study's conclusions and limitations. Heterogeneity between the studies was assessed using the I2 statistic and Cochran's Q test. Pooled estimates of the majority types of cancers show no or low evidence of heterogeneity (I2 ≤50% and Cochran's Q test P ≥ 0.10), fixed effect model was applied to pool results.
Initially, one review author (RK) extracted the information, which was then crosschecked and verified by the second review author (CT). Discrepancies or disagreements were resolved through discussion with a third author (KU).
Quality assessment
The quality of the studies was assessed using the A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2) tool by two reviewers independently (RK and CT), and conflicts were resolved by discussion or the involvement of a third author (KU). AMSTAR 2 has 16 items, of which seven domains are crucial for evaluating the validity of a review, and the evaluation of each item divides into “Yes,” “Partial Yes,” and “No.” The included studies' quality was divided into four levels: High, moderate, low, and critically low.[9]
| Results | | |
Literature search and study characteristics
This updated overview of meta-analyses included 33 new studies and 38 old studies[7] from the previous report. Overall, 71 studies[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80] based on 14 site-specific cancer studies as outcomes of statin use were included in the present study. These include ten meta-analyses published on liver cancer,[44],[45],[46],[47],[48],[49],[50],[51],[52],[53] followed by nine colorectal cancer studies,[18],[19],[20],[21],[22],[23],[24],[25],[26] eight prostate cancer studies,[68],[69],[70],[71],[72],[73],[74],[75] seven gynecological cancer studies,[31],[32],[33],[34],[35],[36],[37] six pancreatic cancer studies,[62],[63],[64],[65],[66],[67] six breast cancer studies,[12],[13],[14],[15],[16],[17] five hematological cancer studies,[38],[39],[40],[41],[42] five esophageal cancer,[57],[58],[59],[60],[61] five skin cancer studies,[76],[77],[78],[79],[80] four gastric cancer studies,[27],[28],[29],[30] three lung cancer studies,[54],[55],[56] one bladder cancer study,[11] one kidney cancer study,[43] and one biliary tract cancers (BTCs) study.[10] The general characteristics of these studies are summarized in [Table 1].
All meta-analyses included in the study were published between 2005 and 2022, and most studies (13) were published in 2013. The first author of the meta-analysis was predominantly based in China (35 studies), followed by the USA (12 studies), Greece (seven studies), Canada (three studies), the UK (three studies), India (two studies), Italy (two studies), Taiwan (two studies), Australia (one study), the Republic of Korea (one study), Thailand (one study), Iran (one study), and Japan (one study). Except for two studies[21],[70] where the information on databases searched was not available, the majority of the studies (48 studies [26%]) searched in EMBASE for relevant studies, followed by PUBMED (39 studies [21%]), MEDLINE (34 studies [19%]), Web of Science (20 studies [11%]), Cochrane Library (15 studies [8%]), Google scholar (nine studies [5%]), Scopus (six studies [10%]), Ovid (five studies [3%]), Science Citation Index (four studies [2%]), and CINAHL/Biosis (four studies [2%]).
Out of all included studies, 43 (62%) studies included both randomized controlled trials (RCTs) and observational studies, 22 (31%) studies included only observational studies, five (7%) studies included only RCTs, and for two studies information was not available.[58],[70] For the assessment of heterogeneity, 66 studies used both the Cochrane Q test and I2 test, and for five studies, information was unavailable.[19],[20],[21],[37],[70] Majority of the studies 61 (86%) assessed publication bias using Begg and Mazumdar's adjusted rank correlation test and the Egger regression asymmetry test or funnel plot. Ten studies[15],[25],[27],[32],[44],[57],[59],[61],[67],[70] did not assess publication bias, and no information was available for the two studies.[27],[44]
Quality appraisal results
The overall methodological quality of the 71 included studies is summarized and included in [Table 1]. Based on the overall confidence rating obtained using AMSTAR 2, the overall confidence in the results of 29 (44%) reviews was rated as “Critically low”. In addition, the confidence in 22 reviews was “Moderate” (33%), and the confidence in 12 reviews was “Low” (18%). Only three reviews (5%) were rated as “High”. Five studies did not have sufficient information to generate AMSTAR 2 overall quality.[19],[20],[21],[22],[58] Among the critical domains, the most common problem was not considering the risk of bias when interpreting the results. Among the noncritical domains, most studies did not report the source(s) of funding for their study and explained their selection of the study designs for inclusion in the review.
Outcome result
The pooled relative risk with a 95% confidence interval for the primary outcome of all studies is shown in the forest plot [Figure 2] and is depicted with a subgroup analysis based on cancer type. | Figure 2: Forest plot of pooled relative risk with 95% confidence interval of primary outcome from all included studies
Click here to view |
Statin use and risk of biliary tract cancer
A meta-analysis in 2022 by Cheung et al.[10] found that statins, both lipophilic and hydrophobic, were associated with a lower risk of BTCs, particularly cholangiocarcinoma and gallbladder cancer (RR: 0.67; 95% CI: 0.51–0.88; P = 0.004).
Statin use and risk of bladder cancer
A meta-analysis reported evidence between statin use and bladder cancer. The study showed no association between statin use and the risk of bladder cancer (RR: 1.07; 95% CI: 0.95–1.21; P = 0.26), and the result was the same even after subgroup analysis according to study design and long-term statin use.[11]
Statin use and risk of breast cancer
Most meta-analyses found no significant association between statin use and the risk of breast cancer, and their subgroup analysis reached the same conclusions. The overall pooled estimate also shows no association between statin use and breast cancer (RR: 1.00; 95% CI: 0.97–1.03; P = 0.91). However, a meta-analysis by Liu et al. in 2016[15] indicated that Fluvastatin reduced the risk of breast cancer.
Statin use and risk of colorectal cancer
In 2016, Jung et al.[25] reported that statin use was associated with a reduced risk of advanced adenoma; however, it did not significantly reduce the risk of any adenoma. In 2019, Li et al.[26] demonstrated that both prediagnosis and postdiagnosis statin uses were associated with reduced “All cancer mortality and cancer-specific Mortality “ for CRC patients. Overall, pooled estimates found that statins significantly reduced the risk of colorectal cancer (RR: 0.91; 95% CI: 0.90–0.92; P < 0.00001).
Statin use and risk of gastric cancer
We did not find any newly published studies for updated meta-analysis. Previous studies have indicated that statins can reduce the risk of gastric cancer (RR: 0.71; 95% CI: 0.60–0.83; P < 0.0001).
Statins use and risk of gynecological cancer
Two meta-analyses published by Li et al. in 2018[33] and Mohammadian-Hafshejani et al. in 2020[36] suggested that statin use reduced the risk of ovarian cancer and significantly increased survival. In 2022, Chen et al.[37] showed that statins significantly reduce the risk of endometrial cancer. Furthermore, Undela et al. in 2017[7] showed that in subgroup analysis, case–control studies alone showed a 39% decreased risk of gynecological cancer among statin users. Our review concluded that statins significantly lowered the risk of gynecological cancer (RR: 0.88; 95% CI: 0.84-0.92; P < 0.00001).
Statin use and risk of hematological cancer
In 2020, Zhang et al.[41] and Ponvilawan et al.[42] estimated the association between statin use and the risk of multiple myeloma (MM). They found that statin use significantly reduced the risk for MM by 20%. In 2017, Ye et al.[40] suggested that statin use reduced the risk of non-Hodgkin's lymphoma (NHL). The subgroup analysis also yielded the same conclusions. The overall pooled analysis shows that statins significantly reduced hematological cancer risk (RR: 0.81; 95% CI: 0.75–0.87; P < 0.00001).
Statin use and risk of kidney cancer
Previous studies found no significant association between statin use and the risk of kidney cancer (RR: 0.92; 95% CI: 0.71–1.19; P = 0.53).
Statin use and risk of liver cancer
In 2016, Zhong et al.[48] found that all individual statins significantly reduced the risk of primary liver cancer (PLC), and the risk reduction was more evident with rosuvastatin. Subgroup analyses revealed a significant decrease in PLC risk with statins in high-risk populations. In 2017, Yi et al.[49] conducted a dose-response meta-analysis that indicated statin use significantly reduced the risk of liver cancer. The subgroup analysis showed statin intake reduced the risk of liver cancer in Asian and Caucasian populations. In 2020, Chang et al.[50] and Islam et al.[51] found that statin use significantly reduced the risk of developing hepatocellular carcinoma (HCC). In 2022, Khazaaleh et al.[52] and Wang et al.[53] indicated that statin use significantly reduced the risk of HCC by 43% compared to statin nonusers. Subgroup analyses of meta-analyses yielded similar results. The overall pooled estimate shows statins significantly reduced the risk of liver cancer (RR: 0.58; 95% CI: 0.55–0.61; P < 0.00001).
Statin use and risk of lung cancer
Previous studies found no significant association between statin use and the risk of lung cancer (RR: 0.98; 95% CI: 0.93–1.04; P = 0.48).
Statin use and risk of esophageal cancer
A meta-analysis found that statin use was associated with a significantly reduced risk of esophageal adenocarcinoma.[61] The overall analysis also found that statin use was associated with a significantly reduced risk of esophageal cancer (RR: 0.81; 95% CI: 0.77–0.85; P < 0.00001).
Statin use and risk of pancreatic cancer
A meta-analysis published by Archibugi et al.[64] in 2019 showed an association between statin use and an overall pancreatic cancer risk reduction of 30%; a higher positive impact was observed with atorvastatin in males. Another three meta-analyses also revealed that statin use might reduce the risk of pancreatic cancer.[65],[66],[67] In the secondary analysis, both short- and long-term statin uses showed a significant reduction in the risk of pancreatic cancer. The overall pooled estimate shows that statin use significantly reduced the risk of pancreatic cancer (RR: 0.82; 95% CI: 0.76–0.87; P < 0.00001).
Statin use and risk of prostate cancer
In 2016, Raval et al.[71] found that statins significantly reduce the risk of prostate cancer. In 2016, Meng et al.[72] identified that pre- and post-diagnostic statin use was associated with a reduced risk of prostate cancer. However, three meta-analyses were published by Tan et al.[73],[74] in 2016 and 2022, and Xu et al.[75] in 2022 estimated that statins did not affect prostate cancer. The overall analysis found a 6% significant reduction in prostate cancer risk with statin use (RR: 0.94; 95% CI: 0.89–0.98; P = 0.006).
Statin use and risk of skin cancer (melanoma)
In 2017, Yang et al.[80] published a meta-analysis that showed a significant increase in the risk of nonmelanoma skin cancer with long-term lipophilic statin use compared with nonusers. Interestingly, one RCT suggested that lovastatin decreases the risk of melanoma by 48%. From the overall analysis, no significant association was found between statin use and the risk of skin cancer (RR: 0.95; 95% CI: 0.87–1.03; P = 0.23).
| Discussion | | |
In this updated overview meta-analysis, we covered 14 site-specific cancers that revealed statin use significantly reduced the risk of certain types of cancer, including biliary tract (33%), colorectal (9%), gastric (29%), gynecological (12%), hematological (19%), liver (42%), esophageal (19%), pancreatic (18%), and prostate (6%) cancers. Nevertheless, some evidence suggests no significant association between statin use and bladder, breast, kidney, lung, and skin cancer risk. However, the association varied among study designs, geographical region, duration of statin therapy, doses, pre- or post-diagnostic statins, properties of statins, and different kinds of statins.
We attempted to identify the change in cancer risk among different types, doses, and durations of statin use using the available information. Some meta-analyses categorized statins according to whether they were lipophilic or hydrophilic and showed that both statins might reduce the risk of liver[50],[51],[53] and BTC.[10] However, a meta-analysis showed that only lipophilic statins (RR 0.88, 95% CI 0.69–1.12) reduce the risk of ovarian cancer compared to hydrophilic statins.[35] A study showed that > 365 higher cumulative doses (cDDD) (RR 0.47 (95% CI: 0.36–0.61) of statin use were associated with more significant risk reductions of liver cancer than ≤365 lower cDDD (RR 0.55, 95% CI: 0.46–0.65) of statins.[49] A meta-analysis also showed that >600 cDDD (RR 0.44, 95% CI: 0.28–0.70) of statin use was associated with a lower risk of prostate cancer. Some studies have also shown that long-term statin use (≥5 years) reduced the risk of ovarian,[31] esophageal,[58],[60] pancreatic cancer,[65] and prostate.[75]
The positive results of animal and clinical studies have encouraged scientists to look for new approaches to cancer treatment.[81] Statins were currently being evaluated in several ongoing clinical trials in cancer patients. Furthermore, published findings indicated that statin therapy has some benefits in several types of cancer, including an increased survival rate; however, some studies found no such effects.[82] Previous evidence has shown a direct correlation between statin use and reduced risk of cancer onset or improvement in cancer outcomes.[83] The majority of studies had concentrated on pancreatic, breast, and colorectal cancers because cholesterol plays a significant role in these cancers and has yielded statistically significant results.[84] An earlier meta-analysis found that statins significantly reduce the risk of only four site-specific cancers: esophageal, hematological, leukemia, and liver. In addition, there was only weak evidence of a link between breast, colorectal, gastric, lung, lymphoma, and prostate cancer.[85]
Despite the numerous preclinical and epidemiological studies linking statin use with anti-cancer activity across various cancer types, there is little evidence from RCTs that treatment with these drugs improves cancer patient outcomes. On the other hand, statins were one of the world's most widely prescribed drug classes, with well-established safety and dosage profiles. Their low toxicity, low cost, and ease of use make them ideal for repurposing as anti-cancer drugs.[86]
Study limitations
We managed to minimize the risk of bias in every step of this overview. However, this overview has a few limitations. First, we only assessed individual studies from systematic reviews and meta-analyses eligible for re-analysis; therefore, some very recent individual studies might have been missed. However, considering that even a very recent updated meta-analysis for one cancer missed many individual studies, even though a thorough search strategy was performed using many search sites, such as PubMed, Google Scholar, and Cochrane database, we believe that one should also check the individual studies from previous meta-analyses when updating the meta-analysis. Second, as most of the findings come from observational studies, there may be a chance of presenting a “healthy-user bias” for some of the beneficial effects of statins. Third, exploring the association between the dose and type of statins and cancer incidence is beyond the scope of this study. Likewise, owing to a lack of applicable data, we could not stratify the effect of statins by participant age or treatment duration, which may be the parameter considered necessary to evaluate the true association. Fourth, this study had statistical limitations. A 95% CI and Egger's P value could not be assessed if only two or fewer studies were conducted. There were also some missing data in the enormous study effect when there were no population data in individual studies. Finally, 95% CI, between-study heterogeneity, and publication bias may not be the definitive criteria for assessing the strength of evidence.
| Conclusions | | |
Cancer is a significant health issue worldwide. To improve outcomes, clinicians and scientists have sought methods to incorporate different management strategies into patients with cancer. Repurposing currently available medications for cancer patients has merits and should be encouraged, especially if such agents are safe, cheap, and readily accessible. In conclusion, statin use was associated with reduced risk for a biliary tract, colorectal, gastric, gynecological, hematological, liver, esophageal, prostate, and pancreatic cancer.
Acknowledgment
The authors sincerely acknowledge the Department of Pharmaceuticals under the Ministry of Chemicals and Fertilizers, Government of India, and Dr. USN Murty, Director, National Institute of Pharmaceutical Education and Research Guwahati for their extensive support.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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