You are viewing the site in preview mode

Skip to main content
Download PDF

Statin use and risk of HCC in patients with MASLD and T2DM: an umbrella review and meta-analysis

BMC Cancer volume 25, Article number: 875 (2025) Cite this article

Abstract

Background

The effect of statin use on hepatocellular carcinoma (HCC) in patients with metabolic dysfunction–associated steatotic liver disease (MASLD) or type two diabetes mellitus (T2DM) is still unclear. In this umbrella review, we aimed to assess the available evidence for the association of statin use and HCC risk in the target population.

Methods

We carried out an umbrella review of previous systematic reviews/meta-analyses indexed in Cochrane, Embase, Scopus, and PubMed databases and published between Jan 1st, 2013, and Oct 22, 2024. We used random effects models to recalculate summary risk estimates for HCC incidence. Using A Measurement Tool to Assess methodological quality of systematic Review (AMSTAR2) tool, two independent reviewers evaluated each article for eligibility and methodologic quality and gathered data from the included studies.

Results

Of the initially identified 1,038 systematic reviews/meta-analyses, three non-overlapping studies with medium/high quality were included for qualitative synthesis. Statin use in people with T2DM was reported in six studies belonging to two meta-analyses. The results showed that statins were associated with a decreased risk of HCC (RR: 0.16, 95% CI: [0.03, 0.98]). However, the association was nonsignificant in patients with MASLD comprising five studies from one meta-analysis (RR: 0.89, 95% CI: [0.56, 1.40]).

Conclusion

Statin use is associated with a decreased incidence of HCC in people with T2DM. In patients with MASLD, the association is not significant. However, the effects of other variables including the stage of inflammation and/or liver fibrosis on the outcome need to be explored in future studies.

Peer Review reports

Introduction

Hepatocellular carcinoma (HCC) is the fifth and the sixth most common cancer in men and women, worldwide, respectively [1, 2]. The rate of newly diagnosed HCC is approximately 0.5 million cases annually [3]. Subsequently, this malignancy is the second most frequent cause of cancer death [1].

Hepatitis B (HBV), and hepatitis C (HCV) viral infections, genetic factors, and lifestyle-associated risk factors including smoking, alcohol consumption, and obesity are considered common risk factors for HCC development [4]. While HBV is more prevalent in Asian and African countries; HCV is predominantly presented in Western Europe and North America. On the other hand, in central and eastern Europe, 30 to 40% of HCC cases occur in patients without common risk factors and are probably attributable to metabolism-associated diseases such as diabetes mellitus type 2 (T2DM), and metabolic dysfunction–associated steatotic liver disease (MASLD) previously known as nonalcoholic fatty liver disease (NAFLD) [5]. T2DM is one of the critical features of metabolic syndrome, and its association with several cancers, including HCC, has long been established. Furthermore, nonalcoholic fatty liver disease (MASLD), a spectrum of liver diseases including simple steatosis (MASLD) and nonalcoholic steatohepatitis (NASH), with or without fibrosis or cirrhosis, is most likely responsible for a large percentage of HCC cases [6]. In a study on 756 patients in Italy, Piscaglia et al. showed that the survival rate and prognosis of MASLD-HCC are lower and poorer than HCV-HCC without MASLD [7]. The prevalence of MASLD has grown worldwide, rising from 26% in studies conducted in 2005 or before, to 38% in research conducted in 2016 or later [8]. In addition, in patients with non-cirrhotic MASLD, the incidence of HCC ranges from 0.1 to 1.3 cases per 1,000 patient years [9]. Similarly, the prevalence of T2DM is growing and has reached 10.5% globally in 2021 according to the International Diabetes Federation report [10]. As a result, concerns over the increased risk of HCC have been raised by the high prevalence of these two metabolic-related diseases [11].

In addition to traditional curative techniques such as surgery, liver transplantation, and chemotherapy, several lines of research have focused on lowering the chance of developing HCC through several preventive variables [12]. The HBV vaccine and antiviral medications for HBV and HCV are the most well-established protective factors. Furthermore, aspirin and certain T2DM drugs (such as pioglitazone and metformin) were shown to protect against HCC development.

[13,14,15]. As the most widely used lipid-lowering medications, statins have also been shown to have anti-inflammatory, antiproliferative, proapoptotic, antiangiogenic, immunomodulatory, and anti-infective properties that inhibit the growth and metastasis of cancer [16,17,18,19,20]. A cytostatic effect, which prolongs the survival of cancerous patients, is detected by statins [21]. Nonetheless, there are some concerns about the potential hepatotoxicity of statins. Statins modulate cholesterol synthesis in liver, and there is some evidence that statin use can elevate liver enzymes level [22]. The current guidelines continue to recommend underutilization of statin in patients with MASLD owing to concerns regarding hepatotoxicity [23].

Clinical research on the incidence of cancer linked to statin use has produced contradictory findings. While some recent observational, RCTs, and meta-analysis studies have shown that statins may be associated with a reduced risk of HCC [20, 24,25,26,27,28,29,30,31], others have shown their neutral effect on HCC incidence [32, 33]. Statin treatment improves clinical outcomes and might lower the HCC occurrence in cirrhotic patients [34] and patients with HBV or HCV infections [26, 35,36,37,38,39,40,41,42,43]. The benefits of statins on chronic hepatitis C are defined by their effects on the related metabolic disorders, progression (reduction of HCV viral load), and improvement of therapeutic response by interferon-α plus ribavirin [44, 45].

To better investigate the protective role of statin against HCC development in patients with T2DM and MASLD, this umbrella review was designed on the existing systematic reviews and meta-analyses that investigated the association between statin use and the risk of HCC.

Subjects and methods

Search strategy

A systematic literature search was carried out using the Cochrane, Embase, Scopus, and PubMed databases between January 1, 2013, and October 22, 2024. Two study investigators (N.H. and S.J.) independently reviewed all relevant articles on the effect of statin use on the risk of HCC. Keywords used in the search included “Statin*”, “Atorvastatin”, “Lovastatin”, “Fluvastatin”, “Rosuvastatin”, “Pravastatin”, “Simvastatin”, “Pitavastatin”, “Hydroxymethylglutaryl CoA Reductase Inhibitors”, “HMG-CoA Reductase Inhibitor (HMG-CoA Reductase Inhibitors)”, “(HMG-CoA)”, “Hydroxymethylglutaryl CoA Reductase Inhibitors”, “HMG-CoA Reductase Inhibitor” AND “Cancer (cancerous growth)”, “Carcinoma”, “Tumor(tumour)”, “Neoplasm(neoplasia, neoplas*)”, “Malignancy (malignant growth)”, “Lymphoma”, “Melanom”, “Lymphoma”, “Sarcoma”, “neurofibroma”, “teratoma”, “fibroadenoma, oncolog*” AND “Meta-analysis”, “Systematic review”, “Systematic Literature review”, “Systematic scoping review”, “Systematic narrative review”, “Systematic qualitative review”, “Systematic evidence review”, “Systematic quantitative review”, “Systematic meta review”, “Systematic critical review”, “Systematic mixed studies”, “Systematic mapping review”, “Systematic cochrane review”, “Systematic search and review”, “Systematic integrative review”.

Our target population for measuring the effect of statins on the risk of HCC was patients with two metabolic diseases namely; T2DM and MASLD. Studies on patients with HBV or HCV were excluded from this umbrella review.

Two authors (N.H, S.J) independently reviewed the titles and abstracts of studies found in the search to exclude studies that did not address the research question of interest.

The remainder of the full text of the article, including references, was examined to determine whether they contained relevant information. In case of insufficient data, an attempt was made to contact the authors of the respective studies to obtain additional information.

AMSTAR2 quality assessment

Critical appraisal of the systematic reviews was performed by two reviewers) N.H., S.J.(using AMSTAR2 [46] (A Measurement Tool to Assess Systematic Reviews) tool to independently assess the methodological quality of each systematic review included in the sample. Each of the sixteen questions in the AMSTAR2 tool was answered “yes”, “no”, or “partial yes”, and discrepancies between reviewers for individual AMSTAR2 items were resolved via consensus or third-party adjudication.

Overlapping reviews

To avoid bias in the interpretation of results, the overlaps among included reviews in this umbrella review were assessed. First, systematic reviews and meta-analyses with both the same exposure and the same clinical conditions (Diabetes and/or MASLD) were grouped. Then, the following criteria were also considered: (1) for the systematic reviews/meta-analyses from the same authors, the last update was chosen; (2) the degree of overlap between overlapping reviews was evaluated. For this second step, a graphical citation matrix was constructed between the overlapping systematic reviews/meta-analyses (columns), and the included primary studies (rows).The corrected covered area (CCA) was estimated as a percentage:

$$CCA=\frac{N-r}{r\times c-r} \times 100$$

In the CCA formula ‘N’denotes total number of primary studies from all reviews, ‘r’ shows the number of unique primary publication, and ‘c’represents the number of systematic reviews included in the study.

The overlapping is rated as: very high (CCA > 15%), high (CCA 11–15%), moderate (CCA 6–10%), and slight (CCA 0–5%) [47]. Both reviews were kept if the degree of overlap was slight or moderate. If the degree of overlap was high or very high, the systematic review/meta-analysis with the highest quality according to the AMSTAR2 was chosen. In the case of the same quality, the most recent one was included.

Data extraction

We extracted the following data from the included systematic reviews/meta-analyses: first author names’, year of publication, number of studies included, gender, study type(case–control, cohort, randomized clinical trials, and …), type of statin, statin dosage, period of statin use, other treatment beside statin, whether the main goal of statin use was cancer or coronary microvascular disease(CMD), databases used, number of patients included, summary risk estimates(relative risk(RR), hazard ratio(HR), and odds ratio(OR) with their corresponding 95% interval, statistical heterogeneity(I2) and corresponding p-value, and quality assessment using JADAD or Newcastle–Ottawa (NOS) scales.

Statistical analysis

We re-calculated summary risk estimates (represented as RR) for HCC incidence in statin users vs. non-users with T2DM or MASLD. For statistical analysis, we combined the individual studies from the included meta-analyses and screened individual studies.

We used a random effect model for meta-analysis. By using the Metafor package in R 4.4.1 we calculated pooled risk ratio (RR) values and 95% CI for studies focused on patients with T2DM and MASLD as a pooled group and also exclusively for T2DM and MASLD. RR of more than 1 indicates that statin use would increase the risk of HCC in patients with diabetes mellitus and MASLD, and RR of less than 1 indicates that statin use can reduce the risk of HCC in these patients. I2 statistic and Cochran’s Q statistic were applied to detect possible heterogeneity between studies. I2 reflects the proportion of the total variation across studies. An I2 value > 50% or P < 0.01 for the Q statistic was considered highly heterogenous.

Results

Literature selection

The specific literature screening process is shown in Fig. 1. In brief, 1038 studies were initially identified. After removing duplicates, 983 studies were obtained which were screened for unrelated studies, other type of cancers, adverse effects of statins, no abstract available, experiment design, not systematic review, full text unavailable, and books. Twenty-six studies on HCC were obtained from the screening step (Table 1).

Fig. 1
figure 1

Prisma flow diagram for study selection

Full size image
Table 1 Critical appraisal of the selected systematic reviews/meta-analysis by AMSTAR2.Bolds are the non-overlapping selected studies
Full size table

Quality assessment of studies

Quality assessment of the obtained 26 studies results in 13 studies as moderate or high quality from which 4 studies published between 2020 and 2023 consisting of HCC patients with T2DM and/or MASLD, were finally selected (Table 1). Two studies were scored as moderate quality (Islam, et al., 2020, and Wang, et al., 2023), and two were scored as high quality (Zhang, et al., 2023).

Overlapping evaluation

Islam M, et al. 2020 and Li X, et al. 2020 had a high degree of overlap according to the CCA measure (22%). Since both of these studies had moderate quality and both were published in the same year, we selected Islam M et al. which included a larger number of studies (6 vs. 5) and a larger number of patients (86,827 vs. 11,260) and removed Li X,et al.

Characteristics of included systematic reviews and meta-analyses

Table 2 summarizes the basic characteristics of the included reviews. All three included papers were meta-analyses. Except for the Zhang et al., 2023 study, which primarily examined the function of statins in lowering the risk of HCC incidence in individuals with MASLD, the other two studies only included a subset of understudied patients with T2DM. The included patients in the three studies ranged from 86,827 to 684,363.

Table 2 Characteristics of the systematic reviews/meta-analysis included in the umbrella review
Full size table

Statins use and risk of HCC in patients with T2DM and MASLD

In total, 11 individual studies from 3 systematic reviews were selected for statistical analysis. Six out of eleven studies focused on the association of T2DM with HCC and five studies explored this link in patients with MASLD.

The meta-analysis of the merged results of T2DM and MASLD showed that statin users are less likely to develop liver cancer than non-users (RR: 0.33, 95% CI:[0.11, 0.98], I2: 99.59%, P < 0.0001). The results of statin users with T2DM showed that statin use in DM patients (RR: 0.16, 95% CI:[0.03, 0.98], I2: 99.52%, P < 0.0001) plays a preventive role in HCC.

However, studies on statin use in MASLD showed an insignificant effect of statin in HCC prevention(RR: 0.89, 95% CI: [0.56, 1.4], I2: 92.45%, P < 0.0001). From five studies on statin use in HCC prevention in patients with MASLD, two studies (Lee and Pinyopornpanish-2) reported a negative effect of statin on HCC risk in patients with MASLD (Lee, ALT(Alanine aminotransferase) elevation, RR: 2.30, 95% CI:[1.02, 5.16], Lee, no ALT elevation, RR: 1.56, 95% CI:[0.58, 4.21], Pinyopornpanish-2, non-cirrhotic, RR: 1.54, 95% CI:[1.13, 2.09]), and cirrhotic RR: 0.85, 95% CI:[0.75, 0.96]) (Fig. 2.c). However, three studies showed the beneficial effect of statin use on HCC in patients with MASLD (Pinyopornpanish-1, RR: 0.49, 95% CI: [0.3, 0.79], German, RR: 0.35, 95% CI: [0.16, 0.78], Zou, RR: 0.67, 95% CI: [0.55, 0.81]).

Fig. 2
figure 2

Meta-analysis of the association between statin use and HCC risk in patients with a. T2DM or MASLD, b. T2DM, and c. MASLD studies

Full size image

Discussion

Liver cancer is strongly linked to dyslipidemia and metabolic disruption [73]. This umbrella review sought to explore the data addressing the associations between statin use and the risk of HCC in patients with metabolic diseases such as T2DM and MASLD. To that purpose, we merged data from three medium/high-quality studies (1 MASLD and 2 T2DM), which included 153,064 T2DM patients and 648,363 MASLD patients. We discovered statistically significant favorable relationships between statin use and reduced risk of HCC in persons with T2DM. However, the findings in MASLD patients were not significant.

Despite the fact that the relationship between statin use and lowering the risk of several cancer types has already been extensively studied, we discovered only 24 articles on HCC, with only three nonoverlapping systematic reviews/meta-analyses of moderate or high quality investigating the role of statin use on HCC risk in patients with MASLD (Zhang et al., 2023) or T2DM (Islam et al., 2020, and Wang et al., 2022).

There was significant heterogeneity among the included studies in both T2DM and MASLD investigations (I2: 99.59% and 95.28%, respectively). Heterogeneity in systematic reviews/meta-analyses can be caused by differences in sample size, study design, medication information such as duration of exposure, dose, and type of statins (lipophilic vs hydrophilic), reported estimates, control selection, confounders, or follow-up duration. In addition to the previously mentioned sources of heterogeneity in meta-analyses, in this meta-analysis, the concomitant use of other medications with statins, such as aspirin, which is frequently administered along with statin, especially in older adults, may be the reason for the observed heterogeneity within studies [74, 75].

The meta-analysis included studies with follow-up times ranging from six months to over thirteen years, which may explain the observed heterogeneity in the impact of statins on cancer risk reduction among included studies. A longer duration of statin use (> 5 years) has recently been shown to significantly reduce the incidence of liver cancer (HR:0.26, 95% CI: [0.11–0.64]) [76].

The primary causes of neoplastic change in people with type 2 diabetes are endogenous or exogenous hyperinsulinemia, hyperglycemia, and/or chronic inflammation [77]. Moreover, it has long been indicated that T2DM is related to low plasma HDL cholesterol, and hypertriglyceridemia [78]. According to several studies, dyslipidemia may be associated with an increased risk of liver cancer [79]. Additionally, the rapid proliferation of cancer cells requires cholesterol for modulating various cancer signaling pathways [80]. These can partly explain the high prevalence of HCC in patients with T2DM.

Despite the large degree of heterogeneity among studies in individuals with T2DM, all studies found that statin treatment was related with lower HCC risk. The type of antihyperglycemic medicine is one of the primary explanations of the variability in statins'impact on cancer risk reduction. In a comprehensive study involving 1,847,051 hospitalized patients with T2DM, Kautzky-Willer et al. [81] found that concomitant use of statins and insulin-sparing glucose-lowering medications has an impact on HCC risk reduction in both genders (men: OR: 0.54, 95% CI: [0.47–0.61]; women: OR: 0.60, 95% CI: [0.51–0.71]). The results for insulin were comparable (men: OR: 0.70, 95% CI: [0.62–0.8]; women: OR: 0.77, 95% CI: [0.64–0.94]).

MASLD and T2DM are the major manifestations of metabolic syndrome that often coexist. The prevalence of T2DM in patients with MASLD is approximately 60% [82, 83]. The focus of included studies in this umbrella review were on T2DM or MASLD exclusively and they had not explicitly mentioned what percentage of T2DM patients also had MASLD and vice versa.

We reviewed the characteristics of patients in the five MASLD studies to explore the rationale for heterogeneity and also the insignificant effect of statin treatment on HCC prevention. The demographic and clinical characteristics of statin users/nonusers have not been included in two studies that have claimed HCC is more frequent in statin users (Pinyopornpanish-2 and Lee).

In studies demonstrating statins'favorable benefits on lowering the risk of HCC, there were no significant differences in the mean age of statin users versus nonusers. ALT, along with other liver enzymes like aspartate aminotransferase (AST), alkaline phosphatase (ALP), and γ-glutamyltransferase (GGT), is a marker of liver dysfunction. High ALT or AST levels are independent risk factors for the development of cirrhosis and HCC, according to several studies [84]. However, one study (Pinyopornpanish-1) found that statin users and non-users had comparable levels of ALT [85]. Furthermore, aspirin and metformin use was higher in statin users than in nonusers, according to three studies showing the role of statins in lowering the incidence of HCC. The result of a 20-year cohort study on the association between aspirin use and cancer risk showed that long-term (≥ 5 or ≥ 10 years) aspirin use can reduce cancer incidence by 10% in several types of cancers including liver cancer [86]. Aspirin can decrease cancer by several mechanisms including inhibition of cancer signaling pathways through the inhibition of cyclooxygenase (COX) enzyme [87] and decreasing cancer-associated inflammation and cancer proliferation [88]. Similarly, the correlation between metformin use and decreased risk of liver cancer has been established [89].

Study limitations

The primary limitation of our investigation was the absence of comprehensive statin user/nonuser characteristics in two studies that reported a greater frequency of HCC among statin users with MASLD. This made it impossible for us to determine the actual impact of statins on the risk of HCC in MASLD patients. The availability of data regarding confounding variables such as ALT level, and concurrent use of statin and aspirin and glucose-lowering medications could also help us to find subgroups of patients for whom statin use might be protective against HCC development.

Conclusions

Statin use seems to have a protective effect on HCC risk among people with T2DM. However, it is still unclear if statin use might have beneficial effect on HCC risk in specific subgroups.

Data availability

All data generated or analyzed during this study are included in this published article.

Abbreviations

HCC:

Hepatocellular carcinoma

T2DM:

Type 2 Diabetes

MASLD:

Nonalcoholic fatty liver disease

HR:

Hazard ratio

OR:

ODDs ratio

RR:

Risk ratio

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

ALP:

Alkaline phosphatase

HDL:

High density lipoprotein

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.

  2. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.

    Article  PubMed  CAS  Google Scholar 

  3. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301–14.

    Article  PubMed  Google Scholar 

  4. Chavez-Tapia NC, Murúa-Beltrán Gall S, Ordoñez-Vázquez AL, Nuño-Lambarri N, Vidal-Cevallos P, Uribe M. Understanding the role of metabolic syndrome as a risk factor for hepatocellular carcinoma. J Hepatocell Carcinoma. 2022;9:583–593.

  5. Vetrano E, Rinaldi L, Mormone A, Giorgione C, Galiero R, Caturano A, Nevola R, Marfella R, Sasso FC. Non-alcoholic fatty liver disease (NAFLD), type 2 diabetes, and non-viral hepatocarcinoma: Pathophysiological mechanisms and new therapeutic strategies. Biomedicines. 2023;11(2):468.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Agosti P, Sabbà C, Mazzocca A. Emerging metabolic risk factors in hepatocellular carcinoma and their influence on the liver microenvironment. Biochim Biophys Acta Mol Basis Dis. 2018;1864(2):607–617.

    CAS  Google Scholar 

  7. Bellentani S, Baroni GS, Piscaglia F, Tiribelli C. Natural history of nonalcoholic steatohepatitis-associated hepatocellular carcinoma. Clin Liver Dis. 2016;8(4):105–107.

    Article  Google Scholar 

  8. Teng ML, Ng CH, Huang DQ, Chan KE, Tan DJ, Lim WH, Yang JD, Tan E, Muthiah MD. Global incidence and prevalence of nonalcoholic fatty liver disease. Clin Mol Hepatol. 2023;29(Suppl):S32.

    Article  PubMed  Google Scholar 

  9. Huang DQ, El-Serag HB, Loomba R. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2021;18(4):223–38.

    Article  PubMed  Google Scholar 

  10. Ye J, Wu Y, Yang S, Zhu D, Chen F, Chen J, Ji X, Hou K. The global, regional and national burden of type 2 diabetes mellitus in the past, present and future: a systematic analysis of the Global Burden of Disease Study 2019. Front Endocrinol. 2023;14:1192629.

    Article  Google Scholar 

  11. Talamantes S, Lisjak M, Gilglioni EH, Llamoza-Torres CJ, Ramos-Molina B, Gurzov EN. Non-alcoholic fatty liver disease and diabetes mellitus as growing aetiologies of hepatocellular carcinoma. JHEP Reports. 2023;5(9):100811.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Capuano G, Daniele B, Gaeta GB, Gallo C, Perrone F. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients. Hepatology. 1998;28:751–5.

    Article  Google Scholar 

  13. Memel ZN, Arvind A, Moninuola O, Philpotts L, Chung RT, Corey KE, Simon TG. Aspirin use is associated with a reduced incidence of hepatocellular carcinoma: a systematic review and meta-analysis. Hepatol Commun. 2021;5(1):133–43.

    Article  PubMed  CAS  Google Scholar 

  14. Cunha V, Cotrim HP, Rocha R, Carvalho K, Lins-Kusterer L. Metformin in the prevention of hepatocellular carcinoma in diabetic patients: a systematic review. Ann Hepatol. 2020;19(3):232–7.

    Article  PubMed  CAS  Google Scholar 

  15. Zeng RW, Yong JN, Tan DJ, Fu CE, Lim WH, Xiao J, Chan KE, Tan C, Goh XL, Chee D. Meta-analysis: Chemoprevention of hepatocellular carcinoma with statins, aspirin and metformin. Aliment Pharmacol Ther. 2023;57(6):600–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Demierre M-F, Higgins PD, Gruber SB, Hawk E, Lippman SM. Statins and cancer prevention. Nat Rev Cancer. 2005;5(12):930–42.

    Article  PubMed  CAS  Google Scholar 

  17. Sun H-Y, Singh N. Antimicrobial and immunomodulatory attributes of statins: relevance in solid-organ transplant recipients. Clin Infect Dis. 2009;48(6):745–55.

    Article  PubMed  Google Scholar 

  18. Bonovas S, Filioussi K, Tsavaris N, Sitaras NM. Statins and cancer risk: a literature-based meta-analysis and meta-regression analysis of 35 randomized controlled trials. J Clin Oncol. 2006;24(30):4808–17.

    Article  PubMed  CAS  Google Scholar 

  19. Zeichner S, Mihos CG, Santana O. The pleiotropic effects and therapeutic potential of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in malignancies: a comprehensive review. J Cancer Res Ther. 2012;8(2):176–83.

    Article  PubMed  CAS  Google Scholar 

  20. Lonardo A, Loria P. Potential for statins in the chemoprevention and management of hepatocellular carcinoma. J Gastroenterol Hepatol. 2012;27(11):1654–64.

    Article  PubMed  CAS  Google Scholar 

  21. Simons M. Molecular multitasking: statins lead to more arteries, less plaque. Nat Med. 2000;6(9):965–6.

    Article  PubMed  CAS  Google Scholar 

  22. Hawk E, Viner JL. Statins and cancer--beyond the "one drug, one disease" model. N Engl J Med. 2005;352(21):2238–9.

  23. Shang Y, Hagström H. Statins are underused in women with NAFLD after cardiovascular events compared with matched control subjects. Clin Gastroenterol Hepatol. 2023;21(5):1359–1361.e1352.

    Article  PubMed  Google Scholar 

  24. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology. 2013;144(2):323–32.

    Article  PubMed  CAS  Google Scholar 

  25. Chiu HF, Ho SC, Chen CC, Yang CY. Statin use and the risk of liver cancer: a population-based case–control study. Am J Gastroenterol. 2011;106(5):894–8.

    Article  PubMed  Google Scholar 

  26. Tsan Y-T, Lee C-H, Wang J-D, Chen P-C. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J Clin Oncol. 2012;30(6):623–30.

    Article  PubMed  Google Scholar 

  27. El Serag HB, Johnson ML, Hachem C, Morgana RO. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology. 2009;136(5):1601–8.

    Article  PubMed  Google Scholar 

  28. Shi M, Zheng H, Nie B, Gong W, Cui X. Statin use and risk of liver cancer: an update meta-analysis. BMJ Open. 2014;4(9):e005399.

  29. Wang Y, Wang W, Wang M, Shi J, Jia X, Dang S. A meta-analysis of statin use and risk of hepatocellular carcinoma. Can J Gastroenterol Hepatol. 2022;2022:5389044.

  30. Facciorusso A. Abd El Aziz MA, Singh S, Pusceddu S, Milione M, Giacomelli L, Sacco R: Statin use decreases the incidence of hepatocellular carcinoma: an updated meta-analysis. Cancers. 2020;12(4):874.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Graf H, Jüngst C, Straub G, Dogan S, Hoffmann R-T, Jakobs T, Reiser M, Waggershauser T, Helmberger T, Walter A. Chemoembolization combined with pravastatin improves survival in patients with hepatocellular carcinoma. Digestion. 2008;78(1):34–8.

    Article  PubMed  CAS  Google Scholar 

  32. Friis S, Poulsen AH, Johnsen SP, McLaughlin JK, Fryzek JP, Dalton SO, Sørensen HT, Olsen JH. Cancer risk among statin users: a population-based cohort study. Int J Cancer. 2005;114(4):643–7.

    Article  PubMed  CAS  Google Scholar 

  33. Emberson JR, Kearney PM, Blackwell L, Newman C, Reith C, Bhala N, Holland L, Peto R, Keech A, Collins R, Simes J, Baigent C. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One. 2012;7(1):e29849.

  34. Gu Y, Yang X, Liang H, Li D. Comprehensive evaluation of effects and safety of statin on the progression of liver cirrhosis: a systematic review and meta-analysis. BMC Gastroenterol. 2019;19:1–13.

    Article  Google Scholar 

  35. Tsan Y-T, Lee C-H, Ho W-C, Lin M-H, Wang J-D, Chen P-C. Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection. J Clin Oncol. 2013;31(12):1514–21.

    Article  PubMed  Google Scholar 

  36. Butt AA, Yan P, Bonilla H, Abou-Samra AB, Shaikh OS, Simon TG, Chung RT, Rogal SS, Team ES. Effect of addition of statins to antiviral therapy in hepatitis C virus–infected persons: results from ERCHIVES. Hepatology. 2015;62(2):365–74.

    Article  Google Scholar 

  37. Chen CI, Kuan CF, Fang YA, Liu SH, Liu JC, Wu LL, Chang CJ, Yang HC, Hwang J, Miser JS, Wu SY. Cancer risk in HBV patients with statin and metformin use: a population-based cohort study. Med. 2015;94(6):e462.

  38. Hsiang JC. Wong GL-H, Tse Y-K, Wong VW-S, Yip TC-F, Chan HL-Y: Statin and the risk of hepatocellular carcinoma and death in a hospital-based hepatitis B-infected population: a propensity score landmark analysis. J Hepatol. 2015;63(5):1190–7.

    Article  PubMed  CAS  Google Scholar 

  39. Mohanty A, Tate JP, Garcia-Tsao G. Statins are associated with a decreased risk of decompensation and death in veterans with hepatitis C–related compensated cirrhosis. Gastroenterology. 2016;150(2):430–440.e431.

    Article  PubMed  CAS  Google Scholar 

  40. Kim G, Jang SY, Han E, Lee Yh. Park Sy, Nam CM, Kang ES. Effect of statin on hepatocellular carcinoma in patients with type 2 diabetes: a nationwide nested case-control study. Int J Cancer. 2017;140(4):798–806.

    Article  PubMed  CAS  Google Scholar 

  41. Goh MJ, Sinn DH, Kim S, Woo SY, Cho H, Kang W, Gwak GY, Paik YH, Choi MS, Lee JH. Statin use and the risk of hepatocellular carcinoma in patients with chronic hepatitis B. Hepatology. 2020;71(6):2023–32.

    Article  PubMed  CAS  Google Scholar 

  42. Lee T-Y, Hsu Y-C, Tseng H-C, Yu S-H, Lin J-T, Wu M-S, Wu C-Y. Association of daily aspirin therapy with risk of hepatocellular carcinoma in patients with chronic hepatitis B. JAMA Intern Med. 2019;179(5):633–40.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Simon TG, Duberg A-S, Aleman S, Hagstrom H, Nguyen LH, Khalili H, Chung RT, Ludvigsson JF. Lipophilic statins and risk for hepatocellular carcinoma and death in patients with chronic viral hepatitis: results from a nationwide Swedish population. Ann Intern Med. 2019;171(5):318–27.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Zheng Y-X, Zhou P-C, Zhou R-R, Fan X-G. The benefit of statins in chronic hepatitis C patients: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2017;29(7):759–66.

    Article  PubMed  CAS  Google Scholar 

  45. Grammatikos G, Farnik H, Bon D, Böhlig A, Bader T, Berg T, Zeuzem S, Herrmann E. The impact of antihyperlipidemic drugs on the viral load of patients with chronic hepatitis C infection: a meta-analysis. J Viral Hepatitis. 2014;21(8):533–41.

    Article  CAS  Google Scholar 

  46. Li L, Asemota I, Liu B, Gomez-Valencia J, Lin L, Arif AW, Siddiqi TJ, Usman MS. AMSTAR 2 appraisal of systematic reviews and meta-analyses in the field of heart failure from high-impact journals. Syst Rev. 2022;11(1):147.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Hennessy EA, Johnson BT. Examining overlap of included studies in meta-reviews: guidance for using the corrected covered area index. Res Synth Methods. 2020;11(1):134–145.

    Article  PubMed  Google Scholar 

  48. Islam MM, Poly TN, Walther BA, Yang H-C, Li Y-C. Statin use and the risk of hepatocellular carcinoma: a meta-analysis of observational studies. Cancers. 2020;12(3):671.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Khajeh E, Moghadam AD, Eslami P, Ali-Hasan-Al-Saegh S, Ramouz A, Shafiei S, Ghamarnejad O, Dezfouli SA, Rupp C, Springfeld CJBc. Statin use is associated with the reduction in hepatocellular carcinoma recurrence after liver surgery. BMC Cancer. 2022;22(1):91.

    CAS  Google Scholar 

  50. Khazaaleh S, Sarmini MT, Alomari M, Al Momani L, El Kurdi B, Asfari M, Almomani Z, Romero-Marrero C. Statin use reduces the risk of hepatocellular carcinoma: an updated meta-analysis and systematic review. Cureus. 2022;14(7):e27032.

  51. Li X, Sheng L, Liu L, Hu Y, Chen Y, Lou L. Statin and the risk of hepatocellular carcinoma in patients with hepatitis B virus or hepatitis C virus infection: a meta-analysis. BMC Gastroenterol. 2020;20(1):98.

    Article  Google Scholar 

  52. Li X, Yu Y, Liu L. Influence of aspirin use on clinical outcomes of patients with hepatocellular carcinoma: a meta-analysis. Clin Res Hepatol Gastroenterol. 2021;45(6):101545.

    CAS  Google Scholar 

  53. Pradelli D, Soranna D, Scotti L, Zambon A, Catapano A, Mancia G, La Vecchia C, Corrao G. Statins and primary liver cancer: a meta-analysis of observational studies. Eur J Cancer Prev. 2013;22(3):229–34.

    CAS  Google Scholar 

  54. Wang J, Li X. Impact of statin use on the risk and prognosis of hepatocellular carcinoma: a meta-analysis. Eur J Gastroenterol Hepatol. 2021;33(12):1603–1609.

  55. Wong YJ, Qiu TY, Ng GK, Zheng Q, Teo EK. Efficacy and safety of statin for hepatocellular carcinoma prevention among chronic liver disease patients: a systematic review and meta-analysis. J Clin Gastroenterol. 2021;55(7):615–623.

    CAS  Google Scholar 

  56. Yi C, Song Z, Wan M, Chen Y, Cheng X. Statins intake and risk of liver cancer: a dose-response meta analysis of prospective cohort studies. Med. 2017;96(27):e7435.

  57. Zhang J, Fu S, Liu D, Wang Y, Tan Y. Statin can reduce the risk of hepatocellular carcinoma among patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol. 2023;35(4):353–8.

    Article  PubMed  CAS  Google Scholar 

  58. Zhong GC, Liu Y, Ye YY, Hao FB, Wang K, Gong JP. Meta-analysis of studies using statins as a reducer for primary liver cancer risk. Sci Rep. 2016;6:26256.

    CAS  Google Scholar 

  59. Zhou Y-Y, Zhu G-Q, Wang Y, Zheng J-N, Ruan L-Y, Cheng Z, Hu B, Fu S-W, Zheng M-H. Systematic review with network meta-analysis: statins and risk of hepatocellular carcinoma. Oncotarget. 2016;7(16):21753.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Chang Y, Liu Q, Zhou Z, Ding Y, Yang M, Xu W, Chen K, Zhang Q, Wang Z, Li H. Can statin treatment reduce the risk of hepatocellular carcinoma? a systematic review and meta-Analysis. Technol Cancer Res Treat. 2020;19:1533033820934881.

  61. Vahedian-Azimi A, Shojaie S, Banach M, Heidari F, Cicero AFG, Khoshfetrat M, Jamialahmadi T, Sahebkar A. Statin therapy in chronic viral hepatitis: a systematic review and meta-analysis of nine studies with 195,602 participants. Ann Med. 2021;53(1):1227–1242.

  62. Li Z, Li Y, Li X, Zhang L, Zhao N, Du H, Zhou B, Ye Y. Statins in hepatitis B or C patients is associated with reduced hepatocellular carcinoma risk: a systematic review and meta-analysis. Turk J Gastroenterol. 2022;33(2):136–144.

    PubMed  PubMed Central  Google Scholar 

  63. Wang S, Zuo L, Lin Z, Yang Z, Chen R, Xu Y. The relationship between aspirin consumption and hepatocellular carcinoma: a systematic review and meta-analysis. Eur J Med Res. 2023;28(1):226.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Zhang X, Lou D, Fu R, Wu F, Zheng D, Ma X. Association between statins types with incidence of liver cancer: an updated meta-analysis. Curr Med Chem. 2023;31(6):762–775.

    PubMed Central  Google Scholar 

  65. Tran KT, McMenamin ÚC, Coleman HG, Cardwell CR, Murchie P, Iversen L, Lee AJ, Thrift AP. Statin use and risk of liver cancer: evidence from two population-based studies. Int J Cancer. 2020;146(5):1250–60.

    Article  PubMed  CAS  Google Scholar 

  66. McGlynn KA, Hagberg K, Chen J, Graubard BI, London WT, Jick S, Sahasrabuddhe VV. Statin use and risk for primary liver cancer in the clinical practice research datalink. J Natl Cancer Inst. 2015;107(4):djv009.

  67. German MN, Lutz MK, Pickhardt PJ, Bruce RJ, Said A. Statin use is protective against hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: a case-control study. J Clin Gastroenterol. 2020;54(8):733–40.

    Article  PubMed  CAS  Google Scholar 

  68. Lee TY, Wu JC, Yu SH, Lin JT, Wu MS, Wu CY. The occurrence of hepatocellular carcinoma in different risk stratifications of clinically noncirrhotic nonalcoholic fatty liver disease. Int J Cancer. 2017;141(7):1307–14.

    Article  PubMed  CAS  Google Scholar 

  69. Pinyopornpanish K, Al-Yaman W, Butler RS, Carey W, McCullough A, Romero-Marrero C.Chemopreventive effect of statin on hepatocellular carcinoma in patients with nonalcoholic steatohepatitis cirrhosis. Am J Gastroenterol. 2021;116(11):2258–69.

    Article  PubMed  CAS  Google Scholar 

  70. Pinyopornpanish K, Khoudari G, Saleh MA, Angkurawaranon C, Pinyopornpanish K, Mansoor E, Dasarathy S, McCullough A. Hepatocellular carcinoma in nonalcoholic fatty liver disease with or without cirrhosis: a population-based study. BMC Gastroenterol. 2021;21(1):394.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Zou B, Odden MC, Nguyen MH. Statin use and reduced hepatocellular carcinoma risk in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2023;21(2):435–444.e436.

    Article  PubMed  CAS  Google Scholar 

  72. Tseng CH. Metformin and risk of hepatocellular carcinoma in patients with type 2 diabetes. Liver Int. 2018;38(11):2018–27.

    Article  PubMed  CAS  Google Scholar 

  73. Zhang Z, Xu S, Song M, Huang W, Yan M, Li X. Association between blood lipid levels and the risk ofliver cancer: a systematic review and meta-analysis. Cancer Causes Control. 2024;35(6):943–953.

  74. Lin JR, Han DD, Wei W, Zeng Q, Rong ZX, Bai X, Zhang YP, Wang J, Cai XT, Rao XG. Regular use of aspirin and statins reduces the risk of cancer in individuals with systemic inflammatory diseases. Can Res. 2024;84(11):1889–97.

    Article  CAS  Google Scholar 

  75. Löfling LL, Støer NC, Andreassen BK, Ursin G, Botteri E. Low-dose aspirin, statins, and metformin and survival in patients with breast cancers: a Norwegian population-based cohort study. Breast Cancer Res. 2023;25(1):101.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Okita Y, Sobue T, Zha L, Kitamura T, Iwasaki M, Inoue M, Yamaji T, Tsugane S, Sawada N. Long-term use of anti-cholesterol drugs and cancer risks in a Japanese population. Sci Rep. 2024;14(1):2896.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Li X, Wang X, Gao P. Diabetes mellitus and risk of hepatocellular carcinoma. Biomed Res Int. 2017;2017(1):5202684.

    PubMed  PubMed Central  Google Scholar 

  78. Goldberg IJ. Diabetic dyslipidemia: causes and consequences. J Clin Endocrinol Metab. 2001;86(3):965–71.

    Article  PubMed  CAS  Google Scholar 

  79. Liang JQ, Teoh N, Xu L, Pok S, Li X, Chu ES, Chiu J, Dong L, Arfianti E, Haigh WG. Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling. Nat Commun. 2018;9(1):4490.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Wang C, Li P, Xuan J, Zhu C, Liu J, Shan L, Du Q, Ren Y, Ye J. Cholesterol enhances colorectal cancer progression via ROS elevation and MAPK signaling pathway activation. Cell Physiol Biochem. 2017;42(2):729–42.

    Article  PubMed  CAS  Google Scholar 

  81. Kautzky-Willer A, Thurner S, Klimek P. Use of statins offsets insulin-related cancer risk. J Intern Med. 2017;281(2):206–16.

    Article  PubMed  CAS  Google Scholar 

  82. Targher G, Corey KE, Byrne CD, Roden M. The complex link between NAFLD and type 2 diabetes mellitus—mechanisms and treatments. Nat Rev Gastroenterol Hepatol. 2021;18(9):599–612.

    Article  PubMed  Google Scholar 

  83. Dharmalingam M, Yamasandhi PG. Nonalcoholic fatty liver disease and type 2 diabetes mellitus. Indian J Endocrinol Metab. 2018;22(3):421–428.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Wang F, Gao S, Wu M, Zhao D, Sun H, Yav S, Chen Y, Zhang Z, Yang M, Dong Y. The prognostic role of the AST/ALT ratio in hepatocellular carcinoma patients receiving thermal ablation combined with simultaneous TACE. BMC Gastroenterol. 2023;23(1):80.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Qin S, Wang J, Yuan H, He J, Luan S, Deng Y. Liver function indicators and risk of hepatocellular carcinoma: a bidirectional mendelian randomization study. Front Genet. 2024;14:1260352.

    Article  PubMed  PubMed Central  Google Scholar 

  86. 86. Skriver C, Maltesen T, Dehlendorff C, Skovlund CW, Schmidt M, Sørensen HT, Friis S. Long-term aspirin use and cancer risk: a 20-year cohort study. J Natl Cancer Inst. 2024; 116(4):530–538.

  87. Patrignani P, Patrono C. Aspirin and cancer. J Am Coll Cardiol. 2016;68(9):967–76.

    Article  PubMed  CAS  Google Scholar 

  88. Elwood P, Protty M, Morgan G, Pickering J, Delon C, Watkins J. Aspirin and cancer: biological mechanisms and clinical outcomes. Open Biol. 2022;12(9):220124.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Yu H, Zhong X, Gao P, Shi J, Wu Z, Guo Z, Wang Z, Song Y. The potential effect of metformin on cancer: an umbrella review. Front Endocrinol. 2019;10:470115.

    Article  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This research was supported by Iran University of Medical Sciences for their support (Grant ID: 25292).

Author information

Author notes

  1. Nazanin Hosseinkhan and Laily Najafi co-first authors.

Authors and Affiliations

  1. Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran, No 10, Firoozeh St, Vali Asr Sq

    Nazanin Hosseinkhan, Laily Najafi, Soodeh Jahangiri, Zahra Emami & Mohammad E. Khamseh

Authors
  1. Nazanin Hosseinkhan
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Laily Najafi
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Soodeh Jahangiri
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Zahra Emami
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Mohammad E. Khamseh
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

N.H. and ME. K. contributed to the study design. Z.E. conducted the literature search. N.H. and S.J. performed study selection, extracted the data and assessed the methodological quality, any disagreement was solved by LN, N.H. conducted the statistical analysis.N.H. and L.N. wrote the paper, ME.K. reviewed the manuscript.

Corresponding author

Correspondence to Mohammad E. Khamseh.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hosseinkhan, N., Najafi, L., Jahangiri, S. et al. Statin use and risk of HCC in patients with MASLD and T2DM: an umbrella review and meta-analysis. BMC Cancer 25, 875 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-14299-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-14299-2

Keywords

BMC Cancer

ISSN: 1471-2407

Contact us