Meta-analysis

Chemoprevention of Hepatocellular Carcinoma With Statins, Aspirin and Metformin

Rebecca W. Zeng; Jie Ning Yong; Darren J. H. Tan; Clarissa E. Fu; Wen Hui Lim; Jieling Xiao; Kai En Chan; Caitlyn Tan; Xin Lei Goh; Douglas Chee; Nicholas Syn; Eunice X. Tan; Mark D. Muthiah; Cheng Han Ng; Nobuharu Tamaki; Sung Won Lee; Beom Kyung Kim; Mindie H. Nguyen; Rohit Loomba; Daniel Q. Huang

Disclosures

Aliment Pharmacol Ther. 2023;57(6):600-609.

Abstract and Introduction

Abstract

Background: Emerging data suggest that statins, aspirin and metformin may protect against hepatocellular carcinoma (HCC) development. However, prior meta-analyses were limited by heterogeneity and inclusion of studies without adequate adjustment for baseline risks.

Aim: To examine by an updated meta-analysis the association between these medications and HCC risk.

Methods: Medline and Embase databases were searched from inception to March 2022 for studies that balanced baseline risks between study groups via propensity score matching or inverse probability of treatment weighting, that reported the impact of statins, aspirin or metformin on HCC risk. Multivariable-adjusted hazard ratios (HRs) for HCC were pooled using a random effects model.

Results: Statin use was associated with reduced HCC risk overall (HR: 0.52; 95% CI: 0.37–0.72) (10 studies, 1,774,476), and in subgroup analyses for cirrhosis, hepatitis B/C, non-alcoholic fatty liver disease, studies accounting for concurrent aspirin and metformin consumption and lipophilic statins. Aspirin use was associated with reduced HCC risk overall (HR: 0.48; 95% CI: 0.27–0.87) (11 studies, 2,190,285 patients) but not in studies accounting for concurrent statin and metformin use. Metformin use was not associated with reduced HCC risk overall (HR: 0.57; 95% CI: 0.31–1.06) (3 studies, 125,458 patients). Most analyses had moderate/substantial heterogeneity, except in follow-up <60 months for aspirin (I ² = 0%).

Conclusion: Although statin and aspirin use were associated with reduced HCC risk, only statin use was significant in subgroup analyses accounting for concurrent medications. Metformin use was not associated with reduced HCC risk. These data have implications for future clinical trial design.

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide.^[1,2] Patients with HCC have a 5-year survival of less than 20% overall.^[3–7] The poor prognosis of HCC, in general, has led to increased interest in HCC prevention. Emerging data suggest that the use of statins, aspirin and metformin may be chemoprotective against HCC.^[8–12] However, prior meta-analyses on this topic had some limitations such as pooling odds ratios that are not time-to-event measurements,^[11,13–16] or pooling data that had not been adequately adjusted for background differences in treated versus untreated patients. There have also been several recent relevant large studies that were not included in previous meta-analyses.^[17–20]

In light of these considerations, we performed an updated meta-analysis to determine the association between the risk of HCC and the use of statins, aspirin or metformin. We included cohort studies that balanced patient baseline characteristics between groups by propensity score matching (PSM) or inverse probability of treatment weighting (IPTW) to provide robust estimates of the comparative risk of HCC between study groups.^[21–24] We performed a pooled analysis of co-variate-adjusted hazard ratios (HRs) to account for censoring of events and investigated heterogeneity by performing multiple subgroup analyses for relevant factors such as cirrhosis, sex, liver disease aetiology, method of HCC diagnosis, concurrent medication use, follow-up duration and the use of competing risks of death.

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Next Section

Abstract and Introduction
Methods
Results
Discussion
Conclusion
References

Table 1. Hepatocellular carcinoma risk among statin users
	No. of studies	Sample size	HR	95% confidence interval	p value	I ² (%)	p value for Cochran Q test of heterogeneity	Subgroup difference
Statins
Overall	10	1,774,476	0.52	0.37–0.72	<0.01*	97.80	<0.01
Cirrhosis	3	21,584	0.95	0.91–0.99	0.04*	90.20	<0.01
Hepatitis B	5	152,716	0.53	0.32–0.88	0.01*	96.70	<0.01
Hepatitis C	3	16,058	0.79	0.64–0.99	0.04*	81.70	<0.01
NAFLD	2	242,751	0.68	0.59–0.77	<0.01*	90.80	<0.01
Accounted for competing risk of death without HCC	5	980,486	0.51	0.32–0.81	<0.01*	97.50	<0.01
Sex
Male	2	115,411	0.45	0.24–0.85	0.01*	85.90	<0.01	0.83
Female	2	115,411	0.50	0.22–1.17	0.11	75.00	0.01
HCC diagnosis method
Verified by imaging/histology	2	66,445	0.60	0.33–1.09	0.09	95.10	<0.01	0.59
ICD codes	8	1,708,031	0.49	0.31–0.78	<0.01*	98.60	<0.01
Statin type
Lipophilic	3	1,083,952	0.46	0.37–0.57	<0.01	64.00	0.06	0.93
Hydrophilic	3	1,083,952	0.48	0.18–1.27	0.14	99.10	<0.01
Accounted for concurrent use of aspirin, NSAIDs and metformin
Yes	9	1,534,926	0.52	0.37–0.75	<0.01*	98.10	<0.01
Mean follow-up duration
<60 months	4	814,691	0.49	0.39–0.62	<0.01*	49.50	0.12	0.10
≥60 months	4	865,093	0.67	0.49–0.92	0.01*	96.20	<0.01	0.10

Abbreviations: HCC, hepatocellular carcinoma; LT, liver transplantation; NAFLD, non-alcoholic fatty liver disease; ICD, International Classification of Diseases; HR, hazard ratio; I ², level of heterogeneity.
*Bolded p ≤ 0.05 denotes statistical significance.

Table 2. Hepatocellular carcinoma risk among aspirin users
	No. of studies	Sample size	HR	95% confidence interval	p value	I ² (%)	p value for Cochran Q test of heterogeneity	Subgroup difference
Aspirin
Overall	11	2,190,285	0.48	0.27–0.87	0.01*	99.50	0.00
Cirrhosis	5	46,526	0.68	0.51–0.91	0.01*	84.90	<0.01
Hepatitis B	5	97,848	0.45	0.12–1.60	0.22	99.80	<0.01
Hepatitis C	3	48,255	0.69	0.59–0.80	<0.01*	50.20	0.13
Accounted for competing risk of death without HCC	6	142,281	0.50	0.18–1.36	0.17	99.70	<0.01	-
Sex
Male	3	365,231	0.78	0.67–0.90	<0.01*	0.00	0.39	0.66
Female	3	365,231	0.71	0.48–1.04	0.08	67.00	0.05
HCC diagnosis method
Verified by imaging/histology	4	58,907	0.28	0.06–1.19	0.08	99.80	<0.01	0.24
ICD codes	7	2,131,378	0.66	0.54–0.82	<0.01*	93.40	<0.01	0.24
Accounted for concurrent use of statins, NSAIDs and metformin
Yes	8	493,285	0.53	0.23–1.21	0.13	99.60	<0.0	0.60
No	3	1,697,000	0.42	0.27–0.64	<0.01*	93.40	<0.01
Mean follow-up duration
<60 months	2	42,545	0.74	0.63–0.87	<0.01*	0.00	0.35	0.93
≥60 months	2	1,134,408	0.69	0.63–0.75	<0.01*	0.00	0.89	0.93

Abbreviations: HCC, hepatocellular carcinoma; LT, liver transplantation; ICD, International Classification of Diseases; HR, hazard ratio; I ², level of heterogeneity.
*Bolded p ≤ 0.05 denotes statistical significance.

Table 3. Hepatocellular carcinoma risk in metformin users
	No. of studies	Sample size	HR	95% confidence interval	p value	I ² (%)	p value for Cochran Q test of heterogeneity
Metformin
Overall	3	125,458	0.57	0.31–1.06	0.08	95.90	<0.01
Confirmation of HCC diagnosis
ICD codes	3	125,458	0.57	0.31–1.06	0.08	95.90	<0.01
Accounted for use of statins, aspirin and NSAIDs
Yes	2	101,611	0.97	0.60–1.58	0.91	95.70	<0.01
Mean follow-up duration
<60 months	2	67,647	0.23	0.02–2.71	0.24	96.00	<0.01
≥60 months	1	–

Abbreviations: HCC, hepatocellular carcinoma; LT, liver transplantation; ICD, International Classification of Diseases; HR, hazard ratio; I ², level of heterogeneity.

Authors and Disclosures

Rebecca W. Zeng¹, Jie Ning Yong¹, Darren J. H. Tan¹, Clarissa E. Fu¹, Wen Hui Lim¹, Jieling Xiao¹, Kai En Chan¹, Caitlyn Tan¹, Xin Lei Goh¹, Douglas Chee², Nicholas Syn¹, Eunice X. Tan^1–3, Mark D. Muthiah^1–3, Cheng Han Ng¹, Nobuharu Tamaki⁴, Sung Won Lee^5,6, Beom Kyung Kim^7,8, Mindie H. Nguyen⁹, Rohit Loomba¹⁰ and Daniel Q. Huang^1–3,10

¹Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
²Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
³National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
⁴Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
⁵Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
⁶The Catholic University Liver Research Centre, Seoul, Korea
⁷Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
⁸Yonsei Liver Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea
⁹Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
¹⁰NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, San Diego, California, USA

Correspondence
Daniel Q. Huang, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, National University Health System, Singapore, Singapore. Email: daniel_huang@nus.edu.sg

Rebecca W. Zeng, Jie N. Yong and Darren J. H. Tan contributed equally to this work and share the first authorship.

Rohit Loomba and Daniel Q. Huang contributed equally to this work and share the senior authorship.

Author Contributions
Rebecca Wenling Zeng: Data curation (equal); formal analysis (equal); writing – original draft (equal); writing – review and editing (equal). Jie Ning Yong: Data curation (equal); formal analysis (equal); writing – original draft (equal); writing – review and editing (equal). Darren Jun Hao Tan: Data curation (equal); formal analysis (equal); writing – original draft (equal); writing – review and editing (equal). Clarissa Elysia Fu: Data curation (equal); writing – review and editing (equal). Wen Hui Lim: Data curation (equal); validation (equal); writing – review and editing (equal). Jieling Xiao: Data curation (equal); validation (equal); writing – review and editing (equal). Kai En Chan: Data curation (equal); validation (equal); writing – review and editing (equal). Caitlyn Tan: Data curation (equal); validation (equal); writing – review and editing (equal). Xin Lei Goh: Writing – review and editing (equal). Douglas Chee: Writing – review and editing (equal). Nicholas Syn: Formal analysis (equal); writing – review and editing (equal). Eunice Tan: Writing – review and editing (equal). Mark Dhinesh Muthiah: Writing – review and editing (equal). Cheng Han Ng: Formal analysis (equal); writing – original draft (equal); writing – review and editing (equal). Nobuharu Tamaki: Writing – review and editing (equal). Sung Won Lee: Writing – review and editing (equal). Beom Kyung Kim: Writing – review and editing (equal). Mindie H. Nguyen: Supervision (equal); writing – review and editing (equal). Rohit Loomba: Writing – review and editing (equal). Daniel Huang: Conceptualization (equal); supervision (equal); writing – original draft (equal); writing – review and editing (equal). All authors have read and approved the final version of the manuscript for submission.

Conflict of Interest
MHN: Research support: Pfizer, Enanta, Gilead, Exact Sciences, Vir Biotech, Helio Health, National Cancer Institute, Glycotest, B.K. Kee Foundation. Consulting and/or Advisory Board: Intercept, Exact Science, Gilead, GSK, Eli Lilly, Laboratory of Advanced Medicine, Janssen. R.L. receives funding support from NIAAA (U01AA029019), NIEHS (5P42ES010337), NCATS (5UL1TR001442), NIDDK (U01DK130190, U01DK061734, R01DK106419, P30DK120515, R01DK121378, R01DK124318), NHLBI (P01HL147835) and DOD PRCRP (W81XWH-18-2-0026). RL serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myer Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Madrigal, Metacrine, Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89 bio, Terns Pharmaceuticals and Viking Therapeutics. In addition, his institutions received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Novo Nordisk, Merck, Pfizer, Sonic Incytes and Terns Pharmaceuticals. Co-founder of LipoNexus Inc. D.H. receives funding support from Singapore Ministry of Health's National Medical Research Council under its NMRC Research Training Fellowship (MOH-000595-01). In addition, he has served as an advisory board member for Eisai. The other authors declare no conflict of interest.