Clinical ScienceThiazolidinediones, alpha-glucosidase inhibitors, meglitinides, sulfonylureas, and hepatocellular carcinoma risk: A meta-analysis
Introduction
As the global incidence of hepatocellular carcinoma (HCC) continues to rise, clinical outcomes remain exceptionally poor, due to a combination of inadequate cancer surveillance and a paucity of effective treatment options [1]. Type 2 diabetes mellitus independently increases the risk of multiple cancers, including HCC [[2], [3], [4]], and occurs frequently with concurrent liver disease. Informed selection of antidiabetic regimens may enable providers to mitigate risk of HCC development in high-risk patients with diabetes. Given the rapidly increasing prevalence of diabetes, such a strategy could translate to a considerable decline in overall HCC incidence.
Robust evidence from clinical and epidemiological studies indicates that the risk of HCC in diabetic subjects increases with insulin use, and decreases with metformin use [[5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]]. However, the effects of second-line oral antidiabetic agents are less well-characterized, and published data are limited and conflicting. Two prior meta-analyses have reported thiazolidinedione use to be associated with significantly decreased HCC incidence [17,18], however, Singh et al. did not identify a significant protective association [15], and several recent studies examining thiazolidinediones in relation to HCC incidence were not included in those prior meta-analyses [19,20]. Similarly, while prior meta-analyses have indicated use of sulfonylureas to be associated with significantly increased risk of incident HCC [8,15], they did not include several important, more recent additions to the literature [19,21,22]. Finally, prior meta-analyses of second-line antidiabetic therapies did not evaluate meglitinides, and while a single meta-analysis reported a trend towards decreased risk of liver cancer in users of alpha-glucosidase inhibitors, compared to non-users [23], a subsequent analysis by Bosetti et al. [20] found an increased risk of HCC among users of alpha-glucosidase inhibitors. In light of the growing body of primary literature, an updated review of associations between the use of anti-diabetic medications and risk of incident HCC is warranted.
Therefore, we undertook a systematic review of published literature, and performed a series of meta-analyses to characterize the relationships between use of second-line oral antidiabetic medication classes and risk of incident HCC.
Section snippets
Search strategy
A medical librarian (LP) systematically searched PubMed, Embase and Web of Science databases (inception through March 2020), using keywords and controlled vocabulary (Supplementary Table 1). Titles and abstracts of identified studies were screened by two independent reviewers (AA and ZM), and studies that did not investigate the association of interest were excluded. Full texts of the remaining studies were reviewed, and their references examined to identify additional articles of relevance.
Search results
Our search strategy yielded 10,105 individual articles, of which 56 were assessed in full for eligibility. Of these, 7 studies were published solely in abstract form, and were excluded. 8 studies utilized the Taiwan National Health Insurance claims database to establish their patient cohort [[30], [31], [32], [33], [34], [35], [36], [37]], and 2 studies utilized the South Korean National Health Insurance Service-National Sample Cohort [19,38]: the 2 studies with the largest respective cohort
Discussion
Type 2 diabetes is projected to continue increasing in prevalence during the coming decade [42] and is frequently comorbid with liver disease (in particular non-alcoholic fatty liver disease). Therefore, informed and judicious selection of antidiabetic therapy in patients with concurrent diabetes and liver disease could translate to a meaningful decline in overall rates of incident HCC. We conducted a comprehensive systematic review and a series of meta-analyses, involving more than 19,466
Conclusions and future directions
We conducted a comprehensive systematic review and meta-analysis of studies reporting the risk of incident HCC among users and nonusers of second-line, oral antidiabetic medications. Our findings endorse a protective effect of thiazolidinediones in reducing the risk of HCC development, particularly among Asian subjects. In contrast, use of alpha-glucosidase inhibitors and sulfonylureas were associated with modest but significantly increased risk of developing incident HCC. Collectively, our
CRediT author statement
Ashwini Arvind: Conceptualization, Methodology, Data curation, Writing - original draft, Writing - review & editing. Zoe N. Memel: Methodology, Data curation. Lisa L. Philpotts: Methodology, Data curation. Hui Zheng: Formal analysis. Kathleen E. Corey: Conceptualization, Supervision, Writing - review & editing. Tracey G. Simon: Conceptualization, Supervision, Writing - review & editing.
Funding sources/Acknowledgements
This work was supported by the AASLD Clinical and Translational Research Fellowship in Liver Disease (AA), NIH K23 DK122104 (TGS), Harvard University Center for AIDS Research Career Development Award (TGS), Dana Farber/Harvard Cancer Center GI SPORE Career Enhancement Award (TGS), R01 DK114144 (KEC). Funding sources had no involvement in study design, the collection, analysis and interpretation of data, the writing of the report, or in the decision to submit the article for publication.
Declaration of competing interest
TGS has served as a consultant to Aetion for work unrelated to this project. KEC serves on the scientific advisory board for Novo Nordisk and BMS and has received grant funding from Boehringer-Ingelheim, BMS and Novartis for work unrelated to this project.
References (59)
- et al.
The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence
Clin Gastroenterol Hepatol
(2006) - et al.
Association of metformin use with cancer incidence and mortality: a meta-analysis
Cancer Epidemiol
(2013) - et al.
Insulin use and cancer risk in patients with type 2 diabetes: a systematic review and meta-analysis of observational studies
Diabetes Metab
(2012) - et al.
Association between insulin therapy and risk of liver cancer among diabetics: a meta-analysis of epidemiological studies
Eur J Gastroenterol Hepatol
(2018) - et al.
Meta-analysis in clinical trials
Control Clin Trials
(1986) - et al.
Publication bias in clinical research
Lancet.
(1991) - et al.
A population-based cohort study in Taiwan--use of insulin sensitizers can decrease cancer risk in diabetic patients?
Ann Oncol
(2013) - et al.
Cancer incidence among patients treated with antidiabetic pharmacotherapy
Diabetes Metab Syndr Clin Res Rev
(2008) Diabetes mellitus, medications for type 2 diabetes mellitus, and cancer risk
Metabolism.
(2011)- et al.
Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis
Gastroenterology.
(2013)
Hepatocellular carcinoma: a review
J Hepatocell Carcinoma
Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: results from two prospective cohort studies
Hepatology.
Antidiabetic Therapy and Increased Risk of Hepatocellular Carcinoma in Chronic Liver Disease
Systematic review: preventive and therapeutic applications of metformin in liver disease
World J Hepatol
Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis
Cancer Prev Res (Phila)
Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis
PLoS One
Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis
Diabetes Metab Res Rev
Cancer incidence and mortality in patients with type 2 diabetes treated with human insulin: a cohort study in Shanghai
PLoS One
Type 2 diabetes: a risk factor for liver mortality and complications in hepatitis B cirrhosis patients
J Gastroenterol Hepatol
Use of insulin and insulin analogs and risk of cancer - systematic review and meta-analysis of observational studies
Curr Drug Saf
Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis
Am J Gastroenterol
Systematic review with network meta-analysis: antidiabetic medication and risk of hepatocellular carcinoma
Sci Rep
Cancer risk for patients using thiazolidinediones for type 2 diabetes: a meta-analysis
Oncologist.
Decreased risk of liver cancer with thiazolidinediones therapy in patients with type 2 diabetes: results from a meta-analysis
Hepatology.
Incident hepatocellular carcinoma risk in patients treated with a sulfonylurea: a nationwide, nested, case-control study
Sci Rep
Insulin and other antidiabetic drugs and hepatocellular carcinoma risk: a nested case-control study based on Italian healthcare utilization databases
Pharmacoepidemiol Drug Saf
Independent of cirrhosis, hepatocellular carcinoma risk is increased with diabetes and metabolic syndrome
Am J Med
Diabetes and insulin therapy, but not metformin, are related to hepatocellular cancer risk
Gastroenterol Res Pract
Alpha-glucosidase inhibitors and risk of cancer in patients with diabetes mellitus: a systematic review and meta-analysis
Oncotarget.
Cited by (0)
- 1
Present address: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.