Elsevier

Metabolism

Volume 120, July 2021, 154780
Metabolism

Clinical Science
Thiazolidinediones, alpha-glucosidase inhibitors, meglitinides, sulfonylureas, and hepatocellular carcinoma risk: A meta-analysis

https://doi.org/10.1016/j.metabol.2021.154780Get rights and content

Highlights

  • Thiazolidinedione use appeared to reduce hepatocellular carcinoma risk in Asians.

  • Alpha-glucosidase inhibitor use appeared to increase hepatocellular carcinoma risk.

  • Sulfonylurea use was associated with increased hepatocellular carcinoma risk.

  • Meglitinide use was not associated with hepatocellular carcinoma incidence.

Abstract

Background & aims

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide. Effects of second-line oral antidiabetic medications on incident HCC risk in individuals with type 2 diabetes mellitus remain unclear. This study evaluated associations between sulfonylureas, thiazolidinediones, meglitinides and alpha-glucosidase inhibitors, and incident HCC risk.

Methods

We systematically reviewed all studies on PubMed, Embase and Web of Science databases. Studies were included if they documented: (1) exposure to oral antidiabetic medication classes; (2) HCC incidence; (3) relative risks/odds ratios (OR) for HCC incidence. Eight eligible observational studies were identified. We performed random-effects meta-analyses to calculate pooled adjusted ORs (aORs) and 95% confidence intervals (CI).

Results

Thiazolidinedione use (7 studies, 280,567 participants, 19,242 HCC cases) was associated with reduced HCC risk (aOR = 0.92, 95% CI = 0.86–0.97, I2 = 43%), including among Asian subjects (aOR = 0.90, 95% CI = 0.83–0.97), but not Western subjects (aOR = 0.95, 95% CI = 0.87–1.04). Alpha-glucosidase inhibitor use (3 studies, 56,791 participants, 11,069 HCC cases) was associated with increased HCC incidence (aOR = 1.08; 95% CI = 1.02–1.14, I2 = 21%). Sulfonylurea use (8 studies, 281,180 participants, 19,466 HCC cases) was associated with increased HCC risk in studies including patients with established liver disease (aOR = 1.06, 95% CI = 1.02–1.11, I2 = 75%). Meglitinide use (4 studies, 58,237 participants, 11,310 HCC cases) was not associated with HCC incidence (aOR = 1.19; 95% CI = 0.89–1.60, I2 = 72%).

Conclusions

Thiazolidinedione use was associated with reduced HCC incidence in Asian individuals with diabetes. Alpha-glucosidase inhibitor or sulfonylurea use was associated with modestly increased HCC risk; future research should determine whether those agents should be avoided in patients with chronic liver disease.

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)

  • J. Balogh et al.

    Hepatocellular carcinoma: a review

    J Hepatocell Carcinoma

    (2016)
  • T.G. Simon et al.

    Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: results from two prospective cohort studies

    Hepatology.

    (2018)
  • V. Donadon et al.

    Antidiabetic Therapy and Increased Risk of Hepatocellular Carcinoma in Chronic Liver Disease

    (2009)
  • A. Bhat et al.

    Systematic review: preventive and therapeutic applications of metformin in liver disease

    World J Hepatol

    (2015)
  • A. Decensi et al.

    Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis

    Cancer Prev Res (Phila)

    (2010)
  • H. Noto et al.

    Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis

    PLoS One

    (2012)
  • P. Wang et al.

    Diabetes mellitus and risk of hepatocellular carcinoma: a systematic review and meta-analysis

    Diabetes Metab Res Rev

    (2012)
  • Y. Gu et al.

    Cancer incidence and mortality in patients with type 2 diabetes treated with human insulin: a cohort study in Shanghai

    PLoS One

    (2013)
  • J.C. Hsiang et al.

    Type 2 diabetes: a risk factor for liver mortality and complications in hepatitis B cirrhosis patients

    J Gastroenterol Hepatol

    (2015)
  • O. Karlstad et al.

    Use of insulin and insulin analogs and risk of cancer - systematic review and meta-analysis of observational studies

    Curr Drug Saf

    (2013)
  • S. Singh et al.

    Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis

    Am J Gastroenterol

    (2013)
  • Y. Zhou et al.

    Systematic review with network meta-analysis: antidiabetic medication and risk of hepatocellular carcinoma

    Sci Rep

    (2016 Sep 19)
  • C. Bosetti et al.

    Cancer risk for patients using thiazolidinediones for type 2 diabetes: a meta-analysis

    Oncologist.

    (2013)
  • F. Wang et al.

    Decreased risk of liver cancer with thiazolidinediones therapy in patients with type 2 diabetes: results from a meta-analysis

    Hepatology.

    (2013)
  • J. Lee et al.

    Incident hepatocellular carcinoma risk in patients treated with a sulfonylurea: a nationwide, nested, case-control study

    Sci Rep

    (2019)
  • C. Bosetti et al.

    Insulin and other antidiabetic drugs and hepatocellular carcinoma risk: a nested case-control study based on Italian healthcare utilization databases

    Pharmacoepidemiol Drug Saf

    (2015)
  • A.J. Kasmari et al.

    Independent of cirrhosis, hepatocellular carcinoma risk is increased with diabetes and metabolic syndrome

    Am J Med

    (2017)
  • L. Miele et al.

    Diabetes and insulin therapy, but not metformin, are related to hepatocellular cancer risk

    Gastroenterol Res Pract

    (2015)
  • Y. Zhao et al.

    Alpha-glucosidase inhibitors and risk of cancer in patients with diabetes mellitus: a systematic review and meta-analysis

    Oncotarget.

    (2017)
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    Present address: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.

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