Lower Risks of New-Onset Hepatocellular Carcinoma in Patients With Type 2 Diabetes Mellitus Treated With SGLT2 Inhibitors Versus DPP4 Inhibitors

Authors:
Oscar Hou In Chou Division of Clinical Pharmacology and Therapeutics, Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
Diabetes Research Unit, Cardiovascular Analytics Group, PowerHealth Research Institute, Hong Kong, China

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Jing Ning Wuwei Hospital of Traditional Chinese Medicine, Wuwei, Gansu, China

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Raymond Ngai Chiu Chan Diabetes Research Unit, Cardiovascular Analytics Group, PowerHealth Research Institute, Hong Kong, China

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Cheuk To Chung Diabetes Research Unit, Cardiovascular Analytics Group, PowerHealth Research Institute, Hong Kong, China

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Helen Huang Diabetes Research Unit, Cardiovascular Analytics Group, PowerHealth Research Institute, Hong Kong, China

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Kenrick Ng Department of Medical Oncology, University College London Hospital, London, UK
Department of Medical Oncology, St Bartholomew’s Hospital, London, UK

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Edward Christopher Dee Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY

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Sharen Lee Diabetes Research Unit, Cardiovascular Analytics Group, PowerHealth Research Institute, Hong Kong, China

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Apichat Kaewdech Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Thailand

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Ariel K Man Chow Department of Health Sciences, School of Nursing and Health Studies, Hong Kong Metropolitan University, Hong Kong, China

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Nancy Kwan Man Department of Surgery, The University of Hong Kong, Hong Kong Special Administrative Region (SAR), and Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hong Kong, China

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Tong Liu Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China

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Fengshi Jing Faculty of Data Science, City University of Macau, Macao SAR, China
UNC Project-China, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC

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Bernard Man Yung Cheung Division of Clinical Pharmacology and Therapeutics, Department of Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China

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Gary Tse Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China
School of Nursing and Health Studies, Hong Kong Metropolitan University, Hong Kong, China

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Jiandong Zhou Department of Family Medicine and Primary Care (host department), Department of Pharmacology and Pharmacy, and School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

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Background: Type 2 diabetes mellitus (T2DM) may be a risk factor for development of hepatocellular carcinoma (HCC). The association between risk of developing HCC and treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP4i) is currently unknown. This study aimed to compare the risk of new-onset HCC in patients treated with SGLT2i versus DPP4i. Methods: This was a retrospective cohort study of patients with T2DM in Hong Kong receiving either SGLT2i or DPP4i between January 1, 2015, and December 31, 2020. Patients with concurrent DPP4i and SGLT2i use were excluded. Propensity score matching (1:1 ratio) was performed by using the nearest neighbor search. Multivariable Cox regression was applied to identify significant predictors. Results: A total of 62,699 patients were included (SGLT2i, n=22,154; DPP4i, n=40,545). After matching (n=44,308), 166 patients (0.37%) developed HCC: 36 in the SGLT2i group and 130 in the DPP4i group over 240,269 person-years. Overall, SGLT2i use was associated with lower risks of HCC (hazard ratio [HR], 0.42; 95% CI, 0.28–0.79) compared with DPP4i after adjustments. The association between SGLT2i and HCC development remained significant in patients with cirrhosis or advanced fibrosis (HR, 0.12; 95% CI, 0.04–0.41), hepatitis B virus (HBV) infection (HR, 0.32; 95% CI, 0.17–0.59), or hepatitis C virus (HCV) infection (HR, 0.41; 95% CI, 0.22–0.80). The results were consistent in different risk models, propensity score approaches, and sensitivity analyses. Conclusions: SGLT2i use was associated with a lower risk of HCC compared with DPP4i use after adjustments, and in the context of cirrhosis, advanced fibrosis, HBV infection, and HCV infection.

Submitted April 15, 2023; final revision received November 25, 2023; accepted for publication November 28, 2023.

O.H.I. Chow and J. Ning contributed equally and are co–first authors.

Author contributions: Data acquisition: Chou, Chung, Lee. Data review: Chou, Ning, Tse, Zhou. Data analysis: Chou, Ning, Zhou. Data interpretation: Chou, Ning, Chan, Chung, Huang. Supervision: Cheung, Tse, Zhou. Manuscript writing: Chou, Huang, Ng, Dee, Lee, Kaewdech, Chow, Man, Liu, Jing. Manuscript revision: Chou, Ning, Dee, Lee, Kaewdech, Chow, Man, Liu, Cheung, Tse, Zhou.

Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Data availability statement: An anonymized version without identifiable or personal information is available from the corresponding authors upon reasonable request for research purposes.

Guarantor statement: All authors approved the final version of the manuscript. G. Tse is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Supplementary material: Supplementary material associated with this article is available online at https://doi.org/10.6004/jnccn.2023.7118. The supplementary material has been supplied by the author(s) and appears in its originally submitted form. It has not been edited or vetted by JNCCN. All contents and opinions are solely those of the author. Any comments or questions related to the supplementary materials should be directed to the corresponding author.

Correspondence: Gary Tse, MD, PhD, Kent and Medway Medical School, Pears Building, Canterbury, CT2 7FS UK. Email: gary.tse@kmms.ac.uk; and
Jiandong Zhou, PhD, Department of Family Medicine and Primary Care, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 3/F., Ap Lei Chau Clinic, 161 Main Street, Ap Lei Chau, Hong Kong, China. Email: jdzhou@hku.hk

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