Highlights
- •Diabetes mellitus is associated with an increased risk of HCC in individuals with CHC.
- •Diabetes mellitus still increases the risk of HCC after successful antiviral therapy.
- •Use of metformin for DM greatly reduces HCC risk after successful antiviral therapy.
- •A simple risk stratification model could predict the risk of HCC and other major liver-related complications.
Background & Aims
Diabetes mellitus (DM) is known to increase the risk of hepatocellular carcinoma (HCC)
among individuals with chronic hepatitis C (CHC). We aimed to evaluate whether metformin
reduces HCC risk among individuals with DM and CHC after successful antiviral therapy.
Methods
Individuals with CHC who achieved a sustained virological response (SVR) after interferon-based
therapy were enrolled in a large-scale, multicenter cohort in Taiwan (T-COACH). Cases
of HCC at least 1 year after SVR were identified through linkage to the catastrophic
illness and cancer registry databases.
Results
Of 7,249 individuals with CHC enrolled in the study, 781 (10.8%) had diabetes and
647 (82.8%) were metformin users. During a median follow-up of 4.4 years, 227 patients
developed new-onset HCC. The 5-year cumulative HCC incidence was 10.9% in non-metformin
users and 2.6% in metformin users, compared to 3.0% in individuals without DM (adjusted
hazard ratio [aHR] 2.83; 95% CI 1.57-5.08 and aHR 1.46; 95% CI 0.98-2.19, respectively).
Cirrhosis was the most important factor significantly associated with higher HCC risk
in Cox regression analysis, followed by DM non-metformin use, older age, male sex,
and obesity; whereas hyperlipidemia with statin use was associated with a lower HCC
risk. Using the two most crucial risk factors, cirrhosis and DM non-metformin use,
we constructed a simple risk model that could predict HCC risk among individuals with
CHC after SVR. Metformin use was shown to reduce the risk of all liver-related complications.
Conclusions
Metformin use greatly reduced HCC risk after successful antiviral therapy in individuals
with diabetes and CHC. A simple risk stratification model comprising cirrhosis and
DM non-metformin use could predict long-term outcomes in individuals with CHC after
SVR.
Impact and implications
The current study provides evidence that metformin could reduce hepatocellular carcinoma
(HCC) incidence after successful antiviral therapy among those with diabetes and chronic
hepatitis C in a large-scale nationwide cohort study. Although successful antiviral
therapy greatly reduces HCC risk in individuals with chronic hepatitis C, those with
cirrhosis, diabetes, obesity, and the elderly remain at high risk of HCC development.
We demonstrated that a simple risk model composed of two crucial unfavorable factors,
cirrhosis and diabetes without metformin use, predicts the risk of HCC and major liver-related
complications after successful antiviral therapy in individuals with chronic hepatitis
C. Metformin use is highly recommended for individuals with diabetes and chronic hepatitis
C after viral eradication to reduce the risk of HCC.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: October 05, 2022
Accepted:
September 14,
2022
Received in revised form:
August 10,
2022
Received:
August 31,
2021
Footnotes
Author names in bold designate shared co-first authorship.
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
