The incidence of liver cancer and related mortality is increasing globally. Liver is a major site for glucose metabolism. People with type 2 diabetes (T2D) had increased risk of liver cancer. However, the association of glycemic burden (GB) with liver cancer in T2D remains unclear. We calculated GB using area under the curve above 5.7% of HbA1c (AUC_A1c) in patients with T2D enrolled in the prospective Hong Kong Diabetes Register established since 1995. Structured baseline data were linked to laboratory and hospitalization records in a territory-wide electronic medical record system with data censored in 2019. We performed Cox regression analysis to investigate the association of GB with incident liver cancer defined as first hospitalization with ICD9 code (155). We included 18,173 patients (50.93% male, age: 58.43±12.48 years, HbA1c: 7.58±1.66%, BMI: 25.51±4.06 kg/m2, disease duration: 20.68 ±7.63 years), who had ≥ 10 years of disease duration, > 3 years of observation, and ≥ 5 HbA1c measurements (21.98±12.33). During a median (IQR) follow up period of 10.62 (8.09, 15.88) years (218,381patient-years), 160 patients developed liver cancer with an incidence of 7.33 per 10,000 patient-years. We excluded 3 years of HbA1c values prior to incident liver cancer to avoid reverse causality. After adjusting for confounders, every 1 unit increase in AUC_A1c increased the hazard ratio (HR) of liver cancer by 1.22 (95% CI: 1.01-1.47), while AUC_A1c top quantile group had a HR of 1.78 (1.01-3.13) versus the lowest quantile group. In subgroup analysis, obese patients (BMI>25 kg/m2) had a HR of 1.34 (1.05-1.70) for liver cancer versus non-obese subjects. Amongst patients who developed liver cancer (n=1420) within 3 years of enrolment, one unit increase of AUC_A1c was associated with a HR of 1.49 (1.07-2.07) for liver cancer. GB and obesity independently increased the risk of liver cancer in T2D, emphasizing the importance of metabolic control for cancer risk reduction.


D. Mao: None. J. C. Chan: Consultant; Self; Bayer AG, Boehringer Ingelheim International GmbH, MSD Corporation, Sanofi, Other Relationship; Self; Asia Diabetes Foundation, GemVCare, Research Support; Self; Applied Therapeutics, AstraZeneca, Hua Medicine, Lilly Diabetes, Merck KGaA. E. S. H. Lau: None. A. Yang: None. H. Wu: None. M. Shi: None. A. P. Kong: Advisory Panel; Self; Lilly Diabetes, Speaker’s Bureau; Self; Abbott, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Lilly Diabetes, Sanofi, Stock/Shareholder; Self; Aptorum. R. C. Ma: Other Relationship; Self; AstraZeneca, Medtronic, Research Support; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Novo Nordisk, Pfizer Inc., Sanofi-Aventis, Tricida, Inc. E. Chow: Research Support; Self; Medtronic, Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi-Aventis. A. Luk: None.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at