Editor's Note: Liver cancer ranks as the third leading cause of cancer deaths globally, with a fatality rate as high as 85%. Diabetes mellitus (DM) emerges as a significant risk factor for Hepatocellular Carcinoma (HCC). The projected increase in the diabetic population, from 537 million in 2021 to 783 million by 2045, underscores the urgency of developing oncological protection strategies and reducing liver-related mortality. The American Diabetes Association advocates glycemic control as a therapeutic goal for diabetic patients. However, the benefits of optimal glycemic control on liver-related outcomes remain unclear. In light of this, Dr Wai-Kay Seto's team at The University of Hong Kong conducted a population-based cohort study to evaluate the independent effect of optimal glycemic control on HCC risk and liver-related mortality, adjusting for demographic, clinical, and medical covariates. This research, published in Aliment Pharmacol Ther (IF=6.6), features Xianhua Mao from The University of Hong Kong as the first author and Dr Wai-Kay Seto and Dr Ka-Shing Cheung as corresponding authors.Introduction
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and the third leading cause of cancer-related deaths globally. What makes HCC particularly dangerous is its high case-fatality rate, which surpasses that of many other malignancies, including common cancers like lung, breast, and colorectal. Alongside liver cancer, the incidence of diabetes mellitus (DM) is skyrocketing. Diabetes, a chronic disease marked by the body’s inability to manage blood sugar levels effectively, affects millions of individuals worldwide. As of 2021, approximately 537 million adults were living with diabetes, and this figure is projected to climb to 783 million by 2045. As the number of diabetes cases rises, it is increasingly important to understand the long-term implications of this disease, including its connection to other severe health conditions, such as liver cancer.
Optimal glycaemic control—achieved through maintaining average blood glucose levels within a specific range—has long been associated with a reduced risk of many diabetes-related complications. However, less is known about how optimal glycaemic control specifically influences the development of HCC and other liver-related outcomes in diabetic patients. This large population-based study aimed to investigate this potential link, assessing how glycaemic control affects the risk of HCC development and liver-related mortality over time.
Study Design and Data Collection
This study was based on a cohort of 146,430 diabetic patients identified from the Clinical Data Analysis and Reporting System (CDARS), a comprehensive health record database that captures information from public hospitals in Hong Kong. Patients included in the study were diagnosed with diabetes between 2001 and 2016, and their glycaemic control was tracked over a period of three years following their diagnosis. Diabetes was defined using the American Diabetes Association’s diagnostic criteria, which include having two abnormal haemoglobin A1c (HbA1c) test results (≥6.5%) or fasting plasma glucose levels ≥7 mmol/L.
Glycaemic control was classified into two categories: optimal control, defined as an HbA1c level of less than 7%, and suboptimal control, defined as an HbA1c level of 7% or higher. Patients with extreme HbA1c values (<4% or >14%) were excluded from the study, as such readings may indicate unreliable data. The study also controlled for various covariates that could impact outcomes, such as age, sex, BMI, smoking status, and medication use. Propensity score matching (PSM) was applied to balance these variables between the two groups and ensure that any differences observed in the outcomes could be attributed to glycaemic control, rather than other confounding factors.
Outcomes Measured
The primary outcome of interest was the development of hepatocellular carcinoma (HCC). Secondary outcomes included liver-related mortality and liver decompensation, which refers to the deterioration of liver function that can result in complications such as ascites (fluid accumulation), variceal bleeding, hepatic encephalopathy (brain dysfunction due to liver disease), and hepatorenal syndrome (kidney failure secondary to liver disease).
Key Results and Findings
HCC Incidence A total of 1,099 patients (0.8%) out of the 146,430 developed HCC during the study’s follow-up period. Notably, patients with optimal glycaemic control experienced a significantly lower incidence of HCC than those with suboptimal control. Specifically, the cumulative incidence of HCC was 1.4% among patients with optimal glycaemic control, compared to 1.7% among those with suboptimal control. This equates to a 30% reduction in HCC risk for those with HbA1c levels below 7% (subdistribution hazard ratio [SHR]: 0.70, 95% CI 0.61–0.79).
Furthermore, the risk of HCC increased progressively as HbA1c levels rose. For example, patients with HbA1c levels between 7.0% and 8.0% had a 29% higher risk of HCC than those with levels below 7% (SHR: 1.29), while patients with HbA1c levels above 9.0% faced an even greater risk, with an SHR of 1.71 (95% CI 1.36–2.14). These findings strongly suggest that maintaining strict glycaemic control can significantly reduce the risk of developing liver cancer in diabetic patients, underscoring the importance of targeting HbA1c levels in diabetes management plans.
Liver-Related Mortality In addition to reducing HCC risk, optimal glycaemic control was associated with a substantial reduction in liver-related mortality. Over the 16-year follow-up period, the cumulative incidence of liver-related mortality was 1.3% in the optimal glycaemic control group, compared to 1.7% in the suboptimal control group. This represents a 30% reduction in liver-related deaths for patients maintaining an HbA1c level below 7% (SHR: 0.70, 95% CI 0.61–0.80).
Liver Decompensation Liver decompensation, which indicates severe liver dysfunction, was another critical outcome explored in this study. Patients with optimal glycaemic control exhibited a 24% lower risk of liver decompensation compared to those with suboptimal control (SHR: 0.76, 95% CI 0.68–0.85). This further highlights the importance of glycaemic control not only for preventing liver cancer but also for maintaining overall liver function and preventing potentially life-threatening complications in diabetic individuals.
Impact of Glycaemic Variability In addition to the absolute level of HbA1c, the study also investigated the impact of glycaemic variability—fluctuations in blood glucose levels—on the risk of HCC and liver-related mortality. Glycaemic variability has emerged as an important factor in diabetes management, as it reflects the consistency of blood sugar control over time. Higher variability in glucose levels can lead to oxidative stress and endothelial dysfunction, both of which contribute to complications in various organs, including the liver.
The study found that patients with lower glycaemic variability had a significantly reduced risk of HCC and liver-related mortality. Specifically, lower variability was associated with a 28–31% reduction in HCC risk and a 35–39% reduction in liver-related mortality. These findings suggest that consistent blood glucose control, in addition to achieving an HbA1c target below 7%, is crucial for reducing liver-related complications. This has important clinical implications, as emerging technologies such as continuous glucose monitoring (CGM) systems can help patients better manage their glycaemic variability and potentially reduce the risk of long-term complications.
Medication and HCC Risk The study also examined the role of various diabetes medications in influencing liver outcomes, particularly HCC risk. Drugs such as sodium-glucose cotransporter-2 inhibitors (SGLT-2i), glucagon-like peptide-1 receptor agonists (GLP-1a), and pioglitazone were of particular interest due to their potential hepatoprotective effects.
Patients taking SGLT-2 inhibitors experienced a significant reduction in HCC risk, particularly when they maintained optimal glycaemic control. The SHR for HCC in patients using SGLT-2 inhibitors was 0.60, indicating a 40% reduction in risk compared to those not using these medications. GLP-1 agonists were similarly associated with a reduced risk of HCC, though data on their specific effects in this cohort were limited.
Pioglitazone, a drug commonly used in type 2 diabetes, was also found to reduce the risk of HCC. Patients on pioglitazone who maintained optimal glycaemic control had an SHR of 0.68 for HCC, further supporting the idea that certain diabetes medications can provide additional benefits beyond blood glucose control.
Subgroup Analysis
Subgroup analysis further emphasized the protective effects of glycaemic control across a wide range of patient characteristics. The results were consistent regardless of age, sex, BMI, smoking status, or the presence of chronic liver conditions such as chronic hepatitis B (CHB). In fact, the benefits of optimal glycaemic control were even more pronounced in patients with chronic viral hepatitis, a known risk factor for HCC.
For example, among patients with CHB, those with optimal glycaemic control had a 46% reduced risk of developing HCC (SHR 0.54, 95% CI 0.45–0.64) compared to those with suboptimal control. Similarly, the reduction in liver-related mortality was greater in patients with CHB, further underscoring the importance of glycaemic control in patients with coexisting liver conditions.
Discussion and Implications
This large-scale population study offers robust evidence that optimal glycaemic control is a key factor in reducing the risk of hepatocellular carcinoma and liver-related mortality in diabetic patients. The results suggest that maintaining an HbA1c level below 7%, along with minimizing glycaemic variability, should be prioritized in diabetes management to mitigate the risk of liver-related complications. These findings have significant implications for clinical practice, particularly in the context of emerging treatments and technologies designed to optimize glycaemic control.
Additionally, the protective effect of certain diabetes medications, such as SGLT-2 inhibitors and pioglitazone, against HCC provides a potential avenue for future research. Understanding how these drugs can be integrated into treatment plans to not only control blood glucose levels but also provide hepatoprotective benefits is a critical area for further investigation.
Conclusion
In conclusion, this study highlights the critical importance of optimal glycaemic control in preventing liver-related complications in diabetic patients. Both the absolute level of glycaemic control and the consistency of blood glucose levels over time (glycaemic variability) play a pivotal role in reducing the risk of hepatocellular carcinoma and liver-related mortality. With diabetes rates rising globally, this research underscores the need for healthcare professionals to adopt comprehensive glycaemic management strategies to protect liver health in diabetic patients. Future studies should continue to explore how optimizing both glycaemic control and variability can further improve outcomes and reduce the burden of liver disease in this population.
