Type 2 diabetes mellitus (T2DM) has long been associated with an increased risk of liver-related complications, including hepatic decompensation, hepatocellular carcinoma, and liver-related mortality.¹ While elevated glycated hemoglobin A1c (HbA1c) levels are a known risk factor, the influence of HbA1c trajectories over time on liver outcomes remains poorly understood.¹ To address this, a territory-wide cohort study was conducted in Hong Kong to evaluate the impact of HbA1c trajectories on the development of liver-related complications in patients with T2DM.¹ During the AASLD Annual Meeting 2024, Dr. Yip, Cheuk-Fung Terry from The Chinese University of Hong Kong, presented the study findings.¹

This retrospective cohort study included adult patients diagnosed with T2DM between 2000 and 2016, identified using an electronic health database covering 80% of Hong Kong’s population.¹ Eligible patients met criteria based on fasting glucose (≥7mmol/L), HbA1c (≥6.5%), antidiabetic medication use, or diagnostic codes.¹ Patients with type 1 diabetes, chronic viral hepatitis, human immunodeficiency virus (HIV) infection, significant alcohol consumption, or pre-existing liver-related complications, or follow-up <5 years were excluded.¹ Follow-up continued until liver-related complications, non-liver-related death, or a maximum of 15 years.¹ Unsupervised trajectory clustering using shape-based distance metrics revealed three distinct HbA1c trajectories during the first five years following T2DM diagnosis: stable (66.8%), mildly decreasing (17.1%), and rapidly decreasing (16.1%).¹ Key outcomes included hepatic decompensation, hepatocellular carcinoma, and liver-related death.¹

The study analyzed 374,286 patients (mean age: 61 years, 51.4% female, baseline HbA1c: 7.8%).¹ Over a median follow-up of 12.4 years, 4,295 patients (1.1%) developed liver-related complications.1 Patients with liver-related complications were relatively older (65.3 vs. 61.2 years old, p<0.001), with liver cirrhosis (5.4% vs. 0.8%, p<0.001), lower platelet counts (227.9 vs. 249.8, p<0.001), on sulphonylurea (71.3 vs. 61.0%, p<0.001), or insulin (20.9% vs. 15.2%, p<0.001).¹

Patients with mildly or rapidly decreasing HbA1c trajectories had a significantly lower risk of liver-related complications compared to those with stable HbA1c levels.¹ The adjusted cause-specific hazard ratios (aCSHRs) were 0.89 (95% CI: 0.86-0.92, p<0.001) for the mildly decreasing trajectory and 0.81 (95% CI: 0.78-0.84, p<0.001) for those with rapidly decreasing trajectory.¹

Multivariate analyses determined that higher HbA1c levels (aCSHR=1.06; 95% CI: 1.04-1.08; p<0.001), older age (aCSHR=1.03; 95% CI: 1.027-1.032; p<0.001), male sex (aCSHR=1.13; 95% CI: 1.06-1.20; p<0.001), cirrhosis (aCSHR=13.41; 95% CI: 10.68-16.83; p<0.001), and the use of sulfonylureas (aCSHR=1.19; 95% CI: 1.11-1.28; p<0.001) or insulin (aCSHR=1.34; 95% CI: 1.24-1.45; p<0.001) were associated with increased risk of developing liver-related complications.¹ Conversely, statin use significantly reduced the risk (aCSHR=0.34; 95% CI: 0.13-0.88; p=0.026).¹

The shape of the HbA1c trajectory was shown to be prognostic, independent of baseline HbA1c levels.¹ Patients with stable HbA1c trajectories had a notably higher incidence of liver-related complications compared to those with declining trajectories.¹ Importantly, the study highlighted that good glycemic control over time, even among patients with initially elevated HbA1c, could mitigate the risk of liver-related complications.¹

In summary, this study underscores the importance of longitudinal glycemic control in predicting liver-related outcomes among T2DM patients.¹ Beyond absolute HbA1c levels, the trajectory of glycemic control provides valuable prognostic information.¹