HbA1c trajectories and the risk of liver-related events in patients with type 2 diabetes mellitus

Background & Aims We assessed associations of time-weighted average haemoglobin A 1c (HbA 1c ), time-to-target HbA 1c , HbA 1c variability, and individual HbA 1c trajectories with liver-related events (LREs) in type 2 diabetes mellitus (T2DM). Methods A territory-wide cohort of adults newly diagnosed with T2DM (Jan 2000–Dec 2016) was identified in Hong Kong. HbA 1c trajectories were identified via time series clustering and externally validated in UK Biobank. Their associations with LREs were estimated in the Hong Kong territory-wide cohort using cause-specific hazards models, with non-liver-related death as competing risk. Results Among 294,096 patients identified (mean age, 60.6 years; 50.6% males), 3,438 (1.2%) developed LREs at a median 7.4 (IQR, 4.5–10.0) years follow-up. Higher time-weighted average HbA 1c (adjusted cause-specific hazard ratio [aCSHR] 1.12 per 1%, 95%CI 1.08–1.16, p <0.001) and high variability were associated with a higher risk of LREs, while more years with HbA 1c <7% were associated with a lower risk (aCSHR 0.95 per year, 95%CI 0.93–0.96, p <0.001). Three trajectories were identified: rapid decreasing (n=43,712; 14.9%), mild decreasing (n=114,413; 38.9%), and increasing (n=135,971; 46.2%). Compared with rapid decreasing, mild decreasing (aCSHR 1.30, 95%CI 1.13–1.50, p <0.001) and increasing (aCSHR 1.37, 95%CI 1.16–1.61, p <0.001) trajectories conferred higher risks. Compared with patients with baseline HbA 1c <7% and mild decreasing trajectory, those with baseline HbA 1c ≥9% and mild decreasing (aCSHR 1.27, 95%CI 1.08–1.50, p <0.001) or increasing (aCSHR 1.84, 95%CI 1.45–2.34, p <0.001) trajectories had higher LRE risks; whereas rapid decreasing trajectory was not associated with a higher risk (aCSHR 1.05, 95%CI 0.90–1.22, p =0.57). Conclusions Time-weighted average HbA 1c , cumulative duration of good glycaemic control, HbA 1c variability and trajectories correlated with LREs in T2DM. Rapid decreasing trajectory may mitigate LRE risk in patients with high baseline HbA 1c . Impact and implications The relationship between long-term glycaemic control and liver-related events (LREs) in patients with type 2 diabetes mellitus (T2DM) remains unclear. In this real-world territory-wide cohort study of 294,096 patients with newly diagnosed T2DM, patients with higher average HbA 1c , cumulative exposure to high HbA 1c and high HbA 1c variability had a higher risk of LREs. Among patients with baseline HbA 1c ≥9%, a rapid decreasing HbA 1c trajectory was associated with a lower risk of LREs, with no statistically significant difference compared to patients whose baseline HbA 1c was <7% and had a mild decreasing HbA 1c trajectory, while those with baseline HbA 1c ≥9% and mild decreasing or increasing HbA 1c trajectories were associated with increased risk of LREs. Our findings suggest that patients with rapid glycaemic control of newly diagnosed T2DM could benefit from reduced risk of LREs, and careful monitoring and intensified intervention should be maintained for patients who develop mild decreasing or increasing HbA 1c trajectories.