A Single‑Center Retrospective Cohort Study: Impact of Glycemic Control on First‑Line TKI Plus PD‑1 Inhibitors versus TKI Alone in Intermediate‑to‑advanced Unresectable Hepatocellular Carcinoma(HCC) with Type 2 Diabetes Mellitus (T2DM).

BACKGROUND AND AIM: Type 2 diabetes mellitus (T2DM) is an independent risk factor for hepatocellular carcinoma (HCC), and the number of HCC patients with comorbid T2DM is increasing. Although tyrosine kinase inhibitor (TKI) monotherapy or combination with programmed death‑1 (PD‑1) inhibitors has become the first‑line standard of care for advanced HCC, most relevant clinical trials excluded patients with poorly controlled glycemia. Consequently, direct comparisons of efficacy and safety between first‑line regimens specifically in T2DM‑combined HCC populations remain insufficiently explored, and the impact of glycemic control on treatment outcomes also remains unclear. Therefore, this study retrospectively compares first‑line TKI monotherapy versus combined regimens in this population, with a focus on the effect of glycemic control status on prognosis, and aims to construct a prognostic nomogram integrating clinical and metabolic indicators to support individualized risk assessment. METHODS: We retrospectively analyzed HCC patients with T2DM who received TKI monotherapy or TKI+PD-1 between January 2019 and January 2024. Overall survival (OS) and progression‑free survival (PFS) was analyzed using Cox regression (HR). Cancer‑specific death (with non‑cancer death as competing event) and PFS were evaluated using Fine‑Gray competing risk models (sHR). A prognostic nomogram incorporating independent predictors was developed and internally validated. RESULTS: A total of 374 patients were enrolled (217 TKI+PD-1, 157 TKI), with 135 per group after Propensity Score Matching (PSM) (1:1). Post-PSM, the TKI group showed significantly inferior median OS (mOS: 20.7 months vs 26.8 months, HR=2.009, 95% CI 1.438-2.807, P<0.001) and PFS (mPFS: 11 months vs 16 months, HR=2.086, 95% CI 1.495-2.911; All P<0.001) compared to the TKI+PD-1 group. In the TKI cohort, poor glycemic control was associated with significantly worse OS (HR=2.125, 95% CI 1.215-3.714, P<0.001) and PFS (HR=2.210, 95% CI 1.292-3.781, P<0.001), but this association was not observed in the TKI+PD-1 cohort. The prognostic nomogram (corrected C index = 0.652) showed acceptable calibration and provided modest stratification patients into three risk groups (median OS: 19.3, 16.5 and 13.8 months, log rank P<0.001). Grade 1-2 diarrhea was lower in the TKI+PD-1 group (16.6% vs 26.8%, P = 0.017), with no increase in high-grade adverse events. CONCLUSION: In HCC patients with T2DM, TKI+PD-1 offers superior OS and PFS compared to TKI alone. Glycemic control significantly impacts prognosis in patients receiving TKI monotherapy but its independent effect is diminished in those on combination immunotherapy. The proposed nomogram provides an individualized prognostic tool for this patient population.