Abstract
BACKGROUND: The Hemoglobin Glycation Index (HGI) quantifies the difference between observed and predicted glycated hemoglobin (HbA1c) values, and has connections to multiple adverse outcomes. However, the relationship between HGI and the risk of diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (T2DM) remains underexplored. The objective of this study was to examine the relationship between baseline HGI and the risk of DN development among patients with T2DM through a retrospective cohort study. METHODS: A single-center retrospective study was conducted on 1050 newly diagnosed T2DM patients with normal renal function at baseline. Participants were categorized into quartiles based on HGI values. The primary outcome was DN development, defined as persistent proteinuria or reduced estimated glomerular filtration rate (eGFR). Multivariable logistic regression, restricted cubic spline (RCS) analysis, and threshold effect models were employed to assess the association between HGI and DN risk. Subgroup and sensitivity analyses were conducted to validate the robustness of our findings, while mediation analysis was employed to explore potential underlying mechanisms. RESULTS: The study revealed a U-shaped relationship between HGI and DN risk. Both excessively low and high HGI levels were associated with an increased risk of DN, with the lowest risk observed at an HGI threshold of -0.648. In fully adjusted models, the highest HGI quartile (Q4) demonstrated a significantly increased risk of DN (OR = 1.54, 95% CI: 1.03-2.30, P = 0.036), while the lowest HGI quartile (Q1) also showed a trend toward higher risk (OR = 1.40, 95% CI: 0.92-2.14, P = 0.115). However, fasting plasma glucose (FPG) (P for overall = 0.217) and glycated hemoglobin (HbA1c) (P for overall = 0.529) did not show an association with the risk of DN. Subgroup and sensitive analyses confirmed the consistency of this U-shaped association across different patient demographics. Mediation analysis indicated that C-reactive protein (CRP) mediated 11.1% of the effect of |HGI| on DN. CONCLUSION: In T2DM patients, baseline HGI exhibits a U-shaped association with DN risk, serving as a potential indicator for assessing DN risk.