Research Article: Nonlinear HbA1c thresholds reveal accelerated atherogenic remodeling and improved risk reclassification in type 2 diabetes
Abstract:
Dysglycemia, lipid metabolism, and cardiovascular disease (CVD) progression in type 2 diabetes (T2D) are closely interconnected, yet the non-linear lipid remodeling processes underlying atherogenic dyslipidemia remain insufficiently defined. This study aimed to identify HbA1c thresholds associated with accelerated lipid-driven atherogenesis, quantify the mediating role of the triglyceride-to-HDL cholesterol ratio (TG/HDL-C)—a surrogate of insulin-resistance–related lipid metabolism—and assess the incremental predictive value of the Atherogenic Index of Plasma (AIP) within the clinically ambiguous “glycemic gray zone.” A total of 271 adults with T2D not receiving lipid-lowering therapy were retrospectively grouped by HbA1c: good (<7.0%), moderate (7.0%–8.49%), and poor (?8.5%) control. Atherogenic lipid burden was evaluated using AIP, Castelli indices, TG/HDL-C, non-HDL cholesterol, and remnant cholesterol. Restricted cubic splines were used to explore non-linear HbA1c–lipid relationships; mediation analysis estimated the TG/HDL-C contribution to the HbA1c–AIP pathway; and Net Reclassification Improvement ( N RI) tested the added predictive value of AIP over conventional lipid markers. All atherogenic indices worsened with deteriorating glycemia ( p <?0.001). Non-linear inflection points were observed at HbA1c 8.0% for TG/HDL-C and 8.5% for AIP (p_non-linearity?<?0.01). TG/HDL-C mediated 56.9% of the HbA1c effect on AIP, indicating its central role in linking hyperglycemia to lipid remodeling. Adding AIP improved cardiovascular risk reclassification, particularly in the 8.0%–8.5% transition range (categorical NRI?=?0.384; 95% CI: 0.184–0.584). These findings identify 8.0%–8.5% as a metabolically vulnerable HbA1c threshold marked by accelerated atherogenic dyslipidemia. AIP functions as a sensitive lipid-based marker for cardiometabolic risk detection within this gray zone, while TG/HDL-C acts as a key mechanistic mediator, supporting the integration of atherogenic lipid indices into individualized risk assessment and precision lipid management strategies in T2D.
Introduction:
Type 2 diabetes (T2D) is a rapidly escalating global health problem and a leading contributor to cardiovascular disease (CVD) morbidity and mortality ( 1 ). While hyperglycemia has long been recognized as a principal driver of diabetic complications, the mechanistic interplay between deteriorating glycemic control and accelerated atherogenic lipid remodeling remains only partially understood ( 2 ). Most prior studies examined linear associations between HbA1c and traditional lipid markers, including LDL-C, HDL-C,…
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