# Nonlinear HbA1c thresholds reveal accelerated atherogenic remodeling and improved risk reclassification in type 2 diabetes

## TL;DR

The study finds that HbA1c levels between 8.0% and 8.5% mark a critical threshold for increased cardiovascular risk in type 2 diabetes due to worsened lipid profiles.

## Contribution

The paper identifies non-linear HbA1c thresholds and demonstrates the added value of the Atherogenic Index of Plasma (AIP) in cardiovascular risk assessment.

## Key findings

- Non-linear inflection points in lipid profiles occur at HbA1c levels of 8.0% and 8.5%.
- TG/HDL-C mediates 56.9% of the HbA1c effect on AIP, linking hyperglycemia to lipid remodeling.
- Adding AIP improves cardiovascular risk reclassification, especially in the HbA1c transition range of 8.0%–8.5%.

## 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 (NRI) 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.