With improvements in lifestyle and shifts in dietary habits, the prevalence of aging- and metabolism-related diseases has increased, making coronary artery disease a major public health concern. With the exploration of the mechanism of atherosclerosis and the development of clinical drug, stent and balloon technologies, the treatment of coronary artery disease has risen to the level of how to prevent in-stent restenosis and the rapid progression of non-target lesions. Identifying potential risk factors for in-stent restenosis and the progression of non-target lesions through large-scale data analysis provides valuable guiding for clinical practice. Accumulating evidence indicates that abnormal glucose metabolism, especially stress-induced and intermittent hyperglycemia, accelerates atherosclerosis by promoting inflammation and oxidative stress. This study integrates retrospective clinical data, animal models, and in vitro experiments to elucidate the predictive significance and underlying mechanisms of glucose dysregulation in the progression of in-stent restenosis (ISR) and non-target lesion (NTL) development.

A total of 1,644 ACS patients were enrolled. During the 2-year follow-up, 12.7% developed in-stent restenosis (ISR) and 24.3% showed non-target lesions (NTLs) progression. Logistic regression identified the stress hyperglycemia ratio (SHR), left ventricular ejection fraction (LVEF), and number of implanted stents as independent risk factors for ISR, while SHR, blood pressure, HDL-c, and the number and severity of NTLs were predictors of NTL progression. After multivariable adjustment, SHR remained independently associated with both ISR and NTLs (OR = 2.33, 95% CI: 1.26–4.31, p = 0.007; OR = 2.12, 95% CI: 1.30–3.44, p = 0.003). Restricted cubic spline analysis revealed a near-linear association between SHR and both outcomes, with significantly increased risk when SHR > 0.96 (p = 0.026; p = 0.0047). The XGBoost model achieved an AUC of 0.70 (95% CI: 0.67–0.78) for ISR prediction, while the hybrid logistic regression and XGBoost model had the best performance for NTL progression (AUC = 0.78, 95% CI: 0.72–0.85). Subgroup analysis indicated that elevated SHR was a stronger predictor of NTL progression in non-diabetic patients (OR = 3.76, p = 0.007) than in diabetics. ApoE⁻/⁻ mice subjected to carotid guide-wire injury exhibited endothelial damage. After a 12-week high-fat diet with intermittent recurrent high glucose stimulation, injured carotid artery (target lesion) developed severe plaque, while the contralateral uninjured carotid artery (non-target lesions) was more severe than that in mice without hyperglycemia or diabetic. For target lesions, ultrasound imaging revealed larger plaque volumes, narrower lumens, and reduced blood flow than the non-target lesion vessels. Histological staining confirmed more severe plaque burden (HE), lipid deposition (Oil Red O) in intermittent current high glucose group, accompanied by elevated circulating IL-6, IL-1β, and TNF-α levels. In HUVECs, intermittent recurrent high glucose exposure markedly reduced cell viability, increased apoptosis (flow cytometry) , and elevated secretion of IL-6, IL-1β and TNF-α, and intracellular ROS levels.

Five-year data indicate that the incidence of ISR has markedly declined since the introduction of drug-coated balloons, falling below 10% in the past two years. However, the progression of NTLs remains consistently high and has become a major source of potential risk and adverse events after PCI in patients with acute coronary syndrome. This study demonstrated that abnormal glucose fluctuations in non-diabetic patients trigger a more pronounced systemic inflammatory and oxidative stress response than sustained hyperglycemia, thereby accelerating the progression of both target and non-target lesions. Compared with in-stent restenosis, the risk of NTLs progression is not only related to the number and severity of NTLs, but also strongly linked to systemic conditions such as dysglycemia, dyslipidemia, and hypertension. Poor control of these risk factors aggravates systemic inflammation and oxidative stress, further promoting atherosclerosis. These findings provide new insights into the long-term management of ACS following PCI and highlight the importance of strict control of glucose to reduce future adverse cardiovascular events.