Current status and mechanistic insights into nontarget coronary lesions in patients with diabetes and early abnormal glucose metabolism

Abstract

The introduction of drug-eluting stents has significantly reduced the incidence of in-stent restenosis. Despite this, recurrent cardiovascular events related to untreated nontarget lesions (NTLs) are becoming more common and accounting for more than 50% of all recurrent cardiovascular events. In patients with diabetes, factors such as prolonged disease duration, poor glycemic control, insulin use, and inadequate lipid management may exacerbate the progression of NTLs and adverse cardiovascular events. Additionally, glycemic fluctuations have been linked to an increased risk of future cardiovascular events in patients with early glucose metabolism abnormalities and acute hyperglycemia. In this review, we explored the clinical and plaque characteristics of patients with diabetes and early glucose metabolism disorders, the percutaneous coronary intervention strategies for NTLs, and their prognostic implications. Furthermore, we investigated the mechanistic links between adverse cardiovascular outcomes and elevated inflammation, oxidative stress, hypercoagulability, and endothelial dysfunction.

Key Words: Nontarget lesion; Nonculprit lesion; Diabetes mellitus; Glucose metabolism abnormalities; Oxidative stress; Endothelial dysfunction

Core Tip: The number of nontarget-related recurrent cardiovascular events is increasing. Poor glycemic control, insulin use, and dyslipidemia contribute to high-risk plaque progression. Early glucose metabolism abnormalities and glycemic fluctuations further increase cardiovascular risk. This review examines the clinical and plaque characteristics of these patients with diabetes and early glucose metabolism abnormalities, percutaneous coronary intervention strategies for nontarget lesions, and the mechanistic roles of inflammation, hypercoagulability, oxidative stress, and endothelial dysfunction in adverse cardiovascular outcomes.

INTRODUCTION

With advancements in coronary stents, the incidence of in-stent restenosis has significantly decreased. However, adverse events related to untreated nonculprit lesions (NCLs) in acute myocardial infarction (AMI) account for over half of all future cardiovascular events[1-3]. These untreated NCLs are nontarget lesions (NTLs) for future follow-up and play a crucial role in recurrent cardiovascular events, especially nonfatal myocardial infarction. Treatment decisions for intermediate lesions are challenging and uncertain, because both overtreatment and culprit-lesion-only revascularization may not be optimal strategies. Lesions associated with recurrent adverse events often present residual high-risk plaque, vascular dysfunction and systemic vulnerability factors. Therefore, careful evaluation of plaque composition, such as lipid-rich content and thin-cap fibroatheromas (TCFAs), is essential when assessing NTLs. Additionally, functional assessments, including fractional flow reserve (FFR) and the instantaneous wave-free ratio, should be considered to avoid overlooking microvascular dysfunction or coronary vasospasm[4-6].

In modern society, the prevalence of metabolic syndrome has increased significantly because of unhealthy diets and lifestyles. Common metabolic disorders such as hypertension, diabetes, hyperglycemia, and insulin resistance are closely associated with coronary atherosclerosis. Elevated blood glucose levels promote atherosclerosis progression by increasing inflammation, oxidative stress, endothelial damage, and advanced glycation end products (AGEs)[7]. This review explores the role of diabetes and other glucose metabolism abnormalities in the progression of coronary NTLs and their underlying mechanisms.

CURRENT STATUS OF NTLS

During acute cardiovascular events, some NTLs are often insufficient to be the primary pathogenic factor of the event. Compared with target lesions, NTLs typically do not exhibit significant blood flow restriction, with a lower degree of luminal stenosis, shorter lesion length, and lower plaque burden. Additionally, hemodynamic parameters, such as the FFR, are greater in NTLs than in target lesions[8], which leads to a reduced sense of urgency among physicians and contributes to the frequent oversight of these lesions. There is currently no standardized definition for nontargeted lesions in clinical guidelines. They are commonly defined in research settings as lesions with a diameter greater than 2.5 mm that are not part of the target lesion percutaneous coronary intervention (PCI). NTLs are primarily defined as lesions located 5-10 mm away from a stent, and NCLs usually refer to noninfarct-related lesions during acute coronary events and include visually estimated coronary artery stenosis of at least 70% (angiographically significant) or 50%-69% stenosis with an FFR of ≤ 0.8[9].

It is debated whether to intervene in nontargeted lesions. This decision relies on comprehensive assessments, including assessments of angiographic stenosis severity, plaque characteristics, and overall disease burden[10-12]. The COMPLETE trial[9] showed that complete revascularization of NCLs with angiography displaying stenosis greater than 70% reduces the risk of myocardial infarction but does not decrease mortality. However, the average degree of stenosis in lesions causing major adverse cardiovascular event (MACE) is only approximately 47%[13], which highlights the need for more precise risk stratification.

The results of functional assessments such as FFR and instantaneous wave-free ratio have been mixed. For example, the FLOWER-MI trial[14] revealed no superiority of FFR-guided PCI over angiography-guided PCI in terms of mortality, one-year myocardial infarction risk, or the need for urgent revascularization[15]. The role of FFR-guided NCL treatment is controversial. Although it may lower the risk of repeat revascularization, it is associated with increased restenosis and stent thrombosis risks[16,17]. In the acute phase, FFR accuracy is reduced due to receptor desensitization, endothelin-1 elevation, left ventricular pressure, and edema, all of which lower values by approximately 0.03[18-21]. Imaging-based evaluations using intravascular ultrasound, optical coherence tomography (OCT), and near-infrared spectroscopy can identify vulnerable plaques (e.g., TCFA, large lipid burden, and thin fibrous caps) at high risk even without severe stenosis[22-26], particularly in diabetic patients[27-30]. However, these techniques increase the procedure time and complexity and may cause additional hemodynamic stress. For myocardial infarction patients with cardiogenic shock, immediate multivessel revascularization results in higher 30-day mortality than does culprit-only revascularization[31], suggesting that excessive treatment may exacerbate the cardiac burden and cause significant procedural trauma.

Noninvasive coronary computed tomography angiography offers an alternative, with features such as low-attenuation plaque or spotty calcification correlating with adverse outcomes[32-34]. Emerging biomarkers, such as epicardial adipose tissue, systemic inflammation indices, and residual synergy between PCI with Taxus and cardiac surgery scores, also have prognostic value[35-39]. Despite advances, no uniform guideline exists: United States guidelines emphasize physiological assessments[40], whereas European guidelines recommend angiography-based decisions for ST-segment elevation myocardial infarction and selective invasive evaluation for non-ST-segment elevation myocardial infarction[41]. Complete revascularization is important in acute coronary syndrome (ACS) to reduce MACEs, but the optimal timing and tools (FFR, OCT, intravascular ultrasound) for assessing NCLs are still evolving. Future directions may include artificial intelligence-assisted multimodal imaging to improve the identification of high-risk plaques and guide more tailored interventions[42].

NTLS IN DIABETIC PATIENTS

Diabetic patients generally exhibit more severe and complex coronary atherosclerosis than nondiabetic individuals do. First, their disease tends to be more diffuse with a greater number of smaller coronary branches involved. In addition, compared with those in nondiabetic patients, the coronary plaques in diabetic patients typically present with a larger necrotic core and more pronounced inflammation that is predominantly composed of macrophages and T lymphocytes[7]. Diabetic patients also have higher incidences of plaque rupture and positive remodeling, indicating a more active atherosclerotic process[43]. Moreover, vascular calcification is more prominent in diabetic patients and takes the form of diffuse and nodular calcification, which further complicates interventional treatment. Post-PCI, the incidence of MACE in diabetic patients is approximately twice that in nondiabetic patients, due to untreated nontarget lesion-related angina and myocardial infarction as well as target lesion restenosis[44,45]. Additionally, diabetic patients often have a greater prevalence of comorbidities, such as hypertension, dyslipidemia, and renal disease, which are known predictors of poor outcomes following myocardial infarction[46,47]. Regardless of diabetic status, complete revascularization appears to confer similar benefits in both diabetic and nondiabetic populations[48]. In fact, studies have shown that, in diabetic patients, complete revascularization is associated with a significant reduction in the rate of any revascularization events over a three-year period, particularly in patients with a residual synergy between PCI with Taxus and cardiac surgery score greater than 7.5. This suggests that the inherent susceptibility of diabetic patients to coronary atherosclerosis results in residual lesions that are more prone to recur, which makes complete revascularization even more beneficial in diabetic patients than in nondiabetic cohorts[49].

Large clinical studies, such as the PROSPECT II diabetic substudy[44], have demonstrated that the presence of diabetes increases the incidence of spontaneous myocardial infarction associated with NCLs nearly threefold. However, this is not directly correlated with the prevalence of high-risk plaque features. In multimodality imaging studies, no specific plaque characteristics have been definitively identified as being responsible for the increased risk of adverse events in diabetic patients[44]. In contrast, another diabetic substudy, the lipid-rich plaque study[50], reported that cholesterol-rich nonculprit plaques are more common in diabetic patients receiving insulin therapy, and are associated with an increased incidence of MACE during follow-up. The discrepancies between these studies may be explained by differences in the severity of diabetes; the former had an average glycated hemoglobin A1c (HbA1c) of 7.1%, whereas the latter, although not reporting HbA1c levels, included a population with a higher prevalence of diabetes and more comorbidities. Furthermore, insulin-treated diabetic patients presented a greater incidence of lipid-rich plaques and greater plaque burden than did those not on insulin. PROSPECT II[44] also indicated that insulin therapy may increase the proportion of MACE, suggesting that increased plaque burden and subsequent adverse events may be related to glycemic control levels, insulin resistance, and disease duration. Studies have shown that patients with HbA1c levels greater than 8% have a significantly increased prevalence of vulnerable NCLs[51], Colayco et al[52] reported that HbA1c levels both below 6% and above 8% are associated with an elevated risk of cardiovascular adverse events. Moreover, the use of insulin and sulfonylureas has also been linked to increased adverse event risk, implying that hypoglycemic episodes during the disease course may contribute to such outcomes. Current research suggests that diabetic status alone is not an ideal indicator of atherosclerotic plaque damage. Rather, glycemic control, disease duration, and related metabolic factors more accurately reflect the extent of high blood glucose-induced injury[53].

At the time of the initial PCI, some diabetic patients may present with plaque characteristics similar to those of nondiabetic patients. However, the already activated oxidative stress, which results in a “metabolic memory” effect, persists despite the subsequent intensification of glycemic and lipid control in a subset of diabetic patients. After PCI, activation of the transforming growth factor-β signaling pathway in diabetic patients further exacerbates high glucose-induced smooth muscle cell migration, accelerating neointimal hyperplasia[54-56]. An increase in the level of intracellular reactive oxygen species (ROS) leads to impaired angiogenesis after ischemia and the activation of multiple proinflammatory pathways. This epigenetic alteration continuously accelerates the progression of culprit and NCLs and still drives the occurrence of future MACE even after normalization of blood glucose levels[57]. Therefore, stricter standards should be adopted for the treatment of NCLs in diabetic patients, and complete revascularization is particularly beneficial.

NTLS IN PATIENTS WITH EARLY GLUCOSE METABOLISM ABNORMALITIES

In nondiabetic patients, abnormal glucose metabolism may also serve as a trigger for adverse cardiovascular events. The following are several indicators that have been frequently used to assess acute elevated blood glucose and blood glucose fluctuations (Table 1). A study by Zhou et al[58] revealed that among nondiabetic individuals, those with acute hyperglycemia, defined as the ratio of admission random blood glucose divided by HbA1c in the highest tertile, exhibit numerous high-risk plaques on OCT, similar to diabetic patients. This ratio was identified as a potential predictor of cardiovascular events in nondiabetic patients.

Table 1 The influence of blood glucose fluctuation indicators on the progression of atherosclerosis in patients with diabetes and early abnormal glucose metabolism.

Ref.	Disease	Diabetic status	Sample size	Factors	Find
Zhou et al[58], 2020	AMI	With diabetes and without diabetes	434	ABG/HbAlc	Patients with the highest ABG/HbAlc levels showed more high-risk plaques on OCT
Liu et al[59], 2023	AMI	With diabetes and without diabetes	4337	SHR	An elevated SHR has been strongly associated with increased one-year and long-term all-cause mortality in nondiabetic individuals
Liu et al[60], 2025	ACS	With diabetes and without diabetes	1234	SHR	An elevated SHR was associated with the rapid progression of nontarget lesions among nondiabetic patients
Karakasis et al[61] 2024	AMI	With diabetes and without diabetes	87974	SHR	The highest SHR quartile had a significantly higher risk of MACEs and MACCEs, as well as increased long-term outcomes
Yang et al[62], 2022	ACS	With diabetes and without diabetes	5562	SHR	There is a U-shaped or J-shaped association between the SHR and early and late cardiovascular outcomes events
Zeng et al[63], 2023	ACS	With diabetes and without diabetes	7662	SHR	Elevated SHR was independently associated with a higher risk of long-term outcomes irrespective of diabetic status
Su et al[64], 2020	ACS	With diabetes	144	1,5-AG	Low 1,5-AG levels were an independent predictor of plaque rupture in diabetic patients
Takahashi et al[65], 2016	CAD with PCI	With diabetes and without diabetes	240	1,5-AG	Serum levels of 1,5-AG were significantly lower in the event (+) group than in the event (-) group
Kataoka et al[66], 2015	ACS	With diabetes and without diabetes	88	GV (MAGE)	Mean MAGE was significantly higher in nonculprit progressors than in nonprogressors. MAGE was an independent predictor of RP
Yamamoto et al[67], 2021	CAD	With diabetes and without diabetes	101	GV (MAGE)	MAGE was significantly higher in the CVE group. MAGE was an independent predictor of CVE and rapid progression
He et al[68], 2024	CAD in ICU	With diabetes and without diabetes	2789	GV (MAGE)	Nondiabetic patients with high SHR levels and high GV were associated with the greatest risk of both in-hospital mortality and 1-year mortality
Chun et al[69], 2022	HF	With diabetes and without diabetes	2617	GV	High GV significantly increased the risk of 1-year mortality in nondiabetic patients but not in diabetic patients
Su et al[70], 2023	Ventricular arrhythmias in ICU	With diabetes and without diabetes	17756	CV of glycose	Each unit increase in log-transformed CV was associated with a 21% increased risk of ventricular arrhythmias and a 30% increased risk of in-hospital death
Tateishi et al[73], 2022	CAD with PCI	Without diabetes	40	GV (MAGE)	MAGE was correlated with maximum lipid core burden index 4 mm in non-diabetic patients
Kuroda et al[74], 2015	CAD with PCI	With diabetes and without diabetes	70	GV (MAGE)	Necrotic core was well correlated with MAGE. MAGE was the only independent predictor of the presence of TCFA.
Akasaka et al[76], 2017	CAD	Without diabetes	65	GV (MAGE)	High MAGE and low RHI (≤ 0.56) were risk factors associated with cardiovascular events

AMI: Acute myocardial infarction; ACS: Acute coronary syndrome; CAD: Coronary artery disease; PCI: Percutaneous coronary intervention; ICU: Intensive care unit; HF: Heart failure; ABG: Arterial blood gas; HbAlc: Glycated hemoglobin A1c; SHR: Stress hyperglycemia ratio; GV: Glycemic variability; MAGE: Mean amplitude of glycemic excursion; CV: Coefficient of variation; MACEs: Major adverse cardiovascular events; MACCEs: Major adverse cardiac and cerebrovascular events; 1,5-AG: 1,5-anhydroglucitol; RP: Rapid progression; CVE: Cardiovascular events; TCFA: Thin-cap fibroatheroma; RHI: Reactive hyperemia index; OCT: Optical coherence tomograph.

Stress hyperglycemia refers to a transient increase in blood glucose due to elevated stress hormones (such as cortisol, catecholamines, glucagon, and growth hormone) in response to severe illness, trauma, infection, or surgery. The stress hyperglycemia ratio (SHR) was also calculated on the basis of admission blood glucose levels and HbA1c. In critically ill patients with AMI, an elevated SHR was strongly associated with increased one-year and long-term all-cause mortality in nondiabetic patients[59]. Our previous study also revealed an elevated SHR during the rapid progression of NTLs among nondiabetic patients with ACS[60]. A meta-analysis that encompassed 26 cohort studies with 87974 patients indicated that, regardless of diabetes status, patients with AMI in the highest SHR quartile had a significantly greater risk of MACEs and cerebrovascular events, and poor long-term outcomes[61]. Notably, SHR elevation was independently associated with worse long-term outcomes, which suggests its potential role as a biomarker for post-ACS risk stratification[62,63]. Further prospective studies are warranted to explore these relationships in greater depth.

Postprandial hyperglycemia is a form of acute glucose metabolism abnormality. The serum level of 1,5-anhydroglucitol (1,5-AG) reflects short-term glycemic control and the frequency and magnitude of postprandial hyperglycemia. In diabetes, reduced 1,5-AG levels indicate poor glycemic control and may predict microvascular and macrovascular complications, such as retinopathy, nephropathy, and cardiovascular disease[64]. In nondiabetic individuals, lower 1,5-AG levels may indicate undiagnosed diabetes or early-stage glucose metabolism abnormalities. A study by Takahashi et al[65] demonstrated that serum 1,5-AG levels were significantly associated with the risk of any revascularization event in patients with coronary artery disease with HbA1c < 7.0%, and outperformed both HbA1c and fasting glucose levels as predictive markers.

Glycemic variability (GV), defined as the difference between peak and nadir glucose levels during continuous monitoring, is commonly assessed using the mean amplitude of glycemic excursion (MAGE). In NCLs, MAGE is linked to the rapid progression of luminal narrowing in patients with ACS[66,67]. GV was significantly associated with in-hospital and one-year mortality, with a stronger correlation observed in nondiabetic individuals[68-70]. During the acute phase of ACS, glycemic fluctuations activate the sympathetic nervous system and increase the risk of myocardial ischemia and arrhythmias. Research has shown that mortality is partially mediated by ventricular arrhythmias[71,72]. In addition, studies have shown that a higher MAGE is associated with increased rates of uncovered stent struts, which leads to abnormal neointimal healing[73]. In nondiabetic individuals, the MAGE is positively correlated with the maximum lipid core burden index 4 mm, necrotic core volume, and the presence of a TCFA[73,74]. Greater MAGE values correlate significantly with impaired endothelial function (measured by the reactive hyperemia index), and fluctuating glucose levels appear to exert a more detrimental effect than persistently elevated glucose levels do[73,75,76], which suggests that diabetic individuals may have a greater tolerance for wider glycemic fluctuations[68,69]. Acute blood glucose fluctuations with abnormal blood glucose metabolism are associated with a higher incidence of MACE and high-risk plaques in patients with ACS and are more dangerous than chronic hyperglycemia in patients with diabetes.

MECHANISM BY WHICH HYPERGLYCEMIA PROMOTES THE PROGRESSION OF NCLS

In diabetes, hyperglycemia, insulin resistance, and excessive fatty acid metabolism disorders lead to excessive production of superoxide and inflammatory factors. These pathological changes contribute to various complications through multiple mechanisms, such as the polyol pathway, increased formation of AGEs, upregulation of AGE receptors and their activating ligands, activation of protein kinase C isoforms, and overactivation of the hexosamine pathway[57]. Additionally, hyperglycemia can directly inactivate antiatherosclerotic enzymes, such as endothelial nitric oxide synthase (eNOS) and prostacyclin synthase, and further exacerbate vascular dysfunction[77,78].

Under hyperglycemic conditions, dysfunction of the mitochondrial electron transport chain leads to reduced adenosine triphosphate production and increased superoxide production. Subsequently, the above five pathways are activated, further enhancing the inflammatory response and oxidative stress. The secretion of pro-inflammatory cytokines (e.g., tumor necrosis factor-α, interleukin-6, interleukin-1β) increases, which promote monocyte and macrophage activation and differentiation, M1-type macrophages further secrete inflammatory factors to intensify the inflammatory response[79-81]. Meanwhile, hyperglycemia increases the release of chemokines such as monocyte chemoattractant protein-1 (MCP-1), facilitating leukocyte infiltration and amplifying vascular inflammation. Additionally, the accumulation of AGEs and the subsequent increase in ROS production exacerbates oxidative stress, impairing endothelial cells and vascular smooth muscle cells. Endothelial dysfunction is an initiating and critical factor in atherosclerotic plaque formation[82,83]. Furthermore, low-density lipoprotein is more prone to oxidation under hyperglycemic conditions, forming oxidized low-density lipoprotein, which further promotes foam cell formation and atherosclerosis[84].

In diabetes, elevated proinsulin levels and insufficient C-peptide secretion result in eNOS dysfunction, which leads to reduced nitric oxide production and impaired vasodilation. Proinsulin, the precursor of insulin, is typically cleaved in pancreatic β-cells to generate insulin and C-peptide. Elevated proinsulin directly damages endothelial cells, whereas reduction of C-peptide loses the protective effect of eNOS. Moreover, hyperglycemia induces endothelial progenitor cell dysfunction and impairs endothelial cell proliferation and repair, which exacerbates vascular constriction and inflammation[85]. Our previous study demonstrated that under hyperglycemic conditions, activation of the nuclear factor-κB/microRNA-425-5p/monocarboxylate transporter 4 axis lead to increased endothelial cell apoptosis, elevated ROS levels, and reduced nitric oxide production, ultimately impairing vascular relaxation[86]. Insulin resistance further exacerbates vascular dysfunction by disrupting insulin signaling pathways. Dysfunction of the phosphoinositide 3-kinase/protein kinase B pathway leads to reduced endothelium-dependent vasodilation. Additionally, insulin resistance activates the renin-angiotensin-aldosterone system, increasing the levels of angiotensin II, which promotes vasoconstriction and inflammation. Vascular smooth muscle cells exhibit abnormal proliferation and migration, contributing to vascular remodeling, increased vascular resistance, and increased atherosclerosis risk. Hyperglycemia and insulin resistance also enhance platelet activation and thrombogenesis while impairing the fibrinolytic system, leading to elevated D-dimer levels and an increased risk of intravascular thrombosis[84].

Compared with chronic hyperglycemia, acute glucose fluctuations have a more profound effect on oxidative stress[87]. Monnier et al[87] demonstrated that acute glucose excursions induce increased oxidative stress levels, as indicated by urinary 8-iso-prostaglandin F2α excretion, and that MAGE is independently associated with oxidative stress levels[77,78,88]. Postprandial glucose spikes lead to excessive superoxide production, which generates peroxynitrite and nitrated tyrosine through interactions with nitric oxide and induces endothelial damage, inflammation, oxidative stress, and thrombogenesis[89]. Similarly, stress-induced glucose surges trigger a vicious cycle of inflammation, leukocyte aggregation, platelet activation, and thrombosis. Elevated glucose levels stimulate mitochondrial ROS production and AGE formation, and initiate epigenetic modifications such as DNA methylation and histone posttranslational modifications (metabolic memory), in which even short-term exposure to hyperglycemia can have long-term adverse cardiovascular effects[90,91]. In vitro, transient hyperglycemia can produce sufficient ROS and cause persistent epigenetic changes. Studies have found that transient hyperglycemia can induce the long-term activation of the p65 promoter of the nuclear factor-κB subunit, thereby persistently activating the expression of P65 and promoting the increase of downstream monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1. This prolonged transcriptional activation is mediated by the enrichment of a specific epigenetic mark, histone 3 Lysine 4 monomethylation, at the proximal promoter region of the p65 gene[92]. Compared with the group with chronic hyperglycemia, the group of increased glucose levels exhibited more pyroptosis reactions mediated by inflammatory responses in diabetic nephropathy[93]. A mouse study using a transient intermittent hyperglycemia model revealed that even short-term glucose spikes enhance myelopoiesis, increasing the number of proinflammatory Ly6Chi monocytes and neutrophils. Glucose uptake via glucose transporter 1 fuels neutrophil glycolysis and S100A8/A9 production, activating receptor for advanced glycation end products signaling and promoting leukocyte adhesion and vascular inflammation. These mechanisms promote atherosclerosis by accelerating plaque formation and hindering regression[94]. CD14+ and CD16+ monocytes are associated with inflammatory responses and atherosclerosis. Studies have shown that the number of CD14+ and CD16+ monocytes is significantly correlated with blood glucose fluctuations, and both are associated with the presence of a greater volume of necrotic cores and virtual histology-TCFA in nondiabetic patients[95]. These findings suggest that glucose fluctuations may alter the balance of monocyte subsets and that the crosstalk between glucose variability and CD14+ and CD16+ monocytes may lead to plaque vulnerability, especially in nondiabetic individuals[96]. Early abnormal glucose metabolism usually has a transient intermittent increase in blood glucose, which is sufficient to trigger atherosclerosis with an unpredictable rate of progression (Figure 1). Hyperglycemia is a systemic change. Both nontarget and target lesions are hit by it, and promoting the progression of atherosclerosis.

Figure 1 A transient increase in blood glucose can cause epigenetic changes by increasing oxidative stress, initiating the process of atherosclerosis.

CONCLUSION

The incidence of adverse events related to NTLs is greater in patients with hyperglycemia, and faster progression of NTLs has also been observed in nondiabetic patients with acute hyperglycemia. The incidence rate of nontargeted lesions has been increasing in recent years, leading to increased attention. Acute elevation and fluctuations in blood glucose promote the development of atherosclerosis through mechanisms such as oxidative stress, endothelial dysfunction and chronic inflammation and affect the progression of NCLs. Several pharmacological agents, including α-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors, have been shown to improve oxidative stress and glucose variability, particularly postprandial hyperglycemia[97,98]. Given that glucose variability contributes to vascular injury, plaque destabilization, and MACE, incorporating GV metrics, such as the MAGE or the SHR, into routine cardiovascular risk stratification could enhance the identification of high-risk patients beyond using traditional markers such as HbA1c or fasting glucose. This approach may facilitate the early implementation of targeted pharmacotherapy aimed at both stabilizing glucose fluctuations and improving cardiovascular outcomes, particularly in individuals with impaired glucose tolerance or in nondiabetic patients exhibiting stress-induced hyperglycemia. Further prospective studies are needed to validate these markers and guide their integration into clinical practice.