Percutaneous coronary intervention (PCI) has ushered in a new era of treatment for coronary artery disease. However, in-stent restenosis (ISR) remains a potential post-PCI complication (1, 2). Despite the fact that drug-eluting stent (DES) implantation significantly lowers the clinical incidence of ISR compared to bare-metal stents, ISR still occurs in 3% to 20% of cases, primarily influenced by patient pathological characteristics, risk factors (especially diabetes), and the type of DES used (3, 4).

The incidence and prevalence of type 2 diabetes mellitus (T2DM) have surged in both developed and developing countries (5). There is a strong correlation between the development of cardiovascular disease and abnormal glucose metabolism (6). Among individuals with diabetes, the prevalence of coronary heart disease can reach as high as 55% (7).

The 2019 ESC and EAC guidelines for blood lipid management recommend that patients with T2DM at very high risk should aim to reduce their low-density lipoprotein cholesterol (LDL-C) levels by 50% from baseline and maintain LDL-C levels below 1.4 mmol/L (55 mg/dl) (8).

The primary objective of this study was to assess the incidence of ISR and the rate of achieving LDL-C targets in patients with T2DM and unstable angina pectoris (UAP) one year after treatment with ezetimibe and rosuvastatin.

This study evaluated the effects of ezetimibe combined with rosuvastatin on the incidence of ISR and the LDL-C target achievement rate in patients with T2DM and UAP at a one-year follow-up. The results demonstrated that the combination therapy group exhibited a significantly lower incidence of ISR (at one year post-procedure) than the intermediate-intensity statin monotherapy group. Furthermore, the rosuvastatin-ezetimibe combination achieved lipid-lowering targets more rapidly than rosuvastatin alone, while maintaining an excellent safety profile. The absence of a high-intensity statin arm limits direct comparison of additive vs. dose-escalation strategies. However, our design reflects regional prescribing patterns where combination therapy increasingly supplements moderate statin doses.

ISR is defined as the progressive narrowing of the treated coronary artery segment due to arterial injury and subsequent neointimal hyperplasia after stent implantation. Typically occurring 6–12 months after PCI, ISR most commonly presents as recurrent angina pectoris but may also manifest as a myocardial infarction. As one of the primary factors compromising the long-term efficacy of PCI, ISR currently lacks standardized treatment strategies (9).

Recent advancements in coronary stent technology and antiplatelet therapies have reduced ISR incidence from historical rates of 40%–50% to approximately 10% (2). However, ISR prevention and management remain significant challenges in the field of cardiovascular medicine. The pathogenesis of ISR involves complex pathological mechanisms with multiple contributing factors, including: Current understanding suggests that various risk factors collectively induce endothelial cell injury or dysfunction, triggering local thrombosis and inflammatory responses in the body. This process, mediated by numerous cytokines, leads to smooth muscle cell proliferation, excessive extracellular matrix production, and vascular wall deposition, ultimately resulting in intimal hyperplasia and ISR (10). Notably, in-stent neoatherosclerosis may accelerate coronary plaque formation, promoting ISR progression.

Diabetes mellitus is an independent risk factor for ISR. Endothelial dysfunction mediated by advanced glycation end products plays a crucial role in ISR pathogenesis (11). These glycation products participate in post-PCI vascular remodeling processes, indicating that glycemic control alone cannot reverse the progression of vascular complications (12). Strict post-PCI glucose management combined with targeted AGE therapy may reduce ISR incidence (13, 14).

Lipid metabolism parameters demonstrate strong associations with ISR risk, with LDL-C being the most extensively studied and primary therapeutic target for dyslipidemia management (15). Substantial evidence indicates a positive correlation between serum LDL-C levels and ISR incidence, and LDL-C reduction effectively suppresses neointimal hyperplasia and delays ISR progression (16).

Abnormal lipid metabolism is the main cause of arteriosclerosis and a risk factor for coronary heart disease. Hyperlipidemia in patients leads to a large amount of lipid deposition on the vascular endothelium, resulting in endothelial cell proliferation and calcification, which results in gradual narrowing or even occlusion of the lumen. Abnormal blood lipid levels can be reflected by increased TG, TC, and LDL-C levels and/or decreased HDL-C levels. Therefore, all blood lipid regulation guidelines stipulate that the main purpose of reducing blood lipids is to reduce LDL-C and TC levels. Ezetimibe is a highly selective drug that interferes with cholesterol absorption. It can inhibit the protein transport of cholesterol in the small intestine, thus inhibiting the function of cholesterol uptake in the intestine, regulating the level of free cholesterol in the plasma, and reducing cholesterol storage in the liver. This product can be combined with statins to reduce LDL-C levels. While controlling the high-fat diet, it can be used independently to regulate blood lipids or in combination with HMG-CoA reductase inhibitors (statins) to treat hypercholesterolemia caused by various reasons, and it can significantly reduce the levels of LDL-C, TC, and apolipoprotein B in plasma. Ezetimibe regulates cholesterol by inhibiting its intestinal reabsorption; therefore, it is a new type of anti-lipid drug compared with statins. The pharmacological mechanism of this drug is to interfere with the transport of cholesterol by the NPC1L1 protein in the brush edge of the small intestine villus, so that the small intestine cannot fully absorb a large amount of cholesterol. It can also prevent the liver from storing and transporting cholesterol, regulate the level of cholesterol in the liver, increase the number of LDL-C receptors, and accelerate the metabolism of cholesterol in the plasma (17). The combination of ezetimibe and statins can play a synergistic role in preventing the generation of blood lipids from endogenous and exogenous sources, significantly reducing the level of cholesterol in plasma, reducing blood lipids, and slowing down the trend of atherosclerosis. These findings are in line with those of the CONNECT trial (18), showing that neoatherosclerosis was lower over a 3-year follow-up in patients undergoing intensive lipid-lowering therapy.

In our study, the sample size was small, and the follow-up period was one year. Therefore, more trials and long-term studies are needed to assess the clinical efficacy of rosuvastatin combined with ezetimibe in the treatment of patients with UAP complicated with T2DM after the first coronary stent implantation. While the observed ISR reduction was statistically significant, its magnitude should be interpreted cautiously given the small absolute event numbers. Confirmatory studies with larger cohorts are warranted.

Compared with rosuvastatin alone, the combined use of ezetimibe can better reduce LDL-C levels, prevent in-stent restenosis, and reduce coronary artery disease and adverse events. Rosuvastatin combined with ezetimibe is safe.