Cardiovascular disease (CVD) prevention and treatment remain major global challenges (Afzal et al., 2024; Jamthikar et al., 2020). According to the World Health Organization (Wang et al., 2023), approximately 120 million people worldwide suffered from CVD in 2024, accounting for 1.5% of the global population—with 60 million cases reported in China alone. CVD is a leading cause of death and disease burden, particularly among older adults. Among all CVDs, carotid atherosclerosis is of particular concern. Studies (Yuriev et al., 2021; Effati et al., 2024; Ruan et al., 2024) have shown that over 80% of individuals aged 50 and older in China have varying degrees of carotid atherosclerotic plaques. These plaques can cause arterial stenosis, reduce cerebral blood flow, and trigger ischemic cerebrovascular events, including life-threatening complications. Currently, no specific drug is approved for the treatment of carotid atherosclerosis, highlighting the urgent need for further research and therapeutic innovation.

According to clinical guidelines, the standard treatment for carotid atherosclerotic plaques involves the use of statins and Bayaspirin (López-Cancio et al., 2014; Hermel et al., 2022). Statins inhibit HMG-CoA reductase, promoting the uptake and degradation of low-density lipoprotein cholesterol (LDL-C) to lower plasma LDL-C levels (Huang et al., 2024; Turongkaravee et al., 2021; Wang et al., 2020b). Bayaspirin, an antiplatelet agent, inhibits COX-1 activity, thereby preventing abnormal platelet aggregation and reducing the risk of thrombosis (Zhang et al., 2023; Tufano et al., 2011). While this dual-drug regimen effectively slows disease progression, its long-term use is often limited by drug-related side effects, highlighting the need for safer and more sustainable alternatives (Benjamin et al., 2024; Vinci et al., 2021).

Panax notoginseng (Sanqi) is a well-established traditional medicine, and its saponin content, particularly ginsenoside Rg1—have become the focus of increasing scientific research (Li et al., 2008; Li et al., 2021). The Rg1-based pharmaceutical QiShengli Tablets (Yunnan Wenshan Teanna Pharmaceutical Co., Ltd.) have been approved for clinical use. Its core active ingredient is ginsenoside Rg1, and the formulation also includes four excipients: starch, dextrin, sucrose, and magnesium stearate. Meanwhile, the above four excipients will not affect the bioavailability and pharmacodynamic characteristics of the small molecule active ingredients within the conventional dosage range (Chen et al., 2013). Despite its approval, clinical evidence supporting its use in treating specific diseases remains limited. Consequently, the drug’s labeling describes its applications only in traditional Chinese medicine (TCM) terms—such as “invigorating the spleen,” “awakening the brain,” “reinforcing vital qi,” and “promoting blood circulation.” The lack of disease-specific indications hinders its widespread adoption in contemporary medical practice. Despite limited clinical evidence, preclinical studies over the past decade suggest that Rg1 can modulate immune function, alleviate obesity-related metabolic disorders, and exert protective effects against carotid and coronary atherosclerosis (Yang et al., 2022; He et al., 2022; Wang et al., 2020c). However, large-scale clinical trials are still needed to validate these findings.

Based on this context, our study examined the effects of ginsenoside Rg1 in patients with carotid atherosclerotic plaques. After 3 months of treatment, we conducted a comprehensive evaluation, including routine biochemical indicators (complete blood count, inflammatory markers, and oxidative stress markers) and carotid artery assessments using B-ultrasound. Ultimately, we aimed to contribute to the prevention of cardiovascular and cerebrovascular diseases and to explore ginsenoside Rg1 as a potential new therapeutic option for carotid atherosclerosis.

As noted in the introduction, carotid atherosclerosis is a specific form of atherosclerosis primarily characterized by lesions in the carotid intima, lipid deposition, luminal narrowing, and subsequent plaque formation (Dong et al., 2022; Liu et al., 2023). Studies have identified several key risk factors for carotid atherosclerotic plaque development, including age, sex, hypertension, hyperglycemia, and levels of HDL-C and LDL-C (Tian et al., 2024; Papazoglou et al., 2024). Current clinical treatment strategies involve a combination of pharmacological interventions—such as blood pressure control, plaque stabilization, and antithrombotic therapy—and lifestyle modifications (e.g., smoking cessation, regular physical activity, and weight management). Additional goals include controlling underlying risk factors, such as diabetes, hypertension, and hyperlipidemia, often through medications like antiplatelet agents, antihypertensives, and lipid-lowering drugs (Cao et al., 2024; Yang et al., 2020; Zhang and Ma, 2022). The combination of Bayaspirin and atorvastatin has been reported to significantly slow disease progression; however, its use may be limited by adverse side effects, underscoring the need for alternative therapies. Ginsenoside Rg1, the primary active component of Panax notoginseng (Sanqi), has demonstrated therapeutic effects in animal models of carotid atherosclerosis. However, its clinical efficacy remains largely unexplored (Wang et al., 2020a; Gu et al., 2022; Hu et al., 2025). Preliminary findings from our team’s preclinical, early clinical observations and access to relevant literature also suggest that ginsenoside Rg1 possesses anticoagulant properties (Liu et al., 2024). Therefore, we aimed to evaluate its therapeutic value by substituting Bayaspirin with ginsenoside Rg1 and comparing the outcomes. Post-treatment outcomes were assessed after a 3-month intervention, with comprehensive comparisons made between pre- and post-treatment results and across study groups.

Carotid color Doppler ultrasound is a key diagnostic tool for vascular health evaluation. It enables the detection of intimal thickening, plaque formation, plaque size, and plaque stiffness and allows for the measurement of blood flow velocity to evaluate stenosis or occlusion (Wen et al., 2022; Saba et al., 2024; Riggin et al., 2021). This modality is particularly valuable for monitoring treatment efficacy in patients with moderate-to-severe carotid stenosis or occlusion. In our study, carotid ultrasound revealed that both exercise therapy alone and exercise combined with ginsenoside Rg1 significantly reduced the number of plaques in both the left and right arteries (P < 0.05). Although no significant difference was found between these two groups in terms of plaque quantity reduction, the group receiving ginsenoside Rg1 exhibited a significantly greater plaque volume than the group receiving exercise plus Bayaspirin, highlighting the superior effect of ginsenoside Rg1.

To further assess the therapeutic benefits of ginsenoside Rg1, we assessed the arterial stiffness index (ASI) and the vascular health index (VHI). ASI is closely associated with carotid atherosclerosis, as elevated values correlate with increased IMT, reflecting disease progression. The VHI offers a broader assessment of an individual’s vascular condition and lifestyle-related cardiovascular risk. Given that the carotid artery is an important conduit supplying blood from the heart to the brain, its integrity directly impacts cerebral perfusion (Csipo et al., 2025). Carotid artery lesions, such as those caused by atherosclerosis, can lead to severe outcomes like stroke. Thus, we jointly evaluated the differences between the ASI and VHI. Although no significant post-treatment differences in ASI were observed between the groups, the ginsenoside Rg1 group showed significant improvements in left and right ankle-brachial PWV. These findings support the relatively higher therapeutic potential of ginsenoside Rg1 compared to Bayaspirin. Additionally, FGF21 levels differed significantly among the groups, while Lumican and Fibulin-1 showed no statistically significant variations. This result further proves that ginsenoside Rg1 can provide additional vascular benefits in managing carotid atherosclerosis compared to Bayaspirin.

Following the aforementioned procedures, we further examined the effects of ginsenoside Rg1 on biochemical parameters in the treated patient groups. Comparative analysis revealed statistically significant intergroup differences (P < 0.05) in LDL-C, TC, Hcy, IL-6, TNF-α, 25(OH)D, and IR levels post-treatment. Notably, LDL-C and TC—both established risk factors for atherosclerosis—demonstrated significant reductions following ginsenoside Rg1 administration, confirming its lipid-lowering potential. Additionally, ginsenoside Rg1 significantly improved five key biomarkers: Hcy, IL-6, TNF-α, 25(OH)D, and IR. Among these, IL-6 and TNF-α are key pro-inflammatory cytokines involved in all stages of carotid atherosclerosis—from plaque formation and progression to rupture. Elevated levels of these cytokines are known to promote inflammatory responses and exacerbate vascular endothelial injury, thereby compromising plaque stability. The inflammatory reaction can promote the rupture of foam cells after phagocytosis of lipids, releasing more lipid content that accelerates the increase in the atherosclerotic core volume; Meanwhile, the inflammatory reaction can also cause carotid vascular remodeling, which leads to further narrowing of the vascular lumen (Jin et al., 2022). Moreover, low levels of 25(OH)D have been associated with hypertensive carotid atherosclerosis, and its concentration is negatively correlated with plaque severity. IR and Hcy are also related to diabetic carotid atherosclerosis, particularly IR, which has been associated with increased IMT, greater arterial stiffness, and reduced vascular compliance and dilation capacity (Sipos et al., 2021; Strisciuglio et al., 2020; Liu et al., 2019). This suggests that IR may negatively impact carotid artery health by altering the structure and function of the vascular wall. The observed improvements in these biomarkers following ginsenoside Rg1 treatment highlight its potential therapeutic value, particularly for patients with hypertension or diabetic carotid atherosclerosis.

Finally, we assessed the three patient groups before and after treatment using the Comprehensive Geriatric Assessment Scales—MoCA, HAMA, PSQI, and HAMD—to evaluate whether ginsenoside Rg1 can improve the overall quality of life in patients with carotid atherosclerosis. Among these scales, the MoCA evaluates cognitive function, the HAMA assesses anxiety levels, the PSQI measures sleep quality, and the HAMD assesses depressive symptoms. Our results indicated that after 3 months of ginsenoside Rg1 treatment, there were no significant changes in HAMA, PSQI, and HAMD scores. This suggests that ginsenoside Rg1 does not significantly improve depression, anxiety, or sleep quality in patients with carotid atherosclerosis. However, the MoCA scores showed a significant difference among the three groups, suggesting that ginsenoside Rg1 may have a positive effect on cognitive function. For some of the indicators that did not reach statistical significance, we analyzed that they might be affected by 1) sample size limitations, especially the small number of cases in some subgroup analyses; 2) heterogeneity of responses to Rg1 due to inter-individual metabolic differences; and 3) the short follow-up period of the study, where changes in some biomarkers had not yet been adequately revealed. Future studies could be further validated by expanding the sample size, extending the intervention time, or using more sensitive assays.

In summary, our clinical study demonstrates that adjunctive ginsenoside Rg1 therapy—when combined with lifestyle modifications, lipid-lowering treatment, and intensive exercise—may reduce carotid plaque volume and number while also improving quality of life and certain metabolic and inflammatory markers. However, several limitations should be acknowledged: 1) The exclusion of high-risk patients with severe carotid atherosclerosis or multiple comorbidities may have introduced selection bias. 2) All participants in this study were older adults with underlying conditions and various geriatric syndromes. Despite efforts to minimize confounding factors, some influences on the outcomes may have been unavoidable. 3) The study was cross-sectional with regional limitations; therefore, the findings may not be generalizable to the broader elderly population. 4) The intervention period was limited to 3 months, and the sample size was relatively small. Although a priori power analysis (G*Power) suggested a minimum of 32 participants per group for detecting a medium effect size, larger sample sizes (e.g., >180 per group) would be required for more robust conclusions. Therefore, in subsequent studies, we plan to expand the sample size and extend the observation period to clarify the therapeutic potential of ginsenoside Rg1 in patients with carotid atherosclerosis and to define the scope of its clinical benefits.