GRAPHICAL ABSTRACT

Highlights

• In T2DM patients, CTZ/EGb therapy significantly reduces carotid IMT compared to aspirin.

• CTZ/EGb improves lipid profiles and liver enzymes without cognitive or safety concerns.

• These findings support CTZ/EGb as a potential strategy to slow atherosclerosis in T2DM.

INTRODUCTION

Diabetes is a well-established risk factor for cardiovascular disease (CVD), including coronary artery disease and stroke. The risk of stroke is 2- to 3-fold higher in patients with type 2 diabetes mellitus (T2DM) compared to the general population [1]. In patients with T2DM, the prevalence of ischemic stroke is higher than that of hemorrhagic stroke compared to those without diabetes [2]. Therefore, preventing the progression of atherosclerosis to reduce CVD risk is crucial for patients with T2DM.

Many international guidelines from the USA, Europe, and Asian countries recommend antiplatelet therapy as part of the management strategy for patients with T2DM at high cardiovascular (CV) risk [3]. To identify individuals at high CV risk, several diagnostic tools have been introduced, including carotid intima-media thickness (IMT) measurement, pulse wave velocity, ankle-brachial index (ABI), and flow-mediated vasodilation [4]. Among these, carotid IMT is widely used as a surrogate marker for assessing atherosclerosis progression or regression in clinical trials due to its noninvasive nature and simplicity [5,6]. Indeed, a previous meta-analysis demonstrated that carotid IMT is a predictor of future vascular events, including stroke [7].

Importantly, recent large, randomized studies have demonstrated that aspirin does not provide significant benefits for the primary prevention of CVD; moreover, it may increase the risk of major bleeding [8-10] and even mortality [11]. Cilostazol (CTZ), a phosphodiesterase (PDE) III inhibitor, increases cyclic adenosine monophosphate concentrations, leading to the inhibition of platelet aggregation and thrombus formation [12]. Previous experimental studies have shown that CTZ treatment reduces inflammation and vascular smooth muscle cell proliferation while improving endothelial function, as well as triglyceride and high-density lipoprotein (HDL) cholesterol metabolism [13-17]. In clinical trials, CTZ treatment has also been shown to slow the progression of carotid atherosclerosis [18,19].

Extract of Ginkgo biloba (EGb) is known to enhance blood circulation by decreasing platelet activation and reducing platelet-activating factor levels [20,21]. EGb consists of two major components: flavonoids and terpenes. The flavonoid fraction exerts antioxidant effects by directly attenuating reactive oxygen species and promoting the expression of antioxidant proteins. This, in turn, increases antioxidant metabolites such as glutathione and facilitates the chelation of pro-oxidant transition metal ions [22,23]. Additionally, EGb treatment has been shown to inhibit amyloid-beta aggregation [24] and exhibit antiapoptotic properties [25].

Elderly individuals with T2DM are at a higher risk of developing vascular dementia compared to their non-diabetic counterparts [26]. This increased risk is primarily attributed to heightened oxidative stress, inflammation, and dysregulated insulin signaling, all of which contribute to neuronal damage [27,28]. The progressive nature of cognitive impairment in patients with T2DM poses significant challenges, affecting their quality of life, daily functioning, and ability to self-manage the disease [29].

Therefore, we conducted a prospective, randomized study to evaluate the efficacy of combined CTZ and EGb treatment and compare it with aspirin in preventing the progression of carotid atherosclerosis and cognitive decline in patients with T2DM.

METHODS

Study population and design

This was a prospective, randomized, active-controlled, parallel-group, open-label, multicenter, phase IV study conducted from July 2021 to June 2023 at five university hospitals in South Korea. Participants eligible for the study were patients with T2DM and peripheral artery disease, aged 20 to 75 years at the time of enrollment, who had an increased carotid IMT greater than 0.9 mm on carotid ultrasound.

The major exclusion criteria included patients with a recent history of CVD, uncontrolled hypertension, poorly controlled diabetes, acute bleeding, recently diagnosed gastric ulcers, severe kidney or liver dysfunction, or those receiving other antiplatelet therapy. Patients who had undergone or required vascular surgery, endovascular intervention, or carotid endarterectomy for peripheral artery occlusion within 1 month prior to screening. Other detailed exclusion criteria are presented in Supplementary Table 1.

Participants were randomly assigned in a 1:1 ratio to one of two treatment groups. One group received controlled-release CTZ (200 mg) and EGb (160 mg) once daily (CTZ/EGb group), while the other group received aspirin (100 mg) once daily (ASA group) for 12 months. To assess compliance, research coordinators checked the remaining pill count at each visit. The randomization order was generated using a computer-generated random number sequence. Safety assessments were performed at each visit and included physical examinations, vital signs, 12-lead electrocardiogram, laboratory tests, and monitoring for adverse events, based on both patient-reported symptoms and investigator observations. In addition, an unscheduled visit was included to allow for safety evaluations in cases of early discontinuation. All participants provided written informed consent. The study protocol was approved by the Institutional Review Board of Seoul National University Bundang Hospital (B-1604-344-002). This study was conducted in accordance with the Declaration of Helsinki and was registered at ClinicalTrials.gov (NCT05906199).

Measurement of anthropometric and biochemical parameters

Height (cm) and body weight (kg) were measured using standard procedures to the nearest 0.1 cm and 0.1 kg, respectively. Body mass index was calculated by dividing body weight by the square of height (kg/m²). Blood pressure was measured using an automated device. Before the measurement, each participant rested for at least 5 minutes while sitting in a chair with both feet flat on the floor and both arms supported at heart level.

After a 12-hour overnight fast, venous blood samples were collected in the morning. Fasting plasma glucose (FPG), total cholesterol, triglycerides, HDL-cholesterol, low-density lipoprotein cholesterol, and creatinine levels were measured using a standard automated chemistry analyzer (Hitachi 747, Hitachi, Tokyo, Japan). Glycosylated hemoglobin (HbA1c) levels were measured using a high-performance liquid chromatography-based Bio-Rad Variant II Turbo analyzer (Bio-Rad Laboratories, Hercules, CA, USA). Serum alkaline phosphatase, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured using an autoanalyzer (TBA-200FR, Toshiba, Tokyo, Japan). Serum high-sensitivity C-reactive protein levels were measured using a high-sensitivity automated immunoturbidimetric method (CRP-Latex (II)X2, Denka Seiken Co., Tokyo, Japan).

Ultrasound imaging

An experienced sonographer at each hospital performed and analyzed the ultrasound images. To reduce bias, the radiologist was blinded to both the treatment group and the imaging time point (baseline or follow-up). The interobserver reproducibility of IMT was excellent, with an intraclass correlation coefficient (ICC) of 0.969, while the reproducibility of plaque volume was good, with an ICC of 0.805.

Carotid IMT measurement was performed offline using six clips obtained from the bulb area, the common carotid artery (CCA), and the internal carotid artery (ICA), recorded in longitudinal mode, ensuring that the carotid artery was parallel to the transducer surface (horizontal in the image). The focal zone was set to the far walls of each site, and the intima-lumen and media-adventitia interfaces were traced, followed by processing using a previously described algorithm [30].

Carotid plaque was defined as a local thickening of the carotid IMT greater than 50% compared to the surrounding vessel wall, an IMT greater than 1.5 mm, or a local thickening greater than 0.5 mm [31]. If plaque was identified during the review of gray-scale serial images from three-dimensional (3D) sweep recordings, the beginning and end frames of the plaque were specified. The quantification laboratory-vascular plaque quantification (QLAB-VPQ) plug-in was used to outline the vessel walls and residual lumen in contiguous frames where plaque was present. For plaque volume measurement, each image was analyzed using an automated value provided by QLAB-VPQ, which was manually adjusted if the plaque contour was unclear. The plaque areas from all images in the entire sequence of each carotid artery (right/left) were summed to calculate the plaque burden [32].

Mini-Mental Status Examination

Although clinically distinct from dementia, the diagnosis of mild cognitive impairment (MCI) remains challenging due to the lack of clear diagnostic criteria and its primary reliance on clinical judgment. MCI is characterized by impaired cognition with minimal impact on instrumental activities of daily living [33]. Mini-Mental State Examination (MMSE) scores between 25 and 28 indicate a suboptimal cognitive status, suggestive of MCI [33,34]. The MMSE score was assessed using the validated Korean version (K-MMSE 2) (Hakjisa Publisher & Inpsyt Inc., Seoul, Korea).

End points

The primary endpoint was the change in maximum carotid IMT at the bulb, measured by 3D carotid ultrasound after 12 months of treatment. The secondary endpoints included changes in the maximum IMT of the right and left CCA and ICA from baseline. Other secondary endpoints involved changes in risk factors for atherosclerosis, such as lipid parameters, as well as changes in liver and kidney function.

Statistical analysis

Continuous data are presented as the mean±standard deviation, while categorical data are presented as numbers (%). The baseline characteristics were compared using Student’s t-test for continuous variables and the chi-squared test for categorical parameters. The Student’s t-test was applied after confirming normality using Kolmogorov-Smirnov Z test. A paired t-test was used to evaluate changes between baseline and post-treatment time points. All statistical analyses were conducted using SPSS for Windows version. 22.0 (IBM, Armonk, NY, USA). Statistical significance was set at P<0.05.

For the power calculation, since no studies have evaluated the effect of CTZ on carotid artery plaque volume, we referred to a previous study that assessed the efficacy of CTZ in preventing the progression of intracranial arterial stenosis. In that study, after 6 months of treatment with either CTZ or aspirin, 6.7% of patients in the CTZ group and 28.8% in the aspirin group showed progression of intracranial stenosis [35]. Based on these results, we conservatively assumed a 10% progression of carotid artery stenosis in the CTZ group and a 30% progression in the aspirin group after 12 months of treatment for carotid atherosclerosis. With an α-level of 0.05, a β-level of 0.20 for a superiority design, and a 15% drop-out rate, the minimum required sample size was 100 patients in total (50 per group, with 1:1 randomization).

RESULTS

Subject allocation and baseline characteristics

A total of 120 patients were screened, and 105 were randomized: 52 patients in the CTZ/EGb group and 53 in the ASA group. The mean duration of T2DM was over 10 years in both groups. After excluding those with poor adherence, early withdrawal, or protocol violations, 37 patients in the CTZ/EGb group and 39 in the ASA group were included in the per-protocol set, which was used for the primary analysis of changes in carotid IMT. Reasons for exclusion and participant disposition are shown in Supplementary Fig. 1.

The demographic and clinical characteristics of the participants enrolled in the study are presented in Table 1. The two groups were well-matched with respect to these characteristics. More than 40% of patients were being treated for hypertension, and over 80% were being treated for dyslipidemia.

Changes in carotid atherosclerosis after the 12-month treatment

Table 2, Fig. 1 summarize the changes in carotid atherosclerosis observed after treatment, as assessed by carotid ultrasound. The CTZ/EGb treatment resulted in a decrease in the maximum IMT at both the right and left bulb areas (from 1.435±0.690 to 1.346±0.688 mm at the right bulb; from 1.359±0.528 to 1.299±0.528 mm at the left bulb, with P=0.044 and P=0.041, respectively). In contrast, the maximum IMT at the bulb areas in the ASA group did not show significant changes during treatment. As a result, the delta change in IMT was significantly different between the two groups (Table 2, Fig. 1). However, no significant differences were observed in the CCA and ICA areas between the two groups

Changes in anthropometric and laboratory parameters after the 12-month treatment

Table 3 shows the changes in various parameters after treatment. There were no significant changes in systolic or diastolic blood pressure in either group after the 12-month treatment period. Heart rate also showed no significant change in either group.

FPG levels did not change significantly in either group. Among the lipid parameters, there was a significant decrease in triglyceride levels by 17.9 mg/dL and a significant increase in HDL-cholesterol levels by 5.6 mg/dL only in the CTZ/EGb group. In contrast, triglyceride levels increased insignificantly, and HDL-cholesterol levels did not change in the ASA group. As a result, the delta changes in triglyceride and HDL-cholesterol levels were significantly different between the two groups (Table 3).

Regarding liver enzymes, a significant reduction in AST and ALT levels was observed only in the CTZ/EGb group, resulting in significant differences in AST levels between the two groups.

Changes in the MMSE score

The changes in MMSE scores over 12 months are shown in Table 3. At 12 months, the CTZ/EGb group exhibited a slight increase in MMSE scores, from 27.00±2.57 to 27.27±2.42, whereas the MMSE score in the ASA group remained unchanged, resulting in no meaningful difference between the two groups.

Adverse events

Overall, 12 patients (27.5%) in the CTZ/EGb group reported any adverse events, compared to seven patients (13.7%) in the ASA group, as shown in Table 4. This difference was not statistically significant. Treatment-emergent adverse events were also similar between the groups: five patients (9.8%) in the CTZ/EGb group versus two patients (3.9%) in the ASA group. No serious adverse events, such as bleeding, were reported in this study. Headache was reported by five patients in the CTZ/EGb group, but none in the ASA group. Additionally, one patient in the CTZ/EGb group complained of palpitations.

DISCUSSION

In this prospective, randomized study, treatment with a combination of CTZ and EGb for 12 months significantly reduced the IMT of the carotid arteries compared to aspirin in patients with T2DM. The beneficial effects of CTZ on the vessels were accompanied by increases in HDL-cholesterol levels and decreases in triglycerides, as well as liver enzyme levels.

Carotid atherosclerosis is a well-known risk factor for ischemic cerebrovascular disease [36]. Carotid ultrasound is frequently used to assess carotid atherosclerosis due to its noninvasive nature and simplicity [37,38]. In particular, carotid IMT measured by carotid ultrasound is commonly used to assess the progression or regression of atherosclerosis, both in clinical practice and clinical trials.

The measurement of IMT in carotid arteries has become widely used for evaluating the severity of atherosclerosis because of its noninvasive nature and simplicity. Several studies have evaluated the effects of CTZ on carotid atherosclerosis or cerebrovascular disease [18,19,35,39]. In a randomized trial, treatment with CTZ for 2 years resulted in regression of the maximum carotid IMT compared to aspirin treatment [19]. In that study, the patients had T2DM and peripheral artery disease, as confirmed by the ABI test (<1.0). Another study of patients with T2DM without evident CVD found that CTZ treatment led to a greater reduction in carotid IMT compared to aspirin over a 3-year treatment period [40]. More recently, our study also demonstrated a decrease in maximum carotid IMT following CTZ treatment [41].

CTZ is known to have beneficial effects on endothelial function by modulating the expression of PDE III in endothelial cells. It also enhances vascular sensitivity to endogenous vasodilators, such as prostaglandins, and inhibits both primary and secondary platelet aggregation induced by collagen, adenosine diphosphate, arachidonic acid, and epinephrine [42].

In this study, a significant increase in serum HDL-cholesterol and a significant decrease in triglyceride levels were observed only in the CTZ/EGb group, which is in accordance with the findings of previous studies [18,19,43]. CTZ therapy increases lipoprotein lipase activity, which plays a crucial role in lipid metabolism in adipose tissue [17]. Furthermore, the decrease in hepatic triglyceride secretion by potentiating the effect of glucagon to inhibit very-low-density lipoprotein secretion may also contribute to the beneficial effects of CTZ on lipid metabolism [17]. In a previous study, CTZ treatment induced changes in lipid components in carotid plaque, as assessed by magnetic resonance imaging [39]. These results suggest that CTZ has a favorable effect on atheromatous plaque composition by altering lipid metabolism and reducing fat content. Another finding in this study was a decrease in AST and ALT levels in the CTZ/EGb group. Elevated liver enzyme activity is linked to fatty infiltration in the liver, which is associated with CVD [44]. This result may further support CTZ’s role in improving vascular health.

We previously published a clinical study in which treatment with CTZ for 1 year decreased the plaque volume in the coronary arteries in patients with T2DM [43]. We also found that CTZ treatment may improve endothelial function in the arteries of the lower extremities, assessed by a specific laser Doppler, a novel technology that can evaluate vascular circulation in the early phase [45,46]. Another recent study suggested CTZ’s potential as an effective treatment for diabetic endothelial dysfunction and vascular disease by reducing inflammasome activity [47]. These data support the idea that improvement in vascular function can be expected following CTZ treatment.

Previously, it was reported that treatment with EGb decreased homocysteine-induced intimal thickening following balloon injury in the rabbit abdominal aorta [48]. They found that EGb treatment was associated with the suppression of matrix metalloproteinase-9 (MMP-9) expression and an increase in endogenous p21 expression. We also reported that EGb761 treatment mitigated the development of carotid atherosclerosis in obese diabetic rats [49]. EGb761 significantly suppressed the proliferation and migration of vascular smooth muscle cells, promoted apoptosis, and reduced inflammatory processes [49].

In this study, no significant change was observed in the MMSE scores over 12 months in the CTZ/EGb combination treatment group. Considering the high baseline MMSE scores (around 27) in both groups, meaningful changes were unlikely with in either the CTZ/EGb or ASA treatment groups.

Regarding adverse events, overall and treatment-emergent adverse events did not differ between the two groups. Among adverse events of specific interest, major bleeding was not reported in either group. Headache was reported in five patients in the CTZ/EGb group but none in the ASA group. Additionally, one patient in the CTZ/EGb group reported palpitation, while one case of angina pectoris was reported in the ASA group.

Our study had several strengths. First, we evaluated carotid atherosclerosis at three different sites. Second, the study employed a prospective, randomized design over 12 months. Third, we assessed various markers associated with atherosclerosis, including liver enzymes, glucose, lipid profiles, and inflammatory markers. However, several limitations should be noted. First, we did not measure hard endpoints, such as CV or cerebrovascular events. Second, the baseline MMSE scores were relatively high, which may explain why no significant improvement was observed in the MMSE score. Third, although we did not specifically monitor individual medications such as sodium-glucose cotransporter 2 (SGLT2) inhibitors or statins throughout the study period, we did monitor the overall use of glucose-lowering and lipid-lowering agents. Participants were required to have been on stable doses for at least 30 days before enrollment, and dose adjustments were restricted during the study. Given that baseline use of these medications was comparable between groups and major dose changes were avoided, their impact on study outcomes is likely to have been minimal. Fourth, we did not collect data on body weight changes during the follow-up period. Although the study medications are not known to affect body weight, body weight can influence lipid markers, such as triglycerides and HDL-cholesterol. Therefore, caution is needed when interpreting the lipid outcomes. Fifth, while the decrease in liver enzymes may suggest improved hepatic function, it is uncertain whether this reflects changes in hepatic steatosis due to the absence of imaging or other assessments. Finally, a major limitation of this study was the absence of data on smoking status, a well-established risk factor for atherosclerosis.

In conclusion, the combined treatment of CTZ and EGb for 12 months significantly reduced carotid IMT in patients with T2DM compared to treatment with aspirin. These results suggest that the combination of CTZ and EGb may be an effective treatment option for the primary prevention of CVD in patients with T2DM. Longer-term, large-scale studies are needed to confirm these findings.

SUPPLEMENTARY MATERIALS

NOTES

CONFLICTS OF INTEREST

Sang Yong Kim has been associate editors of the Diabetes & Metabolism Journal since 2022. They were not involved in the review process of this article. Otherwise, there was no conflict of interest.

AUTHOR CONTRIBUTIONS

Conception or design: S.L.

Acquisition, analysis, or interpretation of data: Y.C.H., M.K.K., J.H.P., H.M.Y., S.Y.K., S.L.

Drafting the work or revising: Y.C.H., S.Y.K., S.L.

Final approval of the manuscript: all authors.

FUNDING

This research was funded by SK Chem. (Seoul, Korea) through a subcontract with Seoul National University Bundang Hospital (Seongnam, Korea). The funding agency had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

ACKNOWLEDGMENTS

None

Fig. 1.

Changes in maximum intima-media thickness (IMT) at the right and left bulb areas (A, B), right and left common carotid arteries (CCA) (C, D), and right and left internal carotid arteries (ICA) (E, F) after the 12-month treatment with cilostazol/extract of Ginkgo biloba (EGb) and aspirin. ^aP<0.05, which was calculated using a paired t-test between the values recorded at the baseline and after treatment.

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Hwang YC, Kim MK, Park JH, Yun HM, Kim SY, Lim S. Comparison of Efficacy and Safety of Cilostazol/Extract of Ginkgo biloba vs. Aspirin in Carotid Atherosclerosis in Patients with Diabetes Mellitus. Diabetes Metab J. 2025 Aug 13. doi: 10.4093/dmj.2025.0146. Epub ahead of print.

Received: Feb 24, 2025; Accepted: May 16, 2025

DOI: https://doi.org/10.4093/dmj.2025.0146.

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