Diabetes & Metabolism Journal

Original Article

Complications
Comparison of Efficacy and Safety of Cilostazol/Extract of Ginkgo biloba vs. Aspirin in Carotid Atherosclerosis in Patients with Diabetes Mellitus: You-Cheol Hwang, Mi Kyung Kim, Jung Hwan Park, Han Mi Yun, Sang Yong Kim, Soo Lim; Diabetes Metab J. 2026;50(2):357-367. Published online August 13, 2025; DOI: https://doi.org/10.4093/dmj.2025.0146

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Background
We conducted a prospective, randomized study to evaluate the combination of cilostazol (CTZ) and extract of Ginkgo biloba (EGb) and compare it with aspirin for the prevention of atherosclerosis progression in patients with type 2 diabetes mellitus (T2DM).
Methods
One hundred five patients with T2DM and increased carotid intima-media thickness (IMT) were randomly assigned to receive either CTZ 200 mg plus EGb 160 mg once daily or aspirin (ASA) 100 mg/day for 12 months. The primary endpoint was the change in maximum carotid IMT.
Results
The mean age and body mass index were 61.6±8.4 years and 25.2±3.1 kg/m² in the CTZ/EGb group and 61.6±7.6 years and 24.5±3.3 kg/m² in the ASA group, respectively. CTZ/EGb treatment reduced the maximum IMT in the bulb area (from 1.435±0.690 to 1.346±0.688 mm on the right; from 1.359±0.528 to 1.299±0.528 mm on the left), whereas ASA treatment did not, resulting in significant between-group differences (P<0.05). No significant differences were observed in the common carotid and internal carotid arteries. The CTZ/EGb group showed a reduction in triglycerides and an increase in high-density lipoprotein cholesterol levels. Additionally, aspartate and alanine aminotransferase levels decreased only in the CTZ/EGb group. There were no significant differences in Mini-Mental State Examination (MMSE) score changes or adverse events (ClinicalTrials.gov number: NCT05906199).
Conclusion
Twelve months of CTZ/EGb combination therapy significantly attenuated the progression of carotid atherosclerosis compared with aspirin in patients with T2DM.

Citations

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Cilostazol/Extract of Ginkgo biloba or Aspirin, What Is the Treatment in Atherosclerosis Prevention? (Diabetes Metab J 2026;50:357-67)
Christian Saleh, Ivanka Maduna, Hrvoje Budincevic
Diabetes & Metabolism Journal.2026; 50(2): 414. CrossRef
Comparison of Efficacy and Safety of Cilostazol/Extract of Ginkgo biloba vs. Aspirin in Carotid Atherosclerosis in Patients with Diabetes Mellitus (Diabetes Metab J 2026;50:357-67)
You-Cheol Hwang, Sang Yong Kim, Soo Lim
Diabetes & Metabolism Journal.2026; 50(2): 428. CrossRef

Randomized Controlled Trial

Titration with an Initially Lower Dose Increased Compliance of Cilostazol (Pletaal(R)) in Diabetic Patients.: Hyo Jeong Kim, Kyung Ah Han, Hyun Jin Kim, Kang Seo Park, Eung Jin Kim, Kyung Wan Min; Korean Diabetes J. 2006;30(5):388-397. Published online September 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.5.388

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Abstract PDF: BACKGROUND
Headache is frequently reported by patients using cilostazol, which is a potent inhibitor of platelet aggregation with vasodilatory effects, for preventing atherosclerotic disease. The aims of this study were to think out a dosing schedule for improving compliance on headache and to investigate the possible mechanisms of headache associated with atherosclerosis measured as carotid intimal-media thickness (IMT) in Korean diabetic patients. METHODS: We therefore randomized patients into three groups according to the different dosing regimens for 6 weeks (1) group 1; 50 mg once daily, followed by 50 mg twice daily, and then 100 mg twice daily or (2) group 2; 50 mg twice daily, followed by 100 mg twice daily or (3) group 3; 100 mg twice daily without titration. We evaluated severity of the headache by visual analog scaled (VAS) symptom score from zero to ten and measured carotid IMT using high resolution ultrasound. RESULTS: A total of 122 diabetic patients were analyzed. The mean values of age, sex, duration of diabetes, BMI, HbA1c, lipid profiles, blood pressure, and smoking were not different among three groups. The proportion of headache was significantly lower in group 1 than group 2 and 3 (26% vs. 48% and 51%, P < 0.05). The proportion of severe headache was significantly lower in group 1 than group 2 and 3 (3% vs. 19% , 27%, P < 0.05). Among patients who had headache, the proportion of severe headache was significantly lower in group 1 than group 3. (10% vs. 52%, P < 0.05). The VAS symptom score of headache was significantly lower in group 1 than group 3 (4.9+/-2.1 vs. 7.0+/-2.4, P < 0.05). The proportion of the discontinuation of medication due to headache was significantly lower in group 1 than other two groups (8% vs. 24% and 29%, P < 0.05). The patients who had discontinued medication due to headache had lower carotid IMT than in whom were tolerable (Mean carotid IMT; 0.65+/-0.12 vs. 0.77+/-0.16 mm, P < 0.01, Maximal carotid IMT; 0.80+/-0.17 vs. 0.94+/-0.23 mm, P < 0.01). The proportion of patients who had discontinued medication due to headache was significantly lower in group 1 than other two groups (8% vs. 24%, 29%, P < 0.05] CONCLUSION: Titration with an initially lower dose of cilostazol could be considered to reduce the proportion and severity of headache and thereby increase compliance. Atherosclerosis estimated as carotid IMT may contribute to the tolerability of cilostazol.

Original Articles

The Effect of cAMP-Elevating Agents on High Glucose-Induced Apoptosis of Isolated Islets of Rat Pancreas.: Gwan Pyo Koh, Kwang Sik Suh, Suk Chon, Seung Joon Oh, Jeong Taek Woo, Sung Woon Kim, Jin Woo Kim, Young Seol Kim, Sun Hee Kwon; Korean Diabetes J. 2004;28(6):490-500. Published online December 1, 2004

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Abstract PDF: BACKGROUND
High glucose-induced apoptosis has been implicated in the loss of beta-cells of the pancreatic islets in animal models of type 2 diabetes. GLP-1 has been shown to reduce apoptosis by the cAMP-dependent mechanism in beta-cells. Other studies have also shown that elevated levels of intracellular cyclic AMP delayed apoptosis in other types of cells. We investigated whether cAMP-elevating agents could suppress the high glucose-induced apoptosis of isolated rat islets. METHODS: Pancreatic islets were isolated from Sprague-Dawley (SD) rats. The expression of phosphodiesterase (PDE) 3 subtypes was investigated by using extracts of freshly isolated islets and analyzing them by RT-PCR. After 2 days of isolation, the islets were cultured in RPMI-1640 media containing 5% FBS with various glucose concentrations (11.1, 16.7 and 27.8 mM), 5x10-6 M forskolin, 2x10-4 M 3-isobutyl-1-methylxanthine (IBMX), 10-5 M cilostazol, and 10-6, 5x10-6 and 10-5 M H-89 for 5 days. The islet apoptosis was measured by a sandwich enzyme-immunoassay using antihistone antibody. RESULTS: Apoptosis was lowest at 11.1 mM glucose concentration, and increased at higher glucose concentrations (1.00 +/- 0.04 A.U. (arbitrary unit) at 11.1 mM, 1.17 +/- 0.12 A.U. at 16.7 mM, and 1.65 +/-0.13 A.U. at 27.8 mM (P <0.05 for 11.1 mM). Both PDE 3A and 3B mRNA were expressed in the islet extracts. In 16.7 and 27.8 mM glucose concentrations, forskolin (P <0.01), IBMX (P <0.05) and cilostazol (P < 0.05) suppressed apoptosis of the islet cells. Protein kinase A (PKA) nhibitor, H-89, did not prevent the inhibition of apoptosis by forskolin. CONCLUSION: These results show that high glucose-induced apoptosis of the cells in rat islet is attenuated by such cAMP-elevating agents as cilostazol. However, cyclic AMP regulation of islet apoptosis may occur via a PKA-independent signaling pathway.

Effects of Cilostazol on Insulin Resistance in OLETF Rats.: Sung Rae Kim, Ki Hyun Baek, Seung Hyun Ko, Jung Min Lee, Sang Ah Chang, Yoo Bae Ahn, Soon Jib Yoo, Jong Min Lee, Hyun Shik Son, Kun Ho Yoon, Moo Il Kang, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; Korean Diabetes J. 2001;25(1):63-70. Published online February 1, 2001

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Abstract PDF: BACKGROUND
Insulin resistance is one of the major pathophysiology of type 2 diabetes mellitus. It is reported that cilostazol and cyclic AMP phosphodiesterase inhibitor has the anti-platelet effect as well as an improvement of hypertriglyceridemia in addition to vasodilatation. Furthermore, the previous reports indicated that there is a positive relationship between insulin resistance and dyslipidemia. Thus, we investigated the effects of cilostazol on insulin resistance in OLETF rats using the euglycemic hyperinsulinemic glucose clamp technique, and lipid levels. METHODS: Fifteen five months old OLETF rats were fed for 4 weeks(8 treated with cilostazol and 7 were control), and compare to 20 same aged LETO rats (8 treated with cilostazol and 12 were control) through the glucose infusion rate on euglycemic hyperinsulinemic glucose clamp and lipid profiles. RESULTS: The glucose infusion rate was higher in the cilostazol treated OLETF rats than in the non-cilostazol treated OLETF rats (0.021+/-0.0031 vs 0.027+/-0.0036 mL/min). The levels of free fatty acids (2424.8+/-652.7 vs 1061.8+/-223.2 Eq/L), total cholesterol (145.7+/-17.9 vs 115.4+/-7.6 mg/dL) and triglyceride (146.5+/-46.6 vs 76.1+/-12.5 mg/dL) of cilostazol treated OLETF rats were significantly lower than those of non-cilostazol treated OLETF rats. CONCLUSION: This study result suggest that cilostazol may improve the insulin resistance through the improvement of dyslipidemia in OLETF rats.

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