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

doi:10.4093/dmj.2025.0817

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Letter Cilostazol/Extract of Ginkgo biloba or Aspirin, What Is the Treatment in Atherosclerosis Prevention? (Diabetes Metab J 2026;50:357-67): Christian Saleh¹, Ivanka Maduna^2,3, Hrvoje Budincevic^2,4,5,6; Diabetes & Metabolism Journal 2026;50(2):414-415.
DOI: https://doi.org/10.4093/dmj.2025.0817
Published online: December 18, 2025

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¹Independent Scholar, Basel, Switzerland

²Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia

³Health Center of Osijek-Baranja County (Dom zdravlja Osječko-baranjske županije), Osijek, Croatia

⁴Department of Neurology and Neurosurgery, Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia

⁵Department of Psychiatry and Neurology, Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia

⁶Department of Neurology, Sveti Duh University Hospital, Zagreb, Croatia

Corresponding author: Christian Saleh

Independent Scholar, Basel, Switzerland E-mail: chs12us75010@yahoo.com

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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See the reply "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)" in Volume 50 on page 428.

See the article "Comparison of Efficacy and Safety of Cilostazol/Extract of Ginkgo biloba vs. Aspirin in Carotid Atherosclerosis in Patients with Diabetes Mellitus" on page 357.

Hwang et al. [1] published in a recent issue a prospective, randomized study comparing the combination of cilostazol (CTZ) and extract of Ginkgo biloba (EGb) with aspirin for the prevention of atherosclerosis progression in patients with type 2 diabetes mellitus (T2DM) [1]. As surrogate marker for atherosclerosis the authors used the carotid intima-media thickness (cIMT) measured by ultrasound [1]. One hundred five patients with T2DM and increased cIMT were randomly assigned to receive either CTZ 200 mg plus EGb 160 mg once daily or aspirin 100 mg/day for 12 months [1]. The primary endpoint was the change in maximum cIMT. CTZ/EGb treatment reduced the maximum cIMT 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 aspirin treatment did not, resulting in significant between-group differences (P<0.05) [1]. No significant differences were observed in the common carotid artery (CCA) and internal carotid artery (ICA) [1]. The authors concluded that the combination of CTZ and EGb may be an effective treatment option for the primary prevention of CVD in patients with T2DM [1]. Some comments are needed to evaluate the results of this study in a more balanced way. The authors measured the cIMT in three sections of the carotid artery (CA) tree, the CCA, the bulb and the ICA [1]. The authors stated that cIMT measurement was based on ‘a previously described algorithm,’ hereby referring to the Polak et al. [2] 2011 study [1]. However, the Polak et al. [2] study does not describe any algorithm, but it compares two different measurement techniques, namely edge-detected to manual traced cIMT based measurement. Furthermore, the Polak et al. [2] study measured the cIMT solely at the CCA, while Hwang et al. [1] included three different CA segments. Therefore, it remains totally unclear which measurement algorithm was used by Hwang et al. [1] and why the Polak et al. [2] study was cited. Furthermore, Hwang et al. [1] determined the rate of change of the cIMT over a 12-month period. Within this context of critical importance, it is to retrieve the baseline CA segment used for cIMT measurement. If the follow-up measurement is not performed in the exact same artery segment, the baseline/follow-up cIMT results cannot be compared for (1) potential diverging wall characteristics of different CA segments and (2) for the asymmetric presentation of atherosclerosis [3]: The calculated rate of change will be inaccurate and wrongly be attributed to the treatment intervention. Furthermore, as it is unclear which measurement algorithm was used, it is also unclear if Hwang et al. [1] synchronized cIMT measurement as recommended with the end-diastolic cardiac phase [4]. Difference between the two cardiac phases (due to vessel diameter changes) of 0.041 mm were reported by Polak et al. [2] and Silva et al. [5] reported in their recent excellent study median range variations from 0.06 mm (far left and right CCA walls) to 0.2 mm (near right CCA). Consequently, without synchronization the cIMT results cannot be compared cross-sectionally/longitudinally nor intra-individually/inter-individually.

In conclusion, ultrasonographic cIMT evaluation are safe, cost-effective and non-invasive examinations. However, cIMT is a highly delicate surrogate marker and represents several limitations. Foremost, its normal range is given at a submillimeter level (0.6 to 0.9 mm), consequently smallest inaccuracies (or due to measurement bias or due to a sub-optimal defined measurement protocol) suffice to misclassify subjects into different cIMT categories, from which important conclusions are drawn. Given these fundamental methodological issues in the Hwang et al. [1] study, the conclusion, ‘In T2DM patients, CTZ/EGb therapy significantly reduces carotid intima-media thickness compared to aspirin’ should be considered with great caution. A clarification by the authors is needed to evaluate in a more balanced way the cIMT results of this study [1].

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CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

REFERENCES

1. 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 [Epub]. https://doi.org/10.4093/dmj.2025.0146.Article PubMed
2. Polak JF, Pencina MJ, Herrington D, O’Leary DH. Associations of edge-detected and manual-traced common carotid intimamedia thickness measurements with Framingham risk factors: the multi-ethnic study of atherosclerosis. Stroke 2011;42:1912-6.Article PubMed PMC
3. Tajik P, Meijer R, Duivenvoorden R, Peters SA, Kastelein JJ, Visseren FJ, et al. Asymmetrical distribution of atherosclerosis in the carotid artery: identical patterns across age, race, and gender. Eur J Prev Cardiol 2012;19:687-97.Article PubMed PDF
4. Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N, et al. Mannheim carotid intima-media thickness and plaque consensus (2004-2006-2011): an update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011. Cerebrovasc Dis 2012;34:290-6.Article PubMed PMC PDF
5. Silva YC, Bensenor IM, Meireles DP, Goulart AC, Lotufo PA, Santos IS. Effects of the cardiac cycle on carotid intima-media thickness in ELSA-Brasil baseline assessment. Clinics (Sao Paulo) 2025;80:100744.Article PubMed PMC

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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)

Diabetes Metab J. 2026;50(2):414-415. Published online December 18, 2025

DOI: https://doi.org/10.4093/dmj.2025.0817

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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)

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Saleh C, Maduna I, Budincevic H. Cilostazol/Extract of Ginkgo biloba or Aspirin, What Is the Treatment in Atherosclerosis Prevention? (Diabetes Metab J 2026;50:357-67). Diabetes Metab J. 2026;50(2):414-415.

DOI: https://doi.org/10.4093/dmj.2025.0817.

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