Document Type : Original Article(s)
Authors
- Hadi Sabat Sani 1
- Shalaleh Aghaei 2
- Soroor Kalantari 1
- Reza Madadi 3
- Zahra Kalantari 3
- Alireza Amir Maafi 1
1 Department of Radiology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
2 Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
3 Department of Cardiology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
Abstract
Background: Patients with type 2 diabetes (T2D) and recent ST-elevation myocardial infarction (STEMI) face accelerated atherosclerosis and a high risk of recurrent cardiovascular events. Sodium-glucose cotransporter-2 inhibitors (SGLT2i), particularly empagliflozin, offer proven cardioprotection in T2D. This study investigated the 3-month effects of empagliflozin on carotid intima-media thickness (CIMT) and Doppler hemodynamic parameters (resistive index [RI] and pulsatility index [PI]) in T2D patients post-STEMI.
Methods: In this randomized clinical trial, 80 patients with T2D and a recent STEMI from Ayatollah Mousavi Hospital, Zanjan, Iran (from July to December 2025), were randomized in a 1:1 ratio to empagliflozin 10 mg daily or an identical placebo, in addition to standard therapy. The primary endpoint was the change in CIMT at 3 months, assessed using B-mode ultrasound. Secondary endpoints included changes in RI and PI, measured via Doppler ultrasound.
Results: Follow-up data were available for 78 patients (two deaths in the intervention arm, both unrelated to the study drug). In the primary intention-to-treat analysis (n=80), empagliflozin was associated with a significant reduction in left CIMT compared with controls (median change=-0.13 mm vs. -0.01; within-group P=0.002; between-group ΔCIMT P=0.004; ANCOVA-adjusted P<0.001) versus controls (-0.01 mm). A smaller though statistically significant difference was also observed for right CIMT (ΔCIMT, P=0.021; ANCOVA-adjusted P=0.006). These findings remained consistent in the per-protocol analysis. After Bonferroni correction, the reduction in left CIMT remained significant, whereas the effect on right CIMT became more modest. No significant changes were observed in RI or PI.
Conclusion: Short-term empagliflozin suggested favorable changes in CIMT in high-risk T2D patients post-STEMI, without detectable effects on RI or PI.
Highlights
Hadi Sabat Sani (Google Scholar)
Soroor Kalantari (Google Scholar)
Keywords
- Dal Canto E, Ceriello A, Ryden L, Ferrini M, Hansen TB, Schnell O, et al. Diabetes as a cardiovascular risk factor: An overview of global trends of macro and micro vascular complications. Eur J Prev Cardiol. 2019;26:25-32. doi: 10.1177/2047487319878371. PubMed PMID: 31722562.
- Lin MJ, Chen CY, Lin HD, Wu HP. Impact of diabetes and hypertension on cardiovascular outcomes in patients with coronary artery disease receiving percutaneous coronary intervention. BMC Cardiovasc Disord. 2017;17:12. doi: 10.1186/s12872-016-0454-5. PubMed PMID: 28056847; PubMed Central PMCID: PMC5217339.
- Lingman M, Albertsson P, Herlitz J, Bergfeldt L, Lagerqvist B. The impact of hypertension and diabetes on outcome in patients undergoing percutaneous coronary intervention. Am J Med. 2011;124:265-75. doi: 10.1016/j.amjmed.2010.09.015. PubMed PMID: 21396511.
- Libby P, Buring JE, Badimon L, Hansson GK, Deanfield J, Bittencourt MS, et al. Atherosclerosis. Nat Rev Dis Primers. 2019;5:56. doi: 10.1038/s41572-019-0106-z. PubMed PMID: 31420554.
- Insull W, Jr. The pathology of atherosclerosis: plaque development and plaque responses to medical treatment. Am J Med. 2009;122:S3-S14. doi: 10.1016/j.amjmed.2008.10.013. PubMed PMID: 19110086.
- Pyxaras SA, Wijns W, Reiber JHC, Bax JJ. Invasive assessment of coronary artery disease. J Nucl Cardiol. 2018;25:860-71. doi: 10.1007/s12350-017-1050-5. PubMed PMID: 28849416.
- Lim MJ, White CJ. Coronary angiography is the gold standard for patients with significant left ventricular dysfunction. Prog Cardiovasc Dis. 2013;55:504-8. doi: 10.1016/j.pcad.2013.01.003. PubMed PMID: 23518380.
- Daghem M, Bing R, Fayad ZA, Dweck MR. Noninvasive Imaging to Assess Atherosclerotic Plaque Composition and Disease Activity: Coronary and Carotid Applications. JACC Cardiovasc Imaging. 2020;13:1055-68. doi: 10.1016/j.jcmg.2019.03.033. PubMed PMID: 31422147; PubMed Central PMCID: PMC10661368.
- 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. doi: 10.1159/000343145. PubMed PMID: 23128470; PubMed Central PMCID: PMC3760791.
- Kaur H, Ranjan RK, Xalxo AR, Rai N, Toppo SK, Kumari A, et al. Sonographic and Doppler Evaluation of Carotid Artery in Hypertensive and Normotensive Individuals. J Pharm Bioallied Sci. 2024;16:S3673-S5. doi: 10.4103/jpbs.jpbs_1112_24. PubMed PMID: 39926974; PubMed Central PMCID: PMC11805154.
- Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation. 2007;115:459-67. doi: 10.1161/CIRCULATIONAHA.106.628875. PubMed PMID: 17242284.
- Frauchiger B, Schmid HP, Roedel C, Moosmann P, Staub D. Comparison of carotid arterial resistive indices with intima-media thickness as sonographic markers of atherosclerosis. Stroke. 2001;32:836-41. doi: 10.1161/01.str.32.4.836. PubMed PMID: 11283379.
- Wanner C, Lachin JM, Inzucchi SE, Fitchett D, Mattheus M, George J, et al. Empagliflozin and Clinical Outcomes in Patients With Type 2 Diabetes Mellitus, Established Cardiovascular Disease, and Chronic Kidney Disease. Circulation. 2018;137:119-29. doi: 10.1161/CIRCULATIONAHA.117.028268. PubMed PMID: 28904068.
- Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur Heart J. 2016;37:1526-34. doi: 10.1093/eurheartj/ehv728. PubMed PMID: 26819227; PubMed Central PMCID: PMC4872285.
- Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373:2117-28. doi: 10.1056/NEJMoa1504720. PubMed PMID: 26378978.
- Mason T, Coelho-Filho OR, Verma S, Chowdhury B, Zuo F, Quan A, et al. Empagliflozin Reduces Myocardial Extracellular Volume in Patients With Type 2 Diabetes and Coronary Artery Disease. JACC Cardiovasc Imaging. 2021;14:1164-73. doi: 10.1016/j.jcmg.2020.10.017. PubMed PMID: 33454272.
- Irace C, Casciaro F, Scavelli FB, Oliverio R, Cutruzzola A, Cortese C, et al. Empagliflozin influences blood viscosity and wall shear stress in subjects with type 2 diabetes mellitus compared with incretin-based therapy. Cardiovasc Diabetol. 2018;17:52. doi: 10.1186/s12933-018-0695-y. PubMed PMID: 29631585; PubMed Central PMCID: PMC5891980.
- Zhang W, Li X, Li M, He H, Yang C, Wang M, et al. Empagliflozin inhibits neointimal hyperplasia through attenuating endothelial-to-mesenchymal transition via TAK-1/NF-kappaB pathway. Eur J Pharmacol. 2023;954:175826. doi: 10.1016/j.ejphar.2023.175826. PubMed PMID: 37321472.
- Ardahanlı İ, Aslan R, Çelik M, Akgün O, Akyüz O. Effects of empagliflozin on carotid intima-media thickness and epicardial fat tissue volume in patients with type-2 diabetes mellitus. Lokman Hekim J. 2021;1:74-80.doi: 10.14744/lhhs.2021.80001.
- Ikonomidis I, Papageorgiou A, Pavlidis G, Georgiopoulos G, Katogiannis K, Maratou E, et al. GLP-1 receptor agonists, SGLT-2 inhibitors, and their combination: effects on carotid atherosclerosis regression, oxidative stress, and amyloid-beta1-40 in diabetes. Am J Physiol Heart Circ Physiol. 2026;330:H610-H9. doi: 10.1152/ajpheart.00996.2025. PubMed PMID: 41579346.
- Katakami N, Mita T, Yoshii H, Shiraiwa T, Yasuda T, Okada Y, et al. Effect of Tofogliflozin on Carotid Intima-Media Thickness in Patients with Type 2 Diabetes: Results from the Prospective, Randomized, Open-Label, Parallel-Group Comparative UTOPIA Trial. SSRN. 2020. doi: 10.2139/ssrn.3516137.
- Tanaka A, Sata M, Okada Y, Teragawa H, Eguchi K, Shimabukuro M, et al. Effect of ipragliflozin on carotid intima-media thickness in patients with type 2 diabetes: a multicenter, randomized, controlled trial. Eur Heart J Cardiovasc Pharmacother. 2023;9:165-72. doi: 10.1093/ehjcvp/pvac059. PubMed PMID: 36308299; PubMed Central PMCID: PMC9892869.
- Kufazvinei TTJ, Chai J, Boden KA, Channon KM, Choudhury RP. Emerging opportunities to target inflammation: myocardial infarction and type 2 diabetes. Cardiovasc Res. 2024;120:1241-52. doi: 10.1093/cvr/cvae142. PubMed PMID: 39027945; PubMed Central PMCID: PMC11416061.
- Gamrat A, Surdacki MA, Chyrchel B, Surdacki A. Endothelial Dysfunction: A Contributor to Adverse Cardiovascular Remodeling and Heart Failure Development in Type 2 Diabetes beyond Accelerated Atherogenesis. J Clin Med. 2020;9. doi: 10.3390/jcm9072090. PubMed PMID: 32635218; PubMed Central PMCID: PMC7408687.
- Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39:175-91. doi: 10.3758/bf03193146. PubMed PMID: 17695343.
- Polak JF, Pencina MJ, Pencina KM, O'Donnell CJ, Wolf PA, D'Agostino RB, Sr. Carotid-wall intima-media thickness and cardiovascular events. N Engl J Med. 2011;365:213-21. doi: 10.1056/NEJMoa1012592. PubMed PMID: 21774709; PubMed Central PMCID: PMC3153949.
- Willeit P, Tschiderer L, Allara E, Reuber K, Seekircher L, Gao L, et al. Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients. Circulation. 2020;142:621-42. doi: 10.1161/CIRCULATIONAHA.120.046361. PubMed PMID: 32546049; PubMed Central PMCID: PMC7115957.
- Liu Z, Ma X, Ilyas I, Zheng X, Luo S, Little PJ, et al. Impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on atherosclerosis: from pharmacology to pre-clinical and clinical therapeutics. Theranostics. 2021;11:4502-15. doi: 10.7150/thno.54498. PubMed PMID: 33754074; PubMed Central PMCID: PMC7977463.
- Ceasovschih A, Balta A, Aldeen ES, Bianconi V, Barkas F, Sener YZ, et al. Sodium-glucose cotransporter 2 inhibitors and atherosclerosis. Am J Prev Cardiol. 2025;23:101061. doi: 10.1016/j.ajpc.2025.101061. PubMed PMID: 40777543; PubMed Central PMCID: PMC12329282.
- Pahud de Mortanges A, Salvador D, Jr., Laimer M, Muka T, Wilhelm M, Bano A. The Role of SGLT2 Inhibitors in Atherosclerosis: A Narrative Mini-Review. Front Pharmacol. 2021;12:751214. doi: 10.3389/fphar.2021.751214. PubMed PMID: 34803693; PubMed Central PMCID: PMC8602558.
- Nomiyama T, Shimono D, Horikawa T, Fujimura Y, Ohsako T, Terawaki Y, et al. Efficacy and safety of sodium-glucose cotransporter 2 inhibitor ipragliflozin on glycemic control and cardiovascular parameters in Japanese patients with type 2 diabetes mellitus; Fukuoka Study of Ipragliflozin (FUSION). Endocr J. 2018;65:859-67. doi: 10.1507/endocrj.EJ18-0022. PubMed PMID: 29806620.
- Stachteas P, Karakasis P, Patoulias D, Clemenza F, Fragakis N, Rizzo M. The effect of sodium-glucose co-transporter-2 inhibitors on markers of subclinical atherosclerosis. Ann Med. 2023;55:2304667. doi: 10.1080/07853890.2024.2304667. PubMed PMID: 38233735; PubMed Central PMCID: PMC10798275.
- Climie RE, Gallo A, Picone DS, Di Lascio N, van Sloten TT, Guala A, et al. Measuring the Interaction Between the Macro- and Micro-Vasculature. Front Cardiovasc Med. 2019;6:169. doi: 10.3389/fcvm.2019.00169. PubMed PMID: 31824963; PubMed Central PMCID: PMC6882776.
- Resistive index (vascular ultrasound). Melbourne: Radiopaedia; 2024 [cited 2025]. Available from: https://radiopaedia.org/articles/resistive-index-vascular-ultrasound
- Liu CC, Chou CL, Chen CF, Cheng CF, Lu SX, Wu YJ, et al. Carotid Resistance and Pulsatility: Non-Invasive Markers for Diabetes Mellitus-Related Vascular Diseases. J Clin Med. 2025;14. doi: 10.3390/jcm14072523. PubMed PMID: 40217973; PubMed Central PMCID: PMC11989898.
- Krejza J, Arkuszewski M, Kasner SE, Weigele J, Ustymowicz A, Hurst RW, et al. Carotid artery diameter in men and women and the relation to body and neck size. Stroke. 2006;37:1103-5. doi: 10.1161/01.STR.0000206440.48756.f7. PubMed PMID: 16497983.
- Bude RO, Rubin JM. Relationship between the resistive index and vascular compliance and resistance. Radiology. 1999;211:411-7. doi: 10.1148/radiology.211.2.r99ma48411. PubMed PMID: 10228522.
- Fiori G, Fuiano F, Scorza A, Conforto S, Sciuto SA. Non-Invasive Methods for PWV Measurement in Blood Vessel Stiffness Assessment. IEEE Rev Biomed Eng. 2022;15:169-83. doi: 10.1109/RBME.2021.3092208. PubMed PMID: 34166202.
- Patoulias D, Papadopoulos C, Kassimis G, Fragakis N, Vassilikos V, Karagiannis A, et al. Effect of sodium-glucose co-transporter-2 inhibitors on arterial stiffness: A systematic review and meta-analysis of randomized controlled trials. Vasc Med. 2022;27:433-9. doi: 10.1177/1358863X221101653. PubMed PMID: 35754338.