Effects of Sodium-Glucose Co-Transporter-2 Inhibitors on Markers of Vascular Damage
by
, , and
Christodoula Kourtidou
1, 
Vasileios Rafailidis
2,
Garyfallia Varouktsi
3,
Efthimios Kanakis
1,
Vassilios Liakopoulos
3
,
Timoleon-Achilleas Vyzantiadis
4
,
Christos Savopoulos
1, 
Smaragdi Marinaki
5, 
Maria Stangou
6 and
Konstantinos Tziomalos
1,*
1
First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece
2
Department of Radiology, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece
3
Department of Nephrology, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, 54636 Thessaloniki, Greece
4
First Department of Microbiology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
5
Department of Nephrology and Renal Transplantation, Medical School, National and Kapodistrian University of Athens, Laiko Hospital, 11527 Athens, Greece
6
Department of Nephrology, Medical School, Aristotle University of Thessaloniki, Hippokration Hospital, 54642 Thessaloniki, Greece
*
Author to whom correspondence should be addressed.
J. Pers. Med. 2023, 13(3), 536; https://doi.org/10.3390/jpm13030536
Submission received: 17 February 2023
/
Revised: 12 March 2023
/
Accepted: 16 March 2023
/
Published: 16 March 2023
Abstract
Background: Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular morbidity and delay the progression of kidney disease in patients with type 2 diabetes mellitus (T2DM). However, the mechanisms underpinning these benefits are not entirely clear. More specifically, it is uncertain whether these agents exert cardiorenal protective effects through a direct action on the vascular wall. The aim of the present study was to evaluate the effects of SGLT2 inhibitors on markers of subclinical vascular damage. Methods: In total, 40 adult patients with T2DM and glomerular filtration rate (GFR) < 60 mL/min/1.73 m2 and age- and gender-matched patients with T2DM and GFR > 60 mL/min/1.73 m2 were consecutively enrolled. Indices of arterial stiffness (pulse wave velocity, augmentation index (AIx), AIx adjusted to a heart rate of 75 beats/min (Alx@75) and central systolic, diastolic, pulse and mean pressure), carotid atherosclerosis (stenosis, intima-media thickness (cIMT) and maximal plaque thickness) and peripheral arterial disease (ankle brachial index (ABI)) were determined. The chi-squared and Mann–Whitney U-test were used to detect differences in categorical and continuous variables between groups, respectively. Results: In total, 15 patients were treated with SGLT2 inhibitors and 25 patients were not receiving these agents. Serum low-density lipoprotein cholesterol levels were lower in the former whereas other cardiovascular risk factors, the prevalence of established cardiovascular disease, anthropometric and demographic characteristics, and vital signs did not differ between the 2 groups. The AIx was lower in patients treated with SGLT2 inhibitors (21.9 ± 11.3 vs. 29.7 ± 12% in patients not treated with SGLT2 inhibitors; p < 0.05). The AIx@75 was also lower in the former (21.3 ± 10.9 and 32.6 ± 11.3%, respectively, p < 0.005). Other markers of arterial stiffness were similar in the 2 groups. In addition, markers of carotid atherosclerosis and the ABI did not differ between patients treated and not treated with SGLT2 inhibitors. Conclusions: Treatment with SGLT2 inhibitors appears to reduce arterial stiffness. Accordingly, these agents might improve cardiovascular outcomes not only in patients with T2DM and established cardiorenal disease but also in lower-risk patients.
1. Introduction
Sodium glucose co-transporter 2 (SGLT2) inhibitors are the antidiabetic agents of choice, along with glucagon-like peptide 1 receptor agonists, in patients with type 2 diabetes mellitus (T2DM) who also have established atherosclerotic cardiovascular disease (CVD), are at high risk for CVD, have established heart failure (HF) and/or have chronic kidney disease (CKD) [1,2]. Notably, SGLT2 inhibitors should be considered in these patients independently of baseline HbA1c, individualized HbA1c target and the use of metformin [1,2]. These recommendations are based on the findings of several randomized clinical trials that showed a beneficial effect of SGLT2 inhibitors on cardiovascular and renal outcomes [3,4,5]. Indeed, SGLT2 inhibitors reduce the risk for hospitalization for heart failure and delay the progression of diabetic kidney disease [3].
The mechanisms underpinning the salutary cardiorenal actions of SGLT2 inhibitors are not fully clarified [6,7]. In addition to glucose- and blood pressure-lowering and natriuretic effects, a direct action on the vascular wall has been suggested to play a role in the reduction in cardiovascular and renal morbidity conferred by these agents [8,9,10,11]. However, data on the effects of SGLT2 inhibitors on subclinical vascular disease, including arterial stiffness, carotid atherosclerosis and peripheral arterial disease (PAD) are conflicting and limited [12,13,14,15,16]. Whether SGLT2 inhibitors exert beneficial effects in patients without established CVD but with subclinical vascular disease is particularly pertinent, given the increased cardiovascular risk of this patient population [17,18,19]. Moreover, even though SGLT2 inhibitors reduce the risk of atherosclerotic cardiovascular events in patients with established CVD, this benefit is less clear in patients without CVD [3].
The aim of the present study was to evaluate the effects of SGLT2 inhibitors on arterial stiffness, carotid atherosclerosis and PAD.
2. Materials and Methods
Methods have been reported in detail previously [20]. In brief, this is a prespecified analysis of a cross-sectional study in which we enrolled all adult patients with diabetic kidney disease (DKD) [21] who visited the Internal Medicine Outpatients Clinic of the First Propedeutic Department of Internal Medicine between August 2021 and April 2022. Age- and gender-matched patients with T2DM but without DKD who visited the same outpatient clinic during this period were enrolled as controls. Demographic data, presence of cardiovascular risk factors or established cardiovascular disease, anthropometric parameters and vital signs were recorded. Lipid profile, HbA1c and creatinine were measured in fasting blood samples and the urinary albumin/creatinine ratio was determined in a morning spot urine sample. SGLT2 inhibitors were prescribed according to current guidelines, i.e., were administered to all patients with HF and/or CKD in the absence of contraindications and were also an option in patients who could not achieve HbA1c targets despite treatment with metformin [1,2].
The following indices of arterial stiffness were measured using the Sphygmocor device (Atcor Medical, Sydney, Australia): pulse wave velocity (PWV), augmentation index (AIx), AIx adjusted to a heart rate of 75 beats/min (Alx@75) and central systolic, diastolic, pulse and mean pressure [22]. Stenosis, intima-media thickness (cIMT) and maximal plaque thickness were measured in both carotid arteries using a Logiq S8 ultrasound device (GE Healthcare, Milwaukee, Wisconsin) according to current guidelines [23,24,25]. The ankle brachial index (ABI) was measured in both legs to determine the presence of PAD [26].
IBM SPSS Statistics for Windows (version 27: IBM Corp: Armonk, NY, USA) was used for statistical analysis. The chi-square test was used to detect differences in categorical variables between groups. The Mann–Whitney U-test was used to detect differences in continuous variables between groups.
The study was conducted according to the Declaration of Helsinki and was approved by the Ethics Committee of the Medical School of the Aristotle University of Thessaloniki. All patients provided written informed consent.
3. Results
Forty patients with T2DM were enrolled in the study (Table 1). Fifteen patients were treated with SGLT2 inhibitors (73.3% males, age 68.9 ± 7.3 years) and 25 patients were not treated with SGLT2 inhibitors (68% males, age 73.2 ± 9.6 years). The mean duration of treatment with SGLT2 inhibitors was 3.6 ± 1.2 years. Among the 15 patients who were treated with SGLT2 inhibitors, 13patients were receiving empagliflozin and 2 patients were receiving dapagliflozin. Serum low-density lipoprotein cholesterol (LDL-C) levels were lower in patients treated with SGLT2 inhibitors (43.1 ± 19.1 vs. 67.8 ± 46.9 mg/dL in patients not treated with SGLT2 inhibitors; p < 0.05). Other cardiovascular risk factors, the prevalence of established CVD, anthropometric and demographic characteristics, and vital signs did not differ between the twogroups.
Markers of subclinical vascular disease according to treatment with SGLT2 inhibitors are shown in Table 2. The AIx was lower in patients treated with these agents (21.9 ± 11.3 vs. 29.7 ± 12% in patients not treated with SGLT2 inhibitors; p < 0.05). The AIx@75 was also lower in the former (21.3 ± 10.9 and 32.6 ± 11.3%, respectively, p< 0.005). Other markers of arterial stiffness (PWV, cSBP, cDBP, cPP and cMP) were similar in the 2 groups. cIMT of the left carotid artery showed a trend for being lower in patients treated with SGLT2 inhibitors (0.07 ± 0.02 vs. 0.09 ± 0.02 mm in patients not treated with SGLT2 inhibitors; p = 0.065). Other markers of carotid atherosclerosis (stenosis and maximal plaque thickness) did not differ between the 2 groups. The ABI was also similar in both legs in patients treated and not treated with SGLT2 inhibitors.
One of the patients who received SGLT2 inhibitors developed a urinary tract infection which was managed with antibiotic therapy and did not require discontinuation of the SGLT2 inhibitor. No other adverse events were observed in the twogroups.
4. Discussion
In the present study, AΙx and AΙx@75, which are surrogate markers of arterial stiffness [27], were lower in patients receiving SGLT2 inhibitors than in those not treated with these agents. Notably, age and the prevalence of hypertension, which are the major risk factors promoting arterial stiffening, did not differ between these 2 groups [22]. In accordance with our findings, a reduction in AIx@75 was observed after 12 weeks of treatment with dapaglifozin in a recent study in 44 patients with T2DM [12]. Similarly, AIx and AIx@75 improved after 8 weeks of empaglifozin administration in 40 normotensive patients with type 1 diabetes [13]. Given the association between arterial stiffness and cardiovascular morbidity and mortality [17,28,29], the improvement in arterial stiffness with SGLT2 inhibitors might contribute to the reduced risk for cardiovascular events during treatment with these agents. In contrast to these findings, AIx and AIx@75 did not change after 2 days of dapaglifozin treatment in another study in 16 patients with T2DM [14]. However, the small size and the short duration of treatment might explain these negative results [14].
We observed a trend for lower cIMT in the left carotid artery in patients treated with SGLT2 inhibitors, where other markers of carotid atherosclerosis were not affected by this treatment. There are limited and conflicting data on the effects of SGLT2 inhibitors on carotid atherosclerosis. In twostudies in Japanese patients, tofogliflozin reduced cIMT to a similar degree with other antidiabetic agents [15], whereas SGLT2 inhibitors had no effect on cIMT in patients with T2DM and heart failure [16]. Notably, treatment with SGLT2 inhibitors was shown to stabilize carotid plaque in patients with T2DM [30]. Given the paucity of the data, further research is needed to clarify the role of SGLT2 inhibitors in delaying the progression of carotid atherosclerosis.
In our study, the ABI in both legs did not differ between patients who were receiving SGLT2 inhibitors and those who were not. To the best of our knowledge, this is the first study that evaluated the effects of SGLT2 inhibitors on ABI in patients with T2DM. These findings are potentially important, given the increased risk for lower limb amputation in patients treated with canagliflozin [31,32]. On the other hand, other SGLT2 inhibitors do not appear to increase the risk of adverse lower limb events in patients with PAD [31,32,33,34]. Nevertheless, more studies are needed to evaluate the effects of SGLT2 inhibitors on PAD, given its high prevalence in patients with T2DM and its association with increased risk for cardiovascular events [18].
The major limitation of our study is that it is a cross-sectional analysis of the association between treatment with SGLT2 inhibitors and the presence of subclinical vascular disease in a small number of patients. Therefore, our study cannot provide definitive evidence of a protective effect of these agents against vascular damage. Indeed, it is possible that patients who were at higher risk for vascular disease were preferentially treated with SGLT2 inhibitors. However, there were no differences in cardiovascular risk factors between patients treated and not treated with these agents (except for LDL-C levels, which were lower in the former) suggesting that SGLT2 inhibitors might indeed protect agains vascular damage. In addition, there are very few adequately designed, large, randomized, placebo-controlled studies that evaluated the effects of these agents on arterial stiffness, carotid atherosclerosis and subclinical PAD and therefore our study might be a potentially useful addition to this research field. On the other hand, our findings are too preliminary to be translated to changes in the current management of patients with T2DM and must be validated in more rigorously designed and larger studies.
5. Conclusions
Treatment with SGLT2 inhibitors appears to reduce arterial stiffness and also tends to reduce the atherosclerotic burden in the carotid arteries. Accordingly, these agents might improve cardiovascular outcomes not only in patients with T2DM and established CVD but also in lower-risk patients. More specifically, patients with T2DM and increased arterial stiffness and/or carotid atherosclerosis might represent potential candidates for treatment with SGLT2 inhibitors. However, more data are needed to define the role of SGLT2 inhibitors in the management of patients with T2DM without clinically evident atherosclerosis.
Author Contributions
Conceptualization, C.K., M.S., S.M. and K.T.; methodology, C.K., M.S., S.M. and K.T.; data curation, C.K. and K.T.; formal analysis, C.K. and K.T.; investigation, C.K., V.R., G.V., E.K., V.L., T.-A.V., C.S., M.S., S.M. and K.T.; project administration, C.K., M.S., S.M. and K.T.; resources, C.K. and K.T.; writing-original draft preparation, C.K.; writing-review and editing, K.T.; visualization, V.R.; supervision, M.S., S.M. and K.T. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Aristotle University of Thessaloniki (102805/2022 and 14/04/2022). All patients provided written informed consent.
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
Data are available upon request.
Conflicts of Interest
The authors declare no conflict of interest.
References
- American Diabetes Association Professional Practice Committee; Draznin, B.; Aroda, V.R.; Bakris, G.; Benson, G.; Brown, F.M.; Freeman, R.; Green, J.; Huang, E.; Isaacs, D.; et al. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care 2022, 45, S125–S143. [Google Scholar]
- Buse, J.B.; Wexler, D.J.; Tsapas, A.; Rossing, P.; Mingrone, G.; Mathieu, C.; D’Alessio, D.A.; Davies, M.J. 2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2020, 63, 221–228. [Google Scholar] [CrossRef] [PubMed]
- Zelniker, T.A.; Wiviott, S.D.; Raz, I.; Im, K.; Goodrich, E.L.; Bonaca, M.P.; Mosenzon, O.; Kato, E.T.; Cahn, A.; Furtado, R.H.; et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019, 393, 31–39. [Google Scholar] [CrossRef] [PubMed]
- Packer, M.; Anker, S.D.; Butler, J.; Filippatos, G.; Pocock, S.J.; Carson, P.; EMPEROR-Reduced Trial Investigators. EMPEROR-Reduced Trial Investigators. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N. Engl. J. Med. 2020, 383, 1413–1424. [Google Scholar] [CrossRef] [PubMed]
- McMurray, J.J.; Wheeler, D.C.; Stefánsson, B.V.; Jongs, N.; Postmus, D.; Correa-Rotter, R.; Chertow, G.M.; Greene, T.; Held, C.; Hou, F.F.; et al. DAPA-CKD Trial Committees and Investigators. Effect of Dapagliflozin on Clinical Outcomes in Patients with Chronic Kidney Disease, With and Without Cardiovascular Disease. Circulation 2021, 143, 438–448. [Google Scholar] [CrossRef]
- Lytvyn, Y.; Bjornstad, P.; Udell, J.A.; Lovshin, J.A.; Cherney, D.Z.I. Sodium Glucose Cotransporter-2 Inhibition in Heart Failure: Potential Mechanisms, Clinical Applications, and Summary of Clinical Trials. Circulation 2017, 136, 1643–1658. [Google Scholar] [CrossRef]
- Lopaschuk, G.D.; Verma, S. Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: A State-of-the-Art Review. JACC Basic Transl. Sci. 2020, 5, 632–644. [Google Scholar] [CrossRef]
- Vallon, V.; Thomson, S.C. Targeting renal glucose reabsorption to treat hyperglycaemia: The pleiotropic effects of SGLT2 inhibition. Diabetologia 2017, 60, 215–225. [Google Scholar] [CrossRef]
- Shigiyama, F.; Kumashiro, N.; Miyagi, M.; Ikehara, K.; Kanda, E.; Uchino, H.; Hirose, T. Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early-stage type 2 diabetes mellitus: DEFENCE study. Cardiovasc. Diabetol. 2017, 16, 84. [Google Scholar] [CrossRef]
- Jensen, J.; Omar, M.; Kistorp, C.; Tuxen, C.; Gustafsson, I.; Køber, L.; Gustafsson, F.; Faber, J.; Malik, M.E.; Fosbøl, E.L.; et al. Effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate in patients with heart failure (Empire HF Renal): A prespecified substudy of a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2021, 9, 106–116. [Google Scholar] [CrossRef]
- Griffin, M.; Rao, V.S.; Ivey-Miranda, J.; Fleming, J.; Mahoney, D.; Maulion, C.; Suda, N.; Siwakoti, K.; Ahmad, T.; Jacoby, D.; et al. Empagliflozin in Heart Failure: Diuretic and Cardiorenal Effects. Circulation 2020, 142, 1028–1039. [Google Scholar] [CrossRef] [PubMed]
- Van Bommel, E.J.; Smits, M.M.; Ruiter, D.; Muskiet, M.H.; Kramer, M.H.; Nieuwdorp, M.; Touw, D.J.; Heerspink, H.J.; Joles, J.A.; van Raalte, D.H. Effects of dapagliflozin and gliclazide on the cardiorenal axis in people with type 2 diabetes. J. Hypertens. 2020, 38, 1811–1819. [Google Scholar] [CrossRef] [PubMed]
- Cherney, D.Z.; Perkins, B.A.; Soleymanlou, N.; Har, R.; Fagan, N.; Johansen, O.E.; Woerle, H.J.; von Eynatten, M.; Broedl, U.C. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc. Diabetol. 2014, 13, 28. [Google Scholar] [CrossRef]
- Solini, A.; Giannini, L.; Seghieri, M.; Vitolo, E.; Taddei, S.; Ghiadoni, L.; Bruno, R.M. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: A pilot study. Cardiovasc. Diabetol. 2017, 16, 138. [Google Scholar] [CrossRef] [PubMed]
- Katakami, N.; Mita, T.; Yoshii, H.; Shiraiwa, T.; Yasuda, T.; Okada, Y.; Torimoto, K.; Umayahara, Y.; Kaneto, H.; Osonoi, T.; et al. UTOPIA study investigators. Tofogliflozin does not delay progression of carotid atherosclerosis in patients with type 2 diabetes: A prospective, randomized, open-label, parallel-group comparative study. Cardiovasc. Diabetol. 2020, 19, 110. [Google Scholar] [CrossRef]
- Sakai, T.; Miura, S. Effects of Sodium-Glucose Cotransporter 2 Inhibitor on Vascular Endothelial and Diastolic Function in Heart Failure with Preserved Ejection Fraction–Novel Prospective Cohort Study. Circ. Rep. 2019, 1, 286–295. [Google Scholar] [CrossRef]
- Sharif, S.; Visseren, F.L.J.; Spiering, W.; de Jong, P.A.; Bots, M.L.; Westerink, J. SMART study group. Arterial stiffness as a risk factor for cardiovascular events and all-cause mortality in people with Type 2 diabetes. Diabet Med. 2019, 36, 1125–1132. [Google Scholar] [CrossRef]
- Caro, J.; Migliaccio-Walle, K.; Ishak, K.J.; Proskorovsky, I. The morbidity and mortality following a diagnosis of peripheral arterial disease: Long-term follow-up of a large database. BMC Cardiovasc.Disord. 2005, 5, 14. [Google Scholar] [CrossRef]
- Novo, S.; Carità, P.; Corrado, E.; Muratori, I.; Pernice, C.; Tantillo, R.; Novo, G. Preclinical carotid atherosclerosis enhances the global cardiovascular risk and increases the rate of cerebro- and cardiovascular events in a five-year follow-up. Atherosclerosis 2010, 211, 287–290. [Google Scholar] [CrossRef]
- Kourtidou, C.; Rafailidis, V.; Varouktsi, G.; Kanakis, E.; Liakopoulos, V.; Vyzantiadis, T.A.; Stangou, M.; Marinaki, S.; Tziomalos, K. Evaluation of Subclinical Vascular Disease in Diabetic Kidney Disease: A Tool for Personalization of Management of a High-Risk Population. J. Pers. Med. 2022, 12, 1139. [Google Scholar] [CrossRef]
- Levey, A.S.; Stevens, L.A.; Schmid, C.H.; Zhang, Y.; Castro, I.I.I.A.F.; Feldman, H.I.; Kusek, J.W.; Eggers, P.; Van Lente, F.; Greene, T.; et al. A new equation to estimate glomerular filtration rate. Ann. Intern. Med. 2009, 150, 604–612. [Google Scholar] [CrossRef] [PubMed]
- Townsend, R.R.; Wilkinson, I.B.; Schiffrin, E.L.; Avolio, A.P.; Chirinos, J.A.; Cockcroft, J.R.; Heffernan, K.S.; Lakatta, E.G.; McEniery, C.M.; Mitchell, G.F.; et al. American Heart Association Council on Hypertension. Recommendations for Improving and Standardizing Vascular Research on Arterial Stiffness: A Scientific Statement from the American Heart Association. Hypertension 2015, 66, 698–722. [Google Scholar] [CrossRef] [PubMed]
- European Carotid Surgery Trialists’ Collaborative Group. MRC European Carotid Surgery Trial: Interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis. Lancet 1991, 337, 1235–1243. [Google Scholar] [CrossRef]
- De Groot, E.; Van Leuven, S.I.; Duivenvoorden, R.; Meuwese, M.C.; Akdim, F.; Bots, M.L.; Kastelein, J.J. Measurement of carotid intima-media thickness to assess progression and regression of atherosclerosis. Nat. Clin. Pract. Cardiovasc. Med. 2008, 5, 280–288. [Google Scholar] [CrossRef] [PubMed]
- Johri, A.M.; Nambi, V.; Naqvi, T.Z.; Feinstein, S.B.; Kim, E.S.; Park, M.M.; Becher, H.; Sillesen, H. Recommendations for the Assessment of Carotid Arterial Plaque by Ultrasound for the Characterization of Atherosclerosis and Evaluation of Cardiovascular Risk: From the American Society of Echocardiography. J. Am. Soc. Echocardiogr. 2020, 33, 917–933. [Google Scholar] [CrossRef]
- Gerhard-Herman, M.D.; Gornik, H.L.; Barrett, C.; Barshes, N.R.; Corriere, M.A.; Drachman, D.E.; Fleisher, L.A.; Fowkes, F.G.; Hamburg, N.M.; Kinlay, S.; et al. 2016 AHA/ACC Guideline on the Management of Patients with Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2017, 135, e726–e779. [Google Scholar] [PubMed]
- Laurent, S.; Cockcroft, J.; Van Bortel, L.; Boutouyrie, P.; Giannattasio, C.; Hayoz, D.; Pannier, B.; Vlachopoulos, C.; Wilkinson, I.; Struijker-Boudier, H. European Network for Non-invasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: Methodological issues and clinical applications. Eur. Heart J. 2006, 27, 2588–2605. [Google Scholar] [CrossRef] [PubMed]
- Kim, J.M.; Kim, S.S.; Kim, I.J.; Kim, J.H.; Kim, B.H.; Kim, M.K.; Lee, S.H.; Lee, C.W.; Kim, M.C.; Ahn, J.H.; et al. Relationship between Cardiovascular disease and Brachial-ankle Pulse Wave Velocity (baPWV) in Patients with Type 2 Diabetes (REBOUND) Study Group. Arterial stiffness is an independent predictor for risk of mortality in patients with type 2 diabetes mellitus: The REBOUND study. Cardiovasc. Diabetol. 2020, 19, 143. [Google Scholar]
- Cardoso, C.R.L.; Leite, N.C.; Salles, G.F. Prognostic impact of changes in aortic tiffness for cardiovascular and mortality outcomes in individuals with type 2 diabetes: The Rio de Janeiro cohort study. Cardiovasc. Diabetol. 2022, 21, 76. [Google Scholar] [CrossRef]
- D’Onofrio, N.; Sardu, C.; Trotta, M.C.; Scisciola, L.; Turriziani, F.; Ferraraccio, F.; Panarese, I.; Petrella, L.; Fanelli, M.; Modugno, P.; et al. Sodium-glucose co-transporter2 expression and inflammatory activity in diabetic atherosclerotic plaques: Effects of sodium-glucose co-transporter2 inhibitor treatment. Mol. Metab. 2021, 54, 101337. [Google Scholar] [CrossRef]
- Lin, C.; Zhu, X.; Cai, X.; Yang, W.; Lv, F.; Nie, L.; Ji, L. SGLT2 inhibitors and lower limb complications: An updated meta-analysis. Cardiovasc. Diabetol. 2021, 20, 91. [Google Scholar] [CrossRef] [PubMed]
- Dicembrini, I.; Tomberli, B.; Nreu, B.; Baldereschi, G.I.; Fanelli, F.; Mannucci, E.; Monami, M. Peripheral artery disease and amputations with Sodium-Glucose co-Transporter-2 (SGLT-2) inhibitors: A meta-analysis of randomized controlled trials. Diabetes Res. Clin. Pract. 2019, 153, 138–144. [Google Scholar] [CrossRef] [PubMed]
- Bonaca, M.P.; Wiviott, S.D.; Zelniker, T.A.; Mosenzon, O.; Bhatt, D.L.; Leiter, L.A.; McGuire, D.K.; Goodrich, E.L.; De Mendonca Furtado, R.H.; Wilding, J.P.; et al. Dapagliflozin and Cardiac, Kidney, and Limb Outcomes in Patients with and Without Peripheral Artery Disease in DECLARE-TIMI 58. Circulation 2020, 142, 734–747. [Google Scholar] [CrossRef] [PubMed]
- Verma, S.; Mazer, C.D.; Al-Omran, M.; Inzucchi, S.E.; Fitchett, D.; Hehnke, U.; George, J.T.; Zinman, B. Cardiovascular Outcomes and Safety of Empagliflozin in Patients with Type 2 Diabetes Mellitus and Peripheral Artery Disease: A Subanalysis of EMPA-REG OUTCOME. Circulation 2018, 137, 405–407. [Google Scholar] [CrossRef] [PubMed]
Table 1.
Characteristics of patients treated and not treated with sodium-glucose co-transporter 2 (SGLT2) inhibitors (cases and controls, respectively).
Table 1.
Characteristics of patients treated and not treated with sodium-glucose co-transporter 2 (SGLT2) inhibitors (cases and controls, respectively).
| Cases | Controls | p | |
|---|---|---|---|
| (n = 15) | (n = 25) | ||
| Age (years) | 68.9 ± 7.3 | 73.2 ± 9.6 | NS |
| Males (%) | 73.3 | 68.0 | NS |
| Systolic blood pressure (mmHg) | 138.1 ± 14.2 | 142.8 ± 14.6 | NS |
| Diastolic blood pressure (mmHg) | 81.9 ± 10.5 | 81.7 ± 14.7 | NS |
| Heart rate | 70.6 ± 10.6 | 74.7 ± 9.9 | NS |
| Hypertension (%) | 86.7 | 88.0 | NS |
| Hypertension duration (years) | 15.9 ± 8.3 | 17.5 ± 6.5 | NS |
| Type 2 diabetes mellitus duration (years) | 12.6 ± 9.1 | 13.3 ± 7.1 | NS |
| Smoking (current/past, %) | 20.0/40.0 | 12.0/40.0 | NS |
| Package-years | 57.5 ± 37.1 | 37.7 ± 22.7 | NS |
| Alcohol intake (units/week) | 0.8 ± 1.4 | 0.7 ± 1.6 | NS |
| Atrial fibrillation (%) | 13.3 | 32.0 | NS |
| Family history of cardiovascular disease (%) | 6.7 | 32.0 | NS |
| Coronary heart disease (%) | 40.0 | 40.0 | NS |
| Prior ischemic stroke (%) | 0.0 | 4.0 | NS |
| Heart failure (%) | 13.3 | 20.0 | NS |
| Weight (kg) | 80.7 ± 10.4 | 84.6 ± 19.2 | NS |
| Body mass index (kg/m2) | 28.1 ± 3.4 | 29.4 ± 5.7 | NS |
| Waist circumference (cm) | 102.8 ± 7.9 | 107.4 ± 13.2 | NS |
| Total cholesterol (mg/dL) | 112.7 ± 21.9 | 134.3 ± 55.5 | NS |
| Low-density lipoprotein cholesterol (mg/dL) | 43.1 ± 19.1 | 67.8 ± 46.9 | <0.05 |
| High-density lipoprotein cholesterol (mg/dL) | 42.1 ± 11.4 | 41.9 ± 19.1 | NS |
| Triglycerides (mg/dL) | 136.6 ± 48.8 | 147.7 ± 77.4 | NS |
| HbA1c (%) | 7.1 ± 0.7 | 7.4 ± 1.5 | NS |
| Chronic kidney disease (%) | 33.3 | 52.0 | NS |
| Estimated glomerular filtration rate (mL/min/1.73m2) | 72.3 ± 25.4 | 59.7 ± 28.5 | NS |
| Urinary albumin/creatinine ratio (mg/g) | 94.3 ± 127.4 | 181.9 ± 415.3 | NS |
| Lipid-lowering treatment (%) | 100.0 | 100.0 | NS |
| Antihypertensive treatment (%) | 86.7 | 88.0 | NS |
| Antidiabetic treatment (%) | |||
| Metformin | 93.3 | 92.0 | NS |
| Dipeptidyl peptidase-4 inhibitors | 33.3 | 48.0 | NS |
| Insulin | 20.0 | 24.0 | NS |
| Other | 13.3 | 12.0 | NS |
Table 2.
Markers of subclinical vascular disease in patients treated and not treated with sodium-glucose co-transporter 2 (SGLT2) inhibitors (cases and controls, respectively).
Table 2.
Markers of subclinical vascular disease in patients treated and not treated with sodium-glucose co-transporter 2 (SGLT2) inhibitors (cases and controls, respectively).
| Cases | Controls | p | |
|---|---|---|---|
| (n = 15) | (n = 25) | ||
| Ankle-brachial index (left) | 1.17 ± 0.21 | 1.03 ± 0.26 | NS |
| Ankle-brachial index (right) | 1.09 ± 0.21 | 1.06 ± 0.26 | NS |
| Augmentation index (%) | 21.9 ± 11.3 | 29.7 ± 12.0 | <0.05 |
| Augmentation index @75 (%) | 21.3 ± 10.9 | 32.6 ± 11.3 | <0.005 |
| Pulse wave velocity (m/sec) | 7.2 ± 4.7 | 8.6 ± 5.3 | NS |
| Central systolic blood pressure (mmHg) | 125.9 ± 11.8 | 128.9 ± 10.3 | NS |
| Central diastolic blood pressure (mmHg) | 79.4 ± 11.6 | 78.8 ± 13.1 | NS |
| Central mean blood pressure (mmHg) | 99.9 ± 11.4 | 100.9 ± 11.9 | NS |
| Central pulse pressure (mmHg) | 46.5 ± 15.3 | 48.6 ± 12.4 | NS |
| Carotid stenosis (left)(%) | 31.7 ± 18.2 | 29.7 ± 14.9 | NS |
| Carotid intima-media thickness (left)(cm) | 0.07 ± 0.02 | 0.09 ± 0.02 | NS |
| Maximal plaque thickness (left)(cm) | 0.20 ± 0.14 | 0.22 ± 0.10 | NS |
| Carotid stenosis (right)(%) | 21.5 ± 18.1 | 31.5 ± 17.9 | NS |
| Carotid intima-media thickness (right)(cm) | 0.08 ± 0.02 | 0.09 ± 0.03 | NS |
| Maximal plaque thickness (right)(cm) | 0.23 ± 0.29 | 0.23 ± 0.11 | NS |
| Carotid intima-media thickness ≥ 0.1 cm on either side (%) | 33.3 | 60.0 | NS |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
MDPI and ACS Style
Kourtidou, C.; Rafailidis, V.; Varouktsi, G.; Kanakis, E.; Liakopoulos, V.; Vyzantiadis, T.-A.; Savopoulos, C.; Marinaki, S.; Stangou, M.; Tziomalos, K. Effects of Sodium-Glucose Co-Transporter-2 Inhibitors on Markers of Vascular Damage. J. Pers. Med. 2023, 13, 536. https://doi.org/10.3390/jpm13030536
AMA Style
Kourtidou C, Rafailidis V, Varouktsi G, Kanakis E, Liakopoulos V, Vyzantiadis T-A, Savopoulos C, Marinaki S, Stangou M, Tziomalos K. Effects of Sodium-Glucose Co-Transporter-2 Inhibitors on Markers of Vascular Damage. Journal of Personalized Medicine. 2023; 13(3):536. https://doi.org/10.3390/jpm13030536
Chicago/Turabian StyleKourtidou, Christodoula, Vasileios Rafailidis, Garyfallia Varouktsi, Efthimios Kanakis, Vassilios Liakopoulos, Timoleon-Achilleas Vyzantiadis, Christos Savopoulos, Smaragdi Marinaki, Maria Stangou, and Konstantinos Tziomalos. 2023. "Effects of Sodium-Glucose Co-Transporter-2 Inhibitors on Markers of Vascular Damage" Journal of Personalized Medicine 13, no. 3: 536. https://doi.org/10.3390/jpm13030536
APA StyleKourtidou, C., Rafailidis, V., Varouktsi, G., Kanakis, E., Liakopoulos, V., Vyzantiadis, T.-A., Savopoulos, C., Marinaki, S., Stangou, M., & Tziomalos, K. (2023). Effects of Sodium-Glucose Co-Transporter-2 Inhibitors on Markers of Vascular Damage. Journal of Personalized Medicine, 13(3), 536. https://doi.org/10.3390/jpm13030536
Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.
