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2000
Volume 23, Issue 4
  • ISSN: 1570-1611
  • E-ISSN: 1875-6212

Abstract

Introduction

Sodium Glucose cotransporter-2 inhibitors (SGLT2is) possess pleiotropic effects, such as antioxidant, antifibrotic, anti-inflammatory, and vascular remodeling activities. Considering the lack of literature, a network meta-analysis was conducted to explore the impact of SGLT2is on endothelial dysfunction and arterial stiffness in the diabetic population.

Methods

Electronic databases were searched to identify randomized clinical trials evaluating the effects of SGLT2is on outcomes, such as Flow-mediated Vasodilation (FMV), Pulse Wave Velocity (PWV), and Augmentation Index (AIx). Direct, indirect, and mixed treatment comparisons generated pooled estimates using random-effects modeling. Effect sizes were reported as Hedges' g with 95% Confidence Interval (95% CI). Bootstrap and permutation meta-analyses were performed using ranking plots. The certainty of evidence was graded.

Results

Twelve articles (706 participants) were included. SGLT2is were associated with significant improvements in FMV (g: 0.48; 95% CI: 0.08, 0.88), confirmed by bootstrap meta-analysis (g: 0.48; 95% CI: 0.1, 0.85) and permutation meta-analysis of FMV (g: 0.48; 95% CI: 0.05, 0.9). Within SGLT2is, dapagliflozin (g: 0.39; 95% CI: 0.14, 0.65) significantly improved FMV, and dapagliflozin (g: -0.61, 95% CI: -0.98, -0.24) and tofogliflozin (g: -3.51; 95% CI: -4.05, -2.98) significantly improved PWV. A low risk of publication bias was observed, and the ranking plots revealed dapagliflozin to have the best probability (0.99) of being the most effective for improving FMV. Low certainty of evidence was observed for all outcomes.

Conclusion

SGLT2 inhibitors improve endothelial function and arterial stiffness in the diabetic population. Clinical studies evaluating the association between improvements in endothelial function with SGLT2is and reduced adverse cardiovascular and cardiorenal events and mortality are urgently needed.

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References

  1. ChungL.C.E. Comprehensive review of SGLT2 inhibitors’ efficacy through their diuretic mode of action in diabetic patients.Front. Endocrinol.202314117469210.3389/fendo.2023.1174692 37547306
    [Google Scholar]
  2. GermayD.S. PambrunE. ParienteA. GrenetG. BezinJ. FaillieJ.L. Use of sodium‐glucose cotransporter‐2 inhibitors in France: Analysis of French nationwide health insurance database.Diabetes Obes. Metab.20242651678168610.1111/dom.15472 38288619
    [Google Scholar]
  3. SridharanK. SivaramakrishnanG. Risk of diabetic ketoacidosis associated with sodium glucose cotransporter-2 inhibitors: A network meta-analysis and meta-regression.J. Clin. Med.2024136174810.3390/jcm13061748 38541972
    [Google Scholar]
  4. SridharanK. SivaramakrishnanG. Genito-urinary infectious adverse events related to sodium glucose cotransporter-2 inhibitors: A network meta-analysis and meta-regression.Expert Rev. Clin. Pharmacol.2024175-651552410.1080/17512433.2024.2355287 38733378
    [Google Scholar]
  5. HsiaD.S. GroveO. CefaluW.T. An update on sodium-glucose co-transporter-2 inhibitors for the treatment of diabetes mellitus.Curr. Opin. Endocrinol. Diabetes Obes.2017241737910.1097/MED.0000000000000311 27898586
    [Google Scholar]
  6. O’HaraD.V. LamC.S.P. McMurrayJ.J.V. Applications of SGLT2 inhibitors beyond glycaemic control.Nat. Rev. Nephrol.202420851352910.1038/s41581‑024‑00836‑y 38671190
    [Google Scholar]
  7. CorreaF.J.I. RotterC.R. Sodium-glucose cotransporter 2 inhibitors mechanisms of action: A review.Front. Med.2021877786110.3389/fmed.2021.777861 34988095
    [Google Scholar]
  8. ShentuY. LiY. XieS. Empagliflozin, a sodium glucose cotransporter-2 inhibitor, ameliorates peritoneal fibrosis via suppressing TGF-β/Smad signaling.Int. Immunopharmacol.20219310737410.1016/j.intimp.2021.107374 33517222
    [Google Scholar]
  9. MitchellG.F. Arterial stiffness in aging: Does it have a place in clinical practice?Hypertension202177376878010.1161/HYPERTENSIONAHA.120.14515 33517682
    [Google Scholar]
  10. ZiemanS.J. MelenovskyV. KassD.A. Mechanisms, pathophysiology, and therapy of arterial stiffness.Arterioscler. Thromb. Vasc. Biol.200525593294310.1161/01.ATV.0000160548.78317.29 15731494
    [Google Scholar]
  11. BoutouyrieP. ChowienczykP. HumphreyJ.D. MitchellG.F. Arterial stiffness and cardiovascular risk in hypertension.Circ. Res.2021128786488610.1161/CIRCRESAHA.121.318061 33793325
    [Google Scholar]
  12. IzzardA.S. RizzoniD. RoseiA.E. HeagertyA.M. Small artery structure and hypertension: Adaptive changes and target organ damage.J. Hypertens.200523224725010.1097/00004872‑200502000‑00002 15662208
    [Google Scholar]
  13. WagenseilJ.E. MechamR.P. Elastin in large artery stiffness and hypertension.J. Cardiovasc. Transl. Res.20125326427310.1007/s12265‑012‑9349‑8 22290157
    [Google Scholar]
  14. McEnieryC.M. WilkinsonI.B. AvolioA.P. Age, hypertension and arterial function.Clin. Exp. Pharmacol. Physiol.200734766567110.1111/j.1440‑1681.2007.04657.x 17581227
    [Google Scholar]
  15. WangM. LakattaE.G. Altered regulation of matrix metalloproteinase-2 in aortic remodeling during aging.Hypertension200239486587310.1161/01.HYP.0000014506.13322.66 11967241
    [Google Scholar]
  16. LiW. LingW. TengX. QuanC. CaiS. HuS. Effect of advanced glycation end products, extracellular matrix metalloproteinase inducer and matrix metalloproteinases on type-I collagen metabolism.Biomed. Rep.20164669169310.3892/br.2016.641 27284408
    [Google Scholar]
  17. VasanR.S. PanS. XanthakisV. Arterial stiffness and long-term risk of health outcomes: The framingham heart study.Hypertension20227951045105610.1161/HYPERTENSIONAHA.121.18776 35168368
    [Google Scholar]
  18. SalimH.M. FukudaD. YagiS. SoekiT. ShimabukuroM. SataM. Glycemic control with Ipragliflozin, a novel selective SGLT2 inhibitor, ameliorated endothelial dysfunction in streptozotocin-induced diabetic mouse.Front. Cardiovasc. Med.201634310.3389/fcvm.2016.00043 27833913
    [Google Scholar]
  19. AdamC.A. AnghelR. MarcuD.T.M. MituO. RocaM. MituF. Impact of sodium–glucose cotransporter 2 (SGLT2) inhibitors on arterial stiffness and vascular aging—what do we know so far? (A Narrative Review).Life202212680310.3390/life12060803 35743834
    [Google Scholar]
  20. MitchellG.F. Effects of central arterial aging on the structure and function of the peripheral vasculature: Implications for end-organ damage.J. Appl. Physiol.200810551652166010.1152/japplphysiol.90549.2008 18772322
    [Google Scholar]
  21. AngoffR. MosarlaR.C. TsaoC.W. Aortic stiffness: Epidemiology, risk factors, and relevant biomarkers.Front. Cardiovasc. Med.2021870939610.3389/fcvm.2021.709396 34820427
    [Google Scholar]
  22. ShirwanyN.A. ZouM. Arterial stiffness: A brief review.Acta Pharmacol. Sin.201031101267127610.1038/aps.2010.123 20802505
    [Google Scholar]
  23. RaitakariO.T. CelermajerD.S. Flow-mediated dilatation.Br. J. Clin. Pharmacol.200050539740410.1046/j.1365‑2125.2000.00277.x 11069434
    [Google Scholar]
  24. WeiR. WangW. PanQ. GuoL. Effects of SGLT-2 inhibitors on vascular endothelial function and arterial stiffness in subjects with type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials.Front. Endocrinol.20221382660410.3389/fendo.2022.826604 35250882
    [Google Scholar]
  25. Open science framework2024Available from: https://osf.io/5fwyk [Accessed on: 18th June 2024].
  26. HuttonB. SalantiG. CaldwellD.M. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: Checklist and explanations.Ann. Intern. Med.20151621177778410.7326/M14‑2385 26030634
    [Google Scholar]
  27. HigginsJPT AltmanDG GøtzschePC The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials.BMJ2011343oct18 2d5928.10.1136/bmj.d5928 22008217
    [Google Scholar]
  28. LinL. ChuH. Quantifying publication bias in meta-analysis.Biometrics201874378579410.1111/biom.12817 29141096
    [Google Scholar]
  29. HigginsJ.P.T. ThompsonS.G. Quantifying heterogeneity in a meta‐analysis.Stat. Med.200221111539155810.1002/sim.1186 12111919
    [Google Scholar]
  30. GRADE HandbookIntroduction to GRADE handbook.2024Available from: https://gdt.gradepro.org/app/handbook/handbook.html [Accessed on: 12 May 2024].
    [Google Scholar]
  31. BechlioulisA. MarkozannesG. ChionidiI. The effect of SGLT2 inhibitors, GLP1 agonists, and their sequential combination on cardiometabolic parameters: A randomized, prospective, intervention study.J Diab Compl202337410843610.1016/j.jdiacomp.2023.108436 36842186
    [Google Scholar]
  32. KarallieddeJ. FountoulakisN. StathiD. Does dapagliflozin influence arterial stiffness and levels of circulating anti-aging hormone soluble klotho in people with type 2 diabetes and kidney disease? Results of a randomized parallel group clinical trial.Front. Cardiovasc. Med.2022999232710.3389/fcvm.2022.992327 36247425
    [Google Scholar]
  33. KatakamiN. MitaT. YoshiiH. Effect of tofogliflozin on arterial stiffness in patients with type 2 diabetes: Prespecified sub-analysis of the prospective, randomized, open-label, parallel-group comparative UTOPIA trial.Cardiovasc. Diabetol.2021201410.1186/s12933‑020‑01206‑1 33397376
    [Google Scholar]
  34. KishimotoS. HigashiY. ImaiT. Lack of impact of ipragliflozin on endothelial function in patients with type 2 diabetes: Sub-analysis of the PROTECT study.Cardiovasc. Diabetol.202322111910.1186/s12933‑023‑01856‑x 37210524
    [Google Scholar]
  35. NavodnikM.P. JanežA. ŽuranI. The effect of additional treatment with empagliflozin or semaglutide on endothelial function and arterial stiffness in subjects with type 1 diabetes mellitus—ENDIS study.Pharmaceutics2023157194510.3390/pharmaceutics15071945 37514131
    [Google Scholar]
  36. PapadopoulouE. LoutradisC. TzatzagouG. Dapagliflozin decreases ambulatory central blood pressure and pulse wave velocity in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled clinical trial.J. Hypertens.202139474975810.1097/HJH.0000000000002690 33186325
    [Google Scholar]
  37. ShigiyamaF. KumashiroN. MiyagiM. Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early-stage type 2 diabetes mellitus: DEFENCE study.Cardiovasc. Diabetol.20171618410.1186/s12933‑017‑0564‑0 28683796
    [Google Scholar]
  38. SpositoA.C. BrederI. SoaresA.A.S. Dapagliflozin effect on endothelial dysfunction in diabetic patients with atherosclerotic disease: A randomized active-controlled trial.Cardiovasc. Diabetol.20212017410.1186/s12933‑021‑01264‑z 33771149
    [Google Scholar]
  39. StriepeK. JumarA. OttC. Effects of the selective sodium-glucose cotransporter 2 inhibitor empagliflozin on vascular function and central hemodynamics in patients with type 2 diabetes mellitus.Circulation2017136121167116910.1161/CIRCULATIONAHA.117.029529 28923906
    [Google Scholar]
  40. TanakaA. ShimabukuroM. MachiiN. Effect of empagliflozin on endothelial function in patients with type 2 diabetes and cardiovascular disease: Results from the multicenter, randomized, placebo-controlled, double-blind EMBLEM trial.Diabetes Care20194210e159e16110.2337/dc19‑1177 31533913
    [Google Scholar]
  41. TanakaA. ShimabukuroM. MachiiN. Secondary analyses to assess the profound effects of empagliflozin on endothelial function in patients with type 2 diabetes and established cardiovascular diseases: The placebo‐controlled double‐blind randomized effect of empagliflozin on endothelial function in cardiovascular high risk diabetes mellitus: Multi‐center placebo‐controlled double‐blind randomized trial.J. Diabetes Investig.20201161551156310.1111/jdi.13289 32537887
    [Google Scholar]
  42. ZainordinN.A. HattaS.F.W.M. ShahM.F.Z. Effects of dapagliflozin on endothelial dysfunction in type 2 diabetes with established ischemic heart disease (EDIFIED).J. Endocr. Soc.202041bvz01710.1210/jendso/bvz017 31993550
    [Google Scholar]
  43. SealsD.R. JablonskiK.L. DonatoA.J. Aging and vascular endothelial function in humans.Clin. Sci.2011120935737510.1042/CS20100476 21244363
    [Google Scholar]
  44. DubskyM. VelebaJ. SojakovaD. MarhefkovaN. FejfarovaV. JudeE.B. Endothelial dysfunction in diabetes mellitus: New insights.Int. J. Mol. Sci.202324131070510.3390/ijms241310705 37445881
    [Google Scholar]
  45. MoneP. VarzidehF. JankauskasS.S. SGLT2 inhibition via empagliflozin improves endothelial function and reduces mitochondrial oxidative stress: Insights from frail hypertensive and diabetic patients.Hypertension20227981633164310.1161/HYPERTENSIONAHA.122.19586 35703100
    [Google Scholar]
  46. DuranteW. BehnammaneshG. PeytonK.J. Effects of sodium-glucose co-transporter 2 inhibitors on vascular cell function and arterial remodeling.Int. J. Mol. Sci.20212216878610.3390/ijms22168786 34445519
    [Google Scholar]
  47. YanaiH. AdachiH. HakoshimaM. KatsuyamaH. Significance of endothelial dysfunction amelioration for sodium–glucose cotransporter 2 inhibitor-induced improvements in heart failure and chronic kidney disease in diabetic patients.Metabolites202313673610.3390/metabo13060736 37367894
    [Google Scholar]
  48. WangY. YaoM. WangJ. Effects of antidiabetic drugs on endothelial function in patients with type 2 diabetes mellitus: A bayesian network meta-analysis.Front. Endocrinol.20221381853710.3389/fendo.2022.818537 35370959
    [Google Scholar]
  49. CorrealeM. MazzeoP. MallardiA. Switch to SGLT2 inhibitors and improved endothelial function in diabetic patients with chronic heart failure.Cardiovasc. Drugs Ther.20223661157116410.1007/s10557‑021‑07254‑3 34519913
    [Google Scholar]
  50. InabaY. ChenJ.A. BergmannS.R. Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: A meta-analysis.Int. J. Cardiovasc. Imaging201026663164010.1007/s10554‑010‑9616‑1 20339920
    [Google Scholar]
  51. LiuT. FanZ. XiaoB. HeC. WangS. Association of sodium-glucose cotransporter 2 inhibitors with risk of major adverse cardiovascular events in type 2 diabetes patients with acute coronary syndrome: A propensity score matched analysis.Cardiovasc. Diabetol.202423110610.1186/s12933‑024‑02200‑7 38528542
    [Google Scholar]
  52. Dell’OroR. MalobertiA. NicoliF. Long-term saxagliptin treatment improves endothelial function but not pulse wave velocity and intima-media thickness in type 2 diabetic patients.High Blood Press. Cardiovasc. Prev.201724439340010.1007/s40292‑017‑0215‑2 28608024
    [Google Scholar]
  53. AgarwalN. RiceS.P.L. BolusaniH. Metformin reduces arterial stiffness and improves endothelial function in young women with polycystic ovary syndrome: A randomized, placebo-controlled, crossover trial.J. Clin. Endocrinol. Metab.201095272273010.1210/jc.2009‑1985 19996308
    [Google Scholar]
  54. RyanK.E. McCanceD.R. PowellL. McMahonR. TrimbleE.R. Fenofibrate and pioglitazone improve endothelial function and reduce arterial stiffness in obese glucose tolerant men.Atherosclerosis20071942e123e13010.1016/j.atherosclerosis.2006.11.007 17145061
    [Google Scholar]
  55. KavurmaM.M. BursillC. StanleyC.P. Endothelial cell dysfunction: Implications for the pathogenesis of peripheral artery disease.Front. Cardiovasc. Med.20229105457610.3389/fcvm.2022.1054576 36465438
    [Google Scholar]
  56. KurakulaK. SmoldersV.F.E.D. CeideT.O. JukemaJ.W. QuaxP.H.A. GoumansM.J. Endothelial dysfunction in pulmonary hypertension: Cause or consequence?Biomedicines2021915710.3390/biomedicines9010057 33435311
    [Google Scholar]
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  • Article Type:
    Research Article
Keyword(s): arterial stiffness; dapagliflozin; empagliflozin; SGLT2i; tofogliflozin; vascular remodeling
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