Cardiovascular Diabetology (Mar 2021)

Dapagliflozin effect on endothelial dysfunction in diabetic patients with atherosclerotic disease: a randomized active-controlled trial

  • Andrei C. Sposito,
  • Ikaro Breder,
  • Alexandre A. S. Soares,
  • Sheila T. Kimura-Medorima,
  • Daniel B. Munhoz,
  • Riobaldo M. R. Cintra,
  • Isabella Bonilha,
  • Daniela C. Oliveira,
  • Jessica Cunha Breder,
  • Pamela Cavalcante,
  • Camila Moreira,
  • Filipe A. Moura,
  • Jose Carlos de Lima-Junior,
  • Helison R. P. do Carmo,
  • Joaquim Barreto,
  • Wilson Nadruz,
  • Luiz Sergio F. Carvalho,
  • Thiago Quinaglia,
  • ADDENDA-BHS2 trial investigators

DOI
https://doi.org/10.1186/s12933-021-01264-z
Journal volume & issue
Vol. 20, no. 1
pp. 1 – 12

Abstract

Read online

Abstract Background The glucose-lowering independent effect of sodium glucose cotransporter-2 inhibitors (SGLT2i) on arterial wall function has not yet been clarified. This study aims to assess whether SGLT2i treatment can attenuate endothelial dysfunction related to type 2 diabetes mellitus (T2D) compared with glucose-lowering equivalent therapy. Methods In a prospective, open-label, single-center, randomized clinical trial, 98 patients with T2DM and carotid intima-media thickness above the 75th percentile were randomized 1:1 to 12 weeks of therapy with dapagliflozin or glibenclamide in addition to metformin in glucose-lowering equivalent regimens. The coprimary endpoints were 1-min flow-mediated dilation (FMD) at rest and 1-min FMD after 15 min of ischemia followed by 15 min of reperfusion time (I/R). Results Ninety-seven patients (61% males, 57 ± 7 years) completed the study. The median HbA1c decreased by − 0.8 (0.7)% and -0.7 (0.95)% following dapagliflozin and glibenclamide, respectively. The first coprimary endpoint, i.e., rest FMD changed by + 3.3(8.2)% and − 1.2(7.5)% for the dapagliflozin and glibenclamide arms, respectively (p = 0.0001). Differences between study arms in the second coprimary endpoint were not significant. Plasma nitrite 1 min after rest FMD was higher for dapagliflozin [308(220) nmol/L] than for glibenclamide (258[110] nmol/L; p = 0.028). The resistive indices at 1 min [0.90 (0.11) vs. 0.93 (0.07); p = 0.03] and 5 min [0.93 (0.07) vs. 0.95 (0.05); p = 0.02] were higher for the glibenclamide group than for the dapagliflozin group. Plasma biomarkers for inflammation and oxidative stress did not differ between the treatments. Conclusions Dapagliflozin improved micro- and macrovascular endothelial function compared to glibenclamide, regardless of glycemic control in patients with T2DM and subclinical carotid atherosclerotic disease.

Keywords