Dapagliflozin-Induced Myocardial Flow Reserve Improvement is not Associated with HDL Ability to Stimulate Endothelial Nitric Oxide Production.
Coronary microvascular dysfunction
Dapagliflozin
Diabetes
Endothelium
HDL
Myocardial flow reserve
Nitric oxide
SGLT2i
Journal
Diabetes therapy : research, treatment and education of diabetes and related disorders
ISSN: 1869-6953
Titre abrégé: Diabetes Ther
Pays: United States
ID NLM: 101539025
Informations de publication
Date de publication:
26 Oct 2023
26 Oct 2023
Historique:
received:
01
08
2023
accepted:
09
10
2023
medline:
26
10
2023
pubmed:
26
10
2023
entrez:
26
10
2023
Statut:
aheadofprint
Résumé
Sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown controversial results in modulating plasma lipids in clinical trials. Most studies found slight increases in high-density lipoprotein (HDL) cholesterol but few have provided evidence on HDL functionality with disappointing results. However, there is broad agreement that these drugs provide cardiovascular protection through several mechanisms. Our group demonstrated that dapagliflozin improves myocardial flow reserve (MFR) in patients with type 2 diabetes (T2D) with coronary artery disease (CAD). The underlying mechanisms are still unknown, although in vitro studies have suggested the involvement of nitric oxide (NO). To investigate changes in HDL-mediated modulation of NO production with dapagliflozin and whether there is an association with MFR. Sixteen patients with CAD-T2D were enrolled and randomized 1:1 to dapagliflozin or placebo for 4 weeks. Blood samples were collected before and after treatment for each group. The ability of HDL to stimulate NO production in endothelial cells was tested in vitro by incubating human umbilical vein endothelial cells (HUVEC) with apoB-depleted (apoB-D) serum of these patients. The production of NO was assessed by fluorescent assay, and results were expressed as fold versus untreated cells. Change in HDL-mediated NO production remained similar in dapagliflozin and placebo group, even after adjustment for confounders. There were no significant correlations between HDL-mediated NO production and MFR either at baseline or after treatment. No changes were found in HDL cholesterol in either group, while low-density lipoprotein cholesterol (LDL cholesterol) significantly decreased compared to baseline only in treatment group (p = 0.043). In patients with T2D-CAD, beneficial effects of dapagliflozin on coronary microcirculation seem to be unrelated to HDL functions. However, HDL capacity to stimulate NO production is not impaired at baseline; thus, the effect of drug treatments would be negligible. To conclude, we can assume that HDL-independent molecular pathways are involved in the improvement of MFR in this population. EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752.
Sections du résumé
BACKGROUND
BACKGROUND
Sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown controversial results in modulating plasma lipids in clinical trials. Most studies found slight increases in high-density lipoprotein (HDL) cholesterol but few have provided evidence on HDL functionality with disappointing results. However, there is broad agreement that these drugs provide cardiovascular protection through several mechanisms. Our group demonstrated that dapagliflozin improves myocardial flow reserve (MFR) in patients with type 2 diabetes (T2D) with coronary artery disease (CAD). The underlying mechanisms are still unknown, although in vitro studies have suggested the involvement of nitric oxide (NO).
AIM
OBJECTIVE
To investigate changes in HDL-mediated modulation of NO production with dapagliflozin and whether there is an association with MFR.
METHODS
METHODS
Sixteen patients with CAD-T2D were enrolled and randomized 1:1 to dapagliflozin or placebo for 4 weeks. Blood samples were collected before and after treatment for each group. The ability of HDL to stimulate NO production in endothelial cells was tested in vitro by incubating human umbilical vein endothelial cells (HUVEC) with apoB-depleted (apoB-D) serum of these patients. The production of NO was assessed by fluorescent assay, and results were expressed as fold versus untreated cells.
RESULTS
RESULTS
Change in HDL-mediated NO production remained similar in dapagliflozin and placebo group, even after adjustment for confounders. There were no significant correlations between HDL-mediated NO production and MFR either at baseline or after treatment. No changes were found in HDL cholesterol in either group, while low-density lipoprotein cholesterol (LDL cholesterol) significantly decreased compared to baseline only in treatment group (p = 0.043).
CONCLUSIONS
CONCLUSIONS
In patients with T2D-CAD, beneficial effects of dapagliflozin on coronary microcirculation seem to be unrelated to HDL functions. However, HDL capacity to stimulate NO production is not impaired at baseline; thus, the effect of drug treatments would be negligible. To conclude, we can assume that HDL-independent molecular pathways are involved in the improvement of MFR in this population.
TRIAL REGISTRATION
BACKGROUND
EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752.
Identifiants
pubmed: 37883003
doi: 10.1007/s13300-023-01491-5
pii: 10.1007/s13300-023-01491-5
doi:
Banques de données
ClinicalTrials.gov
['NCT03313752']
Types de publication
Journal Article
Langues
eng
Informations de copyright
© 2023. The Author(s).
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