Dapagliflozin-Induced Myocardial Flow Reserve Improvement is not Associated with HDL Ability to Stimulate Endothelial Nitric Oxide Production

Abstract

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: To investigate changes in HDL-mediated modulation of NO production with dapagliflozin and whether there is an association with MFR.

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: 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: 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: EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752.

Keywords: Coronary microvascular dysfunction; Dapagliflozin; Diabetes; Endothelium; HDL; Myocardial flow reserve; Nitric oxide; SGLT2i.

Fig. 1

A HDL-mediated NO production, at baseline and after treatment, in placebo and dapagliflozin group, respectively. Data are expressed as unadjusted mean ± SEM. N = 8 placebo and N = 8 dapagliflozin. P vs placebo = 0.829. B Percent change in HDL-mediated NO production after treatment: Data are expressed as adjusted mean ± SEM. P vs placebo = 0.547 adjusted for age, BMI, apoA-I, HDL cholesterol, LDL cholesterol and statin treatment. HDL high-density lipoproteins; NO nitric oxide; BMI body mass index; SEM standard error of the mean; apoA-I apolipoprotein A-I; LDL low-density lipoproteins