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.

Precision Pharmacotherapy With Zibotentan in Microvascular Angina: a randomized, placebo-controlled, cross-over trial.

“…In addition, in patients with type 2 diabetes, SGLT2 inhibition improves myocardial blood flow reserve measured using 13 N-ammonia PET/CT raising the possibility of a benefit from SGLT2 inhibition in the microvascular angina population. 29 This suggests a similar strategy to that used in the ZENITH-CKD trial combining low-dose zibotentan with an SGLT-2 inhibitor may be additive NMED-A129750A from the efficacy point of view and mitigate fluid retentive effects of the endothelin A antagonist. 18,30 Limitations Fifty (42.2%) participants had a change in zibotentan trial medication and 22 (18.6%) participants permanently discontinued zibotentan treatment.…”

Antioxidant and Anti-Inflammatory Functions of High-Density Lipoprotein in Type 1 and Type 2 Diabetes

“…Dapagliflozin downregulated NADPH oxidase-dependent ROS production and malondialdehyde levels in mouse cardiac tissues [162], while canagliflozin reduces NADPH oxidase expression and lipid peroxides in the kidneys of diabetic rats [163]. But dapagliflozin treatment did not improve PON1 activity after 12 weeks in 15 patients with T2D [164], as well as HDL-mediated endothelial NO production after 4 weeks in eight patients with both T2D and CAD [165]. Further investigations with larger study populations are required to draw conclusive findings.…”

Dapagliflozin treatment is associated with a reduction of epicardial adipose tissue thickness and epicardial glucose uptake in human type 2 diabetes

“…However, the mechanism by which they provide CV protection remains unclear. We recently demonstrated that treatment with the SGLT-2i dapagliflozin in T2D patients with stable coronary artery disease (CAD), can increase myocardial flow reserve (MFR), and we speculated that this increase could be caused by an improvement in coronary microvascular dysfunction [ 2 , 3 ]. Indeed, coronary microvascular dysfunction, in the absence of obstructive CAD and myocardial diseases, is considered a reversible condition, and MFR can be used to assess efficacy of treatment [ 4 ].…”