Sodium-glucose cotransporter-2 inhibitors and their combination with glucagon like peptide-1 receptor agonists improve endothelial glycocalyx and arterial stiffness in type-2 diabetes

Abstract

Background/Introduction: Type-2 diabetes mellitus (T2DM) is associated with endothelial and arterial dysfunction. Purpose: We investigated the effects of insulin, glucagon like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i)and their combination on endothelial and arterial function of T2DM patients. Methods: A hundred-sixty T2DM patients (age: 58±10 years) were randomized to insulin (n=40) , liraglutide (n=40), empagliflozin (n=40) or their combination (GLP-1RA+SGLT-2i) (n=40)as add-on to metformin. We measured at baseline, 4 and 12 months post-treatment: a) perfused boundary region (PBR) of the sublingual arterial microvessels (ranged from 5 to 25$μ$m) using Sideview Darkfield imaging. Increased PBR indicates reduced glucocalyx thickness, b) pulse wave velocity (PWV-Complior), central systolic blood pressure (cSBP) and augmentation index (AI) of the aortic pulse wave. Results: Twelve months post-treatment, all patients improved PBR, PWV and AI (p<0.05). GLP-1RA, SGLT-2i and their combination showed a greater reduction of PBR, PWV and cSBP than insulin, despite a similar HbA1c reduction (p<0.05). SGLT-2i or combined therapy with GLP-1RA and SGLT-2i showed a greater decrease of PWV (-10.1% and -13% vs. -3.6% and -8.6%) and cSBP (-3% and -5.5% vs. -0.8% and -1.5%)than insulin or GLP-1RA (p<0.05 for all comparisons). GLP-1RA or GLP- 1RA+SGLT-2i provided a greater decrease of AI (-42.7% and -48.6% vs. +6.2% vs. -3.8%) compared with insulin or SGLT-2i (Table). The dual therapy showed the greatest effect on measured markers in patients with LVEF <55% (p<0.05). Conclusions: Twelve-month treatment with SGLT-2i and its combination with GLP-1RA, showed a greater improvement on arterial elastic properties than GLP1RA or insulin treatment in T2DM. The combined therapy as second line was superior to either insulin, or GLP-1RA and SGLT-2i separately.