Effects of Glucagon-Like Peptide-1 Receptor Agonists, Sodium-Glucose Cotransporter-2 Inhibitors, and Their Combination on Endothelial Glycocalyx, Arterial Function, and Myocardial Work Index in Patients With Type 2 Diabetes Mellitus After 12-Month Treatment

Abstract

Background 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 vascular and cardiac function of patients with type 2 diabetes mellitus. Methods and Results A total of 160 patients with type 2 diabetes mellitus 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 and 4 and 12 months posttreatment: (a) perfused boundary region of the sublingual arterial microvessels (marker of endothelial glycocalyx thickness), (b) pulse wave velocity (PWV) and central systolic blood pressure, (c) global left ventricular longitudinal, circumferential, and radial strain, (d) myocardial work index (global work index) derived by pressure-myocardial strain loops using speckle tracking imaging. Twelve months posttreatment, all patients improved perfused boundary region, PWV, global longitudinal strain, global circumferential strain, and global radial strain (P<0.05). GLP-1RA, SGLT-2i, and their combination showed a greater reduction of perfused boundary region, PWV, and central systolic blood pressure than insulin, despite a similar glycosylated hemoglobin reduction (P<0.05). GLP-1RA or GLP-1RA+SGLT-2i provided a greater increase of global work index (12.7% and 17.4%) compared with insulin or SGLT-2i (3.1% and 2%). SGLT-2i or GLP-1RA and SGLT-2i showed a greater decrease of PWV (10.1% and 13%) and central and brachial systolic blood pressure than insulin or GLP-1RA (PWV, 3.6% and 8.6%) (P<0.05 for all comparisons). The dual therapy showed the greatest effect on measured markers in patients with left ventricular ejection fraction <55% (P<0.05). Conclusions Twelve-month treatment with GLP-1RA, SGLT-2i, and their combination showed a greater improvement of vascular markers and effective cardiac work than insulin treatment in type 2 diabetes mellitus. The combined therapy as second line was superior to either insulin or GLP-1RA and SGLT-2i separately. Registration URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT03878706.

Keywords: arterial stiffness; endothelial glycocalyx; glucagon‐like peptide‐1 receptor agonists; left ventricular function; sodium‐glucose cotransporter‐2 inhibitors.

Figures

Figure 1. Percentage changes (Δs) from baseline in perfused boundary region (PBR) (A), pulse wave velocity (PWV) (B), central systolic blood pressure (cSBP) (C), left ventricular global longitudinal strain (GLS) (D), PWV/GLS ratio (E), and myocardial global work index (GWI) (F) at 4 and 12 months in the 4 study groups.

Data shown are means±SD. *P<0.05, **P<0.01, ***P<0.001 vs baseline. GLP‐1RA indicates glucagon‐like peptide‐1 receptor agonists; and SGLT‐2i, sodium‐glucose cotransporter‐2 inhibitors.

Figure 2. Representative images of myocardial work index derived by pressure–left ventricular (LV) longitudinal myocardial strain loop during one cardiac cycle by speckle tracking echocardiography in 2 patients under combination therapy with glucagon‐like peptide‐1 receptor agonists+sodium‐glucose cotransporter‐2 inhibitors.

The bull's eye shows the myocardial work index in each one of the 17 LV myocardial segments. The perfused boundary region of sublingual microvessels ranging from 5 to 25 μm diameter (PBR 5‐25), reflecting glycocalyx thickness (higher PBR indicates thinner glycolaxyx), is shown as bars by Glycocheck software. The first patient had an LV ejection fraction (LVEF) of 45% and impaired global longitundinal strain (GLS), myocardial work index, and endothelial glycocalyx thickness (a GLS of −13%, a global work index [GWI] of 1433 mm Hg%, and a PBR 5‐25 of 2.24 μm) at baseline and showed a significant improvement (a GLS of −16%, a GWI of 1751 mm Hg%, and a PBR 5‐25 of 1.79 μm) after 12 months treatment (A through D). The second patient with an LVEF of 60%, a GLS of −17%, a GWI of 1851 mm Hg%, and a PBR 5‐25 of 1.87 μm at baseline showed a further improvement to a GLS of −21%, a GWI of 2114 mm Hg%, and a PBR 5‐25 of 1.64 μm after 12 months treatment (E through H). Images provided as courtesy by Dr I. Ikonomidis, Laboratory of Preventive Cardiology and Echocardiography Department, Attikon Hospital, National and Kapodistrian University of Athens (NKUA), Athens, Greece. ANT indicates anterior segments; BP, blood pressure; GCW, global constructive work; GWW, global wasted work; GWE, global work efficiency; INF, inferior segments; LAT, lateral segments; LVP, left ventricular pressure; P50, Median width of red blood cell column; POST, posterior segments; and SEPT, septal segments.

Figure 3. Representative images of myocardial work index derived by pressure–left ventricular (LV) longitudinal myocardial strain loop during one cardiac cycle by speckle tracking echocardiography in a patient under treatment with insulin at baseline and 12 months posttreatment (A and B).

The bull's eye shows the myocardial work index in each one of the 17 LV myocardial segments. The perfused boundary region of sublingual microvessels ranging from 5 to 25 μm diameter (PBR 5‐25), reflecting glycocalyx thickness (higher PBR indicates thinner glycolaxyx), is shown as bars by Glycocheck software (C and D). The patient at baseline had an LV ejection fraction of 50%, a global longitundinal strain (GLS) of −17%, a global work index (GWI) of 1735 mm Hg%, and a PBR 5‐25 of 2.58 μm; and 12 months posttreatment, the patient maintained a GLS of −17%, a GWI of 1823 mm Hg%, and a PBR 5‐25 of 2.46 μm. Images provided as courtesy by Dr I. Ikonomidis, Laboratory of Preventive Cardiology and Echocardiography Department, Attikon Hospital, National and Kapodistrian University of Athens (NKUA), Athens, Greece. ANT indicates anterior segments; BP, blood pressure; GCW, global constructive work; GWW, global wasted work; GWE, global work efficiency; INF, inferior segments; LAT, lateral segments; LVP, left ventricular pressure; P50, Median width of red blood cell column; POST, posterior segments; and SEPT, septal segments.