Effects of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors and their combination on mitochondrial-derived peptide-c and on markers of neurohumoral activation

Abstract

Background/Introduction: Type‐2 diabetes mellitus (T2DM) is associated with increased prevalence of cardiovascular disease. 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 mitochondrial‐derived peptide‐c (MOTS‐c), N‐terminal pro B‐type natriuretic peptide (NT‐proBNP), growth differentiation factor (GDF)‐15, oxidant and antioxidant biomarkers and cardiovascular function of T2DM patients. Methods: A total of 160 T2DM patients 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, at 4 and at 12 months of treatment: a) plasma levels of MOTS‐c, NT‐proBNP and GDF‐15, b) thiobarbituric acid reactive substances (TBARS), as an oxidant biomarkers, and 2,2?‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS), as an antioxidant biomarker, and c) global left ventricular longitudinal strain (GLS) and global work index (GWI) using speckle‐tracking imaging. Results: Twelve months after treatment, treatment with SGLT‐2i and GLP‐1RA+SGLT‐2i improved MOTS‐c (14.89 ± 11.27 vs. 7.26 ± 4.21 ng/ mL, p=0.009, 6.49 ± 3.91 vs. 5.6 ± 3.38 ng/mL, p=0.029, respectively), while treatment with insulin and GLP‐1RA had a neutral effect on this biomarker (p > 0.05; Table). GLP‐1RA, SGLT‐2i and their combination showed a greater reduction of NT‐proBNP (‐43.1% vs. ‐54.2% vs. ‐56.9% vs. ‐14.7%; Figure) and GDF‐15 (‐14.8% vs. ‐15.2% vs. ‐16.1% vs. ‐0.9%) than insulin (p < 0.05 for all comparisons), despite the fact that all patient achieved adequate glycemic control. GLP‐1RA or GLP��1RA+SGLT‐2i provided a remarkable reduction of TBARS and increase of GLS and GWI compared to insulin or SGLT‐2i (p < 0.05). In all patients, at 4 and at 12 months, the percentage reduction of NT‐proBNP was associated with the improvement of TBARS, GLS and GWI (p < 0.05). The percentage reduction of GDF‐15 was correlated with the increase of ABTS and with the improvement of GLS at 4 and 12 months (p < 0.05). In SGLT‐2i group, the percentage increase of MOTS‐c was related with the percentage reduction of GDF‐15 (r = 0.81, p = 0.005) at 12 months. Conclusions: Twelve‐month treatment with GLP‐1RA, SGLT‐2i and their combination resulted in reduction of cardiac biomarkers in parallel with a greater decrease of oxidative stress than insulin in T2DM. SGLT‐2i appears more effective in the improvement of MOTS‐c and markers of neurohumoral activation.