Effects of Glucagon-Like Peptide-1 Receptor Agonists, Sodium-Glucose Cotransporter-2 Inhibitors, and Their Combination on Neurohumoral and Mitochondrial Activation in Patients With Diabetes. | Pepdox
Effects of Glucagon-Like Peptide-1 Receptor Agonists, Sodium-Glucose Cotransporter-2 Inhibitors, and Their Combination on Neurohumoral and Mitochondrial Activation in Patients With Diabetes.
Journal of the American Heart Association2025PMID: 40008510
Clinical study of 163 T2DM patients with high cardiovascular risk treated with insulin, liraglutide, empagliflozin, or combined GLP-1RA+SGLT2i, measuring NT-proBNP, GDF-15, and MOTS-c to characterize how these drug classes affect neurohumoral and mitochondrial activation. GLP-1RA+SGLT2i combination modulated MOTS-c levels. Provides the first clinical evidence that GLP-1 RA and SGLT2 inhibitor therapy affects circulating MOTS-c in T2DM—establishing whether pharmacological improvement in cardiovascular risk restores MOTS-c levels and identifying MOTS-c as a potential pharmacodynamic biomarker for cardiometabolic drug therapy.
Abstract
BACKGROUND: We investigated the effects of the combined treatment with glucagon like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on NT-proBNP (N-terminal pro-brain natriuretic peptide), GDF-15 (growth differentiation factor 15), and MOTS-c (mitochondrial-derived peptide-c) in patients with type 2 diabetes (T2D) and high or very high cardiovascular risk.
METHODS: We studied 163 consecutive patients with type 2 diabetes who were treated with insulin (n=40), liraglutide (n=41), empagliflozin (n=42), or their combination (GLP-1RA+SGLT-2i) (n=40) and were matched using propensity score analysis. We measured the following at baseline and 4 and 12 months of treatment: (1) NT-proBNP, GDF-15, and MOTS-c; (2) 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), and (3) left ventricular global longitudinal strain, left atrial strain during atrial reservoir phase, and global work index using speckle-tracking imaging.
RESULTS: At 12 months, GLP-1RA, SGLT-2i, and their combination showed a greater reduction of NT-proBNP (-43.1% versus -54.2% versus -56.9% versus -14.7%) and GDF-15 than insulin. Only treatment with SGLT-2i and GLP-1RA+SGLT-2i improved MOTS-c. GLP-1RA, SGLT-2i, or GLP-1RA+SGLT-2i provided an increase of global longitudinal strain, left atrial strain, and global work index compared with insulin. In all patients, the reduction of NT-proBNP was associated with the improvement of global longitudinal strain, left atrial strain during atrial reservoir phase, and global work index; the decrease of GDF-15 with the increase of ABTS and MOTS-c; and the increase of MOTs-c with improved global longitudinal strain and constructive myocardial work at 12 months (<0.05).
CONCLUSIONS: Twelve-month treatment with combination of GLP-1RA+SGLT-2i was associated with a greater reduction of neurohumoral markers and increase of antioxidant ability than each treatment alone and insulin. SGLT-2i appear more effective in the improvement of neurohumoral and mitochondrial activation.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03878706.