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

🥉 Top 5% JournalFeb 26, 2025Journal of the American Heart Association

How Diabetes Drugs Alone and Together Affect Nervous System and Mitochondrial Activity in People with Diabetes

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Abstract

At 12 months, treatment with GLP-1 receptor agonists and SGLT-2 inhibitors resulted in a 56.9% reduction of NT-proBNP, compared to a 14.7% reduction with insulin.

GLP-1 receptor agonists and SGLT-2 inhibitors significantly reduced NT-proBNP and GDF-15 levels compared to insulin.
Only SGLT-2 inhibitors and the combination therapy improved levels of MOTS-c.
Treatment with GLP-1 receptor agonists, SGLT-2 inhibitors, or their combination enhanced global longitudinal strain, left atrial strain, and global work index compared to insulin.
A reduction in NT-proBNP was linked to improvements in global longitudinal strain and left atrial strain.
The decrease in GDF-15 correlated with increased antioxidant ability and levels of MOTS-c.

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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). P

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.

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