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

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 (P<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.

Keywords: N‐terminal pro‐brain natriuretic peptide; glucagon like peptide‐1 receptor agonists; growth differentiation factor 15; mitochondrial‐derived peptide‐c; sodium‐glucose cotransporter‐2 inhibitors.

Figure 1. Flow chart of the study cohort.

CV indicates cardiovascular; GLP‐1RA, glucagon like peptide‐1 receptor agonists; SGLT‐2i, sodium‐glucose cotransporter‐2 inhibitors; and T2D, type 2 diabetes.

Figure 2. Percentage of changes (Δ) from baseline of (A) N‐terminal pro‐brain natriuretic peptide and (B) growth differentiation factor 15 at 4 and 12 months in the 4 study groups.

Data are presented as means±SD. *P<0.05; ^† P<0.01 vs baseline. All data were analyzed by ANOVA using post hoc test with Bonferroni correction. GDF‐15 indicates growth differentiation factor 15; GLP‐1RA, glucagon like peptide‐1 receptor agonists; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide; and SGLT‐2i, sodium‐glucose cotransporter‐2 inhibitors.

Figure 3. Diabetes induces mitochondrial stress and increases the production of reactive oxygen species, which leads to the activation of stress response pathways, such as integrated stress response.

The latter promotes the induction of growth differentiation factor 15. Sodium‐glucose cotransporter‐2 inhibitors may improve mitochondrial function and increase mitochondrial‐derived peptide‐c resulting in improved insulin sensitivity. GDF‐15 indicates growth differentiation factor 15; MOTS‐c, mitochondrial‐derived peptide‐c; and SGLT‐2i, sodium‐glucose cotransporter‐2 inhibitors.