GLP-1 receptor agonists increased myocardial mitochondrial coupling efficiency, with higher RCR (2.43 vs 1.8, p=0.01) and lower leak respiration (38.09 vs 57.94, p=0.02).
Does GLP-1-RA therapy improve myocardial mitochondrial energetics in heart transplant recipients?
GLP-1 receptor agonists are associated with enhanced mitochondrial coupling efficiency in the human myocardium, providing a potential mechanism for their cardioprotective effects.
Abstract Background/Introduction Glucagon-like peptide-1 receptor agonists (GLP-1-RA) are used to treat diabetes mellitus and obesity and have reduced cardiovascular risk in clinical trials. It has been hypothesized that GLP-1-RA exert cardioprotective effects beyond weight loss or glycemic control, however, the underlying mechanisms are unclear. Animal studies suggest that GLP-1-RA enhance myocardial mitochondrial function, but evidence in humans is lacking. Here, we test whether treatment with GLP-1-RA may improve myocardial mitochondrial energetics in humans. Methods To investigate this, we evaluated myocardial mitochondrial function using high-resolution respirometry (HRR) in transcatheter endomyocardial biopsies obtained from heart transplant recipients (post-HTx) with and without GLP-1-RA therapy within an ongoing single-center, prospective, observational trial. Study participants enrolled between 2017 and 2024 were with and without GLP-1-RA therapy were included and were matched using propensity score matching with the nearest neighbor method, adjusted for body mass index (BMI), age at examination, type 2 diabetes mellitus, sex, and cardiac function. The primary readouts of mitochondrial function were overall mitochondrial oxidative capacity and coupling efficiency in permeabilized myocardial fibers. The maximum oxidative phosphorylation capacity (OXPHOS) was assessed in the presence of the substrates malate, octanoyl-carnitine, glutamate and succinate. Leak respiration was quantified using oligomycin after OXPHOS and used to calculate the Respiratory Control Ratio (RCR; state 3/state 4O) and Leak Control Ratio (LCR; state 4O/state U). Results Nine out of 485 post-HTx study participants received GLP-1-RA at the time of biopsy and were matched to nine controls without GLP-1-RA therapy. After matching, the GLP-1-RA group and the control group had similar demographic characteristics, with comparable age distribution (mean ± SD: 61 ± 9 vs. 61 ± 4 years), sex (88.8% male in both groups), BMI (31.5 ± 3.7 vs. 30.5 ± 3.5 kg/m²), prevalence of type 2 diabetes (both 88.8%), and preserved cardiac function (cardiac index 2.3 l/min/m², LVEF ≥ 55%). The GLP-1-RA group showed a higher RCR (2.43 ± 0.5 vs. 1.8 ± 0.16, p = 0.01) and a lower LCR (0.39 ± 0.03 vs. 0.54 ± 0.16, p = 0.02). While OXPHOS (82.51 ± 31.56 vs. 97.21 ± 28.11, p = 0.31) did not differ between groups, leak respiration was lower among participants with GLP-1-RA therapy (38.09 ± 15.29 vs. 57.94 ± 16.65, p = 0.02). Conclusion Our data suggest that GLP-1-RAs could enhance mitochondrial coupling efficiency in the human myocardium by reducing proton leak and thus improving coupling efficiency, likely due to higher mitochondrial membrane integrity. Improvement of mitochondrial efficiency may play a role in the cardioprotective effects of GLP-1-RA.
Gabert et al. (2025) studied this question. GLP-1 receptor agonists increased myocardial mitochondrial coupling efficiency, with higher RCR (2.43 vs 1.8, p=0.01) and lower leak respiration (38.09 vs 57.94, p=0.02).