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SGLT2 Inhibitors Influence Skeletal Muscle Pathology in Patients With HFrEF
abstract
This abstract is available on the publisher's site.
Access this abstract nowAIMS
Patients with heart failure and reduced ejection fraction (HFrEF) exhibit skeletal muscle pathology, which contributes to symptoms and decreased quality of life. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve clinical outcomes in HFrEF but their mechanism of action remains poorly understood. We aimed, therefore, to determine whether SGLT2i influence skeletal muscle pathology in patients with HFrEF.
METHODS AND RESULTS
Muscle biopsies from 28 male patients with HFrEF (New York Heart association class I-III) treated with SGLT2i (>12 months) or without SGLT2i were compared. Comprehensive analyses of muscle structure (immunohistochemistry), transcriptome (RNA sequencing), and metabolome (liquid chromatography-mass spectrometry) were performed, and serum inflammatory profiling (ELISA). Experiments in mice (n = 16) treated with SGLT2i were also performed. Myofiber atrophy was ~20% less in patients taking SGLT2i (p = 0.07). Transcriptomics and follow-up measures identified a unique signature in patients taking SGLT2i related to beneficial effects on atrophy, metabolism, and inflammation. Metabolomics identified influenced tryptophan metabolism in patients taking SGLT2i: kynurenic acid was 24% higher and kynurenine was 32% lower (p < 0.001). Serum profiling identified that SGLT2i treatment was associated with lower (p < 0.05) pro-inflammatory cytokines by 26-64% alongside downstream muscle interleukin (IL)-6-JAK/STAT3 signalling (p = 008 and 0.09). Serum IL-6 and muscle kynurenine were correlated (R = 0.65; p < 0.05). Muscle pathology was lower in mice treated with SGLT2i indicative of a conserved mammalian response to treatment.
CONCLUSIONS
Treatment with SGLT2i influenced skeletal muscle pathology in patients with HFrEF and was associated with anti-atrophic, anti-inflammatory, and pro-metabolic effects. These changes may be regulated via IL-6-kynurenine signalling. Together, clinical improvements following SGLT2i treatment in patients with HFrEF may be partly explained by their positive effects on skeletal muscle pathology.
Additional Info
Disclosure statements are available on the authors' profiles:
Sodium-glucose cotransporter 2 inhibitors influence skeletal muscle pathology in patients with heart failure and reduced ejection fraction
Eur. J. Heart Fail 2024 Mar 11;[EPub Ahead of Print], N Wood, S Straw, CW Cheng, Y Hirata, MG Pereira, H Gallagher, S Egginton, W Ogawa, SB Wheatcroft, KK Witte, LD Roberts, TS BowenFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Could SGLT2 inhibitors be good for the skeletal muscles?
In recent years, the data on SGLT2 inhibitors (SGLT2i) have been astounding, with benefits observed in patients with heart and renal failure. The exact mechanism by which SGLT2is does all of these things is not clear; however, patients on SGLT2is do better and actually feel better.
This study evaluated the effects of SGLT2i on skeletal muscles. Patients with heart failure often have skeletal muscle weakness and atrophy. Traditionally, we thought that with heart failure, there is lower oxygen supply and energy so patients do not move around, resulting in skeletal muscle atrophy. And yet in SGLT2i trials, patients felt better and could do more activities. Therefore, do SGLT2is have beneficial effects on skeletal muscles as well?
This study compared 28 patients with heart failure; half were on SGLT2is for 12 months, and the other half were on placebo. The authors took muscle biopsies to examine the muscle fibers and study the metabolic changes in the muscle cells.
They found that everything was going in the right direction for the patients receiving SGLT2is. They examined muscle fiber structure, which genes were being activated, what metabolic changes were happening, and the blood levels of inflammatory biomarkers. Again, everything went in the right direction for the patients taking SGLT2is.
The myofiber size was larger by 17% in the SGLT2i group; the fiber types were the same in the two groups, but the fiber size of the SGLT2i group was bigger. In other words, less atrophy.
The authors then examined which genes were turned on and off. The ubiquitin-proteasome gene was reduced by about 60% in the SGLT2i group. This proteasome helps to break down proteins. Hence, a reduction means that there is less destruction of proteins within muscle cells. This would mean bigger muscle cells. The genes responsible for autophagy were reduced by 69% in the patients receiving SGLT2i, translating to less destruction of muscle cells, which is good for the muscles. The genes involved in muscle repair were reduced in the SGLT2i group, which could mean there was less muscle damage, and hence, less need for repair.
Also, tryptophan metabolism was altered in a good way. It was pushed to produce more kynurenic acid instead of kynurenine. Kynurenic acid is neuroprotective, whereas kynurenine is neurotoxic. So, the patients on SGLT2i had more of the good metabolites.
The authors also looked at inflammatory markers such as IL-6. This marker level was reduced by 55.6%, meaning there was less inflammation in the SGLT2i group. IL-6 also drives the production of kynurenine - the bad guy. Thus, if SGLT2i reduces IL-6 levels then less Kynurenine is being produced.
Many of these tests were also conducted on mice where the authors could control for physical activity between the groups, and they saw the same changes that they observed with human data.
Although the sample size was small, this study has given us a glimpse into how far-reaching the effects of SGLT2is really are. SGLT2is were introduced as medications that help an individual urinate glucose; however, we are now discovering the numerous actions of this class of medication.
For our patients with heart failure, SGLT2is can help with their skeletal muscles. They are anti-atrophic, anti-inflammatory, and have pro-metabolic effects on the skeletal muscles. Perhaps this is why patients felt better in the clinical trials.