Sodium–Glucose Cotransporter 2 Inhibitors and Skeletal Muscle

This article refers to ‘Sodium–glucose cotransporter 2 inhibitors influence skeletal muscle pathology in patients with heart failure and reduced ejection fraction’, by N. Wood et al., published in this issue on pages 925–935. In this issue is a small report concerning muscle biopsies taken from patients with heart failure and reduced ejection fraction (HFrEF) who were, or were not, taking a sodium–glucose cotransporter 2 (SGLT2) inhibitor.1 The unique piece of information derived from this paper was that by taking a skeletal muscle biopsy from the pectoralis major muscle group of each patient, the authors could analyse some of the heart failure (HF)-related muscle changes which they hypothesized could be improved by the use of SGLT2 inhibitors. They found that the patients taking an SGLT2 inhibitor had less skeletal muscle pathology, in particular showing relatively less atrophic pathway activation, reduced inflammation and altered metabolism in the muscle compared to a control group not having received an SGLT2 inhibitor. These are potentially very interesting observations, as they may explain some of the mechanisms underlying the benefits of SGLT2 inhibitors in HF (both HFrEF and HF with preserved ejection fraction [HFpEF]) that remain rather uncertain. Major clinical benefits of SGLT2 inhibitors have been shown in terms of composite cardiovascular mortality and HF hospitalization risk in HFrEF, HFpEF and chronic kidney disease as well as in type 2 diabetes mellitus with cardiovascular disease. These are consistently associated with improved quality of life (QoL) in HF as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ). What we do not know is how these major clinical benefits are produced, and in particular the mechanisms underlying the relatively consistent improvement in QoL seen with these agents. If SGLT2 inhibitors could improve the abnormal skeletal muscle, that is so common in HF, it could go some way to explain the link between improved QoL and how the drugs of this class actually work. It also could link improved QoL with improvements in objective exercise tolerance, a clinically valuable endpoint for clinical trials in HF, but one which has not been consistently demonstrated.