Effect of sodium-glucose cotransporter-2 inhibitors on skeletal muscle

Empagliflozin and dapagliflozin, frequently prescribed Sodium-Glucose- Cotransporter2-inhibitors (SGLT2i), are now also recommended for nondiabetic patients with heart failure (HF). Since concerns exist about myopathy and sarcopenia as adverse effects of SGLT2i, the review summarizes effects of dapagliflozin and empagliflozin on skeletal muscle. PubMed was searched for "SGLT2" OR "SGLT2 inhibitors" OR "SGLT2i" OR "dapagliflozin" OR "empagliflozin" AND "myopathy" OR "sarcopenia" OR "skeletal muscle" OR "muscle loss" OR "muscle weakness" OR "muscle wasting" OR "myotoxicity" OR "muscle atrophy" OR "rhabdomyolysis". Excluded were reviews, editorials, study protocols, letters to the editor, in vitro and in vivo studies. Myopathy/rhabdomyolysis were reported in 5 patients, 3 with concomitant statins, whereas 3 clinical/pharmacovigilance studies found no increased myopathy/rhabdomyolysis-risk with a SGLT2i-statin-combination. SGLT2i-associated sarcopenia was studied in small cohorts (<100 patients in 65 % of the studies), with diabetes-mellitus (68 %) and Japanese (53 %). Observation time was >6 months in only 32 % of the studies, HF-patients were included in 26 %. Controversial data are reported for muscle-mass, which decreased in 15 and remained unchanged in 6 studies. Physical-performance-tests remained unchanged under SGLT2i. Muscle-biopsies found SGLT2i-assosciated metabolic changes and myofiber-atrophy, but no correlation with functional tests were reported. Exercise or dietary measures did not influence SGLT2i-associated loss of muscle-mass. Two pharmacovigilance studies identified SGLT2i as risk factors for sarcopenia. Data on SGLT2i-associated effects on skeletal muscle are limited and controversial. There is an urgent need for research, especially in nondiabetic, non-Japanese and HF-patients. Since sarcopenia develops over time, observation periods of >12 months are necessary.