Database search of spontaneous reports and pharmacological investigations on the sulfonylureas and glinides‐induced atrophy in skeletal muscle

The ATP ‐sensitive K + ( KATP ) channel is an emerging pathway in the skeletal muscle atrophy which is a comorbidity condition in diabetes. The “in vitro” effects of the sulfonylureas and glinides were evaluated on the protein content/muscle weight, fibers viability, mitochondrial succinic dehydrogenases ( SDH ) activity, and channel currents in oxidative soleus ( SOL ), glycolitic/oxidative flexor digitorum brevis ( FDB ), and glycolitic extensor digitorum longus ( EDL ) muscle fibers of mice using biochemical and cell‐counting Kit‐8 assay, image analysis, and patch‐clamp techniques. The sulfonylureas were: tolbutamide, glibenclamide, and glimepiride; the glinides were: repaglinide and nateglinide. Food and Drug Administration‐Adverse Effects Reporting System ( FDA ‐ AERS ) database searching of atrophy‐related signals associated with the use of these drugs in humans has been performed. The drugs after 24 h of incubation time reduced the protein content/muscle weight and fibers viability more effectively in FDB and SOL than in the EDL . The order of efficacy of the drugs in reducing the protein content in FDB was: repaglinide (EC50 = 5.21 × 10 −6 ) ≥ glibenclamide(EC50 = 8.84 × 10 −6 ) > glimepiride(EC50 = 2.93 × 10 −5 ) > tolbutamide(EC50 = 1.07 × 10 −4 ) > nateglinide(EC50 = 1.61 × 10 −4 ) and it was: repaglinide(7.15 × 10 −5 ) ≥ glibenclamide(EC50 = 9.10 × 10 −5 ) > nateglinide(EC50 = 1.80 × 10 −4 ) ≥ tolbutamide(EC50 = 2.19 × 10 −4 ) > glimepiride(EC50=–) in SOL . The drug‐induced atrophy can be explained by the KATP channel block and by the enhancement of the mitochondrial SDH activity. In an 8‐month period, muscle atrophy was found in 0.27% of the glibenclamide reports in humans and in 0.022% of the other not sulfonylureas and glinides drugs. No reports of atrophy were found for the other sulfonylureas and glinides in the FDA ‐ AERS . Glibenclamide induces atrophy in animal experiments and in human patients. Glimepiride shows less potential for inducing atrophy.