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

Abstract

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.

Diabetes pharmacotherapy and effects on the musculoskeletal system

“…Recent studies suggest that SUs and glinides can induce muscle atrophy; reduced muscle protein content/muscle weight as well as reduced muscle fiber diameter was shown with SU and glinide treatment in mice . Glibenclamide/glyburide, but not other SUs, has been associated with muscle atrophy in humans, based on reports in the FDA‐Adverse Effects Reporting System (AERS) database over an observation period of 8 months . The underlying suggested mechanisms for muscle atrophy appear to be hypoglycemia and/or KATP channel blocking .…”

“…Glibenclamide/glyburide, but not other SUs, has been associated with muscle atrophy in humans, based on reports in the FDA‐Adverse Effects Reporting System (AERS) database over an observation period of 8 months . The underlying suggested mechanisms for muscle atrophy appear to be hypoglycemia and/or KATP channel blocking . Interestingly, glibenclamide has been shown to increase tension in fatigued slow muscle in mice and in chickens supporting a direct effect of SUs on the KATP channels of skeletal muscle.…”

“…They have direct effects on muscle, affecting glucose uptake, glycogen synthase activity, 489 protein degradation, 490 and mitochondrial function in skeletal muscle. 491,492 Gliclazide can improve skeletal muscle glucose uptake, and this effect appears to be mediated by action on the KATP channel 493 and associated with an increase in GLUT-1 membrane content and either no change 494,495 or an increase 496 497 The underlying suggested mechanisms for muscle atrophy appear to be hypoglycemia and/or KATP channel blocking. 497 Interestingly, glibenclamide has been shown to increase tension in fatigued slow muscle in mice 498 and in chickens 499 supporting a direct effect of SUs on the KATP channels of skeletal muscle.…”

Sarcopenia and frailty in older patients with diabetes mellitus

“…Sulfonylureas and glinides, which are ATP‐sensitive potassium channel blockers, stimulate insulin release in pancreatic beta cells. Some reports have shown that the drugs in this class might be associated with muscle atrophy …”

Oral Drugs Related with Muscle Wasting and Sarcopenia. A Review

“…Some in vitro studies have shown an induction of cell apoptosis with therapeutic doses of sulfonylureas [36,37] , which can lead to atrophy [38,39] . Glinides have a mechanism of action similar to sulfonylureas with a shorter half-life [40] , which also can cause atrophy in experimental animals [39] . However, the muscle effects of these drugs in humans are unknown.…”