Upcoming pharmacological and interventional therapies for the treatment of physical frailty and sarcopenia

Abstract

Sarcopenia in cirrhosis is a multifaceted process. As our understanding of the complex biology of skeletal muscle improves, we are getting closer to identifying specific therapies to treat muscle depletion in cirrhotic and non-cirrhotic populations. Anabolic hormones including testosterone and growth factor are often reduced in cirrhosis; pharmacological therapies that replenish these deficiencies may assist in preventing or reversing muscle depletion. In cirrhosis, hyperammonemia and portal hypertension both play important roles in the pathogenesis of sarcopenia. Specific treatments and interventions targeting these physiological abnormalities may also have added anabolic effects on muscle. Myostatin has emerged as key negative regulator of skeletal muscle in many chronic disease states including cirrhosis. Novel therapies that target different components of the extracellular myostatin signaling pathway are currently in various stages of development. Other drugs in clinical development include selective androgen receptor modulators, ghrelin agonists, and urocortin II agonists. However, while mechanistically these interventions offer possible treatments for sarcopenia in cirrhosis, there is a lack of large randomized trials to support any pharmacological intervention in this population. Therapeutic clinical trials in sarcopenia face significant challenges including a lack of consensus in the definition and assessment methodology for sarcopenia and the heterogenous population who each likely has differing underlying contributors to muscle wasting. Importantly, it is yet to be determined whether increasing muscle mass translates to improved patient outcomes.