GLP1 receptor agonist therapies induce substantial weight loss, but up to 40% of this weight loss is lean mass, particularly muscle. Loss of muscle mass can be caused via activation of type II activin receptors ActRIIA and/or ActRIIB, and blockade of these receptors can lead to muscle growth in humans. A study in Nature Communications describes a strategy for preventing muscle mass loss during GLP1 receptor agonist therapy by dual blockade of the ActRIIA and ActRIIB ligands GDF8 (also known as myostatin) and activin A.

The researchers treated diet-induced obese mice with either a vehicle control, the GLP1 receptor agonist semaglutide alone, GDF8 and activin A antibody blockade alone (αMSTN–αActA) or semaglutide and αMSTN–αActA. The combination therapy of semaglutide and dual GDF8 and activin A blockade resulted in similar levels of total body weight loss to semaglutide alone, but statistically significantly greater protection from lean mass loss and substantially greater reduction in percentage fat mass than with semaglutide alone.

Using the same treatment groups, the researchers then assessed the effect of semaglutide with GDF8 and activin A blockade in non-human primates (cynomolgus monkeys) with obesity. As in mice, both the semaglutide alone and semaglutide with αMSTN–αActA caused significant body weight reduction compared with vehicle controls, and semaglutide with αMSTN–αActA treatment led to increased lean mass compared with both baseline and the semaglutide-only group. In addition, semaglutide with αMSTN–αActA showed the greatest improvement in metabolic parameters out of all treatment groups.

The authors hope that supplementing GLP1 receptor agonist use with GDF8 and activin A blockade can greatly improve the benefits of these therapies, while minimizing potentially harmful loss of lean mass.