Potential new therapies to preserve lean muscle mass loss when used in combination with glucagon-like peptide 1 (GLP-1) receptor agonist being studied

Abstract

Glucagon-like peptide receptor agonist (GLP-1) is a highly effective treatment to improve glucose levels, induced significant weight loss and reduce vascular events. However, ongoing concerns persists regarding its effect to cause loss of lean muscle mass in conjunction with weight loss. Loss of muscle mass in the context of weight loss and weight (fat mass) regain thereafter, is associated with sarcopenic obesity, frailty and shown to be an independent predictor of morbidity and mortality especially in older adults. Furthermore, muscle is an important endocrine organ, accounting for ~70% of glucose disposal. Strategies to preserve loss of muscle mass in the context of GLP-1 therapy induced weight loss is therefore important and has recently gained a lot of interest.

To this end, a variety of medications is currently undergoing clinical trials for use with GLP-1 in people who are at risk of loss of muscle mass due to weight loss. A previous phase 2b trial comparing the antimyostatin intravenous therapy bimagrumab vs placebo have shown improvement in muscle mass but potential increased risk of acute pancreatitis. Another antimyostatin, apitegromab is also undergoing phase 2 trial, with another subcutaneous antimyostatin, taldefgrobep due to enter phase 2 trial this year.

The 2024 American Association of Clinical Endocrinology meeting presented some new data on the efficacy of the selective androgen receptor modulator (SARM), enobasarm in combination with a GLP-1 therapy. One study showed that 3 mg of enobasarm for 14 days in combination with GLP-1 increased total lean mass and decreased total fat mass in healthy young and older men (>60 years old). Another post-hoc analysis of a phase 3 clinical trial in people with advanced cancer showed that 3 mg/daily of enobasarm in a subset of participants aged >60 years with obesity showed reductions in fat mass while preserving lean body mass compared with placebo.

While these are important development, an important aspect that needs to be studied is the effects of these therapies on muscle function. This is important for regulatory approval due to a focus on true rather than surrogate endpoints. Furthermore, long-term safety of these new therapies remains unclear. For example, SARM has previously been shown to increased risks of cardiovascular events and thromboembolic diseases. Maintaining healthy lifestyle and muscle mass should therefore remain to be the mainstay of weight loss management. Studies on exercise intervention with GLP-1 however have provided heterogenous results, depending on type, duration and intensity of exercise interventions. Further studies are therefore needed to clarify the most effective, safe and durable strategy to induce weight loss while preserving loss of muscle mass.

Testosterone deficiency is well recognized to be associated with obesity, type 2 diabetes and the metabolic syndrome, all of which predisposes to increase risks of developing cardiovascular events. While testosterone replacement therapy has been shown to improve well-being, sexual and physical function, its effects on cardiovascular events remains unclear. A previous study known as the TRAVERSE (Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men) was the first randomized, placebo- controlled study to investigate the safety of testosterone therapy for men aged between 45 and 80 years old for major cardiovascular events.¹ The study reassuringly showed that modest doses of testosterone therapy did not increased risk of cardiovascular events in the short-term. In contrast, other studies have provided discordant conclusions. To clarify further the association between testosterone levels and risks of cardiovascular events, investigators from the University of Western Australia undertook a meta-analysis to investigate this clinical question. In this study, prospective cohort studies of community-dwelling men with testosterone measured using mass spectrometry with at least 5 years follow up were included. Primary outcomes were all-cause mortality, cardiovascular death and incident cardiovascular events. Participants were adjusted for all relevant confounders. Nine studies that provided individual participant data (255 830 participant-years) and a total of 11 studies were include to provide summary estimates (n = 24 109). The meta-analysis found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL) and LH concentrations above 10 IU/L had higher all-cause mortality. In addition, those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality and lower CVD mortality. There was also a U-shaped association between levels of Dihydrotestosterone (DHT) with cardiovascular outcomes. Men with lower baseline DHT concentrations had higher risk for all-cause mortality and CVD mortality, but also increased risks with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident cardiovascular events.

This study provided evidence based guidelines of the threshold of testosterone levels which may be associated with adverse cardiovascular events to guide indication for testosterone replacement therapy. It also highlight the potential role of measuring DHT to further clarify cardiovascular risks in people with testosterone deficiency. The study is published in Annals of Internal Medicine.²