Muscle loss in obese patients during and post-GLP-1RA therapy

GLP1-RAs are widely used for weight management including weight loss and weight maintenance in obese patients. 

Obesity itself can lead to loss of muscle mass and function and obese individuals have a high prevalence of underlying chronic diseases that can negatively impact muscle metabolism¹.

In clinical studies of GLP-1Ras, weight reduction is primarily attributed to the loss of fat mass, however, studies have reported that losses of lean body mass can account for approximately 40% of the total weight reduction observed^2,3.

Whilst loss of body fat in an obese population is desirable, in view of the importance of LBM for the maintenance of overall health, the loss of LBM is an unwanted effect and a potentially serious concern, particularly for older or frail patients or patients with co-morbidities. Moreover, cessation of GLP-1RA therapy, can result in a rebound in body weight in favour of fat mass and at the expense of LBM, resulting in a less favourable muscle to fat ratio⁴.

In view of its multi-modal pharmacology, S-pindolol is an obvious candidate to evaluate in this setting. In May 2025, Actimed initiated a new development programme investigating the potential benefits of using S-pindolol benzoate (ACM-001.1) during and post-GLP-1 receptor agonist (GLP-1RA) therapy in the management of obesity and related metabolic conditions.

This new initiative comprises a two-part programme:

1. A preclinical programme, designed to explore the pharmacological mechanisms, safety and efficacy of S-pindolol in a diet-induced model of obesity in animals who are receiving or who have received a GLP-1 RA. The in vivo phase of these studies has completed, and they will be reported in the coming months.
2. PROACT (Preserving, Restoring, and Optimising (lean mass and muscle) with ACTAs) – a Phase 2a , randomised, placebo clinical trial, which will assess the safety and efficacy of S-pindolol benzoate in obese patients during and post-GLP-1 RA therapy. The first patient is expected to be enrolled by mid-year 2025. 

¹Hong SH, Choi KM. (2020) Sarcopenic obesity, insulin resistance, and their implications in cardiovascular and metabolic consequences. Int J Mol Sci.;21(2):494.

²Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (2021) N Engl J Med.;384 (11):989–1002. doi: 10.1056/NEJMoa2032183

³McCrimmon RJ, Catarig A-M, Frias JP, et al.Effects of once-weekly semaglutide vs once-daily canagliflozin on body composition in type 2 diabetes: a substudy of the SUSTAIN 8 randomised controlled clinical trial (2020) Diabetologia.;63:473–485. doi: 10.1007/ s00125-019-05065-8

⁴Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab. 2022; 24(8): 1553-1564. doi:10.1111/dom.14725