Not All Weight Loss Is Equal: Towards Muscle‐Preserving Therapies in Obesity

The pharmaceutical therapies targeting obesity have rapidly evolved with the increased study and use of glucagon-like peptide-1 (GLP-1) medications [1, 2]. Treating obesity and overweight, even in the absence of diabetes mellitus, is shown to have beneficial effects on cardiovascular event outcomes [3, 4]. However, an important limitation of this beneficial weight loss is that not all weight loss is equal: 25%–40% of total weight loss may reflect skeletal muscle mass loss or other fat-free mass [1, 5-7]. The Phase 2 BELIEVE trial represents a compelling conceptual advance by combining semaglutide with bimagrumab, an activin receptor type II (ActRII) antagonist [8]. Bimagrumab promotes skeletal muscle hypertrophy through modulating myostatin/activin signalling. Via inhibition of the ActRII-activin receptor-like kinase 4 (ALK4) pathway, Bimagrumab leads to an anabolic effect in skeletal muscle, and the ActRII-activin receptor-like kinase 7 (ALK7) pathway is recognized as contributing to the regulation of obesity [8-10]. Mechanistically, the muscle weight-loss associated with GLP-1 therapies, such as semaglutide, may be mitigated with ActRII antagonism. The BELIEVE trial clinically demonstrated this composition of weight loss in a multicentre, randomized, double-blind, placebo-controlled trial. A total of 507 patients were randomized to nine groups in an equal ratio: placebo, low- or high-dose Bimagrumab, low- or high-dose Semaglutide or combinations of both. The primary endpoint was absolute change from baseline body weight at Week 48. At 48 weeks, weight reduction was observed across all active treatment groups, with greater reductions seen with semaglutide compared to bimagrumab alone. The combination therapy produced the most pronounced effect, achieving significantly more weight loss than either monotherapy and far exceeding placebo. Of greater relevance, secondary endpoints included measures of body composition: absolute and percent change in total body fat and lean mass at Weeks 48 and 72 as measured by dual-energy X-ray absorptiometry. Although semaglutide monotherapy was observed to have a reduction in lean mass, bimagrumab preserved or even increased lean mass. Combination therapy attenuated the loss of lean mass seen with semaglutide monotherapy. Furthermore, the proportion of total weight loss from adipose mass was highest in combination therapy. These results show that, with pharmaceutical therapy, it is possible to uncouple muscle loss from weight loss [8, 9] (Figure 1). The BELIEVE trial's findings are highly relevant to the field of cachexia and sarcopenia. In sarcopenic obesity, excess adiposity coexists with reduced muscle mass and is associated with worse outcomes [11]. Preservation of muscle is tied to clinical outcomes and is a key determinant of metabolic health, physical function and resilience to stressors [12, 13]. In cardiometabolic disease, including heart failure, skeletal muscle loss is linked to exercise intolerance, reduced quality of life and adverse outcomes [14, 15]. Weight loss strategies that can reduce adipose tissue but preserve skeletal muscle may provide synergistic benefits in these populations. In comparison to bariatric surgery, currently the most effective weight loss intervention, the BELIEVE trial's results are a sign this therapy could encroach on surgery [16]. Surgical approaches, including the Roux-en-Y gastric bypass and sleeve gastrectomy, are associated with total body weight reductions that still comprise of approximately 20%–30% lean mass reduction [17, 18]. Loss of skeletal muscle postbariatric surgery has been associated with reduction in strength and functional capacity. Additionally, bariatric surgeries carry procedural risks, require sustained nutritional support and may present challenges with weight maintenance [17, 19]. In this context, a nonsurgical therapy capable of achieving substantial total weight reduction and preserve or improve muscle mass is favourable. Although bariatric surgery confers additional metabolic and hormonal benefits beyond weight loss alone, including glycemic control and cardiovascular event risk reduction, these effects are not exclusive to surgery. The SELECT trial demonstrated that semaglutide for weight loss reduces cardiovascular risk, and the BELIEVE trial continued to observe the beneficial effects on glycemic control in those that were on semaglutide [3, 8]. Notable strengths of the BELIEVE trial include its study design being randomized, double-blind and placebo controlled across multiple treatment arms. The comparison of different monotherapy and combination therapy dose arms limits confounding and increases the interpretability of treatment effects. Despite these promising signals, there are some limitations. Adverse events were generally consistent with known side effects. Semaglutide predominately had gastrointestinal side effects, and bimagrumab was associated most with muscle spasms [8]. Tolerability of therapy is essential for widespread adoption, as discontinuation of pharmacological weight loss therapies has been associated with regaining weight. Additionally, long-term consequences of sustained activin receptor inhibition are not fully understood [9]. The BELIEVE trial authors accurately point out that bimagrumab is currently administered intravenously, which in its present form could limit utilization. Overall, the BELIEVE trial highlights the need to reframe our target in obesity from absolute weight loss to a more specific body composition. The quality of weight loss may prove to be just as important as the magnitude of weight loss. As our tools, including body mass index, fail to distinguish between adipose tissue and lean skeletal muscle, there is a need to better characterize obesity in patients, particularly those with sarcopenia. Afterall, obesity is fundamentally a disease of excess adiposity, not necessarily weight alone. Future investigations must incorporate functional endpoints including muscle strength and exercise capacity and consider frailty as an endpoint. This strategy is not isolated, as multiple parallel efforts are underway to preserve lean mass, such as with enobosarm, in clinical trials (NCT06282458) [20]. In conclusion, by addressing both incretin-based and activin receptor signalling pathways, the combination of semaglutide with bimagrumab paves the way for muscle-preserving pharmacotherapy in weight loss. Whether this approach will ultimately translate into improved patient outcomes remains to be determined, but I believe it is a clear signal of an advancing paradigm shift in treating obesity and its treatment complications. JDA has no conflicts of interests to declare. SDA has received grants and personal fees from Vifor and Abbott Vascular and personal fees for consultancies, trial committee work and/or lectures from Actimed, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BioVentrix, Brahms, Cardiac Dimensions, Cardior, Cordio, CVRx, Cytokinetics, Edwards, Farraday Pharmaceuticals, GSK, HeartKinetics, Impulse Dynamics, Novartis, Occlutech, Pfizer, Repairon, Sensible Medical, Servier, Vectorious and V-Wave. He is the co-inventor of two patent applications regarding MR-proANP (DE 102007010834 and DE 102007022367), but he does not personally benefit from the related issued patents. MSK has received fees from Bayer, Boehringer Ingelheim and Novartis. Data sharing is not applicable to this article, as no datasets were generated or analysed during the current study.