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The treatment of obesity has been transformed by the advent of highly effective, incretin-based pharmacotherapies, which can deliver weight loss of 15-25% after one year.
Understandably, such impressive weight loss has dominated the headlines and captured people’s attention. However, it is equally important to consider the quality of weight loss to understand the effect these new anti-obesity medications (AOMs) have on patients’ overall health, for example, improvements in cardiometabolic risk factors such as lipids, blood pressure and glucose levels, or their impact on body composition.
Typically, reductions in weight lead to the loss of both fat and some lean mass, which comprises skeletal muscle mass. Given the unprecedented potency of the new AOMs, there is a particular concern about pharmacotherapy-induced weight loss resulting in potentially excessive loss of lean mass, including skeletal muscle, especially in vulnerable patient populations, e.g., those at risk of sarcopenia – the progressive loss of muscle mass, muscle quality and strength as a result of the human aging process.
Skeletal muscle plays an important functional and metabolic role. Not only is it essential for physical strength and mobility, skeletal muscle mass is directly linked to greater insulin sensitivity, a higher metabolic rate and an improved overall metabolic profile.
Absolute and relative loss of total lean body mass, assessed via DXA scan, is often used as surrogate endpoint for measuring the impact on muscle mass, despite its obvious limitations, e.g., including the weight of organs, bones, tissue and fluids in addition to muscle.
While most clinical trials of AOMs focus on measuring weight loss alone, the effect of AOMs on lean body mass was reported in a number of trials, which found that lean mass accounted for 15-45% of total weight loss (see Figure 1).
It is worth noting, however, that these clinical trials did not assess the impact of weight loss, including concomitant loss of lean body mass, on individuals’ physical function, the ultimate measure of patient-relevant outcomes.
The latest FDA draft guidance for developing drugs and biological products for weight reduction, published in January 2025, references the effect of AOMs on body composition and recommends measuring it, however, it does not consider the typical loss of lean mass harmful [1].
Specifically, the draft guidance stipulates that “In pharmacological trials, reduction of fat mass has typically accounted for 60% to 90% of weight reduction, and the accompanying reduction in lean mass has not been considered adverse. To ensure that […] weight reduction is caused primarily by a reduction in fat content, not lean body mass, a representative sample of trial subjects should have a baseline and follow-up measurement of body composition by DXA or a suitable alternative.”
Sarcopenia, the progressive, aging-related loss of muscle, contributes to the development of physical frailty, including weakness, fatigue and balance problems which limit a person’s mobility and increase the risk of falls, fractures and other serious injuries.
Sarcopenia can occur alongside obesity and may be worsened by the accumulation of body fat. Termed sarcopenic obesity, it is characterised by the concurrent decline in muscle mass and function along with increased levels of adipose tissue and is associated with higher risk of disability, metabolic dysfunction, comorbidities, e.g., T2D, chronic kidney disease, cardiovascular disease, and all-cause mortality [2, 3].
The co-existence or these two independent disease states strongly increases with age, and also with body mass index (BMI) regardless of age, making sarcopenic obesity a fairly prevalent condition.
This trend was demonstrated, for example, in a cross-sectional study using data from the CDC’s National Health and Nutrition Examination Survey (NHANES) which analysed the prevalence of sarcopenic obesity in the U.S. population [4].
Note, in this study sarcopenic obesity was termed ‘obesity with low lean muscle mass’ (OLLMM), with obesity defined as BMI ≥27. Low lean mass associated with weakness was established by applying criteria from the Foundation for the National Institutes of Health to measurements of appendicular lean mass from DXA scans. Key findings from this study include (see Figure 2):
When treating such high-risk populations with incretin-based pharmacotherapy for weight loss, preserving muscle mass is crucial for preventing frailty, obesity-related comorbidities, maintaining metabolic health and improving physical function.
To date, no formal guidelines exist for treating older, obese adults with the new AOMs, leaving HCPs to carefully consider, on a case by case basis, the benefits of AOM therapy vs. risks, including the consequences of further loss of lean mass, especially in frail, sarcopenic patients.
At the same time, options for minimising muscle loss are currently limited to non-pharmacotherapy interventions, e.g., increased protein intake and dietary supplements combined with endurance and resistance exercise during AOM-induced weight loss.
The emerging recognition of undesired muscle loss associated with incretin-based treatment of obesity as a potentially serious problem, especially in some populations, has spurred a growing interest in developing pharmacotherapies that can address this issue.
To this end, innovators are exploring two fundamental therapeutic approaches to preserve or improve muscle:
The current pipeline of investigational, muscle-preserving therapies comprises 32 assets, of which 47% are at preclinical stage, 22% in phase 1 and 31% in phase 2, as the most advanced candidates. To date, no muscle-preserving future therapies have reached phase 3 yet, however, several assets are poised to move into phase 3 in the near future, for example, Veru’s enobosarm, Rivus Pharmaceuticals’ HU6 or Lilly’s bimagrumab.
Unsurprisingly, the majority of innovators focus on the myostatin/activin signalling pathway given its pivotal role in controlling muscle growth, with assets targeting activin and myostatin accounting for 41% and 25% of the pipeline, respectively, or two-thirds collectively. Other noteworthy mechanisms of action among muscle-preserving assets include mitochondrial uncouplers (9%), apelin agonist (6%), selective androgen receptor modulator (3%) and leptin receptor agonist (3%) (see Figure 3).
Monoclonal antibodies lead the pipeline of muscle-preserving therapies with a share of 31%, followed by oral, small molecule therapies at 25%. Innovators are also exploring novel modalities to address muscle loss, including siRNA therapies and bispecifics, which represent 16% and 13% of the pipeline, respectively, with other biologics accounting for the remainder.
While some muscle-preserving assets have also delivered weight loss in their own right as mono-therapies, e.g., bimagrumab, their most promising application is nonetheless as adjunct therapies to incretin-based AOMs to synergistically improve body composition. This positioning is reflected in the fact that many innovators choose to investigate their muscle-preserving assets in combination with semaglutide or tirzepatide in clinical trials.
Over the past nine months, several innovators have reported intriguing data from phase 2 clinical trials investigating their respective muscle-preserving assets. Noteworthy examples include:
Veru, phase 2b QUALITY trial: selective androgen receptor modulator (SARM) enobosarm plus semaglutide [5]:
Following its positive phase 2b readout, Veru plans to move enobosarm into phase 3. Veru has indicated a similar trial design to assess enobosarm in combination with a GLP-1-RA, with focus on functional endpoints and body composition, e.g.,
Rivus Pharmaceuticals, phase 2a HuMAIN trial: controlled metabolic accelerator HU6, in patients with obesity-related HFpEF [6]:
Regeneron, phase 2 COURAGE trial: trevogrumab (anti-GDF8/anti-myostatin), or trevogrumab plus garetosmab (anti-activin A), in combination with semaglutide – interim results [7]:
Scholar Rock, phase 2 EMBRAZE trial: myostatin inhibitor apitegromab plus trizepatide [8]:
Lilly, phase 2 BELIEVE trial: activin type II receptor inhibitor bimagrumab plus semaglutide [9]:
These promising mid-stage trial results demonstrate the role pharmacotherapies can play in improving the quality of weight loss by preserving muscle mass.
However, confirmatory data from larger phase 3 trials will be needed to substantiate the potential of muscle-preserving investigational therapies to address likely questions from regulators, for example around longer-term safety and efficacy, and variations across different sub-populations.
Furthermore, it is possible regulators may require evidence of additional benefits beyond body composition for the approval of muscle-preserving therapies, such as incremental weight loss above background therapy for combinations or patient-relevant outcomes.
For muscle-preserving therapies to fulfil their potential, innovators must focus on three priorities as their assets advance through the pipeline:
A multi-asset portfolio strategy will be an important consideration, especially for those innovators with muscle-preserving agents that will be positioned as adjunct therapies to incretin-based AOMs, e.g., being able to synergistically combine proprietary therapies to offer value propositions tailored to the needs of sarcopenic, obese patient segments, without dependence on third parties for a foundational incretin therapy.
As the obesity market continues to evolve beyond its initial hype phase which was dominated by a singular focus on ever greater weight loss achieved, the quality of weight loss is increasingly being recognised as an equally important goal.
Several innovators have embraced this opportunity, while recent mid-stage trial readouts have offered a glimpse of the potential that novel muscle-preserving therapies hold. As these assets progress through clinical development towards approval, and ultimately market entry, will they fulfil their promise? No doubt, addressing the quality of weight loss continues to be an intriguing field to observe.
References
Discover new approaches to cardiovascular clinical trials to bring game-changing therapies to patients faster.