New drugs for the treatment of obesity: do we need approaches to preserve muscle mass?

Abstract

The development of drugs targeting Nutrient Stimulated Hormone receptors has ushered in a dramatic change in our approach to weight management because of their ability to achieve weight losses of 10%, 20%, even 30% in significant numbers of patients. Additionally, disease modifying properties of these medications are compelling. Indications now include cardiovascular risk reduction, obstructive sleep apnea and diabetes management, and emerging evidence supports efficacy for heart failure and chronic kidney disease. These medications would need to be taken long term and the population being treated will be older than the traditional weight management patient. Emerging evidence cautions that the loss of excessive lean mass with some of the newer medications may be problematic. This is not a concern for most patients who will need the medications, but it is a concern in an older population, since loss of muscle and bone accelerates and progresses past age 60. Of weight lost with semaglutide, approximately 45% is from lean mass, while with tirzepatide, it is 25%. Going forward, combining another NuSH such as glucagon or amylin with the GLP-1 receptor agonists may lessen loss of lean mass. Another approach under study is the use of MAPi – myostatin-activin pathway inhibitors. Promising results with bimagrumab are spurring investigaton in this area. For the full potential of disease modification to be achieved, it’s a given that we must demonstrate safe, long term body composition improvement when the new medications are deployed, especially in the older population. This narrative review discusses the justification for focus on lean mass preservation and reviews the status of relevant drugs in development.

Purpose

This narrative review discusses the current efficacy and safety profiles of the new medications derived from Nutrient Stimulated Hormones (NuSHs), including those targeting the glucagon-like peptitde (GLP- 1) receptor (R) and the glucose-dependent insulinotropic polypeptide receptor (GIP R). Further, the disease-modifying attributes of these drugs means that they will be used in an older population in whom loss of muscle and bone is accelerated. The potential for sparing of lean loss by targeting GIP, amylin, and glucagon is discussed. The emerging study of myostatin-activin pathway inhibitors (MAPi) used alone and with other NUSH-targeted medications is reviewed, along with the sparse evidence of use of selective androgen receptor modulators (SARM).

New developments in obesity pharmacotherapy – robust weight loss with the GLP- 1 receptor agonists for obesity

Weight loss efficacy

There has been a transformation in medical approaches to caring for patients with obesity, sparked in 2021 by the US Food and Drug Administration approval of semaglutide 1.7 mg and 2.4 mg for chronic weight management. Semaglutide, a glucagon-like peptide receptor agonist (GLP- 1 RA), was shown in STEP 1 to produce mean weight reduction from baseline to week 68 of − 14.9% for semaglutide versus − 2.4% for placebo, by treatment-policy or treatment-regimen estimand which is reported throughout this manuscript, except where noted [1]. This amount of weight reduction dramatically exceeded the weight reduction achieved by any previous medication approved for chronic weight management [2]. Indeed, liraglutide, the first GLP- 1 RA approved for chronic weight management (in 2014) was shown in the SCALE Phase 3 trial to produce mean weight reduction from baseline to week 56, of − 8.0% with liraglutide 3.0 mg versus − 2.8% with placebo (last-observation-carried-forward imputation—LOCF) [3]. Then, in 2023, the US FDA approved tirzepatide 5 mg, 10 mg and 15 mg for chronic weight management. Tirzepatide is a glucose-dependent insulinotropic polypeptide/GLP- 1 dual receptor agonist (GIP/GLP- 1 RA) and in the Phase 3 SURMOUNT- 1 trial, tirzepatide 5 mg, 10 mg and 15 mg produced mean weight reduction from baseline to week 72 of − 15,0%, − 18.5% and − 20.9%, respectively, versus − 2.4% for placebo.

Perhaps even more meaningful than mean weight loss is that most patients who were randomly assigned to the drug were able to achieve 10%, 15% and 20% benchmarks for weight reduction. For semaglutide¹, 74.8%, 54.8%, and 34.8% achieved those, while for tirzepatide [4] it was 90.1%, 78.2% and 62.9%. Patients find the weight loss efficacy appealing, and the drug class has become very popular. It is estimated that 12% of US adults have taken a GLP- 1 RA based medication (https://www.kff.org/health-costs/poll-finding/kff-health-tracking-poll-may-2024-the-publics-use-and-views-of-glp-1-drugs/). In Table 1 are shown the medications based on GLP- 1 R or GLP- 1/GIP R agonism which are currently approved in the United States. The Table includes the weight loss efficacy at the highest dose from the phase 3 trials, SCALE [3], STEP 1¹ and SURMOUNT 1⁴. Treatment-efficacy or treatment-regimen estimands are noted, except for liraglutide which uses LOCF for mean weight loss calculation.

Table 1.

GLP- 1 RA peptide medications approved for weight management in US: Weight loss efficacy

Target	Name Dose	Mean weight loss (highest dose)	Proportion achieving  > 5%,  > 10%,  > 20% (highest dose shown)
GLP − 1 receptor	Liraglutide 3.0 mg daily	baseline to week 56, mean weight reduction: drug name and doese and weight loss vs. placebo and weight loss liraglutide 3.0 mg − 8.0% vs placebo − 2.8%3	≥ 5% loss: liraglutide 63% placebo 27%  ≥ 10% loss: liraglutide 33% placebo 11%3  < 15% loss: liraglutide 14% placebo 4%
	Semaglutide 1.7 mg and 2.4 mg weekly	baseline to week 68, mean weight reduction: semaglutide 2.4 mg − 14.9% vs placebo − 2.4%1	≥ 5% loss semaglutide 86% placebo 32%  ≥ 10% loss semaglutide 69% placebo 12%  > 15% semaglutide 51% placebo 5%  > 20% semaglutide 32% placebo 2%1
GLP- 1/GIP receptor	Tirzepatide 5 mg, 10 mg, 15 mg weekly	baseline to week 72, mean weight reduction: tirzepatide 15 mg − 20.9% vs placebo − 3.1%4	≥ 5% loss tirzepatide 91% placebo 35%  ≥ 10% tirzepatide 84% placebo 19%  > 15% tirzepatide 71% placebo 9%  > 20% tirzepatide 57% placebo 3%4

The search for medications to treat obesity has expanded to include other nutrient stimulated hormones (NuSH), such as glucagon and amylin [5, 6], as discussed below. Single peptide molecules that target one, two or three receptors are in development, along with dual administration of two molecules, and non-peptide small molecules are also being developed, which would presumably be shelf-stable and easier and less costly to produce. Approaches to oral delivery include oral small molecules and oral peptides.

New developments in obesity pharmacotherapy: disease modifying properties

Semaglutide and tirzepatide are indicated for treatment of diabetes and marketed for both diabetes and chronic weight management under different trade names. Another breakthrough in obesity medication acceptance was the SELECT trial [7], the first cardiovascular outcome trial in persons with overweight and obesity with established cardiovascular disease (prior myocardial infarction, stroke or symptomatic peripheral artery disease) to show reduction in major adverse cardiovascular events (MACE) [7]. SELECT demonstrated a 20% relative risk reduction in time to first occurrence of myocardial infarction, stroke or cardiovascular death (the three point MACE) [7]. This resulted in an indication for cardiovascular risk reduction in the drug’s US FDA label. The early benefits are cardiovascular event reduction also raised the idea that the benefits were being seen before weight loss occurred, implication both the drug and weight loss in mediating the effect. Since SELECT, there has been a steady stream of evidence supporting the disease modifying effects of semaglutide and tirzepatide. In addition to glycemic and weight loss efficacy, for patients with obesity with or without diabetes, benefits are seen in heart failure with preserved ejection fraction (HFpEF) with semaglutide [8–10] and tirzepatide [11]. Another advance is the demonstration that semaglutide can reduce the progression of chronic kidney disease in patients with and without diabetes and even in those taking SGLT2 inhibitors [12–14]. Furthermore, tirzepatide has shown efficacy in reducing symptoms of obstructive sleep apnea [15] and has been given an indication for treatment of obstructive sleep apnea in its US label. Metabolic dysfunction-associated steatohepatitis (MASH) is an attractive target for the medications under development, and two investigational unimolecular agents incorporate glucagon receptor agonism; survodutide [16], a dual GLP- 1/GCG RA, and retatrutide [17], a triple GLP- 1/GIP/GCG RA. Both are exploring the effects of targeting the GCGR for its impact on liver complications of obesity. The US FDA label indications for these molecules are shown in Table 2.

Table 2.

GLP- 1 RA medications and their indications by US food and drug administration

Type 2 Diabetes	Exenatide, once weekly injection Liraglutide, once daily injection Lixisenatide, once daily injection Albiglutide, once weekly injection Dulaglutide, once weekly injection Semaglutide, once weekly injection Semaglutide, once daily oral Tirzepatide, once weekly injection
Chronic weight management in adults	Liraglutide, once daily injection Semaglutide, once weekly injection Tirzepatide once weekly injection
Chronic weight management in adolescents	Liraglutide, once daily injection Semaglutide, once weekly injection
Cardiovascular disease (CVD) risk reduction in persons with obesity and overweight with established CVD	Semaglutide, once weekly injection
Obstructive Sleep Apnea in persons with overweight and obesity	Tirzepatide, once weekly injection

Safety and tolerability

The safety of semaglutide and tirzepatide is well-established. Like all drugs in this class, they carry a boxed warning on the US label that they should not be used in persons with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 because of a signal in rodents that these medications have a dose- and duration-dependent risk of thyroid C-cell tumors [18, 19]. Another concern for all drugs in the class is acute pancreatitis, which is fortunately rare [20]. Prior history of acute pancreatis does not seem to increase the risk for this complication [21]. Otherwise, the principle safety issues are gastrointestinal effects. Some of these are on-target, as native GLP- 1 slows gastric emptying. This can predispose to achalasia-like symptoms and worsening of GERD [18, 19]. There is an increased risk of gall bladder disease with semaglutide and tirzepatide, and rapid weight loss is a contributor to that complication [18, 19]. Nausea and vomiting and other gastrointestinal effects are the chief tolerability issues and the reason for discontinuation in ~ 4% of those in the phase 3 studies of semaglutide and tirzepatide. Hypersensitivity reactions can occur rarely [18, 19]. Otherwise, side effects are observed due to negative energy balance (hypoglycemia in individuals on insulin or insulin secretagogues) or vomiting and hypovolemia (acute kidney injury), or to weight loss (hair loss) are observed. [18, 19]

To summarize, the side effect profiles of semaglutide and tirzepatide are well known. Most individuals can tolerate them and gain their benefits, except for the few individuals who drop the medication for gastrointestinal side effects (~ 4%) or those who don’t achieve adequate therapeutic benefit (10%− 23% do not achieve 10% weight loss for tirzepatide and semaglutide, respectively).

Need for long-term therapy

Obesity is a chronic disease. The evidence would suggest that to sustain weight loss, these medications must be taken indefinitely. In the STEP 1 Trial Extension [22], of the original 1961 participants, 327 were observed off drug for 52 additional weeks. The mean weight loss had been − 17.3% (SD: 9.3%) with semaglutide and 2.0% (SD: 6.1%) with placebo over the initial 68 weeks. Following treatment withdrawal, semaglutide and placebo participants regained and by week 120, the net losses were − 5.6% (SD: 8.9%) and − 0.1% (SD: 5.8%), respectively. Improvements in cardiometabolic risk facts that occurred from week 0 to week 68 with semaglutide reverted towards baseline at week 120. The importance of long-term continuous use is amplified by STEP 4 [23] with semaglutide and SURMOUNT 4 [24] with tirzepatide. In these studies, after 20 weeks treatment with semaglutide or 36 weeks with tirzepatide, participants are randomized to continue drug or to placebo. For both semaglutide and tirzepatide, continuing the drug was associated with additional weight loss and stopping was associated with weight regain and recidivism of health benefits. The message is clear. For these medications to be effective in this chronic disease, they must be taken.

Body composition effects of semaglutide and tirzepatide

Long term use of semaglutide, tirzepatide and other potent medications in development, that produce robust weight loss, highlights the importance of the impact of weight loss on body composition, especially in older individuals. After all, the goal of weight loss is not just reduction in body size; it’s the optimization of body composition and tissue function [25]. When weight is lost and body size is reduced, there is an inevitable reduction in both lean and fat tissues. The proportion of lean mass loss to fat mass loss has generally been recommended that 25% of the lost weight should be fat free mass – the “Quarter FFM Rule.” [26] Before the advent of these newer medications, excessive loss of fat free mass, and particularly muscle mass, has not been a clinical issue. This is due in part to the unavailability of non-surgical approaches to weight management being able to achieve robust weight loss. The most efficacious weight loss tool, bariatric surgery, was employed in individuals who have BMI ≥ 40 kg/m² or in some cases, ≥ 35 kg/m² who were carefully selected and monitored post-operatively. With weight losses exceeding 20% or even 30% in a significant number of individuals, the impact of this amount of weight loss becomes important in terms of body composition effects in individuals who are smaller (BMI < 35 kg/m²) or older. Population studies document that mean weight increases through age ~ 60 years and decreases thereafter [27]. The plateau and decline that is seen in those age 60 or more represents a decline in muscle mass with age [27, 28]. Even in older persons with stable weight, muscle is replaced by fat over time [27, 28]. As these medications are used more often in older individuals for their disease modifying properties, excess lean loss becomes a concern. Of course, the reason for the concern with excessive lean mass loss and especially muscle mass loss in older individuals is the risk of increasing frailty, falls and frailty fractures. This adverse outcome was demonstrated in the Look AHEAD study. This study enrolled more than 5000 individuals with type 2 diabetes and randomly assigned them to a control condition or an Intensive lifestyle Intervention (ILI). This cardiovascular outcome trial did not demonstrate reduction in cardiovascular events [29], but it did demonstrate many benefits, including improvement in risk factors, reduction in need for medication, reduction in medical costs, improvement in quality of life and function of the participants in the ILI [30]. The mean age of Look AHEAD participants was 59 at study start and 69 at study end, allowing for an interesting analysis of moderate weight loss and subsequent regain in the ILI group and comparison to the control condition. Body composition was studied in a subgroup at baseline, year 4 and year 8 [31]. The study shows the expected decline in lean mass in the control condition and relatively stable fat mass. The ILI group lost fat (− 5.6 ± 0.2 kg) and lean mass (− 2.3 ± 0.1 kg) in the first year, but regained fat (∼100%) and lost lean mass between years 1 and 8. Overall, the ILI group had more weight loss at year 8 versus control group (− 4.0 ± 0.4 vs. − 2.3 ± 0.4 kg). The control group had mean lean mass loss of − 2.1 ± 0.17 kg at year 8. The initial loss of lean mass in the ILI condition is of concern because the weight regain in that group brought no increase in lean mass [31]. Look AHEAD also analyzed frailty fractures, defined as first occurrence of a composite occurrence of a hip, pelvis, upper arm or shoulder fracture, and adjudicated with radiography and hospital records in the population [32]. There were 731 participants with frailty fractures in Look AHEAD (358 in control v. 373 in ILI). There were no statistically significant differences in incident total or hip fracture rates between the ILI and DSE groups. However, compared to the DSE group, the ILI group had a statistically significant 39% increased risk of a frailty fracture (HR = 1.39, 95% CI 1.02, 1.89). [32]

The effect of semaglutide and tirzepatide on body composition has not been extensively studied. Table 3 shows the effect of these drugs on DEXA outcomes that were part of the phase 3 substudies in persons with obesity (STEP 1^1,34 and SURMOUNT 1^4.34) as well as a substudy of semaglutide in persons with diabetes as part of SUSTAIN- 8 [33, 34]. Of interest is that the proportion of lean loss with semaglutide was greater than that of tirzepatide, despite tirzepatide producing greater overall weight loss. Of the total weight loss with semaglutide approximately 45% was lean mass and for tirzepatide it was 25.7%. To date, there have been no studies evaluating bone and muscle mass with semaglutide and tirzepatide use, but rather, DEXA scans have been used to report two compartments – lean mass and fat mass. More studies are needed with greater definition of effects on muscle and bone.

Table 3.

Body Composition changes with semaglutide and tirzepatide

Study	Study Population	Time points of measurements	Change in Body Weight kg(%) on drug	Change in Lean Mass kg (%) on drug	Proportion of lost weight as lean mass (%)
STEP 1 substudy1,34 Semaglutide vs Placebo	N = 140 (95 semaglutide, 45 placebo) individuals with overweight or obesity Age 46 ± 13 y	Baseline and week 68	− 15.3 kg (− 14.9%)	− 6.92 kg (− 13.9%)	45.2%
SUSTAIN substudy35 Semaglutide vs Canagliflozin	N = 114 (53 semaglutide, 61 canagliflozin) with type 2 Diabetes Age 57.8 ± 9.9	Baseline and week 52	− 5.3 kg (− 6.0%)	− 2.3 kg (− 4.5%)	43.4%
SURMOUNT 1 Substudy4 Tirzepatide Vs Placebo	N = 160 (allocation to semaglutide or placebo unreported	Baseline and week 72	− 22.1 kg (21.9%)	5.67 kg (10.9%)	25.7%

The mechanism by which tirzepatide might be associated with less lean loss is unknown. A plausible hypothesis is that GLP- 1 agonism might preferentially promote fat oxidation at the expense of carbohydrate and protein. Ravussin et al. [36] reported a decrease in the respiratory quotient (RQ) measured in a metabolic chamber for individuals taking tirzepatide or placebo for 18 weeks. The RQ is defined as the ratio of the volume of carbon dioxide (CO2) produced to the volume of oxygen (O2) consumed during respiration. When carbohydrates are the fuel source, the RQ is 1.0. When more fat is being oxidized, more O2 consumed that CO2 produced and the RQ falls. There was significant reduction in 24-h RQ and sleeping RQ compared to placebo; thus, indicating significantly increased fat oxidation while decreased carbohydrate and protein oxidation rates.

Of additional concern is the report from the SELECT trial of an increase in fractures in this study associated with semaglutide [35]. Overall, there was no imbalance in fractures identified in the study. However, among women and those  age >75, there were increased numerical imbalances. For females, there were more hip fractures with semaglutide (0.3% vs. 0%). For those over age 75, there were more hip fractures (1.3% vs. 0.15%) with semaglutide vs. placebo, respectively. For pelvic fractures the rates were higher in women (0.3% vs. 0.04%) and in those ≥ 75 years (0.4% vs. 0) in the semaglutide and placebo groups, respectively). These results are inconclusive, and additional data must be generated to confirm this association, and in particular, a potential association with frailty fractures. However, given the body composition changes shown in Table 3, this is a concern.

Medications that might preserve muscle mass during weight loss

Approaches targeting the Nutrient Stimulating Hormones (NuSHs)

One of the directions that is occurring in the drug development pipeline is to add the ability to reach additional targets and to consider the GLP- 1 receptor agonist the “backbone.” [37] This term refers to using the GLP- 1 R target to carry weight loss and disease modifying benefits but to add, either in single molecule or in multiple dosing, the ability to target additional NuSH receptors to gain additional benefits. As evidenced above, it appears that tirzepatide, a peptide molecule that targets two receptors (GLP- 1 and GIP) may produce greater weight loss while producing less lean loss than GLP- 1 agonism alone, potentially by promoting fat oxidation [36]. GIP also stimulates bone formation and inhibits bone resorption [38], but we don’t have any clinical evidence to date of an effect on bone preservation with a GLP- 1/GIP dual agonist for weight loss. The potential for bone and muscle sparing aspects of GlP- 1/GIP dual agonism needs to be explored. There will be ample opportunity for this as more combinations are developed. Indeed, MariTide has entered phase 3 (https://www.amgen.com/newsroom/press-releases/2024/11/amgen-announces-robust-weight-loss-with-maritide-in-people-living-with-obesity-or-overweight-at-52-weeks-in-a-phase-2-study). This is a combination monoclonal antibody targeting GIP and the peptide targeting the GLP- 1 receptor. The efficacy seemingly produced by both the antagonism of GIP (MariTide) and its agonism (tirzepatide) is a question that is unresolved.

Additional agents targeting receptors for the Nutrient Stimulated Hormones (NuSHs) are being developed. Glucagon is secreted from pancreatic α-cells and through activation of the glucagon receptor (GCGR), stimulates glycogenolysis and lipolysis. Glucagon has also been shown to increase energy expenditure in animal studies. Because there are glucagon receptors in the liver, MASH is a specific focus for agents targeting glucagon. Survodutide is in phase 3 study; it is a GLP- 1/Glucagon single molecule dual agonist [39]. Further, a triple agonist molecule targeting GLP- 1/GIP/Glucagon, retatrutide, is also in phase 3 [40]. This drug appears to produce the greatest mean weight loss to date [40], but there is no body composition data yet published. The body composition substudies that are part of the phase 3 studies of survodutide and retatrutide will be viewed with great interest. It is unknown whether glucagon will increase energy expenditure in humans and potentially spare lean mass, but this effect could influence body composition, in addition to a GIP effect for retatrutide.

Another NuSH of great interest is amylin. Amylin is a peptide co-secreted with insulin by the pancreatic β-cells. Amylin inhibits glucagon secretion, delays gastric emptying, and enhances satiety. Pramlintide, an analog of amylin, was approved by the FDA for diabetes treatment in 2005 and is given by injection three times daily with meals. In a study of weight loss efficacy in patients with obesity, pramlintide 360 μg bid produced 7.2 ± 2.3 kg (6.8 ± 2.3% body wt. The development of long-acting amylin analogs has been intense with focus on both dual amylin and calcitonin receptor agonists (DACRA) or the selective amyln receptor agonists(SARA). Cagrilintide is a long-acting DACRA and it is phase 3 study in a combination called CagriSema, a combination of semaglutide and cagrilintide [39]. There are other long-acting DACRA and SARA molecules in the pipeline, including eloralintide (https://trials.lilly.com/en-US/trial/533180), petrelintide (https://www.zealandpharma.com/media/vrypyzy1/zealand-pharma-at-obesity-week-2024.pdf), GUB014295 (https://news.abbvie.com/2025-03-03-AbbVie-and-Gubra-Announce-License-Agreement-to-Develop-an-Amylin-Analog-for-the-Treatment-of-Obesity) and AZD6234 (https://www.astrazenecaclinicaltrials.com/study/D8750C00004/). These molecules are being studied as potential stand-alone molecules or in use with the GLP- 1 RA “backbone”. As a stand-alone, they are a potential replacement of the GLP- 1 “backbone”. The body composition effects of the amylin analogs in humans are unknown but there is animal evidence that they spare lean mass. [41]

It's important that going forward, we recognize and explore the pleiotropic effects of the Nutrient Stimulated Hormones and recognize the complexity of body weight and body composition regulation. There are receptors for these hormones distributed across many tissues and their effects are thus pleiotropic. While GLP- 1 RAs were initially exploited for their effects on insulin sensitivity and glucagon secretion, the Nutrient Stimulated Hormones being targeted have effects on muscle protein synthesis and even energy expensiture [42–44]. The effects of these drugs on body weight regulation may be manifest through targets beyond appetite. [25]

Approaches targeting the myostatin-activin pathway inhibitors (MAPi)

Other novel mechanisms under active investigation include directly targeting the activin receptor or its ligands, including myostatin and activin, which may improve body composition and potentially health outcomes. There are several myostatin-activin pathway inhibitors (MAPi) being evaluated for obesity in phase 2, either alone or in combination with a NuSH-based therapy, including bimagrumab (NCT05616013), trevogrumab, garetosmab (NCT06299098), and SRK- 439 (NCT06445075 – proof of concept with apitegromab). Taldefgrobep alfa is not in phase 2 but is being studied for spinal muscular atrophy (NCT05337553) and is in earlier phase for obesity (https://ir.biohaven.com/news-releases/news-release-details/biohaven-provides-update-taldefgrobep-alfa-development-program). These medications were initially developed for use in muscle disease and in muscle wasting conditions. Apitegromab is the first of this class to seek FDA approval in spinal muscular atrophy (https://www.nature.com/articles/d41573-025–00029-7.epdf?no_publisher_access=1&r3_referer=nature). The focus has shifted to their use in obesity, both alone an in combination with the “backbone” GLP- 1 RA (https://www.nature.com/articles/d41573-025–00029-7.epdf?no_publisher_access=1&r3_referer=nature). The companies developing the medications for this indication are also interested in their use to sustain weight loss after stopping the GLP- 1 RA (https://www.nature.com/articles/d41573-025–00029-7.epdf?no_publisher_access=1&r3_referer=nature).

The medications targeting the myostatin-activin pathway act in different ways. Bimagrumab binds and blocks the activin type II receptor rather than the myostatin ligand. This blocks signaling by Activin A and other TGF-β family members. Trevogrumab is a monoclonal antibody to myostatin. Garetosmab is a human antibody specific to Activin A. Apitogromab is a human monoclonal antibody which inhibits myostatin activation by selectively binding to its proforms (promyostatin and latent myostatin). SRK 439 is a monoclonal antibody which selectively binding to pro- and latent myostatin molecules. Taldefgrobep alfa is an Adnectin™ protein which binds myostatin and antagonizes the Activin 2b receptor. Adnectins™ are a new family of manufactured proteins derived from human fibronectin that are smaller than monoclonal antibodies [45]. It is unknown whether any of these approaches are superior.

The most advanced in development for obesity of the MAPi medications is bimagrumab, a monoclonal antibody that inhibits activin receptor type IIB and has been shown to reduce fat mass while preserving or increasing lean mass^. [46] In a 48-week study, adults with type 2 diabetes, body mass index between 28 and 40 kg/m², and glycated hemoglobin (HbA_1c) levels between 6.5% and 10.0%, 77 were enrolled (n = 77). The intervention consisted of diet and exercise counseling and randomization to intravenous infusion of bimagrumab (10 mg/kg up to 1200 mg in 5% dextrose solution) or placebo (5% dextrose solution) treatment every 4 weeks for 48 weeks; both groups received diet and exercise counseling. The results are displayed in Fig. 1. For those receiving bimagrumab, there were significant decreases in fat mass (− 20.5%) compared to placebo (− 0.5%) and increase in lean mass (+ 3.6%) compared to placebo (− 0.8%). Furthermore, there was improvement in A1c favoring bimagrumab (− 0.76% reduction) vs. placebo (− 0.04% reduction). Bimagrumab is being studied in combination with semaglutide in adults with overweight and obesity (NCT05616013), but results are not yet published.

Fig. 1.

Phase 2 Study of Bimagrumab in Individuals with Obesity and Type 2 Diabetes [44]. In this 48-week study, adults with type 2 diabetes, body mass index between 28 and 40, and glycated hemoglobin (HbA_1c) levels between 6.5% and 10.0% were randomly assigned to placebo or control at 9 US and UK sites. At 49 weeks, those assigned to bimagrumab had lost − 20.5% fat mass, gained + 3.6% lean mass and reduced HbA1c by 0.76 percentage points (P < 0.001 compared to placebo for all)

Selective androgen receptor modulators

Selective androgen receptor modulators (SARM) are designed to selectively target androgen receptors in specific tissues such as muscle or bone. There are no FDA approved SARMs. However, these compounds are used recreationally [47]. Enobosarm is one molecule that is being studied in obesity (NCT06282458). There is some evidence supporting enobosarm’s efficacy for lean mass preservation in elderly men and women [48]. Recently, top-line results were released of a study in 168 older individual with overweight and obesity who received semaglutide and either 3 mg or 6 mg enobosarm or placebo daily for 16 weeks (https://ir.verupharma.com/news-events/press-releases/detail/225/veru-announces-positive-topline-data-from-phase-2b-quality). The average weight loss (kg) was − 4.7 ± 4.24 for placebo and − 4.4 ± 3.9 for pooled enobosarm doses. There were striking differences in body composition. Mean percentage lean mass loss for placebo was − 4.1 ± 4.8%. while it was − 1.2 + 5.15% for enobosarm. Percentage mean fat loss was − 8.6 ± 6.26% for placebo and − 10.9 ± 8.07%, and not statistically significant. Of the lost weight, it was 31.9% lean with placebo and 9.4% lean for enobosarm. A measure of functional capacity, losing 10% Stair Climb Power, was experienced by 42.6% of the placebo group and only 19.4% of the enobosarm group. Taken together, the results show lessened loss of lean mass and Stair Climb Power when enobosarm is used with semaglutide (https://ir.verupharma.com/news-events/press-releases/detail/225/veru-announces-positive-topline-data-from-phase-2b-quality).

Conclusion and future directions

The development of medications that can produce and sustain weight loss is a dramatic event in modern medicine, but not just because of the weight loss associated with these drugs. The disease modifying properties achieved through both weight loss and the drugs themselves signal a new era in chronic disease management. They promise a change in our approach to chronic disease management, from treat until failure toward treat to remission. But with these medications comes the imperative that we manage the unforeseen consequences of weight loss. Excessive loss of lean mass is an important issue, especially in an older population, and must be in the forefront of approaches to develop better drugs for chronic weight management and chronic disease management. This may come in the form of using combinations of NuSHs that have more favorable effects on body composition or using combinations of NuSH-based medications with MAPi-based medications. Another potential option would be to replace the GLP- 1 RA as the “backbone” with another agent. Expect to see more studies looking at bone and muscle effects, both in terms of mass and function. While it is early days, the opportunity seems large and by following the science we should achieve the goal of weight management, which is to optimize body composition and organ function. The answer to the question, “Do we need drugs to preserve muscle mass during weight loss?” is a resounding “Yes, especially for an aging population!”.

Author contribution

Donna H. Ryan conceived and wrote the manuscript, and prepared tables and figures. She responded to reviewer comments and revised the manuscript.

Funding

D.H.R. received no funding to produce this manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

D.H.R has received personal remuneration from services as a scientific advisor to Abbvie, Altimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Biohaven, Calibrate, Carmot/Roche, CINRx, Currax, Epitomee, Fractyl, Gila, Lilly, Nestle, Novo Nordisk, Pfizer, Regeneron, Scientific Intake, Source Bio, Structure Therapeutics, Wondr Health, and Zealand, She serves on Speaker’s Bureau for Novo Nordisk and Lilly. She accepted stock options from Epitomee, Calibrate, Roman, Scientific Intake, and Xeno Bioscience. She is remunerated for Data Monitoring Committee service from IQVIA (Rhythm), Lilly and CinRx.