Optimizing Body Composition Changes in the Era of Incretin-Based Weight Loss Therapies

Beyond the Number on the Scale: Why Body Composition Quality Matters

This enduring activity is adapted from the individual talks presented at the live ADA 2026 symposium in New Orleans; the full recorded session, synced to the original slides, is available at the end of this article for those who wish to watch it in full.

Incretin-based therapies—GLP-1 receptor agonists and dual GLP-1/GIP agonists—have changed what is achievable in obesity management, producing weight reductions of 15% to 25% along with meaningful improvements in glycemic control, blood pressure, lipid profiles, and cardiovascular risk.^1–5 As these agents move into broader use across populations with obesity, type 2 diabetes, heart failure, and metabolic liver disease, clinical attention is shifting from how much weight is lost to the quality of tissue lost.^6,7

This shift matters because weight loss, regardless of method, reduces both fat mass and lean tissue.^6,8 Data from incretin trials and their body-composition substudies suggest that roughly 20% to 40% of total weight lost may come from lean mass, depending on the agent, population, and measurement method used.^8,9 Skeletal muscle is not a cosmetic concern—it drives the majority of post-meal insulin-stimulated glucose uptake and contributes substantially to resting energy expenditure.¹⁰ Patients with obesity often start with greater absolute muscle mass than lean individuals, yet many still show reduced muscle quality, more intramuscular fat (myosteatosis), and lower strength relative to body weight ^5,11—patterns especially common among older adults, women, and people with type 2 diabetes or metabolic dysfunction-associated steatotic liver disease.^12,13 Without deliberate attention to muscle preservation, rapid pharmacologic weight loss in these groups may accelerate sarcopenic trajectories.^13,14

Why Words Matter: Getting Body Composition Terminology Right

A recurring source of confusion in clinical conversations about anti-obesity therapy is imprecise language. Terms such as “lean mass,” “fat-free mass” (FFM), “skeletal muscle mass,” and “appendicular lean soft tissue” are frequently used as if they were interchangeable proxies for muscle loss, which is inaccurate.^15,16 Each describes a related but distinct construct, and mixing them is a primary driver of misinterpretation in both research and clinical practice. The infographic below lays out how these three constructs relate to one another and to the shared clinical goal of tracking true muscle loss.

Infographic 1. Body composition terms in obesity research: related, but not synonymous.

As the infographic shows, each construct captures a different slice of the body composition picture, all converging on the same underlying clinical question.

“Fat-free mass” (synonymous with “lean mass”) is a whole-body, non-fat compartment that includes muscle along with organs, water, bone, and other tissues—it is not a direct measure of skeletal muscle alone. “Skeletal muscle mass” refers specifically to the muscle compartment and comes closest to the actual concept of muscle loss. “Appendicular lean soft tissue” is the lean soft tissue in the limbs, frequently used as a practical proxy for appendicular muscle mass because it excludes fat and bone, though it remains an indirect measurement. Notably, many bioelectrical impedance analysis (BIA) devices report an output labeled “skeletal muscle,” but this figure is typically estimated from FFM-based equations rather than measured from direct tissue imaging.

Why does this matter at the bedside? Because mislabeling a reduction in lean mass as “muscle loss” can alarm patients unnecessarily, distort how a clinician counsels a patient on therapy, and obscure whether a true clinical problem exists. Standardized terminology gives clinicians and patients a shared vocabulary for the same underlying goal: losing fat while protecting strength, function, and quality of life.

The Assessment Gap: Why DXA and MRI Tell Different Stories

One of the more conceptually challenging aspects of interpreting body-composition data during incretin-based treatment is understanding why dual-energy X-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) can reach different—and sometimes seemingly contradictory—conclusions about the same patient's muscle and fat. The difficulty is not that one tool is better than the other; it is that the two are not measuring the same thing. DXA and MRI are built on two fundamentally different models of what body composition even is, which is why results do not always align—and why understanding the distinction matters clinically.

Infographic 2. DXA vs. MRI: why results may differ.

As the infographic illustrates, DXA partitions the body at the molecular level: total body weight is divided into water, protein, lipid, and other constituents. Skeletal muscle is never directly isolated in this model—it is embedded within the “water” and “protein” fractions alongside contributions from organs and connective tissue.^15,16,17 MRI and computed tomography (CT), by contrast, partition the body at the tissue/organ level, directly distinguishing skeletal muscle, adipose tissue, bone, blood, and other tissue types as anatomically distinct compartments. ^16,18

This modeling difference has a specific, quantifiable consequence: approximately 15% of adipose tissue is itself composed of water.^19,20 Because DXA's molecular model classifies all body water as fat-free mass (or lean soft tissue), a meaningful fraction of what is physically fat tissue gets counted toward DXA's “lean” compartment. This is not a flaw unique to one device or vendor—it is a structural feature of how the molecular model works, and it helps explain why DXA-based lean mass estimates do not move concordantly with MRI-based skeletal muscle measurements, particularly when fat mass itself is changing rapidly, as it does during incretin-based weight loss.

The clinical takeaway is not that one tool is universally “better,” but that the two methods answer different questions, and results from one cannot be substituted for the other without context. A patient whose DXA suggests significant lean-mass decline may have largely preserved skeletal muscle on MRI—or the reverse may be true. Without routine MRI access, the most reliable path is to interpret whichever imaging tool is available alongside functional measures: handgrip strength, chair-stand performance, and gait speed, since functional decline can precede measurable changes in muscle mass on any imaging modality.²¹ A patient-centered approach means explaining clearly what a given test can and cannot show, rather than reacting to an isolated number, and anchoring the conversation in outcomes that matter most: strength, mobility, and independence. 

Emerging Strategies to Preserve and Build Muscle

Recognition that weight loss quality matters has accelerated interest in approaches that protect skeletal muscle during pharmacologic treatment.²² Established strategies—resistance exercise and adequate protein intake—remain foundational and should anchor every weight-management plan.²³ Beyond lifestyle measures, a genuinely diverse pipeline of investigational therapies targeting obesity-related muscle loss is now emerging, each working through a distinct mechanism and at a different stage of development.

Infographic 3. Emerging and investigational therapies targeting obesity-related muscle loss.

Among these, three classes have advanced furthest into clinical testing. Myostatin inhibitors block myostatin, a natural suppressor of muscle growth, and in early trials have increased lean mass and strength while also reducing fat mass. A related but mechanistically distinct approach, activin receptor ligand traps, blocks both Activin A and myostatin signaling at the receptor level and has shown gains in lean mass and physical performance. Selective androgen receptor modulators (SARMs) work differently still, stimulating muscle protein synthesis directly through the androgen receptor to increase muscle mass and function, with the appeal of fewer androgenic side effects than traditional anabolic steroids.^22,24 All three of these classes are currently in Phase II/III testing. Earlier in development, anabolic/catabolic transforming agents and gene- or RNA-based therapies (including approaches that modulate myostatin expression itself) remain in preclinical or early Phase I/II stages but represent additional, mechanistically distinct avenues for future muscle-directed treatment.

Across all five classes, effects on strength, physical function, and long-term safety vary, and lean-mass gains on imaging do not automatically translate into improved strength or mobility.²⁵ These strategies represent a genuinely emerging frontier—particularly the prospect of eventually pairing them with incretin-based therapy—while clinicians await confirmatory evidence before integrating any of them broadly into practice.²² Notably, even many of the newer trials designed to limit muscle loss or build muscle still rely on DXA rather than MRI for their primary body-composition outcome, a limitation that may itself affect how accurately skeletal muscle change is being captured in this evidence base.^18,26

What Clinicians Can Do Now

Translating these concepts into daily practice does not require waiting for new drugs or routine MRI access:

• Reframe success. Evaluate response by the balance of fat loss and muscle preservation, not by kilograms or BMI alone, since BMI cannot distinguish fat mass from lean mass.
• Use precise, tool-appropriate language. Avoid presenting “lean mass” changes as equivalent to “muscle loss,” and explain clearly what an available assessment tool can and cannot show.
• Pair imaging with function. Whatever tool is accessible—DXA, BIA, or MRI where available—interpret it alongside handgrip strength, chair-stand tests, or gait speed, since functional decline can precede measurable mass loss.
• Identify higher-risk patients proactively. Older adults, those with low baseline muscle reserve, and those with frailty risk warrant closer monitoring during incretin-based treatment, alongside continued reinforcement of resistance training and protein intake.
• Stay alert to the evolving pipeline. Emerging muscle-directed agents may eventually complement incretin therapies, but should be discussed with patients as investigational for now.

Conclusion

The rapid expansion of incretin-based therapy has shifted the central question in obesity care from “how much weight was lost” to “what kind of weight was lost, and at what cost to muscle and function.” Durable, physiologically healthy weight loss requires precise terminology, thoughtful interpretation of assessment tools—particularly what DXA and MRI can and cannot each tell a clinician—and functional measures alongside imaging. As muscle-directed therapies mature, clinicians who understand these distinctions today will be best positioned to individualize care and protect patients’ long-term strength, mobility, and quality of life.

Watch the Full Session

This article is based on individual talks from the live ADA 2026 symposium. The full 90-minute recording (audio synced to the original slides) is available here [recording link], or jump to a specific talk below:

• Donna Ryan — Body Composition in Weight Loss: What Happens to Muscle and Fat During Incretin-Based Therapy? (12:55–32:48)
• Carla Prado — Foundational Concepts: Defining Body Composition Terms in Clinical and Research Contexts (33:00–46:50)
• Lars Johansson — Modern Body Composition Assessment: What Clinicians Need to Know About Imaging and Measurement Tools (47:13–1:01:13)
• Stefan Anker — Preserving and Building Muscle: Emerging Pharmacologic Approaches (1:01:35–1:16:54)
• Panel Discussion — The Present and Future of Optimizing Body Composition (1:20:45–1:31:12)
• Patient Voice — Reynolda Duret (9:43–12:55)

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