New SURPASS-3 Data Links Tirzepatide to Muscle Composition Changes in Type 2 Diabetes
In an increasingly dynamic and rapidly evolving field of metabolic disease management, the nuanced effects of weight loss therapies on body composition are gaining heightened scientific and clinical attention. A new post-hoc analysis, conducted through a collaborative effort between AMRA Medical, the University of Glasgow, University Hospitals Cleveland, and Eli Lilly and Company, is helping to answer key questions about how one of the most promising drugs in this space—tirzepatide—affects muscle and fat tissue composition in people living with type 2 diabetes (T2D).
The study builds on the foundation laid by Lilly’s SURPASS-3 trial, a pivotal investigation into the safety and efficacy of tirzepatide, a dual GIP/GLP-1 receptor agonist that has garnered significant attention for its robust impact on glycemic control and weight reduction. In particular, the post-hoc analysis leverages data from the MRI substudy of SURPASS-3, a substudy that previously explored fat distribution using AMRA’s proprietary, MRI-based z-score biomarkers. The newest findings, now published, take a deeper dive into muscle-related changes by evaluating parameters such as thigh muscle volume, muscle volume z-score, and muscle fat infiltration (myosteatosis), which have not been extensively investigated in prior anti-obesity pharmacotherapy research.
From Fat to Function: Understanding the Significance of Muscle Composition in Weight Loss
Historically, body composition studies in the context of weight loss treatments have leaned heavily on dual-energy X-ray absorptiometry (DEXA), a technique that—while useful for broad assessments of fat mass and lean mass—lacks the resolution to precisely measure muscle quality or intramuscular fat infiltration. With anti-obesity medications, including tirzepatide, achieving weight reductions in the range of 15–20% or more, understanding whether such reductions come at the cost of muscle mass or quality is crucial. Excessive loss of skeletal muscle can have deleterious consequences, especially among older adults or individuals with mobility impairments, potentially leading to frailty, decreased metabolic rate, impaired glucose handling, and diminished functional capacity.
To address these concerns, the new post-hoc analysis utilized AMRA® Researcher, a proprietary software suite designed for precision MRI-based body composition analysis. The inclusion of more than 200 participants from the SURPASS-3 MRI substudy allowed for an in-depth, standardized evaluation of muscle tissue—offering key insights that go well beyond basic lean mass calculations.
Key Findings: Muscle Volume Trends and Fat Infiltration Reductions with Tirzepatide
One of the headline findings from the analysis is that while tirzepatide was associated with a reduction in overall muscle volume, these changes were proportional to overall body weight reductions. In other words, the decrease in muscle volume did not exceed what would be expected based on the amount of weight lost—suggesting that muscle loss was not disproportionate or maladaptive. This contrasts with the common concern that powerful weight-loss agents might selectively deplete lean tissue, compromising metabolic or functional health.
Even more compelling was the observation related to muscle fat infiltration. Participants treated with tirzepatide experienced more pronounced reductions in intramuscular fat content than would be predicted by weight loss alone. These findings hint at a potential positive remodeling effect within muscle tissue, whereby loss of ectopic fat may improve muscle efficiency, insulin sensitivity, and metabolic health.
Professor Naveed Sattar, a renowned expert in metabolic disease at the University of Glasgow and lead author on the publication, highlighted the importance of these findings. “The results of this study are important as many people remain concerned about the muscle effects of newer weight loss drugs,” he stated. “However, these new data suggest that the amount of muscle volume changes with tirzepatide appears to be in line with muscle volume changes seen in the population for similar differences in weight. More importantly, these data suggest a clear reduction in the amount of fat in muscles—changes that may in fact improve muscle efficiency.”
Z-Score Biomarkers: A Powerful Tool for Weight-Invariant Analysis
A distinctive feature of the AMRA methodology is its use of z-score biomarkers—standardized, population-referenced measures that allow researchers to assess fat and muscle tissue independently of body weight. This allows for a more nuanced understanding of whether observed changes are favorable or adverse, relative to normative expectations.
In the earlier SURPASS-3 MRI substudy, this technology was used to demonstrate that tirzepatide led to a favorable redistribution of fat—most notably, reductions in visceral adipose tissue and liver fat, both of which are strongly associated with cardiometabolic risk. Now, with this expanded analysis into skeletal muscle tissue, AMRA has demonstrated the versatility and utility of their z-score framework across a broader set of body composition metrics.
By quantifying changes in both absolute and relative terms, AMRA’s approach allows for greater clarity on whether observed tissue changes reflect adaptive physiological responses or potential adverse effects—providing a sophisticated lens through which to view treatment impact.
A First-of-Its-Kind Look at Incretin-Based Therapy and Muscle Tissue in T2D
This analysis is also notable for being the first published report to examine how incretin-based therapies like tirzepatide affect muscle composition using MRI, a gold-standard imaging modality. Previous research on GLP-1 receptor agonists has largely focused on weight loss, glucose control, and cardiovascular outcomes, with very limited attention paid to skeletal muscle quality or myosteatosis.
Given that individuals with T2D often experience sarcopenic obesity—a condition characterized by both excess fat and reduced muscle mass or quality—any pharmacologic treatment that can reduce fat while preserving or enhancing muscle function offers a highly valuable clinical proposition.
Moreover, the study underscores the importance of moving beyond simple weight or BMI endpoints in drug development and toward a more comprehensive understanding of body composition and tissue-specific changes.
Broader Implications for the Future of Metabolic Drug Development
As the metabolic disease landscape continues to evolve, the ability to meaningfully differentiate between treatments will depend not only on their capacity to drive weight loss or glycemic control but also on their downstream effects on organ and tissue health. AMRA Medical is positioning itself at the forefront of this transformation by providing high-resolution biomarker technologies that uncover therapeutic effects beneath the surface.
The implications of this latest research go well beyond tirzepatide itself. By demonstrating that advanced MRI techniques can deliver granular, reliable data on muscle and fat composition, AMRA is helping to lay the groundwork for more robust clinical trial endpoints in the future—ones that better reflect patient-centric outcomes like mobility, muscle function, and long-term metabolic health.
As more weight-loss and metabolic therapies enter the pipeline—from GLP-1 and GIP agonists to combination approaches and beyond—the need to understand how these agents affect not just body weight, but body quality, becomes increasingly pressing.
This post-hoc analysis of the SURPASS-3 MRI substudy, conducted by a global team of leading researchers in partnership with AMRA Medical and Eli Lilly, provides a compelling glimpse into the body composition dynamics of tirzepatide-treated individuals with type 2 diabetes. The data reveal that muscle volume changes are in line with expected patterns of weight loss, while reductions in muscle fat infiltration suggest potential improvements in muscle quality.
By leveraging state-of-the-art MRI and z-score biomarkers, this research offers a new standard for assessing the multidimensional impacts of metabolic therapies—one that captures not just how much weight is lost, but how the composition and function of the body are altered in meaningful, measurable ways.
As innovation in metabolic health continues at a rapid pace, AMRA’s work reaffirms the vital importance of deep phenotyping and precision body composition analysis in shaping the next generation of safe, effective, and differentiated treatments for people living with obesity, type 2 diabetes, and related conditions.
