Tirzepatide‐induced body composition changes: Implications from the SURPASS ‐3 MRI substudy

Tirzepatide is a once-weekly glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that is currently approved for the treatment of type 2 diabetes, weight management, and obstructive sleep apnea. The “Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes (SURPASS-3)” trial enrolled individuals with type 2 diabetes who were inadequately controlled on metformin with or without a sodium-glucose cotransporter 2 inhibitor and randomized them to tirzepatide or insulin degludec. This magnetic resonance imaging (MRI) substudy1 specifically aimed to examine how weight loss induced by tirzepatide affects skeletal muscle composition, focusing on total muscle volume, muscle volume Z score relative to population norms, and muscle fat infiltration. The investigators further compared the tirzepatide group not only to insulin degludec but also to population-based estimates from the United Kingdom (UK) Biobank in order to adjust for similar degrees of weight loss. The results showed that muscle volume and muscle volume Z score did decrease after tirzepatide treatment compared with insulin degludec; however, when compared with population-based estimates, the degree of reduction was essentially the same for a given amount of weight loss. In the tirzepatide 15 mg group, there was a statistically significant decrease in Z score, but overall, the magnitude of change in muscle volume was not meaningfully different. This indicates that the muscle loss observed with tirzepatide-induced weight reduction is similar to what occurs with weight loss in the general population. In contrast, muscle fat infiltration decreased significantly after tirzepatide use compared with population estimates, suggesting an improvement in muscle composition in addition to the effect of weight loss. A unique methodological feature of this study is the use of the UK Biobank dataset as a reference population to generate population-based estimates of body composition changes. Instead of restricting the analysis to individuals who lost weight, the investigators included all 2,942 participants in the regression models—those with stable weight, weight loss, and weight gain—to build a comprehensive model capturing the natural relationship between body weight change and muscle composition over time. Notably, muscle fat infiltration is expected to increase over time due to aging and the natural course of body composition change1. However, in the observed SURPASS-3 MRI data1, muscle fat infiltration showed a clear decrease with tirzepatide, indicating that the drug not only counteracted the natural age-related increase in muscle fat infiltration but also led to additional reduction. This finding suggests that the improvement in muscle fat infiltration represents a unique effect of tirzepatide, warranting further investigation into its underlying mechanisms. Tirzepatide is a dual GLP-1 and GIP receptor agonist, but unlike GIP receptors (GIPR), GLP-1 receptors are not expressed in adipose tissue2. This means that the direct effects on adipose tissue are primarily mediated through GIPR signaling, which is implicated in several preclinical studies. Whole-body overexpression of GIP in GIP-transgenic heterozygous mice resulted in lower body weight gain compared with wild-type littermates when fed a high-fat diet, along with greater insulin sensitivity and a lower overall fat percentage and adiposity index3. These findings highlight the metabolic role of GIP in regulating adipose tissue biology. Consistent with this preclinical data, clinical evidence suggests that tirzepatide, through GIPR activation in adipose tissue, may promote lipid clearance and partitioning, reduce ectopic fat accumulation, and improve overall metabolic flexibility2. Although tirzepatide-induced weight loss is accompanied by a reduction in lean mass, the magnitude of this loss is similar to that observed in the general population in the SURPASS-3 MRI substudy. However, any decline in muscle mass has the potential to negatively affect muscle strength and functional capacity. At the same time, this substudy also reported that tirzepatide leads to a reduction in intramuscular fat. Previous studies have shown that increased intramuscular fat is associated with reduced muscle contractility, lower strength, and structural alterations such as changes in fiber orientation and pennation angle4. Fat surrounding blood vessels can impair oxygen and nutrient delivery, further compromising muscle function. Intramuscular fat is mechanically stiffer than muscle tissue, increasing connective tissue stiffness and reducing muscle quality. In addition to these structural effects, muscle fat infiltration contributes to insulin resistance through enhanced lipolytic activity, elevated local fatty acid concentrations, and pro-inflammatory signaling4. Therefore, improving intramuscular fat infiltration may enhance muscle function and strength. Since these two opposing effects—loss of muscle mass and reduction of intramuscular fat—occur simultaneously, the net impact on muscle strength remains uncertain. More research is needed to clarify how tirzepatide ultimately influences muscle function. Bimagrumab, an activin type II receptor (ActRII) inhibitor, is currently under active clinical development as a potential therapy that can reduce fat mass while preserving or increasing lean mass. In a phase 2 randomized clinical trial5, ActRII blockade with bimagrumab led to significant reductions in fat mass, gains in lean mass, and improvements in metabolic parameters over 48 weeks in individuals with overweight or obesity and type 2 diabetes. These findings highlight the therapeutic potential of ActRII inhibition as a novel pharmacologic strategy to address excess adiposity and its metabolic consequences. A phase 2 trial registered on ClinicalTrials.gov, titled “A Study to Investigate Weight Management With Bimagrumab (LY3985863) and Tirzepatide (LY3298176), Alone or in Combination, in Adults With Obesity or Overweight,” aims to further evaluate whether combining bimagrumab with tirzepatide can enhance weight loss while minimizing lean mass reduction. If successful, this approach could provide an innovative weight management strategy that preserves or even increases muscle mass while reducing fat, potentially improving metabolic outcomes and physical function compared with existing weight-loss therapies. In conclusion, tirzepatide reduces body weight and intramuscular fat while causing a lean mass loss comparable to that seen in the general population. The SURPASS-3 MRI substudy highlights tirzepatide's unique ability to lower intramuscular fat despite expected age-related increases, suggesting potential functional benefits. However, the simultaneous reduction in muscle mass raises uncertainty about its net effect on strength and performance. Bimagrumab, an ActRII inhibitor, has shown the ability to decrease fat mass while preserving or increasing lean mass. Combining tirzepatide with bimagrumab may offer a strategy to enhance weight loss without sacrificing muscle, potentially improving both metabolic outcomes and physical function (Figure 1). Hung-Yuan Li is an Editorial Board member of the Journal of Diabetes Investigation and a co-author of this article. To minimize bias, he was excluded from all editorial decision-making related to the acceptance of this article for publication. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.