By comparing the results with population-based estimates from the UK Biobank, the study revealed that the observed loss of intramuscular fat exceeded what would typically be expected from a similar weight loss. Meanwhile, reductions in overall muscle volume were consistent with expected physiological changes. These results could provide further insight into the use of weight management medications, particularly for individuals at risk of sarcopenia or for older people with chronic conditions. 

Favourable shift in muscle composition 

“The overall weight loss in SURPASS-3 came predominantly from fat – around two thirds – rather than muscle – around one third,” explains Naveed Sattar, cardiovascular researcher at the University of Glasgow, first author of the study and EASD member. “This is in accordance with most trials involving incretin-based weight loss medicines and suggests that the muscle-to-fat ratio actually improves with such therapies.” 

Sattar highlights: “One key finding of our study was a substantial reduction in the amount of fat within muscles with tirzepatide compared to predictions. Another important finding was that the reduction in muscle volume with tirzepatide was not significantly different to the amount of muscle mass change seen for an equivalent weight difference in the general population. This is reassuring and aligns with the idea that lighter people require less muscle mass to support their body weight.” 

MRI-based muscle composition analysis 

The study included 246 participants from the SURPASS-3 trial, recruited from 45 sites across the globe. All participants underwent MRI imaging at baseline and after 52 weeks of treatment. All participants were insulin-naïve and taking metformin, with 31% also receiving an SGLT2 inhibitor. 

Using gold-standard MRI imaging, the researchers quantified changes in thigh muscle volume, muscle fat infiltration and muscle volume Z-score, which is a measure of muscle volume deviation from the mean value among sex- and BMI-matched individuals. To contextualise these results, the authors compared them with estimates derived from longitudinal MRI data from nearly 3,000 UK Biobank participants. 

Significant reduction in muscle fat infiltration 

Across all doses of tirzepatide (5, 10, and 15 mg), the treatment led to statistically significant reductions in muscle fat infiltration (mean change –0.36 percentage points; see Figure 1A, left), muscle volume (–0.64 L; see Figure 1A, middle), and muscle volume Z-score (–0.22; see Figure 1A, right) over 52 weeks. Importantly, the reductions in muscle fat infiltration exceeded population-based expectations (mean difference –0.42 percentage points, p < 0.0001; see Figure 1B, left), whereas the changes in muscle volume remained within the expected range. In contrast, basal insulin degludec increased muscle volume modestly without altering fat infiltration. 

Potential for improved muscle function 

Reducing intramuscular fat – a key contributor to impaired muscle function – is a particularly noteworthy effect. “This could mean that muscle function is improved, as excess fat within muscles typically impairs normal function,” explains Sattar. These results are consistent with the reduction in liver fat observed in the same trial population, suggesting a broader impact of tirzepatide on ectopic fat deposits. “In other words, tirzepatide-induced weight loss helps to remove fat from places where it doesn’t belong,” Sattar continues. “It also fits with a reduction in blood triglycerides, which is the most pronounced lipid change observed with incretin-based weight loss therapies.” 

Is it weight loss alone or a pharmacological effect? 

“It is difficult to determine whether the improvements in muscle composition are due to weight loss alone, or whether tirzepatide has direct pharmacological effects on muscle tissue,” says Sattar. “One suspects that the muscle volume change is mostly weight-related. However, the reduction in muscle fat content could be due to direct fat clearance within muscles caused by tirzepatide. My guess is that most of it is driven by the caloric restriction due to the tirzepatide treatment and the resulting weight loss.” In addition, adopting a more active lifestyle after losing weight may also help to reduce muscle fat. Nevertheless, a direct metabolic effect on muscle tissue cannot be ruled out at this point. 

Clinical implications and future directions for research 

Although the study did not assess physical performance directly, MRI-derived muscle parameters such as fat infiltration and Z-scores are considered robust surrogates for muscle function. “Muscle health is critical as it is the body’s engine – important for glucose and fat metabolism as well as for physical performance,” says Sattar. According to him, the observed improvements could have meaningful functional implications. 

“What is now needed are trials that assess outcomes such as step count, chair rise and other measures of daily living. I suspect that all of these will improve,” Sattar concludes. “We have underestimated how much obesity affects everyday physical functioning.” 

Key Points: 

• In a post-hoc MRI substudy of the SURPASS-3 trial, treatment with tirzepatide resulted in a greater-than-expected reduction in intramuscular fat, exceeding population-based predictions from the UK Biobank. 

• Muscle volume loss remained proportionate to weight loss, suggesting no muscle wasting under tirzepatide treatment. 

• Further trials are needed to assess functional outcomes, such as mobility and strength, following tirzepatide-induced weight loss. 

To read this paper visit: https://www.thelancet.com/journals/landia/article/PIIS2213-8587(25)00027-0/fulltext   

Author: Hanna Gabriel, BA MSc. Editor: Dr Albert Brugger. Any opinions expressed in this article are the responsibility of EASD e-Learning.