Tirzepatide significantly reduced muscle fat infiltration (mean change -0.36 percentage points; 95% CI -0.48 to -0.25; p<0.0001) and muscle volume from baseline to week 52 in type 2 diabetes.
RCT
Open-label
1:1:1:1
Does tirzepatide improve muscle composition in people with type 2 diabetes compared to insulin degludec?
In patients with type 2 diabetes, tirzepatide treatment is associated with reductions in muscle volume consistent with weight loss, alongside potentially favorable reductions in muscle fat infiltration.
Mean Difference: -0.36 (95% CI -0.48–-0.25)
p-value: p=<0.0001
BACKGROUND: Substantial weight reduction is often associated with loss of muscle mass. Tirzepatide has been associated with significant reductions in body weight in type 2 diabetes trials and a beneficial effect on body fat distribution in the SURPASS-3 MRI substudy. This post-hoc exploratory analysis studied the association of tirzepatide treatment with changes in thigh muscle volume, muscle volume Z score, and muscle fat infiltration, and aimed to contextualise the results using longitudinal MRI data from UK Biobank participants. METHODS: , and a fatty liver index of at least 60. Participants were randomly assigned (1:1:1:1) to receive subcutaneous injection once per week of tirzepatide (5, 10, or 15 mg), or subcutaneous injection once per day of titrated insulin degludec. Thigh muscle fat infiltration, muscle volume, and muscle volume Z score (invariant to sex, height, weight, and BMI) were quantified by MRI at baseline and week 52. In this post-hoc analysis, we assessed the differences between mean baseline and week 52 muscle composition values in the tirzepatide groups (pooled 5 mg, 10 mg, and 15 mg group, and per dose group) and insulin degludec group using paired t tests, and the differences in muscle composition changes with pooled tirzepatide versus insulin degludec via adjusted ANCOVA models. Observed changes in muscle fat infiltration, muscle volume, and muscle volume Z scores were compared using paired t tests to population-based estimates calculated from multiple linear regression models fitted to UK Biobank data (n=2942), capturing associations with change in body weight. Analyses were done by modified intention to treat, in the participants enrolled in the MRI substudy with a valid MRI scan at week 52. The SURPASS-3 clinical trial is registered with ClinicalTrials.gov, NCT03882970, and is complete. FINDINGS: (SD 4·8), and 76 (30·9%) were on an SGLT-2 inhibitor. Mean baseline muscle fat infiltration, muscle volume, and muscle volume Z scores were similar between the pooled tirzepatide group and insulin degludec group. For the pooled and individual tirzepatide dose groups, significant reductions were observed from baseline to week 52 in muscle fat infiltration (for pooled tirzepatide, mean change -0·36 percentage points 95% CI -0·48 to -0·25, p<0·0001), muscle volume (-0·64 L 95% CI -0·74 to -0·54, p<0·0001), and muscle volume Z score (-0·22 95% CI -0·29 to -0·15, p<0·0001), which occurred in the context of significant weight reduction. Insulin degludec was associated with a modest and significant increase in bodyweight and muscle volume, but no significant change in the other variables. The changes in all three muscle composition variables with pooled tirzepatide were significantly different compared to those with insulin degludec. In tirzepatide-treated participants, observed muscle volume changes across all tirzepatide doses were similar to population-based estimated changes (for pooled tirzepatide, mean difference vs population-based estimate, -0·04 L 95% CI -0·11 to 0·03, p=0·22); whereas, observed reductions in muscle fat infiltration across all doses were significantly greater than population-based estimates (for pooled tirzepatide, mean difference -0·42 percentage points 95% CI -0·54 to -0·31, p<0·0001), and the observed reduction in muscle volume Z score with tirzepatide 15 mg was significantly greater than the population-based estimate (mean difference -0·18 95% CI -0·29 to -0·07, p=0·0016). INTERPRETATION: In the SURPASS-3 MRI substudy, in the context of significant improvements in bodyweight and fat distribution, tirzepatide treatment was associated with potentially favourable changes in muscle fat infiltration and reductions in muscle volume broadly in accordance with the general association between changes in muscle volume and bodyweight. The present findings provide additional information on the potential effect of tirzepatide on muscle health that might help health-care providers when deciding among treatment options for individual patients. FUNDING: Eli Lilly and Company.
Sattar et al. (2025) conducted an RCT in Type 2 diabetes. Tirzepatide vs. Titrated insulin degludec once per day was evaluated on Change in muscle fat infiltration from baseline to week 52 (MD -0.36, 95% CI -0.48 to -0.25, p=<0.0001). Tirzepatide significantly reduced muscle fat infiltration (mean change -0.36 percentage points; 95% CI -0.48 to -0.25; p<0.0001) and muscle volume from baseline to week 52 in type 2 diabetes.