Tirzepatide and muscle composition changes in people with type 2 diabetes (SURPASS-3 MRI): a post-hoc analysis of a randomised, open-label, parallel-group, phase 3 trial.
Level 2 - randomized trial
Post-hoc exploratory analysis of an individual randomized controlled trial substudy
PubMed 40318682 · doi:10.1016/S2213-8587(25)00027-0
What was done
This post-hoc exploratory analysis evaluated muscle composition changes in the SURPASS-3 MRI substudy, an open-label, parallel-group phase 3 trial across 45 sites in eight countries. Insulin-naive adults with type 2 diabetes (HbA1c 7.0–10.5%, BMI ≥25 kg/m², fatty liver index ≥60) on metformin with or without an SGLT-2 inhibitor were randomized 1:1:1:1 to subcutaneous weekly tirzepatide (5 mg, 10 mg, or 15 mg) or daily titrated insulin degludec. Thigh MRI at baseline and week 52 measured muscle fat infiltration, muscle volume, and muscle volume Z score. Changes were compared between groups using ANCOVA and contextualized against weight-loss-associated population estimates derived from UK Biobank MRI data (n=2,942).
What was found
Of 296 enrolled participants, 246 completed valid week 52 MRI scans (tirzepatide 5 mg: n=63; 10 mg: n=60; 15 mg: n=67; insulin degludec: n=56). Pooled tirzepatide produced significant reductions from baseline to week 52 in muscle fat infiltration (-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). Insulin degludec was associated with modest increases in body weight and muscle volume. Compared to UK Biobank estimates, observed muscle volume reductions across all tirzepatide doses were similar to expected weight-related changes (mean difference -0.04 L [95% CI -0.11 to 0.03], p=0.22), while reductions in muscle fat infiltration were significantly greater than expected (-0.42 percentage points [95% CI -0.54 to -0.31], p<0.0001).
Why it matters
Tirzepatide-associated reductions in muscle volume appear proportional to overall body weight loss, while concurrently reducing intramuscular fat infiltration to an extent greater than predicted by weight change alone.
Limits
The analysis was post-hoc and exploratory within an open-label trial design. Muscle strength and physical function were not measured. The study was restricted to individuals with a high fatty liver index (≥60) and lost 50 of 296 enrolled participants to missing week 52 MRI scans.
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