Summary: In a phase 2 DXA substudy of 189 adults with type 2 diabetes, the triple agonist retatrutide produced dose-related reductions in total body fat mass at week 36. Versus placebo, the least-squares mean reduction was -21.6% with retatrutide 8 mg pooled (95% CI -27.1 to -16.1, p<0.0001) and -18.7% with 12 mg (95% CI -25.1 to -12.3, p<0.0001), while the 0.5 mg dose did not differ from placebo. The proportion of lean mass lost was comparable to other obesity therapies.
PICO Summary
| Element | Detail |
|---|---|
| Population | 189 adults aged 18-75 with type 2 diabetes (HbA1c 7.0-10.5%, BMI 25-50), enrolled in a body-composition substudy of a phase 2, double-blind, parallel-group RCT across 42 US centres. 155 had a baseline DXA scan; 103 completed both baseline and week-36 DXA scans. |
| Intervention | Once-weekly subcutaneous retatrutide (GIP, GLP-1 and glucagon receptor agonist) at 0.5 mg (n=32), 4 mg pooled (n=31), 8 mg pooled (n=33) or 12 mg (n=30). |
| Comparison | Once-weekly subcutaneous placebo (n=29) or dulaglutide 1.5 mg (n=34). |
| Outcome | Percent change in total body fat mass (DXA) at week 36. Least-squares mean change versus placebo: 0.5 mg -0.4 (95% CI -4.0 to 3.2, p=0.83, not significant); 4 mg pooled -10.7 (-17.2 to -4.2, p=0.0013); 8 mg pooled -21.6 (-27.1 to -16.1, p<0.0001); 12 mg -18.7 (-25.1 to -12.3, p<0.0001). Raw reduction from baseline in total fat mass: 4.9% (0.5 mg), 15.2% (4 mg), 26.1% (8 mg), 23.2% (12 mg), 2.6% (dulaglutide), 4.5% (placebo). Gastrointestinal events were the most common adverse events; serious adverse events were infrequent and similar across groups, with no deaths. No NNT applies to this continuous outcome. |
Retatrutide and body composition
RCT substudy · type 2 diabetes · 36 weeks
Retatrutide produced large, dose-related reductions in total fat mass versus placebo at 36 weeks, with lean-mass loss comparable to other obesity therapies. Phase 2 surrogate data; await confirmatory phase 3 trials.
Expert Commentary
This substudy adds a body-composition lens to retatrutide’s already striking weight effects, and the dose-related reduction in total fat mass is large and statistically robust, with the 8 mg pooled and 12 mg arms separating clearly from both placebo and dulaglutide. The reassuring signal is that the proportion of lean mass lost relative to total weight loss appeared comparable to that seen with other obesity therapies, which matters because preserving muscle is a recurring worry with potent incretin-based agents. The headline verdict is that retatrutide meaningfully shifts fat mass in type 2 diabetes, but several caveats temper enthusiasm. The most important limitation is fragility of the sample: this was an exploratory substudy in which only 103 of 189 participants contributed paired baseline and week-36 DXA scans, so attrition and the modest per-arm numbers leave the precise effect sizes uncertain. It was also funded by Eli Lilly and authored entirely by company employees, and these are phase 2 surrogate-endpoint data, not proven outcomes. Can I use this with my patients? Not yet, because retatrutide is not approved and longer phase 3 evidence is pending. For now this is hypothesis-generating reassurance rather than practice-changing data, and I would await confirmatory trials with clinical endpoints before drawing firm conclusions.
References
Coskun T, Wu Q, Schloot NC, Haupt A, Milicevic Z, Khouli C, et al. Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial. Lancet Diabetes Endocrinol. 2025;13(8):674-684. doi:10.1016/S2213-8587(25)00092-0