Phase 2 Body Composition Substudy
Phase 2 Body Composition Substudy
A substudy of the Phase 2 obesity trial evaluating the effects of retatrutide on body composition using dual-energy X-ray absorptiometry (DXA), assessing changes in fat mass, lean mass, and visceral adipose tissue.
Phase 2 Body Composition Substudy — A substudy of the Phase 2 obesity trial evaluating the effects of retatrutide on body composition using dual-energy X-ray absorptiometry (DXA), assessing changes in fat mass, lean mass, and visceral adipose tissue.
Trial Facts
| Property | Value |
|---|---|
| Trial Name | Phase 2 Body Composition Substudy |
| Phase | 2 |
| Status | results-published |
| Enrollment | 163 participants |
| NCT ID | NCT04881706 |
| Completion | February 1, 2023 |
| Conditions | obesity |
Study Overview
The body composition substudy used dual-energy X-ray absorptiometry (DXA) to quantify changes in fat mass and lean mass during retatrutide treatment. Published by Aronne et al. in Obesity in 2024, the results showed that the majority of weight loss with retatrutide came from fat tissue, with a favorable fat-to-lean mass loss ratio.
Why Body Composition Matters
One of the key concerns with pharmacological weight loss is the preservation of lean body mass (muscle and bone). Ideally, weight loss agents should preferentially reduce fat mass — especially visceral adipose tissue — while minimizing lean mass loss.
The “75:25 Rule”
In most weight loss interventions (dietary, surgical, or pharmacological), approximately 25-35% of total weight lost comes from lean tissue. The retatrutide body composition data showed a fat-to-lean mass loss ratio of approximately 75:25, which is consistent with this expected range and comparable to the ratio seen with tirzepatide and semaglutide.
Results
DXA Findings
| Compartment | Placebo | 4 mg | 8 mg | 12 mg |
|---|---|---|---|---|
| Total weight change | -2.1% | -17.1% | -22.8% | -24.2% |
| Fat mass change | -3% | -28% | -35% | -38% |
| Lean mass change | -1% | -7% | -10% | -11% |
| Visceral fat change | -2% | -30% | -40% | -45% |
Key Observations
- Preferential visceral fat loss: Visceral adipose tissue was reduced to a greater degree than overall fat mass, suggesting targeted metabolic benefit
- Glucagon component effect: The glucagon receptor activation may contribute to preferential mobilization of hepatic and visceral fat stores
- Lean mass preservation: While some lean mass loss occurred, the proportion was within the expected range for this magnitude of total weight loss
Clinical Implications
The favorable body composition changes support the metabolic benefits observed in the main trial:
- Visceral fat reduction correlates with improvements in insulin resistance, blood pressure, and lipid profiles
- Fat mass loss drives the mechanical benefits (joint pain, mobility, sleep apnea improvement)
- Lean mass loss was proportional, not excessive, suggesting muscle preservation strategies (protein intake, exercise) could further optimize outcomes in Phase 3
Publication
Aronne LJ, Sattar N, Horn DB, et al. Retatrutide Phase 2 body composition substudy results. Obesity. 2024;32:1425-1438.
Sources Used On This Page
- 1aronne-2024-obesity
- 2jastreboff-2023-nejm