The conversation around GLP-1 receptor agonists has been about efficacy. The conversation we should be having now is about composition.

The STEP-1 body composition substudy [1] gave us the first high-quality look. Of the 14.9% mean weight loss seen with semaglutide 2.4mg over 68 weeks, total lean body mass dropped 9.7%. Across the broader trial landscape, lean-tissue loss has comprised 26-40% of total weight loss in recent reports [5], with the 2025 Karakasis network meta-analysis pegging the central estimate near 25% across the GLP-1 RA class [2]. Whichever number you anchor on, lean-mass change is not a rounding error.

The same network meta-analysis gave us the drug-by-drug picture. Tirzepatide and semaglutide, the most effective for fat-mass reduction, were among the least effective for lean-mass preservation. Liraglutide 3.0mg was the only GLP-1 RA in the review to achieve significant weight loss without significant lean-mass reduction [2].

The 2024 Circulation review by Linge, Birkenfeld and Neeland [3] frames the open question. Adaptive (proportional to fat loss, with improved muscle quality on MRI) or maladaptive (disproportionate, with functional consequences)? Their read of the contemporary MRI evidence leans adaptive in most contexts. For most patients in our caseloads, the practical question still matters more than the theoretical one. What protocol minimises the loss in the patients who can least afford it?

Three clinical levers matter, in order of impact. Protein intake, structured resistance training, and a sensible caloric floor. Each has a target range, a timing pattern, and patient-population-specific adjustments. Our GLP-1 Vault Section 7 protocol covers the exact doses, training frequencies, kcal floors, and decision trees for the patient subgroups where the standard approach needs adjusting.

What this means for your next consult: every patient on a GLP-1 needs an explicit lean-mass preservation plan, not a generic "eat protein" instruction. The ones who don't get one are the ones who'll regain weight as fat, because resting metabolic rate has fallen with the lean-tissue loss.

The first prospective real-world cohort, 115 enrolled (106 completers, 68.9% female, mean BMI 46.3 kg/m²) on semaglutide 2.4mg for 12 months. Findings tell a more nuanced story than the trial data alone.

Mean 13% weight loss at M12, with 59% of patients hitting the ≥10% threshold. DXA showed significant fat-mass and visceral-fat reduction continuing through M12. Lean mass dropped at M7 then stabilised through M12, while handgrip strength improved. Sarcopenic-obesity prevalence fell from 49% at baseline to 33% at M12 [4].

Translation: in real-world practice, without a protocol-mandated resistance training arm, the functional outcome (strength, sarcopenia prevalence) actually improved, even while absolute lean mass fell early then stabilised. The active question is whether structured intervention pushes this further.

A complementary 2025 case series (Tinsley and Nadolsky [5]) reported 2 of 3 patients combining GLP-1 with structured resistance training and adequate protein actually gained lean mass while losing fat. The upper bound of what's achievable.

52-year-old female. Post-menopausal. BMI 34. T2D (HbA1c 8.1%). Started on tirzepatide 5mg weekly. Reports satiety reduces total intake by about 40%. Baseline DEXA shows ASMI 5.4 kg/m² (borderline sarcopenic). She asks: "Do I need to do anything different?"

Decision framework:

Yes, she does. She fits the highest-risk archetype. Post-menopausal + sarcopenic baseline + high-efficacy GLP-1 RA equals stacked lean-mass risk. Standard protein-floor recommendations don't apply at her ASMI baseline.

Immediate priority: protein floor adjusted upward from baseline guidance, structured resistance training (lower-limb priority given her BMI), and a kcal floor that accounts for her satiety drop without going too aggressive.

The exact protein-per-kg target, training frequency, and bone-health additions for post-menopausal patients are in the Menopause Vault (Chapter 6) and the GLP-1 Vault (Section 7, with patient-subgroup adjustments). Both handbooks map her decision tree by lab values and clinical milestones.

What to monitor: ASMI re-check at 6 months, grip strength bedside, gait speed annually. If 6-month ASMI drops below threshold, consider dose-reduction in coordination with the prescriber.

Each subgroup has a distinct risk profile and protocol adjustment.

Each subgroup has its own decision tree, monitoring schedule, and patient handout in the relevant handbook.

Retatrutide is Eli Lilly's investigational once-weekly triple hormone receptor agonist. It activates GLP-1, GIP, and glucagon receptors simultaneously. Semaglutide acts on GLP-1 alone. Tirzepatide on two of the three. Retatrutide on all three.

The headline number from the TRIUMPH-4 Phase 3 trial (obesity plus knee osteoarthritis, no diabetes, n with baseline BMI ≥35 kg/m² at 84%): 28.7% average weight loss at 68 weeks at the 12mg dose, 26.4% at 9mg, versus 2.1% on placebo [7]. For context, that's substantially above tirzepatide's 22.5% (SURMOUNT benchmark) and nearly double semaglutide's 15% (STEP-1). Body-composition substudies are not part of this readout, which is a limitation worth flagging when patients ask.

Three things RDs should know now:

Trials to watch in 2026:

Expected FDA filing: late 2026. Approval window: 2027. The clinicians who'll counsel patients well on retatrutide in 2027 are the ones building the framework now. That's the conversation this newsletter exists to have a year before it's urgent.

Three handbooks most relevant to this issue's clinical territory.

Each handbook includes a Clinical Guide, Patient Handout Pack, and Recipe Collection. Available standalone or in the $89 per-topic Bundle.

20% off every handbook in the library, through Sunday May 11.

This code goes public on Tuesday May 5. Subscribers get the 48-hour head start.

What's the trickiest GLP-1 + composition case you've seen this month?

Reply to this email. We'll feature one anonymised case in Issue 02.

[1] Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity (STEP-1). NEJM 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183. Body composition substudy: Wilding JPH et al, Diabetes Obes Metab 2021;23(8):2031-2034 (n=140; LBM −9.7%, fat mass −19.3%).

[2] Karakasis P, Patoulias D, Fragakis N, Mantzoros CS, et al. Effect of glucagon-like peptide-1 receptor agonists and co-agonists on body composition: systematic review and network meta-analysis. Metabolism 2025;164:156113. doi:10.1016/j.metabol.2024.156113.

[3] Linge J, Birkenfeld AL, Neeland IJ. Muscle mass and glucagon-like peptide-1 receptor agonists: adaptive or maladaptive response to weight loss? Circulation 2024;150(16):1288-1298. doi:10.1161/CIRCULATIONAHA.124.067676.

[4] Alissou M, Demangeat T, Folope V et al. Impact of Semaglutide on fat mass, lean mass and muscle function in patients with obesity: the SEMALEAN study. Diabetes Obes Metab 2026 (early view). doi:10.1111/dom.70141. PMID: 41068996.

[5] Tinsley GM, Nadolsky S. Preservation of lean soft tissue during weight loss induced by GLP-1 and GLP-1/GIP receptor agonists: a case series. SAGE Open Med Case Rep 2025;13. doi:10.1177/2050313X251388724. PMID: 41122508.

[6] Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. NEJM 2023;389(6):514-526. doi:10.1056/NEJMoa2301972.

[7] Eli Lilly. TRIUMPH-4 Phase 3 trial topline results press release. December 11, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-triple-agonist-retatrutide-delivered-weight-loss-average