44 findings across 18 drug records. Domain pages are descriptive indexes, not advice.
The grade rates how strong the evidence is, not how good or safe the drug is. A low or very-low grade means the evidence is thin, not that an effect is harmful or ruled out.
Most represented records
GLP-1-based therapies, multi-agent (10)
Retatrutide (5)
Liraglutide (3)
Multi-agent review synthesis (3)
Semaglutide (3)
Tirzepatide (3)
Tirzepatide and semaglutide comparison (3)
Bimagrumab plus semaglutide (2)
Evidence spread
High evidence 2Moderate evidence 21Low evidence 12Very low evidence 9
Apitegromab plus tirzepatideINVESTIGATIONAL
body-compositionMixed
Very low evidence
Scholar Rock's phase 2 EMBRAZE trial (NCT06445075) tested apitegromab added to tirzepatide over 24 weeks and reported greater preservation of lean mass than...
SourceScholar Rock, EMBRAZE phase-2 topline press release, 18 Jun 2025; NCT06445075Source
Full findingScholar Rock's phase 2 EMBRAZE trial (NCT06445075) tested apitegromab added to tirzepatide over 24 weeks and reported greater preservation of lean mass than tirzepatide alone. This is a muscle-preservation combination studied with tirzepatide rather than semaglutide. The available efficacy figures are sponsor-issued topline results and have not been peer reviewed.
Fundingindustry - Eli Lilly (trial sponsor; inferred from registration trial)
Comparatorsplacebo + tirzepatide
BimagrumabINVESTIGATIONAL
body-compositionMixed
Moderate evidence
Foundational human readout for muscle preservation: in adults with T2D and overweight/obesity, bimagrumab MONOTHERAPY (no GLP-1RA) produced large fat-mass loss with a...
SourceHeymsfield SB et al., JAMA Netw Open, 2021Source
Full findingFoundational human readout for muscle preservation: in adults with T2D and overweight/obesity, bimagrumab MONOTHERAPY (no GLP-1RA) produced large fat-mass loss with a simultaneous GAIN in lean mass over 48 weeks, establishing that ActRII blockade is anabolic for muscle while reducing adiposity. This is lean-mass GAIN, distinct from the lean-PRESERVATION seen when such agents are added to incretins.
PopulationPhase-2 double-masked placebo-controlled RCT, N=75 randomised (58 completers), 48 weeks, IV q4w, adults with T2D, BMI 28-40; 9 US/UK sites.
BELIEVE phase-2b (Eli Lilly/Versanis) tested bimagrumab alone or added to semaglutide. The combination drove fat-selective weight loss with lean-mass preservation;...
SourceHeymsfield et al., Nat Med 2026; presented ADA 2025Source
Full findingBELIEVE phase-2b (Eli Lilly/Versanis) tested bimagrumab alone or added to semaglutide. The combination drove fat-selective weight loss with lean-mass preservation; bimagrumab monotherapy GAINED lean while semaglutide alone lost it. Now PEER-REVIEWED (Heymsfield et al., Nat Med 2026).
PopulationBELIEVE phase-2b RCT, N=507, 48-week treatment (results to wk72), randomised double-blind placebo-controlled, 9 arms; bimagrumab IV q12w +/- semaglutide sc weekly; adults overweight/obese with >=1 comorbidity.
Muscle-preserving combination landscape: bimagrumab (ActRII blockade) is reported to add lean mass while reducing fat, and is being combined with semaglutide to...
SourceNunn E et al., Mol Metab, 2024 (preclinical); Kaiser M et al., Cardiol Rev, 2025 (review)Source
Full findingMuscle-preserving combination landscape: bimagrumab (ActRII blockade) is reported to add lean mass while reducing fat, and is being combined with semaglutide to counter GLP-1-associated lean-mass loss; preclinical work shows combination preserves muscle while enhancing fat loss vs semaglutide alone.
PopulationPreclinical (diet-induced obese mice) plus clinical-development narrative/review; combination under clinical study
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Comparatorssemaglutide
CagriSemaINVESTIGATIONAL
body-compositionDecrease
Low evidence
REDEFINE-1 DXA subgroup (Week 68): CagriSema produced the greatest weight reduction; of weight lost, 66.9% was fat mass and 33.1% lean soft tissue. In participants...
SourceRavussin E et al., REDEFINE-1 body composition, ObesityWeek 2025 / ECO 2026 presentations...Source
Full findingREDEFINE-1 DXA subgroup (Week 68): CagriSema produced the greatest weight reduction; of weight lost, 66.9% was fat mass and 33.1% lean soft tissue. In participants achieving >=30% weight loss, fat-mass proportion fell from 46.3% to 33.2% while lean-soft-tissue proportion rose from 51.3% to 63.2%.
PopulationDXA subgroup of REDEFINE-1 RCT in overweight/obesity; CagriSema 2.4/2.4 mg vs semaglutide 2.4 mg vs cagrilintide 2.4 mg vs placebo; 68 weeks
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Comparatorssemaglutide; cagrilintide; placebo
Tirzepatide and semaglutide comparisonSTATUS UNKNOWN
body-compositionDecrease
Moderate evidence
Systematic review (Annals of Internal Medicine): across 35 RCTs, incretin therapies consistently reduced fat mass and visceral adiposity; muscle-based-index loss was...
SourceBatsis JA et al., Ann Intern Med, 2026Source
Full findingSystematic review (Annals of Internal Medicine): across 35 RCTs, incretin therapies consistently reduced fat mass and visceral adiposity; muscle-based-index loss was highly heterogeneous, with median 28.3% of total weight loss attributable to muscle-based indices and ~two-thirds of interventions exceeding pre-specified muscle-loss benchmarks. No study reported objective physical-function outcomes.
Population35 RCTs (median duration 26 weeks, median N 78) of liraglutide, semaglutide, tirzepatide or dulaglutide in adults with obesity; BIA/DXA/CT/MRI; Jan 2003-Feb 2026
Narrative review of human studies on GLP-1 therapies and sarcopenia: results are mixed - some studies emphasise excessive skeletal-muscle-mass loss while others argue...
Full findingNarrative review of human studies on GLP-1 therapies and sarcopenia: results are mixed - some studies emphasise excessive skeletal-muscle-mass loss while others argue for a protective effect via improved muscle quality (less myosteatosis); no definitive conclusion on net detriment or benefit to skeletal muscle.
PopulationHuman studies of GLP-1-based therapies assessing skeletal-muscle mass, strength/function and structure/quality
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Tirzepatide and semaglutide comparisonSTATUS UNKNOWN
body-compositionDecrease
Moderate evidence
Systematic review and meta-analysis (20 RCTs, 15,782 adults, DXA/MRI) with absolute lean-mass change (kg) and lean fraction of weight lost as CO-PRIMARY outcomes. Lean...
SourceEisa N, Barood O et al., Diabetes Obes Metab, 2026Source
Full findingSystematic review and meta-analysis (20 RCTs, 15,782 adults, DXA/MRI) with absolute lean-mass change (kg) and lean fraction of weight lost as CO-PRIMARY outcomes. Lean mass was ~25-39% of total weight lost across incretin agents and broadly comparable to lifestyle intervention (no significant difference, p=0.42). The only modality that materially lowered the lean fraction was lifestyle PLUS resistance training (17.5%). Retatrutide is NOT included.
Population20 RCTs, 15,782 adults with overweight/obesity; semaglutide, tirzepatide, liraglutide or lifestyle; DXA or MRI; searched to 20 Jan 2026; random-effects, RoB 2, GRADE.
Fundingacademic / investigator-initiated; no industry sponsor found in indexed metadata (Europe PMC fundingList empty)
Comparatorslifestyle intervention; lifestyle plus resistance training
GLP-1-based therapies, multi-agentSTATUS UNKNOWN
body-compositionMixed
Moderate evidence
Network meta-analysis (22 RCTs, 2258 participants): GLP-1RAs reduced absolute lean mass by ~0.86 kg (~25% of weight lost), but the RELATIVE proportion of body weight...
Full findingNetwork meta-analysis (22 RCTs, 2258 participants): GLP-1RAs reduced absolute lean mass by ~0.86 kg (~25% of weight lost), but the RELATIVE proportion of body weight that is lean was unaffected. The same dataset supports both poles of the debate: 'relative lean unchanged' feeds the adaptive reading; the absolute -0.86 kg and the tirz/sema-least-preserving ordering feed the caution reading.
ADAPTIVE-POLE anchor (both poles preserved): reported lean-mass loss as a proportion of weight lost is heterogeneous (40-60% in some studies, <=15% in others); on...
SourceNeeland IJ et al., Diabetes Obes Metab, 2024Source
Full findingADAPTIVE-POLE anchor (both poles preserved): reported lean-mass loss as a proportion of weight lost is heterogeneous (40-60% in some studies, <=15% in others); on contemporary evidence including MRI muscle-volume work the skeletal-muscle changes appear largely ADAPTIVE (commensurate with the weight loss achieved, with improved insulin sensitivity and reduced muscle fat infiltration suggesting improved muscle QUALITY), rather than pathological wasting. Older age / disease severity flagged as risk modifiers.
PopulationNarrative review of trial + MRI-based evidence on GLP-1RA and dual GLP-1/GIP effects on lean body mass and muscle health in overweight/obesity.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Tirzepatide and semaglutide comparisonSTATUS UNKNOWN
SourceLocatelli JC et al., Diabetes Care 2024Source
Full findingCAUTION-POLE anchor (both poles preserved): narrative review argues incretin agents (liraglutide, semaglutide, tirzepatide, retatrutide named) inducing ~15-24% weight loss also cause rapid lean-mass loss of ~10% / ~6 kg, threatening muscle mass/function and raising sarcopenia/frailty risk, motivating resistance exercise and muscle-preserving adjuncts. The same DXA numbers the adaptive camp reads as benign are read here as a threat: the disagreement is INTERPRETIVE, not over the raw number.
PopulationNarrative review; adults with overweight/obesity on incretin therapy; older-adult sarcopenia/frailty framing.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Multi-agent review synthesisSTATUS UNKNOWN
body-compositionNot directional
Low evidence
DEFINITIONAL YARDSTICK: the ESPEN/EASO consensus defines sarcopenic obesity as excess adiposity PLUS low muscle MASS PLUS low muscle FUNCTION, with a two-step...
SourceDonini LM, Busetto L, Bischoff SC, Barazzoni R, Prado CM et al. (ESPEN/EASO Consensus), O...Source
Full findingDEFINITIONAL YARDSTICK: the ESPEN/EASO consensus defines sarcopenic obesity as excess adiposity PLUS low muscle MASS PLUS low muscle FUNCTION, with a two-step diagnostic pathway that confirms via a muscle-FUNCTION test (e.g. strength) before a mass measure. By this standard, calling incretin lean-mass loss 'sarcopenia' REQUIRES a demonstrated FUNCTION deficit, which the trials have not measured.
PopulationESPEN + EASO international expert consensus statement.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
GLP-1-based therapies, multi-agentSTATUS UNKNOWN
body-compositionNot directional
Low evidence
CLASS GAP (the absence is the finding): direct measurement of muscle FUNCTION (grip strength, gait speed, SPPB, chair-stand) is essentially ABSENT from the pivotal...
Full findingCLASS GAP (the absence is the finding): direct measurement of muscle FUNCTION (grip strength, gait speed, SPPB, chair-stand) is essentially ABSENT from the pivotal incretin weight-loss trials; body composition is captured almost entirely as DXA/MRI MASS. Multiple reviews (Neeland 2024; Dubin/Heymsfield 2024; Conte/Hall/Klein; Drucker 2024) converge that strength/function/mobility were not assessed and call for them. Authoritative safety reviews (Drucker, Diabetes Care 2024, PMID 38843460) list muscle strength as an under-characterised SAFETY domain for the class, including retatrutide, survodutide and MariTide.
PopulationClass-wide gap across STEP / SURMOUNT / SUMMIT / SUSTAIN body-composition substudies; synthesised in reviews + one protocol-stage older-adult RCT.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
GLP-1-based therapies, multi-agentSTATUS UNKNOWN
body-compositionDecrease
Moderate evidence
FOLK-CLAIM VERDICT ('I'm losing MUSCLE not just fat; eat protein and lift'): MIXED, leaning TRUE-but-reframed. Lean-mass loss is real (~25-40% of weight lost is...
SourceBatsis JA et al., Ann Intern Med, 2026Source
Full findingFOLK-CLAIM VERDICT ('I'm losing MUSCLE not just fat; eat protein and lift'): MIXED, leaning TRUE-but-reframed. Lean-mass loss is real (~25-40% of weight lost is fat-free mass), but the 'losing muscle' framing overstates it - most is obligatory for any large weight loss, the split mirrors placebo/lifestyle, and the LEAN FRACTION is NOT worse with the more potent agents (incl. retatrutide), only the absolute kg. The protein+resistance-training rule is mechanistically sound but its GLP-1-specific trial evidence is MIXED. The genuine concern is functional (sarcopenia in older/sarcopenic-obese patients) and is UNDER-MEASURED (no trial assessed physical function).
PopulationSystematic review (35 RCTs) + DXA substudies of SURMOUNT-1 (tirzepatide) and the reta phase-2 T2D trial.
FOLK-CLAIM VERDICT ('Ozempic face'): MIXED - the gaunt/hollow/aged/sagging face is REAL (TRUE), but the attribution to the DRUG is FALSE: it is a WEIGHT-LOSS-mediated...
SourceBarone M et al. GLP-1 receptor agonists and skin quality: a systematic review (incl. faci...Source
Full findingFOLK-CLAIM VERDICT ('Ozempic face'): MIXED - the gaunt/hollow/aged/sagging face is REAL (TRUE), but the attribution to the DRUG is FALSE: it is a WEIGHT-LOSS-mediated effect (non-selective loss of facial fat pads + dermal laxity that fails to retract, worse with age), not a drug-specific facial toxicity. The same occurs with any rapid/large weight loss including bariatric surgery and diet. NOT semaglutide-specific (named for first-mover fame); class-wide - and tirzepatide/retatrutide likely produce MORE facial change purely via GREATER weight loss. Folk preventatives (slower loss, more protein, hydration, fillers/microneedling) are mechanistically coherent with the volume-loss explanation.
PopulationDermatology + plastic-surgery systematic reviews of case reports/cohorts + authoritative clinical commentary (Cleveland Clinic); bariatric-surgery facial-change cohorts as the weight-loss-generic comparator.
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Comparatorsbariatric-surgery weight loss; diet weight loss
GLP-1-based therapies, multi-agentSTATUS UNKNOWN
body-compositionDecrease
Low evidence
In an older mostly-female cohort, semaglutide/tirzepatide-associated bone loss tracked weight loss and was greater in non-diabetic patients.
Fundingacademic / non-commercial (Novo Nordisk Foundation + Danish academic bodies; drug supplied in-kind; disclosed)
GLP-1-based therapies, multi-agentSTATUS UNKNOWN
body-compositionNo change
Moderate evidence
In T2D-only RCTs, GLP-1 RAs showed no fracture excess (RR 0.80, NS) and no detectable BMD loss (BMD point estimates modestly higher than control) - a...
SourceGLP-1 RA bone density and turnover (25-RCT meta-analysis), Acta Diabetol 2025Source
Full findingIn T2D-only RCTs, GLP-1 RAs showed no fracture excess (RR 0.80, NS) and no detectable BMD loss (BMD point estimates modestly higher than control) - a reassurance-of-absence in diabetic bone, NOT a demonstrated bone-building effect. This does NOT generalise to obesity/weight-loss populations, where the direct double-blind Hansen RCT and DXA cohorts show resorption-dominant BMD loss.
Fundingacademic / investigator-initiated; no industry sponsor found in indexed metadata (Europe PMC fundingList empty)
GLP-1-based therapies, multi-agentSTATUS UNKNOWN
body-compositionDecrease
Moderate evidence
In a 52-week double-blind RCT in adults with increased fracture risk (mostly postmenopausal), semaglutide 1.0 mg did NOT raise bone formation (P-PINP null) but RAISED...
SourceHansen MS, Wolfel EM, Jeromdesella S, et al. Once-weekly semaglutide versus placebo in ad...Source
Full findingIn a 52-week double-blind RCT in adults with increased fracture risk (mostly postmenopausal), semaglutide 1.0 mg did NOT raise bone formation (P-PINP null) but RAISED bone resorption (CTX) and LOWERED lumbar-spine and total-hip BMD versus placebo - a resorption-dominant pattern, not bone-building.
PopulationSemaglutide bone phase-2 double-blind RCT (Hansen et al., EClinicalMedicine 2024, NCT04702516); 64 adults at increased fracture risk (T-score < -1.0 and/or recent low-energy fracture), two Danish hospitals.
Fundingacademic/investigator-initiated (Region of Southern Denmark + Novo Nordisk Foundation + Gangsted Foundation; Novo Nordisk supplied study drug only, not sponsor)
Comparatorsplacebo
GLP-1-based therapies, multi-agentSTATUS UNKNOWN
body-compositionNo change
Low evidence
In a 20-week pilot RCT in older adults (n=20), whole-body and regional BMD and bone-turnover markers did not change significantly, but a post-hoc correlation linked...
SourceDinkla L, Beavers KM, Robbins R, ... Trejo J, Stepanenko A, Cortes TM, et al. Bone minera...Source
Full findingIn a 20-week pilot RCT in older adults (n=20), whole-body and regional BMD and bone-turnover markers did not change significantly, but a post-hoc correlation linked greater weight loss to greater pelvis bone loss (r=0.62) - hypothesis-generating support for weight-loss-mediated loss, not proof.
PopulationOlder-adult GLP-1 bone pilot (Trejo/Cortes et al., Front Aging 2025, NCT05786521); 20 community-dwelling adults aged 65+ with prediabetes/T2D + overweight/obesity, UT Health San Antonio.
Fundingacademic/government (NIH/NIA + San Antonio VA GRECC + Colorado CCTSI; no industry sponsor)
Comparatorslifestyle counselling alone
GLP-1-based therapies, multi-agentSTATUS UNKNOWN
body-compositionMixed
Moderate evidence
In T2D, the meta reports a favourable-looking turnover shift (beta-CTX down, formation markers up), but this is CONTESTED as a generalisable bone-building effect -...
SourceGLP-1 RA bone density and turnover (25-RCT meta-analysis), Acta Diabetol 2025Source
Full findingIn T2D, the meta reports a favourable-looking turnover shift (beta-CTX down, formation markers up), but this is CONTESTED as a generalisable bone-building effect - likely low-turnover diabetic-bone normalisation. It is directly contradicted by the Hansen double-blind RCT in weight-losing adults (CTX UP, P1NP null) and so must NOT be read as a class anabolic effect.
Full findingVeru's phase 2b QUALITY trial (NCT06282458) tested enobosarm added to semaglutide in adults aged 60 years or older. Sponsor-issued topline results reported less lean-mass loss and a stair-climb-power responder signal than with placebo plus semaglutide. No peer-reviewed publication of these efficacy results was identified at the catalogue date.
PopulationQUALITY phase-2b dose-finding RCT, N=168, double-blind placebo-controlled, 16 weeks, adults >=60 y on semaglutide; enobosarm 3/6 mg vs placebo.
Fundingindustry - Novo Nordisk (trial sponsor; inferred from registration trial)
Comparatorsplacebo + semaglutide
LiraglutideMARKETED
body-compositionDecrease
High evidence
Phase 4 MRI RCT (high-CV-risk overweight/obesity, no diabetes): liraglutide 3.0 mg significantly lowered visceral adipose tissue over 40 weeks vs placebo (primary...
SourceNeeland IJ et al., Lancet Diabetes Endocrinol, 2021Source
Full findingPhase 4 MRI RCT (high-CV-risk overweight/obesity, no diabetes): liraglutide 3.0 mg significantly lowered visceral adipose tissue over 40 weeks vs placebo (primary endpoint VAT% by MRI).
Fundingacademic-led (University of Texas Southwestern) with Novo Nordisk collaborator
Comparatorsplacebo
LiraglutideMARKETED
body-compositionDecrease
Moderate evidence
Pre-specified MRI secondary analysis: liraglutide 3.0 mg reduced thigh-muscle fat (myosteatosis) and adverse muscle composition vs placebo - a muscle-QUALITY...
SourcePandey A et al., J Cachexia Sarcopenia Muscle, 2024Source
Full findingPre-specified MRI secondary analysis: liraglutide 3.0 mg reduced thigh-muscle fat (myosteatosis) and adverse muscle composition vs placebo - a muscle-QUALITY improvement distinct from muscle quantity.
Populationn=128 with follow-up MRI (liraglutide 73, placebo 55); 92.2% women, 36.7% Black; median 36 wk; same trial as NCT03038620
Fundingindustry-Novo Nordisk
Comparatorsplacebo
MazdutideMARKETED
body-compositionDecrease
Very low evidence
GLORY-1/GLORY-2 phase 3 (Chinese adults with obesity): mazdutide met key secondary endpoints including reduced waist circumference and liver-fat content; dual...
SourceInnovent / Eli Lilly, GLORY-1 and GLORY-2 phase 3 (mazdutide)Source
Full findingGLORY-1/GLORY-2 phase 3 (Chinese adults with obesity): mazdutide met key secondary endpoints including reduced waist circumference and liver-fat content; dual GCG/GLP-1 mechanism described as potentially yielding more favourable fat-vs-muscle partition, but no quantified DXA fat/lean split located.
PopulationGLORY-1 (n=610) and GLORY-2 phase 3 RCTs in Chinese adults with obesity; 48-60 weeks
Fundingindustry - Innovent / Eli Lilly (trial sponsor; inferred from registration trial)
Comparatorsplacebo
Multi-agent review synthesisSTATUS UNKNOWN
body-compositionNot directional
Low evidence
Mechanistic / landscape anchor: incretin weight loss is accompanied by fat-free-mass loss (heterogeneously ~15% to 40-60% of weight lost), motivating adjuncts that...
SourceAimelet V & Holst JJ, Diabetes Obes Metab, 2025Source
Full findingMechanistic / landscape anchor: incretin weight loss is accompanied by fat-free-mass loss (heterogeneously ~15% to 40-60% of weight lost), motivating adjuncts that preserve or add lean mass. The myostatin/activin-ActRII axis is a negative regulator of muscle growth; blocking it (at the receptor, bimagrumab; at ligands, trevogrumab/anti-GDF8, garetosmab/anti-activin A, apitegromab/anti-latent-myostatin) repartitions loss toward fat and can add lean mass. SARMs (enobosarm) anabolise via androgen-receptor selectivity. Bimagrumab and enobosarm have the most human data; most agents remain early-phase with limited long-term safety.
PopulationNarrative reviews of preclinical + phase-2/3 human studies of lean-mass-preserving pharmacotherapy during GLP-1RA / dual-agonist weight loss.
Fundingacademic (Aimelet & Holst, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen; no external funding statement; author COIs disclosed)
PemvidutideINVESTIGATIONAL
body-compositionDecrease
Very low evidence
MOMENTUM phase 2 MRI-based body-composition substudy: pemvidutide reported ~78.1% of weight lost as fat and ~21.9% as lean mass, framed by the sponsor as...
Full findingMOMENTUM phase 2 MRI-based body-composition substudy: pemvidutide reported ~78.1% of weight lost as fat and ~21.9% as lean mass, framed by the sponsor as 'class-leading' lean-mass preservation.
Fundingindustry - Altimmune (trial sponsor; inferred from registration trial)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
body-compositionDecrease
Moderate evidence
Retatrutide phase-2 T2D DXA substudy: fat mass fell dose-dependently; the lean-mass conclusion is a SECONDARY, proportional-only claim ('proportion of lean-mass loss...
SourceCoskun T et al. (Eli Lilly), Lancet Diabetes Endocrinol, 2025Source
Full findingRetatrutide phase-2 T2D DXA substudy: fat mass fell dose-dependently; the lean-mass conclusion is a SECONDARY, proportional-only claim ('proportion of lean-mass loss similar to other obesity treatments'), read by the sponsor as reassurance. CRITICAL: no ABSOLUTE lean-kg is reported, and proportional parity at a larger total loss is fully compatible with the LARGEST absolute lean-kg loss of any agent. Completer-only, T2D, fat-primary endpoint.
PopulationSubstudy of the retatrutide phase-2 T2D RCT (NCT04867785), double-blind placebo- and dulaglutide-controlled; 189 enrolled to substudy, 103 with paired baseline+week-36 DXA (completer-only); DXA at week 36.
SourceSanyal AJ et al., triple agonist retatrutide for MASLD, Nat Med, 2024Source
Full findingPhase 2a MASLD substudy used MRI-PDFF to quantify hepatic fat alongside body-composition assessment; retatrutide markedly reduced liver fat content (ectopic-fat depot adjacent to body-composition remit).
PopulationPre-specified substudy of phase 2 obesity trial, participants with MASLD; MRI-PDFF
Fundingindustry - Eli Lilly (disclosed; retatrutide MASLD substudy)
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
body-compositionNot directional
Moderate evidence
Retatrutide's phase 2 obesity trial reported body weight but no DXA or other body-composition measurement, so absolute lean-mass change at the 12 mg dose is unknown....
SourceGap row derived from absence across the retatrutide phase-2 reports (PMID 37366315 weight...Source
Full findingRetatrutide's phase 2 obesity trial reported body weight but no DXA or other body-composition measurement, so absolute lean-mass change at the 12 mg dose is unknown. The reported retatrutide DXA evidence comes from a type 2 diabetes substudy with less total weight loss, and no reported retatrutide trial has measured muscle strength or physical function. The glucagon-receptor component provides a mechanistic reason to study amino-acid and muscle effects directly, but does not establish excess lean-mass loss. Both the amount and clinical significance of lean-mass change during higher-magnitude retatrutide weight loss therefore remain uncertain.
PopulationRetatrutide programme to date: phase-2 obesity (Jastreboff, NEJM 2023, PMID 37366315, weight only) and phase-2 T2D DXA substudy (Coskun, Lancet D&E 2025, PMID 40609566, fat-mass primary); no function endpoint in any reported reta trial.
Fundingacademic - Canadian Institutes for Health Research (CIHR grant 154321), Drucker review
Comparatorsplacebo; dulaglutide
RetatrutideINVESTIGATIONAL
body-compositionNot directional
Moderate evidence
EXPLICIT ABSENCE: the retatrutide phase-2a MASLD trial (Sanyal 2024) did not report any DXA/BMD, bone-turnover or fracture endpoint.
SourceSanyal AJ et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-as...Source
PopulationRetatrutide phase-2a MASLD substudy (Sanyal et al., NCT04881760); reviewed for any DXA/BMD/bone-turnover/fracture endpoint - none present.
Fundingindustry-Eli Lilly
Comparatorsplacebo
RetatrutideINVESTIGATIONAL
body-compositionNot directional
Moderate evidence
EXPLICIT ABSENCE: the retatrutide phase-2 obesity trial (Jastreboff 2023) did not report any DXA/BMD, bone-turnover or fracture endpoint - no retatrutide bone effect...
SourceJastreboff AM et al. (retatrutide phase 2), NEJM, 2023;389:514-526Source
Full findingEXPLICIT ABSENCE: the retatrutide phase-2 obesity trial (Jastreboff 2023) did not report any DXA/BMD, bone-turnover or fracture endpoint - no retatrutide bone effect can be asserted or excluded; all retatrutide bone inference is indirect class-extrapolation.
PopulationRetatrutide phase-2 obesity trial (Jastreboff et al., NCT04881760); reviewed for any DXA/BMD/bone-turnover/fracture endpoint - none present in the trial report.
Fundingindustry-Eli Lilly
Comparatorsplacebo
SemaglutideMARKETED
body-compositionDecrease
Moderate evidence
SEMALEAN prospective study: semaglutide 2.4 mg reduced total fat mass with an initial lean-mass decline that stabilised after 7 months; handgrip strength improved and...
SourceAlissou M et al. (SEMALEAN), Diabetes Obes Metab, 2025Source
Full findingSEMALEAN prospective study: semaglutide 2.4 mg reduced total fat mass with an initial lean-mass decline that stabilised after 7 months; handgrip strength improved and prevalence of sarcopenic obesity fell from 49% to 33%; REE normalised to lean mass rose from M7 to M12.
Populationn=115 enrolled / 106 completers with obesity (68.9% female, mean BMI 46.3); DXA + handgrip + REE at M0, M7, M12; prospective single-arm
Fundingacademic/investigator - no external funding declared (NOT industry/Novo Nordisk)
SemaglutideMARKETED
body-compositionDecrease
Moderate evidence
SUSTAIN 8 DXA substudy: semaglutide 1.0 mg vs canagliflozin 300 mg in T2D reduced total fat mass, lean mass and visceral fat; proportion of lean mass rose ~1.2...
SourceMcCrimmon RJ et al., Diabetologia, 2020Source
Full findingSUSTAIN 8 DXA substudy: semaglutide 1.0 mg vs canagliflozin 300 mg in T2D reduced total fat mass, lean mass and visceral fat; proportion of lean mass rose ~1.2 percentage points; changes in visceral fat and fat-to-lean ratio comparable between arms.
Populationn=178 randomised to DXA substudy (sema n=88, cana n=90); 114 with end-of-treatment data; T2D on metformin; 52 weeks; RCT (NCT03136484)
Fundingindustry - Novo Nordisk
Comparatorscanagliflozin
SemaglutideMARKETED
body-compositionDecrease
Moderate evidence
STOP randomised trial (T2D): semaglutide reduced epicardial adipose tissue vs comparator over the trial period (epicardial-fat-specific RCT readout).
SourceManubolu VS et al. (STOP trial), J Am Coll Cardiol, 2024Source
PopulationSTOP (Semaglutide Treatment effect On coronary atherosclerosis Progression) randomised trial in T2D; CT-based epicardial adipose tissue
Full findingSYNCHRONIZE (phase 3) prespecified MRI substudy: survodutide reduced visceral adipose tissue ~34%, subcutaneous adipose tissue ~28% and lean body volume ~9.8%; fat mass ~78% / lean mass ~22% of total weight lost reported; lean tissue <=10.8% of total tissue-mass change at the highest dose.
PopulationPhase 2 obesity MRI substudy (survodutide / BI 456906); dose range to ~4.8 mg
Fundingindustry - Boehringer Ingelheim / Zealand
Comparatorsplacebo
TirzepatideMARKETED
body-compositionDecrease
Low evidence
EHR-linked body-composition digital-phenotyping study (LLM extraction) of routine-care users found tirzepatide associated with GREATER relative lean-body-mass loss...
SourceGreater lean-body-mass decline with tirzepatide than semaglutide in routine care (digital...Source
Full findingEHR-linked body-composition digital-phenotyping study (LLM extraction) of routine-care users found tirzepatide associated with GREATER relative lean-body-mass loss than semaglutide at every timepoint; a 'Depletive GLP-1 metabotype' (>20% TBW loss with >5% LBM loss) was more frequent with tirzepatide.
Population670,422 first-episode GLP-1RA users (semaglutide 456,742; tirzepatide 213,680); 7,965 with paired pre/post body-composition over 12 months; retrospective real-world EHR cohort
Fundingacademic/independent analysis (manufacturer not study sponsor; per-study COI not individually audited)
Comparatorssemaglutide
TirzepatideMARKETED
body-compositionDecrease
Moderate evidence
SURMOUNT-1 DXA substudy: tirzepatide's large total loss was accompanied by a PROPORTIONALLY matched lean loss (~25% of weight lost), and crucially the same ~75/25...
SourceLook M et al., Diabetes Obes Metab, 2025Source
Full findingSURMOUNT-1 DXA substudy: tirzepatide's large total loss was accompanied by a PROPORTIONALLY matched lean loss (~25% of weight lost), and crucially the same ~75/25 split held for PLACEBO too, so the lean fraction is a property of weight loss at this magnitude, not specifically of the drug. The decision-relevant corollary: a much larger absolute loss at the same proportion carries a larger ABSOLUTE lean-kg loss.
PopulationSURMOUNT-1 DXA substudy: n=160 of 2539 (pooled tirzepatide n=124, placebo n=36), adults with obesity/overweight, mean weight 102.5 kg; baseline-to-Week-72 DXA; post-hoc substudy of a phase-3 double-blind placebo-controlled RCT.
Fundingindustry-Eli Lilly
Comparatorsplacebo
TirzepatideMARKETED
body-compositionDecrease
Moderate evidence
SUMMIT CMR substudy (obesity-related HFpEF): tirzepatide reduced LV mass and paracardiac (epicardial + pericardial) adipose tissue vs placebo at 52 weeks; the...
SourceKramer CM et al., J Am Coll Cardiol, 2024Source
Full findingSUMMIT CMR substudy (obesity-related HFpEF): tirzepatide reduced LV mass and paracardiac (epicardial + pericardial) adipose tissue vs placebo at 52 weeks; the paracardiac reduction was driven by the pericardial component, with the LV-mass change paralleling weight loss.
Full findingCOURAGE phase-2 (Regeneron, NCT06299098) tests trevogrumab (anti-myostatin) +/- garetosmab (anti-activin A) added to semaglutide. Interim results show dose-ordered lean preservation, with the triplet most lean-preserving but least tolerated. Final readout pending.
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